beta lactam antibiotic monotherapy versus beta lactam ... · this record should be cited as: paul...

Beta lactam antibiotic monotherapy versus beta lactam-

aminoglycoside antibiotic combination therapy for sepsis

(Review)

Paul M, Grozinsky S, Soares-Weiser K, Leibovici L

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 1

http://www.thecochranelibrary.com

Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

18DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

74DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Monotherapy versus combination therapy, Outcome 1 All cause fatality. . . . . . . 78

Analysis 1.2. Comparison 1 Monotherapy versus combination therapy, Outcome 2 All cause fatality by study groups. 82

Analysis 1.3. Comparison 1 Monotherapy versus combination therapy, Outcome 3 All cause fatality (Gram negative

infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Analysis 1.4. Comparison 1 Monotherapy versus combination therapy, Outcome 4 All cause fatality (Gram negative

bacteremia). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Analysis 1.5. Comparison 1 Monotherapy versus combination therapy, Outcome 5 All cause fatality (non urinary tract

infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Analysis 2.1. Comparison 2 Monotherapy versus combination therapy, Outcome 1 Clinical failure. . . . . . . 95

Analysis 2.2. Comparison 2 Monotherapy versus combination therapy, Outcome 2 Clinical failure by study groups. . 101

Analysis 2.3. Comparison 2 Monotherapy versus combination therapy, Outcome 3 Bacteriological failure - all. . . 109

Analysis 2.4. Comparison 2 Monotherapy versus combination therapy, Outcome 4 UTI relapse or re-infection. . . 113

Analysis 2.5. Comparison 2 Monotherapy versus combination therapy, Outcome 5 Clinical failure (Gram negative

infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Analysis 2.6. Comparison 2 Monotherapy versus combination therapy, Outcome 6 Clinical failure (Gram negative

bacteremia). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Analysis 2.7. Comparison 2 Monotherapy versus combination therapy, Outcome 7 Clinical failure (Pseudomonas

aeruginosa infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Analysis 2.8. Comparison 2 Monotherapy versus combination therapy, Outcome 8 Clinical failure (bacteremia). . . 123

Analysis 2.9. Comparison 2 Monotherapy versus combination therapy, Outcome 9 Clinical failure (urinary tract

infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Analysis 2.10. Comparison 2 Monotherapy versus combination therapy, Outcome 10 Clinical failure (non urinary tract

infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

Analysis 3.1. Comparison 3 Monotherapy versus combination therapy, Outcome 1 Bacterial superinfections. . . . 133

Analysis 3.2. Comparison 3 Monotherapy versus combination therapy, Outcome 2 Fungal superinfections. . . . . 134

Analysis 3.3. Comparison 3 Monotherapy versus combination therapy, Outcome 3 Bacterial colonization. . . . . 135

Analysis 3.4. Comparison 3 Monotherapy versus combination therapy, Outcome 4 Fungal colonization. . . . . . 136

Analysis 3.5. Comparison 3 Monotherapy versus combination therapy, Outcome 5 Bacterial colonization - surveillance

cultures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

Analysis 3.6. Comparison 3 Monotherapy versus combination therapy, Outcome 6 Bacterial resistance development. 138

Analysis 4.1. Comparison 4 Monotherapy versus combination therapy, Outcome 1 Any adverse event. . . . . . 139

Analysis 4.2. Comparison 4 Monotherapy versus combination therapy, Outcome 2 Adverse events requiring treatment

discontinuation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

Analysis 4.3. Comparison 4 Monotherapy versus combination therapy, Outcome 3 Any nephrotoxicity. . . . . . 142

Analysis 5.1. Comparison 5 Monotherapy versus combination therapy, Outcome 1 Drop-outs for all cause fatality. . 148

Analysis 5.2. Comparison 5 Monotherapy versus combination therapy, Outcome 2 Drop-outs for clinical failure. . . 150

iBeta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review)


Analysis 6.1. Comparison 6 Monotherapy versus combination therapy, Outcome 1 All cause fatality (Gram positive

infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

Analysis 6.2. Comparison 6 Monotherapy versus combination therapy, Outcome 2 Clinical failure (Gram positive

infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

Analysis 6.3. Comparison 6 Monotherapy versus combination therapy, Outcome 3 Bacteriological failure (Gram positive

infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Analysis 6.4. Comparison 6 Monotherapy versus combination therapy, Outcome 4 Need for operation (endocarditis). 155

Analysis 7.1. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 1 All cause fatality

by allocation concealment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156


by allocation generation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162


by ITT vs. per-protocol analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Analysis 7.4. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 4 Clinical failure by

allocation concealment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177


allocation generation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185


blinding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193


ITT versus per-protocol analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

209APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

210WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

210HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

210CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

210DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

210SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

211INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiBeta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review)


[Intervention Review]

Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis

Mical Paul1, Simona Grozinsky2 , Karla Soares-Weiser3, Leonard Leibovici4

1Infectious Diseases Unit and Department of Medicine E, Rabin Medical Center, Petah-Tikva, Israel. 2Internal Medicine E, Rabin

Medical Center, Petah-Tikva, Israel. 3Enhance Reviews, Kfar-Saba, Israel. 4Department of Medicine E, Beilinson Campus, Rabin

Medical Center, Petah-Tiqva, Israel

Contact address: Mical Paul, Infectious Diseases Unit and Department of Medicine E, Rabin Medical Center, Beilinson Campus,

Petah-Tikva, 49100, Israel. [email protected]. (Editorial group: Cochrane Anaesthesia Group.)

Cochrane Database of Systematic Reviews, Issue 1, 2009 (Status in this issue: Edited)


DOI: 10.1002/14651858.CD003344.pub2

This version first published online: 25 January 2006 in Issue 1, 2006. Re-published online with edits: 21 January 2009 in Issue 1,

2009.

Last assessed as up-to-date: 10 November 2005. (Help document - Dates and Statuses explained)

This record should be cited as: Paul M, Grozinsky S, Soares-Weiser K, Leibovici L. Beta lactam antibiotic monotherapy versus beta

lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.:

CD003344. DOI: 10.1002/14651858.CD003344.pub2.

A B S T R A C T

Background

Optimal antibiotic treatment for sepsis is imperative. Combining a beta-lactam antibiotic with an aminoglycoside antibiotic may have

certain advantages over beta-lactam monotherapy.

Objectives

We compared clinical outcomes for beta lactam-aminoglycoside combination therapy versus beta lactam monotherapy for sepsis.

Search strategy

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2004); MEDLINE

(1966 to July 2004); EMBASE (1980 to March 2003); LILACS (1982 to July 2004); and conference proceedings of the Interscience

Conference of Antimicrobial Agents and Chemotherapy (1995 to 2003). We scanned citations of all identified studies and contacted

all corresponding authors.

Selection criteria

We included randomized and quasi-randomized trials comparing any beta-lactam monotherapy to any combination of one beta-lactam

and one aminoglycoside for sepsis.

Data collection and analysis

The primary outcome was all-cause fatality. Secondary outcomes included treatment failure, superinfections, colonization, and adverse

events. Two authors independently collected data. We pooled relative risks (RR) with their 95% confidence intervals (CI) using the

fixed effect model. We extracted outcomes by intention-to-treat analysis whenever possible.

Main results

We included 64 trials, randomizing 7586 patients. Twenty trials compared the same beta-lactam in both study arms, while the remaining

compared different beta-lactams using a broader spectrum beta-lactam in the monotherapy arm. In studies comparing the same beta-

1Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review)


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lactam, we observed no difference between study groups with regard to all-cause fatality, RR 1.01 (95% CI 0.75-1.35) and clinical

failure, RR 1.11 (95% CI 0.95-1.29). In studies comparing different beta-lactams, we observed an advantage to monotherapy: all

cause fatality RR 0.85 (95% CI 0.71-1.01), clinical failure RR 0.77 (95% CI 0.69-0.86). No significant disparities emerged from

subgroup and sensitivity analyses, including the assessment of patients with Gram-negative and Pseudomonas aeruginosa infections. We

detected no differences in the rate of resistance development. Adverse events rates did not differ significantly between the study groups

overall, although nephrotoxicity was significantly more frequent with combination therapy, RR 0.30 (95% CI 0.23-0.39). We found

no heterogeneity for all comparisons. We included a small subset of studies addressing patients with Gram-positive infections, mainly

endocarditis. We identified no difference between monotherapy and combination therapy in these studies.

Authors’ conclusions

The addition of an aminoglycoside to beta-lactams for sepsis should be discouraged. All-cause fatality rates are unchanged. Combination

treatment carries a significant risk of nephrotoxicity.

P L A I N L A N G U A G E S U M M A R Y

Single versus combination antibiotic treatment for severe infections: beta-lactam monotherapy versus beta-lactam-aminogly-

coside combination therapy

Infections caused by bacteria are a leading cause of preventable death. The mortality associated with severe infections necessitating

hospitalization is about 30%. Antibiotic treatment improves survival.

There are several classes of antibiotics currently in use. The beta-lactam class is one of the most important class in use. Antibiotics

belonging to it (penicillins, cephalosporins, and others) kill bacteria by disrupting their cell wall. Aminoglycosides (e.g. gentamicin) act

though a different mechanism, inhibiting bacterial protein synthesis. Studies of bacteria in cell cultures have shown that combining a

beta-lactam with an aminoglycoside results in bacterial killing superior to the simple additive activity of each of these antibiotics alone,

a phenomenon termed ’synergism’.

In humans, combination therapy may have several drawbacks, such as an increased rate of adverse effects. We therefore decided to

compile clinical studies that compared treatment with a beta-lactam to treatment with a beta-lactam plus an aminoglycoside. Our

objective was to assess whether combination treatment results in better outcomes, mainly survival.

The review included 64 trials randomizing 7586 patients. Patients were hospitalized with urinary tract, intra-abdominal, skin and soft

tissue infections, pneumonia, and infection of unknown origin. Antibiotics were administered intravenously.

Combination antibiotic treatment did not improve the clinical efficacy achieved with the beta-lactam antibiotic alone. One set of studies

compared a new, broad-spectrum beta-lactam to an older, less potent beta-lactam combined with an aminoglycoside (44 studies). In

these studies, mortality and failure were lower with single beta-lactam antibiotic treatment. Mortality was reduced by 15%, but the

difference was not statistically significant. The other set of studies compared one beta-lactam to the same beta-lactam combined with

an aminoglycoside (20 studies). In these trials, no differences between single and combination antibiotic treatment were seen. The

relative risk for mortality was 1.01, denoting equivalence of the two regimens.

Adverse events rates did not differ between the study groups, overall, but renal damage was more frequent with combination therapy.

Combination therapy did not prevent the development of secondary infections.

The reviewers conclude that beta-lactam-aminoglycoside combination therapy offers no advantage to beta-lactams alone. Furthermore,

combination therapy is associated with an increased risk of renal damage. Paucity of trials comparing the same beta-lactam in both

study arms and incompleteness of mortality reporting may limit these conclusions. These results may not apply to locations in which

resistance rates to narrow-spectrum beta-lactams are very low, such as Scandinavian counties.



B A C K G R O U N D

Sepsis is defined as the clinical evidence of infection, accompanied

by a systemic inflammatory response such as fever. When asso-

ciated with organ dysfunction, decreased blood flow in an organ

(hypoperfusion), or abnormally low blood pressure (hypotension),

sepsis is defined as severe (Bone 1992; Mandell 2004). Sepsis may

be a response to direct microbial invasion or may be elicited by

microbial signal molecules or toxin production. Infections may be

lethal, with fatality rates ranging from less than 10% to more than

40% for those with severe sepsis (Moore 2001; Rangel-Frausto

1995; Russell 2000). Appropriate empirical antibiotic treatment,

administered to the patient before identification of the pathogen

or its antibiotic susceptibilities, has been shown to halve the fatal-

ity associated with sepsis (Bryant 1971; Ibrahim 2000; Leibovici

1998; Whitelaw 1992).

Regimens recommended for the empirical treatment of sepsis in-

clude: (1) a single broad-spectrum agent, commonly from the beta

lactam class of antibiotics; and (2) a combination of a beta lac-

tam antibiotic with an aminoglycoside antibiotic (Mandell 2004).

Combination antibiotic therapy has several theoretical advantages.

First, it may have a broader antibiotic spectrum. Second, the com-

bination may possess an enhanced potential (synergism), when

compared to the additive effect of each of the antibiotics assessed

separately (Giamarellou 1986; Klastersky 1982). Third, combina-

tion therapy has been claimed to suppress the emergence of sub-

populations of microorganisms resistant to the antibiotics (Allan

1985; Milatovic 1987). The disadvantages of combination ther-

apy may include additional costs, enhanced drug toxicity, the pos-

sible induction of resistance caused by the broader antibiotic spec-

trum (Manian 1996; Weinstein 1985), and possible antagonism

between specific drug combinations (Moellering 1986).

Aminoglycoside antibiotics are most active against Gram-nega-

tive bacteria (Mandell 2004). In addition, synergism between beta

lactam antibiotics and aminoglycoside antibiotics has been re-

peatedly shown in vitro specifically for Gram-negative bacteria

(Giamarellou 1986; Klastersky 1976; Klastersky 1982). Conse-

quently, the benefit of combination therapy, if existent, may be

more prominent in patients with Gram-negative infections. Other

features related to the infection may affect prognosis. These in-

clude the site of infection and the specific causative pathogen. For

example, infections caused by Pseudomonas aeruginosa have been

shown to portend a poor prognosis (Baine 2001; Geerdes 1991;

Leibovici 1997). We expect to deal with factors such as these, ex-

pected to underlie heterogeneity, using subgroup analysis where

appropriate. Specific guidelines have been instituted for the em-

pirical treatment of cancer patient with neutropenia, basing the

suspicion of sepsis on fever alone (Hughes 2002). The authors

have therefore considered studies addressing these patients in a

separate review (Paul 2001).

Numerous studies have been conducted comparing beta lactam

monotherapy to beta lactam-aminoglycoside combination ther-

apy in patients with suspected or proven bacterial infections. Some

trials have focused specifically on infections commonly caused by

Gram-negative bacteria, such as urinary tract infections and hos-

pital acquired infections, where the benefit of combination ther-

apy may be more prominent. Nevertheless, superiority of either

monotherapy or combination therapy has not been shown con-

clusively in these studies.

O B J E C T I V E S

Our objectives were:

1. to compare beta lactam monotherapy versus beta lac-

tam-aminoglycoside combination therapy in patients

with sepsis; and

2. to estimate the rate of adverse effects with each treat-

ment regimen, including the development of bacterial

resistance to antibiotics.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included randomized or quasi-randomized controlled trials.

Types of participants

We included hospitalized patients with sepsis acquired either in the

community or in the hospital (nosocomial). We defined sepsis as

clinical evidence of infection, plus evidence of a systemic response

to infection (Bone 1992). We excluded neonates and preterm ba-

bies. We also excluded studies including more than 15% neu-

tropenic patients.

Types of interventions

We considered studies comparing the antibiotic regimens de-

scribed below.

1. Any intravenous beta-lactam antibiotic given as

monotherapy, including:

i) penicillins;

ii) beta lactam drugs plus beta lactamase in-

hibitors (eg co-amoxiclav);

iii) cephalosporins (eg ceftazidime, cefotaxime);

iv) carbapenems (eg imipenem, meropenem).

2. Combination therapy of a beta lactam antibiotic (as

specified) with one of the following aminoglycoside an-

tibiotics:

i) gentamicin;

ii) tobramycin;

iii) amikacin;

iv) netilmicin;



v) streptomycin;

vi) isepamicin;

vii) sisomicin.

Types of outcome measures

Primary outcomes

All-cause fatality by the end of the study follow-up.

Secondary outcomes

1. Treatment failure defined as death and/or one or more

serious morbid events (persistence, recurrence, or wors-

ening of clinical signs or symptoms of presenting infec-

tion; any modification of the assigned empirical antibi-

otic treatment; or any therapeutic invasive intervention

required not defined in the protocol).

2. Length of hospital stay.

3. Dropouts: number of patients excluded from the out-

come assessment after randomization.

4. Superinfection: recurrent infections defined as new, per-

sistent, or worsening symptoms and/or signs of infec-

tion associated with the isolation of a new pathogen

(different pathogen, or same pathogen with different

susceptibilities) or the development of a new site of in-

fection.

5. Colonization by resistant bacteria: the isolation of bac-

teria resistant to the beta lactam antibiotic, during or

following antibiotic therapy, with no signs or symptoms

of infection.

6. Adverse effects:

i) life-threatening or associated with permanent

disability (severe nephrotoxicity; ototoxicity;

anaphylaxis; severe skin reactions);

ii) serious: requiring discontinuation of therapy

(other nephrotoxicity; seizures; pseudomem-

branous colitis; other allergic reactions);

iii) any other (other gastrointestinal; other aller-

gic reactions).

Search methods for identification of studies

Electronic searches

We formulated a comprehensive search strategy in an attempt to

identify all relevant studies regardless of language or publication

status (published, unpublished, in press, and in progress). The key

words used for the search strategy are shown in Appendix 1.

We searched the Cochrane Infectious Diseases Group specialized

trials register for relevant trials up to December 2002 using the

search terms: ((aminoglycoside* OR netilmicin* OR gentamicin*

OR amikacin* OR tobramycin* OR streptomycin* OR isepam-

icin* OR sisomicin*) AND (pneumonia* OR infection OR in-

fect* OR sepsis OR bacter* OR bacteremia OR septicemia).

We searched the Cochrane Controlled Trials Register, (CEN-

TRAL), (The Cochrane Library, Issue 3, 2004) using the same

search terms.

We searched the following electronic databases in combination

with the search strategy developed by The Cochrane Collabora-

tion and detailed in the Cochrane Handbook for Systematic Re-

views of Interventions to limit the search for randomized or quasi-

randomized trials (Higgins 2005):

1. MEDLINE (1966 to July 2004) using the search:

(aminoglycoside* OR netilmicin* OR gentamicin* OR

amikacin* OR tobramycin* OR streptomycin* OR

isepamicin* OR sisomicin*) AND (combination OR

combi*). In a second search, the terms (combination

OR combi*) were replaced by endocarditis, Staphylo-

coccus, Streptococcus or pneumonia to enhance the

sensitivity and specificity of our search to these infec-

tions.

2. EMBASE (1980 to March 2003) using the same search

terms.

3. LILACS (1982 to July 2004) using the same search

terms.

Searching other resources

We searched the Interscience Conference of Antimicrobial Agents

and Chemotherapy conference proceedings (1995 to 2003) for

relevant abstracts.

We contacted the first or corresponding author of each included

study, and the researchers active in the field, for information re-

garding unpublished trials or complementary information on their

own trials.

We also checked the citations of major reviews and of all trials

identified by the above methods for additional studies.

We did not have a language restriction.

Data collection and analysis

Study selection

One author (MP) inspected the abstract of each reference identi-

fied in the search and applied the inclusion criteria. Where relevant

articles were identified, the full article was obtained and inspected

independently by two authors (MP, IS or LL).

Quality assessment

We assessed the quality of the trials to be included for allocation

sequence, allocation concealment, blinding, fatality outcome re-

porting, intention-to-treat analysis, and number of patients ex-

cluded from outcome assessment. Two authors (MP, IS or KSW)

independently performed quality assessment. We based method-

ological quality classification on the evidence of a strong associa-

tion between poor allocation concealment and over estimation of

effect. We defined it as: A (low risk of bias; adequate allocation

concealment); B (moderate risk of bias; some doubt about alloca-

tion concealment); and C (high risk of bias; inadequate allocation



concealment) (Schulz 1995). We performed sensitivity analyses

to assess the effect of study quality measures on effect estimates.

We intend to assess the effect of number of exclusions on effect

estimates (above or below 20%) in future updates of the review.

Data collection

Two authors (MP, IS or SG) independently extracted data from

included trials. In case of disagreement between the two authors, a

third author (KSW, LL) independently extracted the data. A third

author (KSW or LL) also extracted the data in 10% of the studies,

selected at random. We discussed data extraction, documented

decisions, and contacted authors of all studies for clarification.

We resolved differences in the data extracted by discussion. We

also documented the justification for excluding studies from the

review.

We identified the trials by the name of the first author and the year

in which the trial was first published, and listed in chronological

order. We extracted, checked and recorded the following data.

Characteristics of trials:

1. date, location, and setting of trial;

2. publication status;

3. country of origin;

4. design (intention-to-treat, method of randomization);

5. duration of study follow-up;

6. performance of surveillance cultures (routine cultures

for the detection of colonization);

7. sponsor of trial.

Characteristics of patients:

1. number of participants in each group;

2. age (mean and standard deviation, or median and

range);

3. number of patients with renal failure before treatment;

4. number of patients with shock.

Characteristics of infection:

1. number of patients with infections caused by bacteria

resistant to the administered beta lactam antibiotic;

2. number of patients with nosocomial infections;

3. number of patients with bacteremia;

4. number of patients with bacteriologically documented

infection;

5. number of patients with infections caused by Gram-

negative bacteria;

6. number of patients with Gram-negative bacteremia;

7. number of patients with documented Pseudomonas in-

fections (Pseudomonas isolated in the blood or speci-

men(s) obtained from suspected site(s) of infection);

8. number of patients with:

i) urinary tract infection;

ii) pneumonia;

iii) intra-abdominal infection;

iv) skin and soft tissue infection; and

v) infection of unknown origin.

Characteristics of interventions:

1. antibiotic type and dose;

2. duration of therapy (mean).

Characteristics of outcome measures:

1. number of deaths at the end of the follow-up period;

2. number of patients failing treatment (as defined);

3. adverse reactions (as defined) in each group;

4. loss of follow-up (dropouts) before the end of the study

in each group;

5. number of patients developing super-infection;

6. number of patients developing colonization (as defined)

with resistant bacteria;

7. duration of fever and hospital stay.

We collected outcome measures on an intention-to-treat basis

whenever possible. Where such data were not presented, we sought

information from the authors, and if unavailable, per-protocol

results were used. For failure outcome, we performed sensitivity

analyses comparing these results with a ’presumed all intention

to treat’, which we achieved by counting all dropouts as failures.

We could not make such an assumption in studies that did not

specify the number of dropouts per study arm, and we analysed

these studies separately.

Data synthesis

We calculated relative risks for dichotomous data. Continuous

outcomes were unavailable for this review. We will use weighted

mean differences for continuous outcomes in future updates of

the review. We initially assessed heterogeneity in the results of the

trials using a chi-squared test of heterogeneity (p < 0.1). We used

a fixed effect model throughout the review, as the I2 measure of

inconsistency was low for all comparisons. We compared results

obtained by the fixed effect model to those obtained by a random

effect model for the major outcomes. We explored the following

factors to explain heterogeneity in relation to the major outcomes:

1. infections caused by Pseudomonas sp. versus all other

infections;

2. Gram-negative versus all other infections; and

3. urinary tract infections versus other sites of infection.

We performed subgroup analysis by these factors where data were

available. For subgroup analyses we extracted all-cause fatality and

treatment failures outcomes. We adjusted the descriptive mean

mortality rate in included studies to the inverse of the mortality

variance between the trials.

We examined a funnel plot of SE(log(relative risk)) versus relative

risk of each study in order to estimate potential selection bias

(publication and language).

R E S U L T S

Description of studies



See: Characteristics of included studies; Characteristics of excluded

studies.

The search strategy resulted in 5568 references. We filtered double

references, and screened 2805 different abstracts for inclusion. We

did not evaluate studies in which the comparator antibiotic reg-

imens were clearly incompatible with inclusion criteria in depth.

We similarly excluded non-randomized and non-human studies.

We retrieved 145 studies for full-text inspection, of which we ex-

cluded 67 publications, representing 63 studies (see table of ’ Char-

acteristics of excluded studies’), and categorized two as awaiting

assessment (see Additional Table 1, and ’Table of studies awaiting

assessment’). Several studies compared monotherapy versus com-

bination therapy among patients with cystic fibrosis. Patients in

these studies typically do not have fever or other signs of sepsis

when entering the trial, and thus did not fulfil inclusion criteria

for this review. These studies are included in a separate review (

Elphick 2001). Seventy-eight studies fulfilled inclusion criteria.

Fourteen were double publications, and thus we have included

64 trials in this review. We requested complementary information

from nearly all the authors, and included complementary data in

22 studies (see references to studies).

Table 1. Table of studies awaiting assessment

Study ID Explanation Contact details

Alberto 1999 According to abstract (LILACS) patients with

community acquired pneumonia were divided (’al

azar’) randomly to ceftazidime versus penicillin +

amikacin. Awaiting full text availability for inclusion

and data extraction.

Figueroa Damian 1996 According to abstract (LILACS) patients were in-

cluded sequentially (Aleatoriamente), and given

piperacillin-tazobactam or ampicillin + gentamicin

for postcaesarean endometiris. Awaiting full text

availability to inspect whether study indeed random-

ized.

We have detailed study characteristics in the table of ’ Character-

istics of included studies’. The included studies were performed

between the years 1968 to 2001. Twenty-two were multi-centred.

Twenty-one were performed in the USA or Canada, 34 in Europe,

and 10 in other countries.

The studies included 7586 patients. The median number of in-

cluded patients per trial was 87.5 (range 20 to 580). Two trials (

Cardozo 2001; Naime Libien 1992) included children, while all

other trials were restricted to or included mostly adults.

The studies differed by the type of population and infection tar-

geted (see table of ’ Characteristics of included studies’). Most tri-

als (designated ’sepsis’) included patients with severe sepsis, sus-

pected Gram-negative infections (25 trials), or pneumonia (16 tri-

als). The adjusted mean fatality rate in these studies was 8.6%.

Eleven trials included patients with intra-abdominal infections,

related mainly to the biliary tract (designated ’abdominal’). The

mean fatality in these trials was 1.7%. Seven trials were restricted

to patients with urinary tract infections (UTIs), all hospitalized,

mainly women (UTI). Five of these studies reported fatality, and

no deaths occurred in four. Finally, five of the studies included in



the review targeted patients with Gram-positive infections, mainly

endocarditis. We will present results for these infections separately,

in addition to their inclusion in the overall analysis.

Most studies compared the initial, empirical antibiotic treatment

administered to the patients. Four studies assessed the empirical

treatment of a specific infection by randomizing patients empiri-

cally and evaluating only those subsequently fulfilling criteria for

the specific infection. Two such studies randomized patients with

suspected endocarditis and evaluated only those with Staphylo-coccus aureus bacteremia and proven endocarditis (Abrams 1979;

Korzeniowski 1982). The other two randomized patients with

suspected biliary tract infections and evaluated only patients with

a surgically proven diagnosis (Gerecht 1989; Yellin 1993). Non-

evaluated patients in these studies were not counted as dropouts,

since the study design defined evaluation only for patients ful-

filling definitive criteria. Eight studies, focusing on patients with

specific infections or pathogens (e.g., cholecystitis, Staphylococcal

infections, etc.), tested the effect of monotherapy versus combina-

tion therapy semi-empirically. In these studies (designated ’semi-

empirical’, see table of ’ Characteristics of included studies’) ran-

domization occurred after the specific infection was documented,

and patients could have received prior antibiotic treatment for this

infection. Analysis of empirical and semi-empirical studies was not

separated.

The specific antibiotic regimens used are detailed in the table of ’

Charcteristics of included studies’. Forty-four studies compared a

single beta-lactam drug to a different, narrower spectrum, beta-lac-

tam combined with an aminoglycoside (designated ’different BL’).

Sixteen ’different BL’ studies reported baseline susceptibility rates

of the pathogens isolated on admission to the beta-lactam. The

beta-lactam used in the combination arm covered less pathogens

than the monotherapy beta-lactam in 13 studies, while the op-

posite occurred in two studies only. Twenty studies compared the

same beta-lactam (designated ’same BL’). Results obtained from

studies comparing same and different beta-lactams were kept sep-

arated throughout all efficacy analyses. The aminoglycoside was

administered once daily in six trials (Cardozo 2001; Jaspers 1998;

Rubinstein 1995; Sandberg 1997; Sexton 1998; Speich 1998).

Other trials administered the aminoglycosides multiple daily (47

trials), or did not specify the administration schedule (11 trials).

Mean antibiotic treatment duration ranged between 4 to 17.5 days

in the sepsis studies, 6.8 to 11.9 in the abdominal studies, 4.1 to

7 days in the UTI studies, and 2 to 4 weeks in the endocarditis

studies.

Risk of bias in included studies

(See Additional Table 2: Study quality assessment table.)

Table 2. Study quality assessment

Study ID Alloc. generation Alloc. concealment Blinding Intention to treat Lost to follow up

Abrams 1979 No information No information None No 12 of 36 randomized

patients, but none

out of patients fulfill-

ing pre-specified in-

clusion cri-

teria (staphylococcus

aureus bacteremia)

Aguilar 1992 No information No information None Unknown No reference to drop-

outs in study

Alvarez-Lerma

2001

Computer gen-

erated in blocks of 6

patients

Central and sealed

opaque envelopes

For mortality only 24 of 140 random-

ized patients for fail-

ure

Arich 1987 Table of random

numbers

Sealed opaque en-

velopes

None No 18 of 65 randomized

patients



Table 2. Study quality assessment (Continued)

Bergeron 1988 No information No information None No 11 of 77 randomized

patients

Biglino 1991 No information No information None Unknown No reference to drop-

outs in study

Brown 1984 Random table No information Single, outcome as-

sessor

So 14 of 48 randomized

patients

Carbon 1987 No information No information None Unknown No reference to drop-

outs in study

Cardozo 2001 Numerical assigna-

tion

No information None Unknown No reference to drop-

outs in study

Cometta 1994 Table of random

numbers

Sealed, opaque

numbered

envelopes

None No 33 of 313 random-

ized patients

Cone 1985 No information No information None No 17 of 57 randomized

patients

Coppens 1983 Consecutively num-

bered envelopes

Envelopes (sealed or

opaque not men-

tioned)


patients

D’Antonio 1992 Table of random

numbers, stratified

according to under-

lying malignancy

Sealed opaque en-

velopes.

None For mortality only 17 of 300 random-


ure

Duff 1982 Based on the last

digit of the hospi-

talization number -

odds/ evens

No information None Yes None

Dupont 2000 Computer gen-

erated in blocks of 4

patients

Central Single, evaluation

committee

No 14 of 241 random-

ized patients

Felisart 1985 Table of random

numbers





Finer 1992 Computer

generated

Sealed, opaque en-

velopes

None For mortality only 56 of 471 random-


ure

Gerecht 1989 Computer gen-

erated table of ran-

dom numbers

No information None No 4 of 50 randomized

patients fulfilling op-

erative and bacteri-

ological criteria for

cholangitis

Gomez 1990 Computer

generated

Sealed, closed en-

velopes


ized pa-

tients, but none out

of patients fulfilling

pre-specified inclu-

sion criteria (gram-

negative bacteremia)

Havig Consecutive accord-

ing to a randomized

list prepared in ad-

vance

No information None No 22 of 90 randomized

patients

Hoepelman 1988 Randomization lists

made by hand

Sealed opaque en-

velopes

none Yes None

Holloway 1985 No information No information None No 10 of 43 randomized

patients

Iakovlev 1998 Parallel groups, us-

ing the envelope

method


opaque not men-

tioned)

None Yes None

Jaspers 1998 Table of random

numbers in consec-

utive envelopes

Sealed opaque en-

velopes

None Yes None

Klastersky 1973 No information No information None No 7 of 75 randomized

patients

Kljucar 1990 Com-

puter generated in

consecutively num-

bered envelopes

Closed envelopes None No 1 of 150 randomized

patients




Koehler 1990 No information No information None For mortality only 17 of 144 random-


ure

Korzeniowski 1982 Table of random

numbers

Central None No 82 of 156 random-

ized

patients, but only 4

of 78 patients fulfill-

ing pre-specified in-

clusion cri-

teria (Staphylococcus

aureus endocarditis)

Landau 1990 According to last

digit of identifica-

tion number

No information None Unknown No reference to drop-

outs in study

Limson 1988 No information No information None No 14 of 54 randomized

patients

Mandell 1987 Consecutive in

blocks of four

Sealed en-

velopes (opaque not

mentioned)


ized patients

Martin 1991 Randomization ta-

ble

No information None No 22 of 116 random-

ized patients

McCormick 1997 Table of random

numbers

Sealed, opaque en-

velopes


ized patients

Mergoni 1987 No information Sealed opaque en-

velopes

None Unknown No reference to drop-

outs in study

Moreno 1997 No information No information None No 12 of 70 randomized

patients

Mouton 1990 No information No information None Yes None

Mouton 1995 No information No information None For mortality only 43 of 272 random-


ure

Muller 1987 Computer

generated lists


ized patients




Naime Libien 1992 No information No information None Unknown No reference to drop-

outs in study

Piccart 1984 No information No information None No 20 of 105 random-

ized patients

Rapp 1984 No information No information None Yes None

Rasmussen 1986 Table of random

numbers


patients

Ribera 1996 Table of random

numbers

Sealed, opaque en-

velopes

None Yes None

Rubinstein 1995 Computer

generated

Sealed,

opaque, numbered

envelopes

Single, outcome as-

sessors blinded

For mortality only 75 of 580 random-


ure

Sage 1987 No information Envelopes None No 13 of 61 randomized

patients from arms

used in review

Sandberg 1997 Com-

puter generated lists

in blocks of four

Sealed opaque en-

velopes

None For mortality only 22 of 73 randomized

patients for failure

Sanfilippo 1989 Computer

generated code

Central Double blind,

placebo controlled

Unknown No reference to drop-

outs in study

Sculier 1982 No information No information None Yes None

Sexton 1998 No information No information None No 16 of 67 randomized

patients

Sieger 1997 No information No information None Yes None

Smith 1984 Table of random

numbers

Central Double blind,

placebo controlled

No 5 of 200 randomized

patients for failure;

13 of 200 random-

ized patients for mor-

tality

Speich 1998 Computer

generated

Sealed opaque en-

velopes.

None For mortality only 5 of 89 randomized

patients for failure




Stille 1992 Computer gener-

ated list of blocks of

16 patients


Sukoh 1994 No information Envelopes (sealed or

opaque not men-

tioned).

None Unknown No reference to drop-

outs in study

Takamoto 1994 Computer

generated


opaque not men-

tioned).


ized patients

Thompson 1990 Computer

generated


ized patients

Thompson 1993 Computer

generated


ized patients

Trujillo 1992 No information No information None Unknown No reference to drop-

outs in study

Vergnon 1985 Tirage a sort No information None Unknown No reference to drop-

outs in study

Verzasconi 1995 No information No information Single No 6 of 93 randomized

patients

Warren 1983 Random numbers

contained within

consecutively num-

bered envelopes

Sealed en-

velopes (opaque not

mentioned).


patients

Wiecek 1986 No information No information None Unknown No reference to drop-

outs in study

Wing 1998 Com-

puter generated ran-

dom number table

Sealed opaque en-

velopes.

None Yes None

Yellin 1993 2:1 (mono.:

combi.), through ta-

ble of random num-

bers

Central Single, provider no 59 of 149 random-

ized

patients, but only 22

of 112 patients ful-

filling pre-spec-

ified inclusion crite-




ria (infection proven

at surgery)

Allocation concealment and generation

Thirty-three percent of the studies (21/64) reported adequate al-

location concealment. Two studies were graded as C (Duff 1982;

Landau 1990). No information was available for the other studies

(34 studies), or envelopes were used but not described as sealed or

opaque (7 studies).

Allocation generation was described as adequate in 53% of the

studies (34/64). No information was available for 28 studies. Two

studies were quasi-randomized, using patient identification num-

bers (Duff 1982; Landau 1990).

Both allocation generation and concealment were considered ad-

equate in 30% of the studies (19/64).

Blinding

Most studies were open. Two studies, including 226 patients, were

double blinded (Sanfilippo 1989; Smith 1984). Outcome asses-

sors were blinded in four studies (Brown 1984; Dupont 2000;

Rubinstein 1995; Verzasconi 1995). Clinicians were blinded to

the treatment in one study (Yellin 1993).

Intention-to-treat versus per-protocol analysis

We separated included studies into four different study types with

relation to outcome reporting:

1. full Intention-to-treat analysis;

2. per-protocol analysis, in which the number of dropouts

was given per study arm;

3. per-protocol analysis, in which the number of dropouts

was known, but not given per study arm;

4. studies which did not distinguish between the number

of randomized and number of evaluated patients. These

studies did not refer to dropouts, yet did not define the

study explicitly as intention-to-treat.

The distribution of included studies by study type was as follows:

All cause fatality (reported in 43 studies):

Type 1: 19 studies (44%);

Type 2 and 3: 18 studies (42%). As authors cannot make assump-

tions can be made regarding dropouts for mortality, we have joined

study groups 2 and 3 are joined for mortality;

Type 4: 6 studies (14%).

Treatment failure: (reported In 63 studies);




Type 4: 11 studies (17%).

Follow-up

Forty-three studies (67%) specified follow-up duration, while only

18 studies defined a specific time for outcome collection (28%).

Follow-up ranged from 48 hours following treatment cessation

to 6 months. Outcomes were extracted preferentially at up to 30

days, with the exception of the Gram-positive infection studies, in

which the type of infection mandated a longer follow-up (3 to 6

months).

Effects of interventions

All cause fatality

(see Analysis 1)

Forty-three trials including 5527 patients were included in this

comparison (see Analysis 1.1). Twelve studies, including 1381 pa-

tients, compared the same beta-lactam. These studies showed near

equivalence, RR 1.01 (95%CI 0.75-1.35), while studies compar-

ing different beta-lactams tended non-significantly in favour of

monotherapy, RR 0.85 (95%CI 0.71-1.01). Analysis was further

broken down according to the main study population, excluding

Gram-positive infection studies (see Analysis 1.2). The advantage

to the monotherapy among studies comparing different beta-lac-

tams was statistically significant in studies addressing ’sepsis’, RR

0.83 (95% CI 0.69-0.99). No heterogeneity was present for these

comparisons (I2 = 0% for the same beta-lactam comparison, I2 =

19.4 for different beta-lactams).

Subgroup analyses

No significant difference between monotherapy and combination

therapy was apparent when analysis was restricted to patients with

any Gram-negative infection (eight studies) or Gram-negative bac-

teremia (four studies, see Analysis 1.3 to Analysis 1.4). Only three

studies permitted mortality outcome extraction among patients

with Pseudomonas aeruginosa infections, and these did not show

a differences, either alone or when combined (graph not shown).

Five UTI studies reported mortality, and mortality was null in

three studies. Excluding patients with urinary tract infection from

the analysis (’non-UTI’ subgroup, see Analysis 1.5) strengthened

the advantage to monotherapy in studies comparing different beta-

lactams (RR 0.70, 95%CI 0.52-0.95).

Sensitivity analyses

Adequate allocation concealment and generation were associated

with relative risk closer to one, both for studies comparing the



same and different beta-lactams. (See Analysis 7.1 and Analysis

7.2). Combination therapy was significantly better among stud-

ies comparing different beta-lactams classified as B. Blinding was

performed in too few studies to assess its effect on mortality. The

combined RR for studies comparing the same beta-lactam report-

ing fatality by intention-to-treat was 0.62 (95% CI 0.27-1.43),

compared to 1.09 (95% CI 0.80-1.51) for studies reporting fa-

tality per-protocol (Analysis 7.3). Comparing intention to treat

to per-protocol studies for different beta-lactams did not reveal a

difference. Re-analysis of the mortality comparison by the random

effect model was very similar (RR 1.02, 95% CI 0.76-1.38 for

same beta-lactam, RR 0.85 95% CI 0.69-1.05 for different beta-

lactam).

Treatment failure

(see Analysis 2)

We included all trials but one (Wiecek 1986) in the clinical failure

analysis, comprising 6616 patients (see Analysis 2.1). We found

a significant advantage to monotherapy among studies compar-

ing different beta-lactams, RR 0.77 (95% CI 0.69-0.86). We de-

tected no difference between monotherapy and combination ther-

apy among studies comparing the same beta-lactam, RR 1.11

(95% CI 0.95-1.29). No heterogeneity was present (I2=0% for

both comparisons).

Grouping studies according to study population highlighted an

advantage to combination therapy among the ’sepsis’ studies that

compared the same beta-lactam, RR 1.25 (95%CI 1.01-1.55).

This group of studies also accentuated the opposing advantage

to monotherapy among studies comparing different beta-lactams

(see Analysis 2.2).

Bacteriological cure occurred more frequently with monotherapy

among studies comparing different beta-lactams, RR 0.81 (95%

CI 0.69-0.94), but did not differ significantly in studies comparing

the same beta-lactam (see Analysis 2.3).

Assessment of efficacy for urinary tract infections included re-

infections and relapse as outcomes (see Analysis 2.4). We noted

no significant difference between monotherapy and combination

therapy , with six trials and 458 patients included in this compar-

ison.

Subgroup analyses

We analysed 28 studies including 1835 patients with Gram-neg-

ative infections and 18 studies including 426 patients with Pseu-domonas aeruginosa infections were analysed (see Analysis 2.5 and

Analysis 2.7). We observed no significant differences between the

study groups, either for studies comparing the same or different

beta-lactams. For studies comparing the same beta-lactam the RR

was 1.23 (95% CI 0.90-1.68) for Gram-negative infections and

1.02 (95% CI 0.68-1.51) for Pseudomonas aeruginosa infections.

We observed no difference between study groups among patients

with Gram-negative bacteremia or any bacteremia (see Analysis

2.6 and Analysis 2.8). The latter comparison mainly comprised of

patients with Gram-negative bacteremias but was available from

a larger number of studies, and showed an advantage to combi-

nation therapy among studies comparing different beta-lactams.

Both the subgroups of patients with urinary tract infections (see

Analysis 2.8), and patients without urinary tract infections main-

tained the trends seen previously (Analysis 2.9).

Sensitivity analyses

The quality of allocation concealment and generation did not af-

fect the relative risks for treatment failure, either among studies

comparing the same or different beta-lactams. The two studies

graded as C compared different beta-lactams, and were non-sig-

nificantly closer to one than the truly randomized studies (see

Analysis 7.4 to Analysis 7.5).

Several studies comparing different beta-lactams used some type

of blinding. The advantage to monotherapy was non-significantly

larger among these studies, compared to non-blinded studies (see

Analysis 7.6).

Among studies comparing the same beta-lactam, we observed an

advantage to combination therapy in the presumed intention to

treat group (type 2 studies), in which we imputed failure for

dropouts. Among studies comparing different beta-lactams, inten-

tion to treat, presumed intention to treat, and per-protocol results

were similar, favouring monotherapy (see Analysis 7.7). Analysis

by the random effect model did not change results (RR 1.09, 95%

CI 0.94-1.27 for same beta lactams, RR 0.76, 95% CI 0.68-0.97,

for different beta-lactams).

Length of hospital stay

Only four studies contained usable information for the compari-

son of hospital stay. Significant heterogeneity precluded their com-

bination. Duration of hospitalization was longer with monother-

apy in one study (McCormick 1997, 128 patients), shorter in an-

other (Arich 1987, 47 patients), and similar in two (Wing 1998;

Yellin 1993, 269 patients).

Summary of gain

Among studies comparing the same beta-lactam there was no ben-

efit to the combination arm for all mortality comparisons, includ-

ing subgroup and sensitivity analyses. Treatment failure tended to

favour the combination arm reaching statistical significance only

among studies addressing ’sepsis’ and when an intention to treat

analysis was imposed on studies performed per-protocol, imput-

ing failure for dropouts.

Studies using different beta-lactam usually compared a broad-spec-

trum beta-lactam to a narrower spectrum beta-lactam combined

with an aminoglycoside. The mortality comparisons favoured

monotherapy reaching statistical significance in several subgroups.



Treatment failure was significantly in favour of monotherapy over-

all, among the ’sepsis’ studies, the non-UTI subgroup and in all

the methodology sensitivity analyses. No comparison favoured the

combination arm.

Resistance development and adverse events

(see ’Analysis’ 3 and 4)

We compared studies comparing same and different beta-lactams

for the assessment of resistance development and adverse events.

These outcomes are intended to assess the antibiotic class effect

of aminoglycoside-beta-lactam combinations versus beta-lactams

alone, whether same or different.

We detected no significant differences between the rates of bac-

terial or fungal superinfections (see Analysis 3.1 to Analysis 3.4).

Bacterial superinfections occurred more frequently with combina-

tion therapy, RR 0.76 (95% CI 0.57-1.01). This was the largest

comparison, including 27 studies and 3085 patients. In outcome

5 we compared bacterial colonization rates only in patients from

whom surveillance cultures were taken (7 studies, 751 patients).

Colonization was, again, non-significantly more frequent with

combination therapy, RR 0.78 (95% CI 0.60-1.01). Few stud-

ies monitored development of resistance among pathogens iso-

lated initially (Analysis 3.6). We observed no difference between

monotherapy and combination therapy.

Any adverse event occurred non-significantly more frequently with

combination therapy, RR 0.92 (95% CI 0.83-1.01; see Analysis

4.1). We found nephrotoxicity to be more common in the combi-

nation arm in nearly all studies, with a highly significant combined

relative risk in favour of monotherapy, RR 0.30 (95% CI 0.23-

0.39, Analysis 4.3). A significantly increased rate of nephrotox-

icity was seen both in studies administering the aminoglycoside

once daily and in those with a multiple-day regimen. Vestibular

and ototoxicity, other known serious side effects of aminoglyco-

side treatment, were not reported routinely and could not be anal-

ysed. Different definitions and detailing of specific adverse events

precluded a meaningful meta-analysis of other adverse events, in-

dividually or grouped.

Dropouts and selection bias

(see ’Analysis’ 5)

The number of patients excluded from each study arm was nearly

equal, both for mortality (RR 1.00, 95% CI 0.66-1.49, Analysis

5.1), and failure (RR 1.04, 95% CI 0.88-1.23, Analysis 5.2) out-

comes assessment. This comparison included studies in which

these outcomes could only be collected per-protocol, and reported

the number of dropouts per study arm. It should be noted that

counting dropouts as failures did affect the combined failure re-

sults (failure sensitivity analysis above). This is because among

studies comparing the same beta-lactam, a slightly higher rate of

dropouts occurred in the monotherapy arm, while the opposite

occurred among studies comparing different beta-lactams.

The funnel plot for treatment failure generated a nearly symmetric

’funnel distribution’ (Figure 1). Funnel plot analysis for all-cause

fatality showed that small studies favouring combination therapy

may be missing (Figure 2). Mortality outcome was unavailable

from 33% of the trials.



Figure 1. Funnel failure.



Figure 2. Funnel mortality.All cause mortality



Gram positive-infections

(see ’Analysis’ 6)

Five studies assessed Gram-positive infections specifically. Four

studies addressed patients with endocarditis caused by Staphylo-coccus aureus (Abrams 1979; Korzeniowski 1982; Ribera 1996), or

streptococci (Sexton 1998). One study included any staphylococ-

cal infection (Coppens 1983). All of these compared the same beta-

lactam, with or without an aminoglycoside. Although small, we

chose to separate this subset of studies and present its meta-anal-

ysis, since the rationale and clinical practice of adding an amino-

glycoside to the beta-lactam in these infections differ from those

underlying combination use in other infections.

The comparison included four outcomes: all cause fatality (three

studies, outcome 1), clinical and bacteriological failure (five stud-

ies, outcomes 2 to 3), and the need for surgery (four endocarditis

studies, outcome 4). None of these comparisons showed an ad-

vantage to combination therapy. The combined relative risk con-

sistently favoured monotherapy, although differences were non-

significant. The combined relative risk for clinical failure was 0.69

(95% CI 0.40-1.19, 5 studies, 305 patients). Clinical failure in

these studies could be and indeed was defined more rigorously

than in other studies. The time of outcome determination was

pre-defined in all the trials and the follow-up was longer (1 to

6 months). Measures of treatment failure included persistence of

bacteremia or signs of endocarditis, relapse, need for valve replace-

ment, and death.

D I S C U S S I O N

This present review compares beta-lactam-aminoglycoside antibi-

otic combinations to beta-lactam monotherapy. The primary out-

come we assessed was all-cause fatality. Most studies compared one

beta-lactam to a different, narrower spectrum beta-lactam, com-

bined with an aminoglycoside. Twenty of the 64 included studies

used the same beta-lactam in both study arms.

A special emphasis should be placed on studies comparing the

same beta-lactam. These are the studies directly testing the hy-

pothesis that the addition of an aminoglycoside to the beta-lactam

is beneficial. Among these studies, all-cause fatality did not differ

between study arms (RR 1.02, 95% CI 0.76-1.38). Treatment fail-

ure occurred more frequently in the monotherapy arm, reaching

statistical significance only in subgroup analyses.

In studies comparing different beta-lactams, both failure and mor-

tality were more common in the combination treatment arm. Fail-

ure was highly significant, while mortality reached significance

only with subgroup analyses. These studies demonstrate an advan-

tage to broad-spectrum beta-lactam monotherapy when compared

to a narrower spectrum beta-lactam combined with an aminogly-

coside, despite an equal in-vitro coverage of the culprit pathogens

in both arms.



Development of resistance was assessed by the occurrence of su-

perinfections and colonization, assuming that bacteria appearing

under antibiotic treatment are resistant to the antibiotic adminis-

tered. No difference between monotherapy and combination ther-

apy was detected. Adverse events occurred more frequently with

combination therapy. Specifically, nephrotoxicity occurred signif-

icantly more frequently in the combination treatment arm (RR

0.30, 95% CI 0.23-0.39).

We defined all-cause fatality as the primary outcome, while most

studies assessed and reported treatment failure as a main outcome.

Obviously, the most significant outcome for the patient is survival

following the infectious episode. Available evidence shows that the

addition of an aminoglycoside to a beta-lactam does not reduce

mortality. Replacing beta-lactam monotherapy with a narrower

spectrum beta-lactam combined with an aminoglycoside may be

associated with increased mortality.

Failure was commonly defined as lack of clinical improvement,

deterioration, relapse, and/or modifications to the antibiotic treat-

ment. These endpoints are highly subjective and do not necessarily

translate to detriments experienced by the patient. Detection bias

is a concern in open trials that compared the same beta-lactam, or

in trials comparing a ’new’ broad spectrum monotherapy to a con-

ventional antibiotic regimen. Thus, the advantage to monother-

apy therapy in studies comparing different beta-lactams, and the

opposing advantage to combination therapy in studies comparing

the same beta-lactams, may be largely biased.

The major adverse event associated with combination therapy was

nephrotoxicity. We did not observe a protective effect of the com-

bination with regard to resistance development. During the last

decade, once daily administration of aminoglycosides has entered

into use, with similar efficacy but lower nephrotoxicity (Barza

1996). Most studies in our review used multiple-day administra-

tion schedules for the complete duration of antibiotic therapy or

until modification. The RR of 0.30 for any nephrotoxicity we

observed may, therefore, be an overestimation. However, the RR

among the few studies that did administer the aminglycoside once

daily was also highly significant in favour of monotherapy (0.17,

0.06-0.53).

The rationale for administering combination therapy arose from

in-vitro studies showing synergistic bactericidal activity of specific

beta-lactam-aminoglycoside antibiotic combinations. Synergy has

been observed for Pseudomonas aeruginosa (Giamarellou 1984),

other Gram-negative bacteria (Giamarellou 1986; Klastersky

1976), and Staphylococci (Sande 1975; Sande 1976). Assessment

of antibiotic efficacy against specific infections in randomized tri-

als must either be limited to definitive treatment (randomisation

performed when infection is microbiologically documented), or

be performed as a subgroup analysis to assess empirical treatment

(randomizing patients empirically and assessing those with doc-

umented infections). Eight studies assessed definitive treatment

(semi-empirical studies), while most assessed empirical treatment.

We did not find an advantage to combination therapy among

patients with any Gram-negative infection, Gram-negative bac-

teremia, or Pseudomonas aeruginosa infections. Lack of data pre-

cluded the assessment of Pseudomonas aeruginosa bacteremia.

In a previous non-randomized prospective study of bacteremic pa-

tients, we showed that appropriate beta-lactam monotherapy was

as effective as appropriate beta-lactam aminoglycoside combina-

tion therapy, both empirically and semi-empirically. Appropriate

single aminoglycoside monotherapy was associated with increased

mortality (Leibovici 1997). Combination therapy was claimed su-

perior to monotherapy in a prospective observational study of pa-

tients with Pseudomonas aeruginosa bacteremia, but most patients

in the monotherapy group received aminoglycosides (Hilf 1989).

In a meta-analysis including non-randomized trials (mostly retro-

spective cohort studies), Safdar and colleagues found a reduction in

mortality with combination therapy for patients with Pseudomonasaeruginosa bacteremia (5 studies; OR 0.50, 95%CI 0.32-0.79),

but not for patients with Gram-negative bacteremia (17 studies;

OR 0.96, 95% CI 0.79-1.32). Monotherapy, however, included

single aminoglycoside treatment, and analysis was not performed

separately for beta-lactam monotherapy (Safdar 2004). Finally, in

a previous systematic review and meta-analysis of randomized tri-

als comparing combination therapy to beta-lactam monotherapy

for febrile neutropenic patients, no advantage was seen for the

combination (Paul 2001). Overall, empirical evidence does not

show the synergy effect when adding an aminoglycoside to a beta-

lactam in the clinical setting. Why does synergy, observed in-vitro,

not translate into clinical benefit? Specific growth conditions in-

vitro, unattainable in-vivo, may induce synergism. Pharmacoki-

netic and pharmacodynamic properties involving specific antibi-

otics, sites of infection, timing and intervals of administration may

prevent synergism in-vivo. Adverse events related directly to the

aminoglycoside, or to the combination, may interfere with an in-

vivo benefit, amounting altogether to no benefit.

A small subset of studies in our review addressed patients with

Gram-positive infections, mainly Staphylococcus aureus endocardi-

tis. No study assessed enterococcal infections specifically. In these,

also, no outcome was improved by the addition of an aminoglyco-

side. Current guidelines for the treatment of Staphylococcus aureusendocarditis advise the addition of an aminoglycoside to the beta-

lactam, at least initially (Bayer 1998). These recommendations

rely mainly on in-vitro data (Sande 1975; Sande 1976). Animal

studies have shown that sterilization of cardiac vegetations may

be achieved more rapidly with combination therapy (Sande 1975;

Sande 1976). One clinical study included in our review showed

that combination therapy shortened the duration of bacteremia,

but this comparison was performed according to the empirical an-

tibiotic regimen, while randomization occurred either empirically

or semi-empirically (Korzeniowski 1982). We could not show an

advantage to combination therapy combining all trials in humans.



On the contrary, all outcomes tended to favour monotherapy, al-

though statistical significance was not reached.

The limitations of our analysis may originate from the quality of

data reported in available studies and from our analysis of these

data. Of these, we emphasize the lack of data for all-cause fatality

from a third of included studies. Survival, with or without the

more subjective assessment of infection-related mortality, must be

reported comparatively in all trials. Data for subgroups most likely

to benefit from combination therapy were also not available from

all studies. In our analysis, we did not correct for the appropriate-

ness of antibiotic treatment, which has been shown conclusively to

correlate with survival (Ibrahim 2000; Leibovici 1998). Data were

not fully available to perform such an analysis. However, among

studies comparing the same beta-lactam, combination therapy by

definition broadened the spectrum of coverage, without improv-

ing outcomes. In studies comparing different beta-lactams, inap-

propriate beta-lactam was used more frequently in the combina-

tion arm, which may partially explain the advantage to monother-

apy.

We conclude that the addition of an aminoglycoside to a beta-lac-

tam does not improve the clinical efficacy achieved with the beta-

lactam alone. Substituting a narrow-spectrum beta-lactam with an

aminoglycoside for a single broad-spectrum beta-lactam, will re-

sult in increased failure rates and may be associated with increased

mortality. Adverse events occur more frequently with combina-

tion treatment. Short-term combination therapy for sepsis does

not prevent development of resistant bacteria, as assessed by su-

perinfection or colonization rates following antibiotic treatment.

Thus, the use of beta-lactam-aminoglycoside combination ther-

apy for sepsis should be discouraged.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Clinicians usually face the dilemma of selecting an antibiotic

treatment on two occasions during an un-complicated infectious

episode. On the initial encounter with a patient the clinician

must prescribe empirical antibiotic treatment, since the causative

pathogen and its susceptibilities are generally unknown. Most

studies addressed this situation, and the results show that there is

no difference in overall mortality whether monotherapy or combi-

nation therapy is used. Adverse effects, most significantly nephro-

toxicity, will occur more frequently with combination therapy. If

the choice is between a narrower-spectrum beta-lactam combined

with an aminoglycoside versus a broad-spectrum beta-lactam, our

results show that treatment will ultimately have to be modified

more frequently if the combination is chosen. We have not iden-

tified a specific site of infection, or disease severity, where combi-

nation treatment has an advantage.

The second decision point occurs when the causative pathogen is

identified. Here, the choice of the antibiotic treatment is dictated

by known susceptibility results. However, the question remains,

whether for specific bacteria beta-lactam-aminoglycoside combi-

nation treatment offers an advantage over single beta-lactam treat-

ment. We addressed this question by subgroup analyses of patients

with documented infections caused by specific pathogens (Gram-

negatives, Pseudomonas aeruginosa, Staphylococcus aureus). In addi-

tion, several semi-empirical studies addressed this question specif-

ically. We have not identified a specific pathogen, or pathogen

group, where combination therapy is advantageous.

Overall, appropriate beta-lactam monotherapy should be used.

Beta-lactam-aminoglycoside combination therapy does not offer

an advantage, and is associated with an increased rate of adverse

events.

Implications for research

We cannot point to a specific patient subgroup that showed a trend

for benefit with combination therapy. The design of existing stud-

ies did not permit a comparison between monotherapy and com-

bination therapy for specific pathogens when all the antibiotics

administered matched the in-vitro susceptibility of the pathogen.

However the large body of studies that were performed did not

point towards any benefit. Thus we do not see the justification for

such future trials.

Exceptions to this are trials addressing patients with endocarditis.

Prolonged combination treatment for endocarditis, including an

aminoglycoside, is well accepted in clinical practice, but does not

seem grounded in clinical evidence. Future trials must examine

the justification for this practice.

Further comparisons between monotherapy and combination, if

performed, should be limited to comparisons involving the same

beta-lactam. This is the only design that explores the benefit of

beta-lactam-aminoglycoside combination therapy. Studies com-

paring broad-spectrum monotherapy, such as new antibiotics, to

an older generation beta-lactam with an aminoglycoside should

not be performed. Patients may be harmed by combination ther-

apy in such trials.

Appropriate antibiotic treatment has been shown to significantly

reduce mortality, and should therefore be reported with results

adjusted to it. Outcomes relevant to patients, such as survival

and hospitalisation duration should be assessed. Survival, if not

assessed as a primary outcome, must at least be reported.

A C K N O W L E D G E M E N T S

We would like to thank all the authors who responded to our re-

quests for additional data (see ’unpublished data’ and ’unpublished

data sought but not used’, ’References to studies’). Dr Solomkin



(Solomkin 1986) and Dr. Sexton (Sexton 1984) supplied supple-

mentary data for their studies, which were not included in the

review. Dr. Finer and Dr. Goustas of the GlaxoSmithKline Com-

pany supplied detailed data for their study (Finer 1992). Dr Kora

Huber sent completed trial results for Kljucar 1990 and supplied

requested additional information. Ms Mary Forrest (Managing ed-

itor, Journal of Chemotherapy), sent several publications that were

not available to us. We would also like to warmly thank Ms Rika

Fujiya who translated the Japanese studies (Sukoh 1994; Takamoto

1994).

We thank Dr Vittoria Lutje, Dr Harriet G. MacLehose, and Ms

Rieve Robb (Review Group Co-ordinator) of the Cochrane Infec-

tious Diseases Group. We thank Dr Harald Herkner, Prof. Nathan

Pace, Kathie Godfrey, Janet Wale and Jane Cracknell (Review

Group Co-ordinator) of the Cochrane Anaesthesia Review Group.

Both groups supported and provided helpful revisions for this re-

view.

This review was initially developed within the Infectious Diseases

Group and supported by a grant from the Department for In-

ternational Development, UK. The review was transferred to the

Anaesthesia Group in May 2005.

R E F E R E N C E S

References to studies included in this review

Abrams 1979 {published data only}

Abrams B, Sklaver A, Hoffman T, Greenman R. Single or combi-

nation therapy of staphylococcal endocarditis in intravenous drug

abusers. Annals of Internal Medicine 1979;90(5):789–91.

Aguilar 1992 {published data only}

Ramirez de Aguilar R. Clinical trial on efficacy and safety of cefti-

zoxime compared with penicillin-gentamicin of managing of adult

severe infections [Estudio clinico para determinar la eficacia y seguri-

dad de ceftizoxima en comparacion con penicilina–gentamicina en

el manejo de las infecciones graves del adulto]. Compend Invest ClinLatinoam 1992;12(3):75–8.

Alvarez-Lerma 2001a {published and unpublished data}

Alvarez-Lerma F. [Efficacy of monotherapy by meropenem in ven-

tilator-associated pneumonia]. Antibiotiki i khimioterapiia 2001;46

(12):42–52.∗ Alvarez Lerma F on behalf of the Serious Infection Study Group.

Efficacy of meropenem as monotherapy in the treatment of venti-

lator- associated pneumonia. Journal of Chemotherapy 2001;13(1):

70–81.

Arich 1987 {published and unpublished data}Arich C, Gouby A, Bengler C, Ardilouze JL, Dubois A, Joubert P, et

al.[Comparison of the efficacy of cefotaxime alone and the combi-

nation cefazolin-tobramycin in the treatment of enterobacterial sep-

ticemia] In French. Pathologie Biologie (Paris) 1987;35(5):613–5.

Bergeron 1988 {published data only}

Bergeron MG, Mendelson J, Harding GK, Mandell L, Fong IW,

Rachlis A, et al.Cefoperazone compared with ampicillin plus to-

bramycin for severe biliary tract infections. 13th International

Congress of Chemotherapy. 1983.∗ Bergeron MG, Mendelson J, Harding GK, Mandell L, Fong IW,

Rachlis A, et al.Cefoperazone compared with ampicillin plus to-

bramycin for severe biliary tract infections. Antimicrobials Agents andChemotherapy 1988;32(8):1231–6.

Biglino 1991 {published data only}

Biglino A, Bonasso M, Gioannini P. Imipenem/cilastatin as empirical

treatment of severe infections in compromised patients. Journal of

Chemotherapy 1991;3 Suppl 1:208–12.

Brown 1984 {published data only}

Brown RB, Lemeshow S, Teres D. Moxalactam vs carbenicillin plus

tobramycin: Treatment of nosocomial gram-negative bacillary pneu-

monias in non-neutropenic patients. Current therapeutic research,clinical and experimental 1984;36(3):557–64.

Carbon 1987 {published data only}

Carbon C, Auboyer C, Becq Giraudon B, Bertrand P, Gallais H,

Mouton Y, et al.Cefotaxime (C) vs cefotaxime + amikacin (C + A)

in the treatment of septicemia due to enterobacteria: a multicenter

study. Chemioterapia 1987;6(2 Suppl):367–8.

Cardozo 2001 {published and unpublished data}

Cardozo M, Basualdo W, Martinez R, Matsumura K, Gonzalez-

Cabello M, Navarro D, et al.Evolution of the association amoxi-

cillin/sulbactam to a amoxicillin/sulbactam more gentamicins in chil-



dren with peritonitis of apendicular origin [Evaluacion de la asocia-

cion amoxicilina/sulbactam frente a amoxicilina/sulbactam mas gen-

tamicina en ninos con peritonitis de origen apendicular]. Pediatr.

(Asuncion) 2001;28(2):15–19.

Cometta 1994 {published and unpublished data}∗ Cometta A, Baumgartner JD, Lew D, Zimmerli W, Pittet D,

Chopart P, et al.Prospective randomized comparison of imipenem

monotherapy with imipenem plus netilmicin for treatment of severe

infections in nonneutropenic patients. Antimicrobial Agents and Che-

motherapy 1994;38(6):1309–13.

Iten A, Cometta A, Eggimann P, Siegrist H, Francioli P. The addi-

tion of netilmicin (NET) to imipenem (IMIP) does not prevent the

emergence of bacteria resistant (R) to IMIP during treatment (ttt)

of severe infections. 32nd Interscience Conference on Antimicrobial

Agents and Chemotherapy. 1992; Vol. Abstract no. 522:198.

Cone 1985 {published data only}Cone LA, Woodard DR, Stoltzman DS, Byrd RG. Ceftazidime ver-

sus tobramycin-ticarcillin in the treatment of pneumonia and bac-

teremia. 23rd Interscience Conference Antimicrobial Agents and

Chemotherapy. 1983; Vol. Abstract no. 843.∗ Cone LA, Woodard DR, Stoltzman DS, Byrd RG. Ceftazidime

versus tobramycin-ticarcillin in the treatment of pneumonia and bac-

teremia. Antimicrobial Agents and Chemotherapy 1985;28(1):33–6.

Coppens 1983 {published data only}

Coppens L, Hanson B, Klastersky J. Therapy of staphylococcal infec-

tions with cefamandole or vancomycin alone or with a combination

of cefamandole and tobramycin. Antimicrobial Agents and Chemo-therapy 1983;23(1):36–41.

D’Antonio 1992 {published and unpublished data}D’Antonio D, Fioritoni G, Iacone A, Dell’Isola M, Natale D,

D’Arcangelo L, et al.Randomized comparison of ceftriaxone versus

ceftriaxone plus amikacin for the empirical treatment of infections

in patients with altered host defense: microbiological and clinical

evaluation. Chemotherapy 1992;38(6):420–7.

Duff 1982 {published and unpublished data}Duff P, Keiser JF. A comparative study of two antibiotic regimens

for the treatment of operative site infections. American Journal ofObstetrics and Gynecology 1982;142(8):996–1003.

Dupont 2000 {published data only}

Dupont H, Carbon C, Carlet J, and the Severe Generalized Peritonitis

Study Group. Monotherapy with a broad-spectrum beta-lactam is as

effective as its combination with an aminoglycoside in treatment of

severe generalized peritonitis: a multicenter randomized controlled

trial. 38th Interscience Conference on Antimicrobial Agents and

Chemotherapy. 1998; Vol. Abstract MN–48:602.∗ Dupont H, Carbon C, Carlet J, for The Severe Generalized Peri-

tonitis Study Group. Monotherapy with a broad-spectrum beta-

lactam is as effective as its combination with an aminoglycoside in

treatment of severe generalized peritonitis: a multicenter randomized

controlled trial. Antimicrobial Agents and Chemotherapy 2000;44(8):

2028–33.

Felisart 1985 {published data only}

Felisart J, Rimola A, Arroyo V, Perez-Ayuso RM, Quintero E, Gines

P, et al.Cefotaxime is more effective than is ampicillin-tobramycin in

cirrhotics with severe infections. Hepatology 1985;5(3):457–62.

Finer 1992 {published and unpublished data}

Finer N, Goustas P. Ceftazidime versus aminoglycoside and

(ureido)penicillin combination in the empirical treatment of serious

infection. Journal of the Royal Society of Medicine 1992;85(9):530–3.

Gerecht 1989 {published data only}

Gerecht WB, Henry NK, Hoffman WW, Muller SM, LaRusso

NF, Rosenblatt JE, et al.Prospective randomized comparison of me-

zlocillin therapy alone with combined ampicillin and gentamicin

therapy for patients with cholangitis. Archives of Internal Medicine

1989;149(6):1279–84.

Gomez 1990a {published and unpublished data}

Gomez J, Moldenauer F, Ruiz G, Canteras M, Redondo C, Molina

B, et al.[Monotherapy (ceftazidime) versus combination therapy

(cefradine + amikacin) in gram-negative bacteremia. A prospective,

randomized study, 1987] In Spanish. Revista Espanola de Quimioter-

apia 1990;3(1):35–40.

Havig 1973 {published data only}Havig O, Hertzberg J. [Effect of ampicillin, chloramphenicol and

penicillin + streptomycin in the treatment of acute cholecystitis].

Tidsskrift for den Norske laegeforening 1975;95(5):298–300.∗ Havig O, Hertzberg J. Effect of ampicillin, chloramphenicol, and

penicillin-streptomycin in acute cholecystitis. Scandinavian Journal

of Gastroenterology 1973;8(1):55–8.

Hoepelman 1988 {published and unpublished data}

Hoepelman IM, Rozenberg-Arska M, Verhoef J. Comparative study

of ceftriaxone monotherapy versus a combination regimen of cefurox-

ime plus gentamicin for treatment of serious bacterial infections: the

efficacy, safety and effect on fecal flora. Chemotherapy 1988;34(Suppl

1):21–9.

Hoepelman IM, Rozenberg-Arska M, Verhoef J. Comparison of once

daily ceftriaxone with gentamicin plus cefuroxime for treatment of

serious bacterial infections. 27th Interscience Conference on An-

timicrobials Agents and Chemotherapy. 1987; Vol. Abstract no. 89.∗ Hoepelman IM, Rozenberg-Arska M, Verhoef J. Comparison of

once daily ceftriaxone with gentamicin plus cefuroxime for treatment

of serious bacterial infections. Lancet 1988;1(8598):1305–9.

Holloway 1985 {published data only (unpublished sought but not used)}Holloway WJ. Treatment of infections in hospitalized patients with

ticarcillin plus clavulanic acid. A comparative study. American jour-nal of Medicine 1985;79(5B):168–71.

Iakovlev 1998 {published data only}Iakovlev SV, Iakovlev VP, Derevianko, II, Kira EF, and the

Meropenem Study Group. [Multicenter open randomized trial of

meropenem in comparison to ceftazidime and amikacin used in com-

bination in severe hospital infections]. In Russian. Antibiotiki iKhimioterapiia 1998;43(1):15–23.

Jaspers 1998 {published and unpublished data}Jaspers CA, Kieft H, Speelberg B, Buiting A, van Marwijk Kooij

M, Ruys GJ, et al.Meropenem versus cefuroxime plus gentamicin

for treatment of serious infections in elderly patients. Antimicrobial

Agents and Chemotherapy 1998;42(5):1233–8.

Klastersky 1973 {published data only}

Klastersky J, Cappel R, Daneau D. Therapy with carbenicillin and

gentamicin for patients with cancer and severe infections caused by

gram-negative rods. Cancer 1973;31(2):331–6.



Kljucar 1990 {published and unpublished data}∗ Kljucar S, Heimesaat M, von Pritzbuer E, Bauernfeind A. Com-

parative clinical trial with ceftazidime (CAZ) versus ceftazidime plus

tobramycin (TOB) versus azlocillin (AZL) plus tobramycin in ven-

tilated patients with nosocomial lower respiratory tract infections

(LRTI). 30th Interscience Conference on Antimicrobial Agents and

Chemotherapy. 1990:Abtract no. 953.

Kljucar S, Heimesaat M, von Pritzbuer E, Olms K. [Ceftazidime

with and without tobramycin versus azlocillin plus tobramycin in the

therapy of bronchopulmonary infections in intensive care patients].

In German. Infection 1987;15(Suppl 4):S185–S191.

Koehler 1990 {published data only}

Koehler CO, Arnold H. Controlled clinical study of ceftazidime (3

x 1 g daily) versus piperacillin + tobramycin in patients with nosoco-

mial pneumonia. International Journal of Experimental and ClinicalChemotherapy 1990;3(4):211–8.

Korzeniowski 1982 {published data only}

Korzeniowski O, Sande MA. Combination antimicrobial therapy for

Staphylococcus aureus endocarditis in patients addicted to parenteral

drugs and in nonaddicts: A prospective study. Annals of InternalMedicine 1982;97(4):496–503.

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gentamicin for complicated urinary tract infections]. In Hebrew.

Harefuah 1990;118(3):152–3.

Limson 1988 {published data only (unpublished sought but not used)}

Limson BM, Navarro Almario E, Litam P, Que E, Kua LT. Cef-

tazidime monotherapy compared with amikacin/ticarcillin combina-

tion therapy in severe infections. Journal of the Philippines MedicalAssociation 1988;64(1):33–5.∗ Limson BM, Navarro Almario E, Litam P, Que E, Kua LT. Cef-

tazidime versus a combination of amikacin and ticarcillin in the treat-

ment of severe infections. Clinical Therapeutics 1988;10(5):589–93.

Mandell 1987 {published data only (unpublished sought but not used)}Mandell LA, Nicolle LE, Ronald AR, Duperval R, Robson HG, Feld

R, et al.A multicentre prospective randomized trial comparing cef-

tazidime with cefazolin/tobramycin in the treatment of hospitalized

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les pyelonehrites aigues]. Reveu Medicale Suisse Romande 1991;111

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Lower Respiratory Infection Group. Empiric treatment of hospi-

tal-acquired lower respiratory tract infections with meropenem or

ceftazidime with tobramycin: a randomized study. Critical Care

Medicine 1997;25(10):1663–70.

Sieger B, Geckler RW. A comparison of meropenem and ceftazidime

plus tobramycin in the treatment of hospital-acquired lower respira-

tory tract infections. 33rd Interscience Conference on Antimicro-

bials Agents and Chemotherapy. 1993; Vol. Abstract no. 640:236.

Smith 1984 {published data only (unpublished sought but not used)}

Moore RD, Smith CR, Holloway JJ, Lietman PS. Cefotaxime vs naf-

cillin and tobramycin for the treatment of serious infection. Com-

parative cost-effectiveness. Archives of Internal Medicine 1986;146

(6):1153–7.

Moore RD, Smith CR, Lietman PS. Increased risk of renal dysfunc-

tion due to interaction of liver disease and aminoglycosides. Ameri-

can Journal of Medicine 1986;80(6):1093–7.∗ Smith CR, Ambinder R, Lipsky JJ, Petty BG, Israel E, Levitt R, et

al.Cefotaxime compared with nafcillin plus tobramycin for serious

bacterial infections. A randomized, double-blind trial. Annals of

Internal Medicine 1984;101(4):469–77.

Speich 1998 {published and unpublished data}

Speich R, Imhof E, Vogt M, Grossenbacher M, Zimmerli W. Effi-

cacy, safety, and tolerance of piperacillin/tazobactam compared to co-

amoxiclav plus an aminoglycoside in the treatment of severe pneu-

monia. European Journal of Clinical Microbiology and Infectious Dis-

eases 1998;17(5):313–17.

Stille 1992 {published data only}

Stille W, Shah PM, Ullmann U, Hoffstedt B, Kreisl C, Bommers-

bach B et al. For the German and Austrian Imipenem/Cilastatin

Study Group. Randomized multicenter clinical trial with

imipenem/cilastatin versus cefotaxime/gentamicin in the treatment

of patients with non-life-threatening infections. European Journal ofClinical Microbiology and Infectious Diseases 1992;11(8):683–92.

Sukoh 1994 {published and unpublished data}Sukoh M, Inoue T, Morita Y, Ito K, Togano Y, Yamanaka

K, et al.[Clinical evaluation of combination therapy of sulbac-

tam/cefoperazone and aminoglycoside in respiratory tract infections].

In Japanese. Japanese Journal of Antibiotics 1994;47(2):170–80.

Takamoto 1994 {published data only}

Takamoto M, Ishibashi T, Toyoshima H, Tanaka H, Tamaru N,

Watanabe K, et al.[Imipenem/cilastatin sodium alone or combined

with amikacin sulfate in respiratory infections]. In Japanese. JapaneseJournal of Antibiotics 1994;47(9):1131–44.

Thompson 1990 {published data only}

Thompson JE Jr, Pitt HA, Doty JE, Coleman J, Irving C. Broad spec-

trum penicillin as an adequate therapy for acute cholangitis. Surgery,

gynecology & obstetrics 1990;171(4):275–82.

Thompson 1993 {published data only}

Thompson JE Jr, Bennion RS, Roettger R, Lally KP, Hopkins JA,

Wilson SE. Cefepime for infections of the biliary tract. Surgery,

gynecology & obstetrics 1993;177(Suppl):30–4.

Trujillo 1992 {published data only}

Zavala Trujillo I. Research on efficacy and safety of ceftizoxime in

treating lower respiratory tract and skin and soft tissues infections

[Busqueda de la eficacia y seguridad de ceftizoxima en el tratamiento

de infecciones del tracto respiratorio inferior y de la piel y de los

tejidos blandos]. Compend Invest Clin Latinoam 1992;12(2):31–41.

Vergnon 1985 {published data only}

Vergnon JM, Vincent M, Ros A, Brun Y, Brune J. [Comparative

clinical trial of cefoperazone versus ampicillin + tobramycin in severe

bronchopulmonary and pleural infectious pathology]. In French.

Revue de pneumologie clinique 1985;41(3):205–11.

Verzasconi 1995 {published data only}Verzasconi R, Rodoni P, Monotti R, Marone C, Mombelli G. [Amox-

icillin and clavulanic acid versus amoxicillin plus gentamicin in the

empirical initial treatment of urinary tract infections in hospital-

ized patients] [In German]. Schweizerische medizinische Wochenschrift1995;125(33):1533–9.

Warren 1983 {published data only}

Warren JW, Miller EH Jr, Fitzpatrick B, DiFranco DE, Caplan ES,

Tenney JH, et al.A randomized, controlled trial of cefoperazone vs.

cefamandole- tobramycin in the treatment of putative, severe infec-

tions with gram- negative bacilli. Reviews in Infectious Diseases 1983;

5(Suppl 1):S173–S180.



Wiecek 1986 {published data only}

Wiecek A, Kokot F, Andrzejowska H, Grzeszczak W. [Clinical evalu-

ation of ceftazidime and the combined administration of cefotaxime

and tobramycin in the treatment of urinary tract infections. Prospec-

tive and randomized studies] In Polish. Polski tygodnik lekarski 1986;

41(39):1242–46.

Wing 1998 {published and unpublished data}

Wing DA, Hendershott CM, Debuque L, Millar LK. A randomized

trial of three antibiotic regimens for the treatment of pyelonephritis

in pregnancy. Obstetrics and gynecology 1998;92(2):249–53.

Yellin 1993 {published and unpublished data}Yellin AE, Berne TV, Appleman MD, Heseltine PN, Gill MA,

Okamoto MP, et al.A randomized study of cefepime versus the com-

bination of gentamicin and mezlocillin as an adjunct to surgical treat-

ment in patients with acute cholecystitis. Surgery, gynecology & ob-stetrics 1993;177(Suppl):23–9.

References to studies excluded from this review

Alvarez-Lerma 2001b {published data only}Alvarez-Lerma F, Insausti-Ordenana J, Jorda-Marcos R, Maravi-

Poma E, Torres-Marti A, Nava J, et al.Efficacy and tolerability

of piperacillin/tazobactam versus ceftazidime in association with

amikacin for treating nosocomial pneumonia in intensive care pa-

tients: a prospective randomized multicenter trial. Intensive Care

Medicine 2001;27(3):493–502.

Badaro 2002 {published data only}Badaro R, Molinar F, Seas C, Stamboulian D, Mendonca J, Massud

J, et al.A multicenter comparative study of cefepime versus broad-

spectrum antibacterial therapy in moderate and severe bacterial in-

fections. Brazilian Journal of Infectious Diseases 2002;6(5):206–18.

Benlloch 1995 {published data only}

Benlloch C, Costa E, Segarra V, Velazquez JA, Ruiz CS. Systemic

antibiotherapy in acute appendicitis. Comparison of three antibiotic

regimes [Antibioterapia sistemica en apendicitis aguda. Compara-

cion entre tres pautas antibioticas]. Acta Pediatrica Espanola 1995;

53(6):367–9.

Blumer 2003 {published data only}∗ Blumer JL, Minkwitz M, Saiman L, San Gabriel P, Iaconis J, Mel-

nick D. Meropenem (MEM) compared with ceftazidime (CAZ) in

combination with tobramycin (TOB) for treatment of actue pul-

monary exacerbations (APE) in patients with cystic fibrosis (CF) in-

fected with Pseudomonas aeruginosa (PA) or burkholderia cepacia

(BC). Pediatric Pulmonology. 2003; Vol. Suppl 25:294.

Cetto 1983 {published data only}

Cetto GL, Todeschini G, Caramaschi G, Vinante F, Benini F, Perona

G. Empiric therapy of infections in hematologic malignancies: a

prospective, randomized trial. Tumori 1983;69(2):155–60.

Ciftci 1997 {published data only}

Ciftci AO, Tanyel FC, Buyukpamukcu N, Hicsonmez A. Compara-

tive trial of four antibiotic combinations for perforated appendicitis

in children. European Journal of Surgery 1997;163(8):591–6.

Crenshaw 1983 {published data only}Crenshaw C, Glanges E, Webber C, McReynolds DB. A prospective

random study of a single agent versus combination antibiotics as

therapy in penetrating injuries of the abdomen. Surgery Gynecology

& Obstetrics 1983;156(3):289–94.

Croce 1993 {published data only}Croce M, Fabian TC, Stewart RM, Pritchard FE, Minard G, Tren-

them L, et al.Empiric monotherapy versus combination therapy of

nosocomial pneumonia in trauma patients. The Journal of Trauma

1993;35(2):303–9.

De Louvois 1992 {published data only}

De Louvois J, Dagan R, Tessin I. A comparison of ceftazidime and

aminoglycoside based regimens as empirical treatment in 1316 cases

of suspected sepsis in the newborn. European Society for Paediatric

Infectious Diseases--Neonatal Sepsis Study Group. European Journal

of Pediatrics 1992;151(12):876–84.

Extermann 1995 {published data only}Extermann M, Regamey C, Humair L, Murisier F, Rhyner K, Von-

willer HM. Initial Treatment of Sepsis in Non-Neutropenic Patients

- Ceftazidime Alone Versus Best Guess Combined Antibiotic-Ther-

apy. Chemotherapy 1995;41:306–15.

Fainstein 1983 {published data only}

Fainstein V, Bodey GP, Elting L, Bolivar R, Keating MJ, McCredie

KB, et al.A randomized study of ceftazidime compared to ceftazidime

and tobramycin for the treatment of infections in cancer patients.

Journal of Antimicrobial Chemotherapy 1983;12 Suppl A:101–10.

Fernandez 1991 {published data only}

Fernandez GM, Gudiol F, Rodriguez TA, Arnau C, Valdes L, Vallve

C. Nosocomial pneumonia: comparative multicentre trial between

monotherapy with cefotaxime and treatment with antibiotic combi-

nations. Infection 1991;19(Suppl 6):S320–S325.

Foord 1985 {published data only}Foord RD. Aspects of clinical trials with ceftazidime worldwide.

American Journal of Medicine 1985;79(2A):110–3.

Gentry 1980 {published data only}Gentry LO, Wood BA, Martin MD, Smythe J. Cefamandole alone

and combined with gentamicin or tobramycin in the treatment

of acute pyelonephritis. Scandinavian Journal of Infectious Diseases

1980;suppl(25):96–100.

Gentry 1984 {published data only}Gentry LO, Feliciano DV, Lea AS, Short HD, Mattox KL, Jordan

GL Jr. Perioperative antibiotic therapy for penetrating injuries of the

abdomen. Annals of Surgery 1984;200(5):561–6.

Gentry 1985 {published data only}

Gentry LO. Treatment of skin, skin structure, bone, and joint infec-

tions with ceftazidime. American Journal of Medicine 1985;79(2A):

67–74.

Gerber 1989 {published data only}

Gerber B, Retzke F, Wilken H. [Effectiveness of perioperative pre-

ventive use of antibiotics with ampicillin/gentamycin or cefotiam in

abdominal cesarean section]. Zentralbl Gynakol 1989;111(10):658–

63.

Gilbert 1998 {published data only}

Gilbert DN, Lee BL, Dworkin RJ, Leggett JL, Chambers HF, Modin

G, et al.A randomized comparison of the safety and efficacy of once-

daily gentamicin or thrice-daily gentamicin in combination with

ticarcillin-clavulanate. American Journal of Medicine 1998;105(3):

182–191.



Giraud 1989 {published data only}

Giraud JR, Chartier M, Ciraru Vigneron N, Becue J, Landes P, Leng

JJ, et al.[A comparison of the efficacy of and tolerance to Augmentin

used alone and as one of three drugs used to treat acute upper genital

tract infections. Results of a multicentre trial 152 cases] [Compara-

ison de l’efficacite et de la tolerance de l’Augmentine en monothera-

pie versus triple association dans le traitment des infections genitales

hautes aigues. Resultats d’une etude multicentrique portant sur 152

cas]. Contracept Fertil Sex 1989;17(10):941–8.

Gold 1985 {published data only}

Gold R, Overmeyer A, Knie B, Fleming PC, Levison H. Controlled

trial of ceftazidime vs. ticarcillin and tobramycin in the treatment of

acute respiratory exacerbations in patients with cystic fibrosis. Pedi-atric Infectious Disease 1985;4(2):172–7.

Gomez 1990b {published data only}Gomez J, Moldenhauer F, Ruiz Gomez J, Ros CM, Martinez Her-

nandez J, Canteras M, et al.Monotherapy versus antibiotic combina-

tions in bacteremias in an internal medicine department. A prospec-

tive study in 1987 [Monoterapia frente a combinaciones antibioticas

en las bacteriemias de un departamento de medicina interna. estudio

prospectivo durante 1987]. Revista Espanola de Microbiologia Clinica1990;5(2):89–93.

Greco 1989 {published data only}

Greco T. Treatment of nosocomial pneumonia: monotherapy versus

combination therapy. Geriatrics 1989;44 Suppl A:28–31.

Gribble 1983 {published data only}

Gribble MJ, Chow AW, Naiman SC, Smith JA, Bowie WR, Sacks SL,

et al.Prospective randomized trial of piperacillin monotherapy ver-

sus carboxypenicillin-aminoglycoside combination regimens in the

empirical treatment of serious bacterial infections. 21st Interscience

Conference on Antimicrobial Agents and Chemotherapy. 1981.∗ Gribble MJ, Chow AW, Naiman SC, Smith JA, Bowie WR, Sacks

SL, et al.Prospective randomized trial of piperacillin monotherapy

versus carboxypenicillin-aminoglycoside combination regimens in

the empirical treatment of serious bacterial infections. AntimicrobialAgents and Chemotherapy 1983;24(3):388–93.

Haffejee 1984 {published data only}

Haffejee IE. A therapeutic trial of cefotaxime versus penicillin-gen-

tamicin for severe infections in children. Journal of Antimicrobial

Chemotherapy 1984;14 Suppl B:147–52.

Hall 1988 {published data only}

Hall MA, Ducker DA, Lowes JA, McMichael J, Clarke P, Rowe

D, et al.A randomised prospective comparison of cefotaxime ver-

sus netilmicin/penicillin for treatment of suspected neonatal sepsis.

Drugs 1988;35(Suppl 2):169–77.

Hammerberg 1989 {published data only}

Hammerberg O, Kurnitzki C, Watts J, Rosenbloom D. Randomized

trial using piperacillin versus ampicillin and amikacin for treatment

of premature neonates with risk factors for sepsis. European Journalof Clinical Microbiology and Infectious Diseases 1989;8(3):241–4.

Hanson 1982 {published data only}Hanson B, Coppens L, Klastersky J. Comparative studies of ticar-

cillin and mezlocillin plus sisomicin in Gram-negative bacillary bac-

teraemia and bronchopneumonia. Journal of Antimicrobial Chemo-

therapy 1982;10(4):335–41.

Hoogkamp 1983 {published data only}

Hoogkamp-Korstanje JA, van der Laag J. Piperacillin and tobramycin

in the treatment of Pseudomonas lung infections in cystic fibrosis.

Journal of Antimicrobial Chemotherapy 1983;12(2):175–83.

Iakovlev 1997 {published data only}Iakovlev SV, Shakhova TV, Dvoretskii LI, Romanovskii I, Eremina

LV, Koroleva TA, et al.[Use of piperacillin/tazobactam as empirical

monotherapy in the treatment of bacterial infections in a resuscitation

department]. Antibiotiki i Khimioterapia 1997;42(2):33–7.

Iakovlev 2000 {published data only}Iakovlev SV, Dvoretskii LI, Shakhova TV. [The clinical efficacy of

ticarcillin/clavulanate in severe pneumonia]. Antibiotiki i Khimioter-apia 2000;45(3):30–4.

Ker 1989 {published data only}

Ker CG, Hou MF, Chen JS, Lee KT, Sheen PC, Akbary MA. A

comparative study of cefotaxime sodium versus a combination of

cefapirin and gentamicin in the prophylactic treatment of patients

undergoing cholecystectomy. Methods and Findings in Experimental

and Clinical Pharmacology 1989;11(11):711–5.

Krumpe 1999 {published data only}

Krumpe PE, Cohn S, Garreltes J, Ramirez J, Coulter H, Haverstock

D, et al.Intravenous and oral mono- or combination-therapy in the

treatment of severe infections: ciprofloxacin versus standard antibi-

otic therapy. Ciprofloxacin Study Group. Journal of Antimicrobial

Chemotherapy 1999;43(Suppl A):117–28.

Ludwig 1980 {published data only}Ludwig G, Knebel L. Cefotaxime in urinary tract infections--com-

parative clinical studies with gentamicin and with cefoxitin. Journalof Antimicrobial Chemotherapy 1980;6 Suppl A:207–11.

Maller 1991 {published data only}

Maller R, Ahrne H, Eilard T, Eriksson I, Lausen I. Efficacy and safety

of amikacin in systemic infections when given as a single daily dose

or in two divided doses. Scandinavian Amikacin Once Daily Study

Group. Journal of Antimicrobial Chemotherapy 1991;27(Suppl C):

121–8.

Mangi 1988 {published data only}Mangi RJ, Greco T, Ryan J, Thornton G, Andriole VT. Cefoperazone

versus combination antibiotic therapy of hospital-acquired pneumo-

nia. American Journal of Medicine 1988;84(1):68–74.

McArdle 1987 {published data only}

McArdle C, Morran C, Greig J, Mason B, Haddock G, Sleigh J, et

al.Comparison of cefotetan and gentamicin/ampicillin in high-risk

biliary tract surgery. Chemioterapia 1987;6(2 Suppl):593–4.

McCarty 1988 {published data only}McCarty JM, Tilden SJ, Black P, Craft JC, Blumer J, Waring W,

et al.Comparison of piperacillin alone versus piperacillin plus to-

bramycin for treatment of respiratory infections in children with cys-

tic fibrosis. Pediatric Pulmonology 1988;4(4):201–4.

McLaughlin 1983 {published data only}McLaughlin FJ, Matthews WJ, Jr, Strieder DJ, Sullivan B, Gold-

mann DA. Randomized, double-blind evaluation of azlocillin for the

treatment of pulmonary exacerbations of cystic fibrosis. Journal of

Antimicrobial Chemotherapy 1983;11(Suppl B):195–203.∗ McLaughlin FJ, Matthews WJ Jr, Strieder DJ, Sullivan B, Taneja

A, Murphy P, Goldmann DA. Clinical and bacteriological responses



to three antibiotic regimens for acute exacerbations of cystic fibrosis:

ticarcillin-tobramycin, azlocillin-tobramycin, and azlocillin-placebo.

Journal of Infectious Diseases 1983;147(3):559–567.

Mondorf 1987 {published data only}Mondorf A, Mondorf W, Banzer S. A multiple-center comparative

study of the kidney tolerance of ceftazidime versus cefotaxime and

tobramycin. Chemioterapia 1987;6(2 Suppl):331–2.

Mondorf 1989 {published data only}

Mondorf AW, Bonsiepe C, Mondorf W. Randomized multi center

study comparing nephrotoxicity of ceftazidime versus the combina-

tion of piperacillin and netilmicin with and without furosemide. Ad-vances in Experimental Medicine and Biology 1989;252:307–12.

Moreno-Martinez 1998 {published data only}Moreno Martinez A, Mensa J, Martinez JA, Marco F, Vila J, Almela

M, et al.Cefixime versus amoxicillin plus netilmicin in the treat-

ment of community-acquired non-complicated acute pyelonephritis.

Medicina Clinica 1998;111(14):521–4.


Mouton Y, Deboscker Y, Beuscart C, Beaucaire G, Fourrier A. Third

generation cephalosporins in combination with aminoglycosides or

in monotherapy for life-threatening infections in an intensive care

unit. 25th Interscience Conference on Antimicrobial Agents and

Chemotherapy. 1985:Abstract no. 958.

Oblinger 1982 {published data only}

Oblinger MJ, Bowers JT, Sande MA, Mandell GL. Moxalactam ther-

apy vs. standard antimicrobial therapy for selected serious infections.

Reviews of Infectious Diseases 1982;4(Suppl):S639–S649.

Odio 1987 {published data only}Odio CM, Umana MA, Saenz A, Salas JL, McCracken GH. Com-

parative efficacy of ceftazidime vs. carbenicillin and amikacin for

treatment of neonatal septicemia. Pediatric Infectious Diseases Journal

1987;6(4):371–7.

Padoan 1987 {published data only}

Padoan R, Cambisano W, Costantini D, Crossignani RM, Danza

ML, Trezzi G, et al.Ceftazidime monotherapy vs. combined therapy

in Pseudomonas pulmonary infections in cystic fibrosis. PediatricInfectious Diseases Journal 1987;6(7):648–53.

Paoletti 1989 {published data only}Paoletti V, Mammarella A, Mariani A, Filippello CP, Franchino L,

Barlattani M. Netilmicin in the treatment of infections of the lower

urinary tract [La netilimicina nel trattamento delle infeziono delle

basse vie urinarie]. Clinical Therapeutics 1989;128(6):405–9.

Rodloff 1998 {published data only}

Rodloff Ac, Kujath P, Lunstedt B, Gaus W. Comparative study of

the cost-effectiveness of initial therapy with imipenem/cilastatin in

secondary peritonitis. Chirurgia 1998;69(10):1093–1100.

Romanelli 2002 {published data only}

Romanelli G, Cravarezza P, Pozzi A, Franchino L, Ravizzola G, Zulli

R, et al.Carbapenems in the treatment of severe community-acquired

pneumonia in hospitalized elderly patients: a comparative study

against standard therapy. Journal of Chemotherapy 2002;14(6):609–

17.

Schoengut 1983 {published data only}Schoengut H, Jelinek R. Comparative study of the effects of cef-

tazidime compared with tobramycin plus cefamandole in the treat-

ment of gall bladder empyema. Journal of Antimicrobial Chemother-

apy 1983;12 Suppl A:219–22.

Schuler 1995 {published data only}

Schuler D, and the Meropenem Paediatric Study Group. Safety and

efficacy of meropenem in hospitalised children: randomised com-

parison with cefotaxime, alone and combined with metronidazole or

amikacin. Journal of Antimicrobial Chemotherapy 1995;36(Suppl A):

99–108.

Scott 1987 {published data only}Scott SD, Saddler B, Lowes JA, Karran SJ. Comparison of cefotetan

versus combination therapy in peritonitis and serious intra-abdomi-

nal sepsis. Chemioterapia 1987;6(2 Suppl):475–6.

Sexton 1984 {published data only}Sexton DJ, Wlodaver CG, Tobey LE, Finn LA, Chubb JM. Cef-

tazidime therapy for Gram-negative bone and joint infections. 24th

Interscience Conference on Antimicrobial Agents and Chemother-

apy. 1984; Vol. Abstract no. 1213:305.

Sheftel 1986 {published data only}Sheftel TG, Mader JT. Randomized evaluation of ceftazidime or ticar-

cillin and tobramycin for the treatment of osteomyelitis caused by

gram-negative bacilli. Antimicrobial Agents and Chemotherapy 1986;

29(1):112–5.

Smith 1999 {published data only}Smith AL, Doershuk C, Goldmann D, Gore E, Hilman B, Marks M,

et al.Comparison of a beta-lactam alone versus beta-lactam and an

aminoglycoside for pulmonary exacerbation in cystic fibrosis. Journal

of Pediatrica 1999;134(4):413–21.

Solberg 1995 {published data only}

Solberg CO, Sjursen H. Safety and efficacy of meropenem in patients

with septicaemia: a randomised comparison with ceftazidime, alone

or combined with amikacin. Journal of Antimicrobial Chemotherapy1995;36(Suppl A):157–66.

Solomkin 1986 {published data only}

Solomkin JS, Cocchetto DM. Ceftazidime versus tobramycin plus

ticarcillin in the treatment of soft-tissue infections. Clinical Thera-

peutics 1986;9(1):123–34.

Stack 1985 {published data only}

Stack BHR, Geddes DM, Williams KJ, Dinwiddie R, Selkon JB,

Godfrey RC, for the British Thoracic Society Research Committee.

Ceftazidime compared with gentamicin and carbenicillin in patients

with cystic fibrosis, pulmonary pseudomonas infection, and an exac-

erbation of respiratory symptoms. Thorax 1985;40(5):358–63.

Tally 1986 {published data only}

Tally FP, Kellum JM, Ho JL, O’Donnell TF, Barza M, Gorbach SL.

Randomized prospective study comparing moxalactam and cefoxitin

with or without tobramycin for the treatment of serious surgical

infections. Antimicrobial Agents and Chemotherapy 1986;29(2):244–

9.

Thompson 1980 {published data only}Thompson SE, Hager WD, Wong KH, Lopez B, Ramsey C, Allen

SD, et al.The microbiology and therapy of acute pelvic inflammatory

disease in hospitalized patients. American Journal of Obstetrics &

Gynecology 1980;136(2):179–86.



Vazquez 1994 {published data only}

Vazquez Vela Sanchez G, De Leon Zavala J, Ochoa Cozares M. Com-

parative study of two preventive antibiotic programs for treatment of

open fractures [Estudio comparativo de dos esquemas de antibioticos

para la prevencion de la infeccion en las fracturas expuestas]. Rev mex

ortoptraumatol 1994;8(5):263–4.

Vetter 1987 {published data only}∗ Vetter N, Feist H, Armbruster C, Drlicek M. Comparison of the

effectiveness of ceftazidime and cefazolin/tobramycin in patients with

inflammatory diseases of the lower respiratory tract. In German

[Efficacy of ceftazidime and cefazolin/tobramycin in lower respiratory

tract infections]. Infection 1987;15(Suppl 4):S192–4.

Vetter N, Feist H, Muhar F, Williams KJ. A comparative study of the

efficacy of ceftazidime versus cefazolin and tobramycin in patients

with acute exacerbations of chronic bronchitis. Journal of Antimicro-

bial Chemotherapy 1983;12(Suppl A):35–9.

Vetter 1992 {published data only}

Vetter N. Efficacy of meropenem in the treatment of respiratory

tract infection:a comparative evaluation. Proceedings of the Eighth

Mediterranean Congress of Chemotherapy. 1992:175.

Vetter N. Efficacy of meropenem in the treatment of respiratory

tract infection: a comparative evaluation. Journal of Chemotherapy.

1993; Vol. 5 Suppl 1.

Watanakunakorn 1997 {published data only}

Watanakunakorn C, Baird IM. Prognostic factors in Staphylococ-

cus aureus endocarditis and results of therapy with a penicillin and

gentamicin. The American journal of Medical Sciences 1977;273(2):

133–9.

References to studies awaiting assessment

Figueroa-Damian 1996 {published data only}

Figueroa-Damian R, Villagrana-Zesati R, San Martin-Herrasti JM,

Arredondo-Garcia JL. Comparison of the therapeutic efficacy of the

piperacillin/tazobactame combination vs. ampicillin and gentamycin

in the management of post-cesarean endometritis [Comparación de

la eficacia terapéutica de piperacilina\tazobactam vs ampicilina más

gentamicina en el tratamiento de endometritis poscesárea]. Ginecolo-

gia y Obstetricia de Mexico 1996;64(5):214–8.

Luis-Alberto 1999 {published data only}

Luis Alberto GR, Enrique RJ, Manuel de Jesus UV, Ana Patricia

MB, Jose Javier LN, Jaime MM. Ceftazidime vs crystalline sodium

penicillin and amikacin in the treatment of nosocomial pneumonia

[Ceftazidima vs penicilina sodica cristalina y amikacina en el manejo

de la neumonia nosocomial]. Medicina interna Mexico 1999;15(4):

135–7.

Additional references

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Allan JD, Moellering RC. Management of infections caused by gram-

negative bacilli: the role of antimicrobial combinations. Reviews of

Infectious Diseases 1985;7 Suppl 4:559–71.

Baine 2001

Baine WB, Yu W, Summe JP. The epidemiology of hospitalization

of elderly Americans for septicemia or bacteremia in 1991-1998.

Application of Medicare claims data. Annals of Epidemiology 2001;

11(2):118–26.

Barza 1996

Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily

doses of aminoglycosides: a meta-analysis. BMJ 1996;312(7027):

338–45.

Bayer 1998

Bayer AS, Bolger AF, Taubert KA, Wilson W, Steckelberg J, Karchmer

AW, et al.Diagnosis and management of infective endocarditis and

its complications. Circulation 1998;98(25):2936–48.

Bone 1992

Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus

conference on sepsis and organ failure. Chest 1992;101(6):1481–3.

Bryant 1971

Bryant RE, Hood AF, Hood CE, Koenig MG. Factors affecting mor-

tality of gram-negative rod bacteremia. Archives of Internal Medicine

1971;127(1):120–8.

Elphick 2001

Elphick HE, Tan A. Single versus combination intravenous antibi-

otic therapy for people with cystic fibrosis (Cochrane Review). In:The Cochrane Library 2004, Issue 3.[Art. No.: CD002007. DOI:

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References to other published versions of this review

Paul 2004

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Abrams 1979

Methods RCT

Empirical and semi-empirical

Gram positive infections

Participants 36 IV drug users with suspected Staphylococcal endocarditis were included. Only those with Staphylococ-

cus aureus bacteraemia and endocarditis according to inclusion criteria were evaluated Patients excluded

because they did not fulfil inclusion criteria for bacteraemia were not considered as dropouts for the review

Interventions Oxacillin 12gr/d vs. oxacillin 12gr/d + gentamicin 80mgX3 (gentamicin administered for the first 2 weeks

of a 4-week treatment protocol)

Outcomes Overall mortality

Treatment failure (clinical and bacteriological)

Adverse events

Duration of fever

Notes USA

Outcomes in subgroups: Bacteraemia.

Cephalothin was permitted instead of oxacillin for patients with penicillin allergy, and oxacillin was

replaced by penicillin for penicillin-susceptible Staphylococcus aureus.

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Aguilar 1992

Methods RCT

Sepsis

Participants 36 patients > 16 yrs. with severe infections

Interventions Ceftizoxime 60-150 mg/kg/d vs. penicillin 20-30mU/d + gentamicin 3-5mg/kg/d

Outcomes Treatment failure (clinical and bacteriological)

Notes Mexico

No outcomes in subgroups



Aguilar 1992 (Continued)

Risk of bias



Alvarez-Lerma 2001a

Methods RCT

Sepsis

Participants 140 adult patients hospitalized in the ICU, mechanically ventilated and diagnosed with pneumonia. All

infections were hospital acquired. 66% of patients were on inotropic drugs upon entry to study

Interventions Meropenem 1grX3 for 9.3 days vs.

ceftazidime 2grX3 + amikacin 7.5mg/kgX2 for 8.3 days



Bacterial superinfections

Adverse events

Duration of treatment

Notes Multicentre

Spain

Outcomes in subgroups: Gram negative and Pseudomonas sp. infections

Risk of bias


Allocation concealment? Yes A - Adequate

Arich 1987

Methods RCT

Partially semi-empirical

Sepsis

Participants Adult patients with enterobacteriacae bacteraemia (at least 2 positive blood cultures with same pathogen).

Patients could enter the trial before or at diagnosis of bacteraemia

Interventions Cefotaxime 1grX3-4 for 17.5 days vs. cefazolin 1grX3 + tobramycin 1.5mg/kgX3 for 10 days



Arich 1987 (Continued)



Superinfection

Adverse events

Duration of hospitalizations, treatment and fever

Notes France (French)

Outcomes in subgroups:

Bacteraemia

Gram-negative infections

Risk of bias



Bergeron 1988

Methods RCT

Abdominal

Participants 77 adult patients with severe biliary tract infections (cholecystitis, cholangitis and necrotizing cholecystitis)

Interventions Cefoperazone 2grX2 for 7.2 days vs. ampicillin 1grX4 + tobramycin 1.5mg/kgX3 following loading dose

2mg/kg for 6.8 days (Surgery in addition to medical treatment was performed in 28/36 monotherapy

patients and in 19/29 combination patients, not counted as failure)



Superinfections

Colonization

Treatment duration

Dropouts

Adverse events

Notes Multicentre

Canada


Bacteraemia

Risk of bias




Bergeron 1988 (Continued)


Biglino 1991

Methods RCT

Sepsis

Participants 22 patients with severe infections. Patients were compromised by background diseases, including some

immune-

compromise in 73%. Randomized to 4 arms monotherapy vs. combination, and high vs. low dose of

imipenem

Interventions Imipenem 0.5-1grX4 vs. imipenem 0.5-1grX4 + netilmicin 5mg/kg

Outcomes Treatment failure (clinical)

Adverse events

Duration of fever and hospital stay

Notes Italy


Risk of bias



Brown 1984

Methods RCT

Sepsis

Participants 48 adult patients (34 evaluated) with hospital acquired pneumonia of a documented Gram-negative origin

(By sputum’s Gram stain or cultures). 85% (29/34) acquired infection in the ICU

Interventions Moxalactam 2grX3 for 10.1 days vs.

carbenicillin 66mg/kgX6 + tobramycin 1.7mg/kgX3 (following a 2-2.5mg/kg loading dose) for 10.6 days


Treatment failure (x-ray non-clearing)

Superinfections

Adverse events




Brown 1984 (Continued)

Notes USA


Gram-negative and Pseudomonas sp. infections

4 deaths among 11 excluded patients not included in outcome assessment

Risk of bias



Carbon 1987

Methods RCT

Probably semi-empirical

Sepsis

Participants 74 patients with bacteraemia due to enterobacteriaceae, with at least 3 positive blood cultures entered the

study

Interventions Cefotaxime 1grX4 for 12.9 days vs. cefotaxime 1grX4 + amikacin 7.5mg/kg loading dose followed by a

renal-function adjusted maintenance dose for 13.2 days


Treatment failure (clinical)

Superinfections

Adverse events

Duration of treatment and fever

Notes Multicentre

France


Gram negative infections

Bacteraemia

Risk of bias





Cardozo 2001

Methods RCT

Abdominal

Participants 110 children <15 years, with acute appendicitis

Interventions Amoxycillin-sulbactam 33mg/kgX3 vs. amoxycillin

-sulbactam 33mg/kgX3 + gentamicin 5mg/kgX1


Treatment failure

Notes Paraguay (Spanish)


Risk of bias



Cometta 1994

Methods RCT

Sepsis

Participants 313 adult patients with nosocomial pneumonia, nosocomial sepsis or severe diffuse peritonitis. 73% were

in ICU and 48% on mechanical ventilation

Interventions Imipenem 500mgX4 for 10.2 days vs. imipenem 500mgX4 + netilmicin 150mgX2 for 10.5 days



Superinfections

Colonization

Adverse events


Notes Multicentre

Switzerland

Outcomes in subgroups: Gram-negative and Pseudomonas sp. infections

A secondary reference, Iten 1992, described 71 patients from this study, for whom surveillance cultures

were performed, and detailed data concerning resistance development are given

Risk of bias



Cometta 1994 (Continued)



Cone 1985

Methods RCT

Sepsis

Participants 57 hospitalized patients with pneumonia or bacteraemia. Pneumonia was community acquired or noso-

comial. Only patients with positive bacteriological cultures were evaluated

Interventions Ceftazidime 2grX3 vs. ticarcillin 3grX4 + tobramycin 1mg/kgX3



Superinfections

Adverse events

Notes USA

Outcomes in subgroups: Bacteraemia

Risk of bias



Coppens 1983

Methods RCT

Semi-empirical


Participants 80 patients in whom staphylococcal infections were clinically and microbiologically suspected. Inclusion

criteria mandated a positive Gram stain showing Staphylococci Patients were randomized to the designated

interventions. 24-48 hours following randomisation, patients with documented methicillin-

resistant Staphylococci were switched to vancomycin, only in the monotherapy group (N=14). These were

excluded from analysis in the review

Interventions Cefamandole 2grX3 vs.

cefamandole 2grX3 + tobramycin 80mgX3



Coppens 1983 (Continued)

Outcomes Treatment failure

(clinical and bacteriological)

Bacterial superinfection and colonization

Notes Belgium


Risk of bias



D’Antonio 1992

Methods RCT

Sepsis

Participants Non-neutropenic adult patients with altered immune defence, with fever > 38 lasting > 8 hours. 88% of

patients with underlying haematological malignancy

Interventions Ceftriaxone 2grX1 for a median of 12 days vs. ceftriaxone 2grX1 + amikacin 5mg/kgX3 for a median of

11 days


Treatment failure

(clinical and bacteriological)

Superinfection and colonization (bacterial and fungal)

Adverse events

Treatment duration

Notes Italy


Gram-negative and Pseudomonas sp. infections Bacteraemia

Urinary tract infection

Risk of bias





Duff 1982

Methods Quasi-randomized

Abdominal

Participants 74 patients included who developed endomyo-

parametritis after caesarian section or vaginal delivery, or who developed pelvic cellulitis after hysterectomy

Interventions Cefoxitin 2grX3

vs. penicillin 5millUX4 + gentamicin 60-80mgX3


Treatment failure

Adverse events

Dropouts

Notes USA

Outcomes in subgroups: Gram-negative infections

Risk of bias


Allocation concealment? No C - Inadequate

Dupont 2000

Methods RCT

Abdominal

Participants 227 patients evaluated with severe generalized peritonitis Modified ITT analysis was performed on 204

patients with surgically proven severe intra-abdominal infections

Interventions Piperacillin- tazobactam 4grX4 for 8.2 days vs.

piperacillin- tazobactam 4grX4 + amikacin 7.5mg/kgX2 for 8.6 days. In addition all patients were operated

on



Adverse events

Dropouts

Treatment duration

Notes Multicentre

France




Dupont 2000 (Continued)

Risk of bias



Felisart 1985

Methods RCT

Sepsis

Participants 73 adult patients with underlying advanced cirrhosis, presenting with severe bacterial infections. Most

patients had spontaneous bacterial peritonitis

Interventions Cefotaxime 2grX6 vs.

ampicillin 2grX6 + tobramycin renal adjusted maintenance dose X3/d following 1.75mg/kg loading dose



Superinfections

Adverse events

Notes Spain


Urinary tract infections

Risk of bias



Finer 1992

Methods RCT

Sepsis

Participants 471 adult patients hospitalized with signs and symptoms of serious bacterial infections, thought by the

physician to require parenteral antibiotic treatment

Interventions Ceftazidime 2grX2 vs. ureidopenillin + aminoglycoside used routinely in specific Center: piperacillin-

gentamicin (73p); ampicillin-

gentamicin (69p); mezlocillin-

netilmicin (44p); piperacillin-



Finer 1992 (Continued)

netilmicin (20p)



Superinfections

Colonization

Drop-outs after randomisation

Adverse events

Notes Multicentre

UK


Risk of bias



Gerecht 1989

Methods RCT

Abdominal

Participants 82 patients with suspected cholangitis were randomized empirically. Only those with bacteraemia or

positive bile cultures, and fulfilling clinical criteria for cholangitis were evaluated. Patients who were not

evaluated because they did not meet inclusion criteria are not considered as dropouts for the review

Interventions Mezlocillin 4grX4 for 11.9 days vs. ampicillin 1grX4 + gentamicin 1.5mg/kgX3 for 10.3 days. In addition

to antibiotic therapy all patients underwent surgical intervention


Superinfections

Adverse events


Notes USA


Risk of bias





Gomez 1990a

Methods RCT

Sepsis

Participants 197 patients with suspected Gram-negative bacteraemia randomized. Patients with proven Gram-negative

bacteraemia (78) were analysed. Patients who were not evaluated because they did not meet inclusion

criteria for bacteraemia were not considered as dropouts

Interventions Ceftazidime 1grX4 for 10 days vs. cefradine 1grX6 + amikacin 7.5mg/kgX2 for 10 days



Superinfection (bacterial and fungal)

Adverse events


Notes Spain (Spanish)


Bacteremia


Risk of bias



Havig 1973

Methods RCT

Abdominal

Participants 68 adult patients evaluated with acute cholecystitis verified histologically or by roengten. Trial included 3

arms, of which 2 are included in the review

Interventions IM ampicillin 0.5grX4

vs. IM chloramphenicol 1grX2 (arm not included in review) vs. IM benzyl-penicillin 400,000IEX2 +

IM streptomycin 0.5grX2. In addition 10/24 patients in the ampicillin arm and 15/26 patients in the

combination arm were operated on



Duration of fever



Havig 1973 (Continued)

Notes Norway


Risk of bias



Hoepelman 1988

Methods RCT

Sepsis

Participants 105 patients with serious bacterial infections were included. Of these 18% were neutropenic and are not

included for the analysis in this review

Interventions Ceftriaxone 2grX1 vs. cefuroxime 1.5grX3 + gentamicin 80mgX3 (following by an initial 1.5mg/kg dose)

Outcomes Overall mortality Treatment failure (clinical)

Superinfections

Fungal colonization

Adverse events

Notes Netherlands Outcomes for subgroups were not extracted, as they are given in the publication for the whole

group including neutropenic patients

Outcomes for non-neutropenic patients were obtained from the author

Risk of bias



Holloway 1985

Methods RCT

Sepsis

Semi-empirical

Participants 43 adult patients with suspected Gram-negative septicaemia, or pneumonia, randomized when blood

cultures were positive for a Gram-negative pathogen



Holloway 1985 (Continued)

Interventions Ticarcillin-clavulanic acid 3.1grX4-6 vs. piperacillin 50mg/kgX4-6 + tobramycin 1-1.5mg/kgX3-4


Adverse events

Notes USA


Bacteremia


Risk of bias



Iakovlev 1998

Methods RCT

Sepsis

Participants 95 adult patients with severe nosocomial infections

Interventions Meropenem 1grX3 for 9 days vs. ceftazidime 1grX3 + amikacin 500mgX2 for 9 days



Adverse events

Notes Multicentre

Russia (Russian)

Outcomes in subgroups: Urinary tract and Pseudomonas sp. infections

Risk of bias





Jaspers 1998

Methods RCT

Sepsis

Participants 79 elderly patients ( > 65yrs.) with sepsis syndrome and suspected bacteraemia, pneumonia, intra-abdom-

inal sepsis, or complicated urinary tract infection

Interventions Meropenem 1grX3 for 7.5 days vs. cefuroxime 1.5grX3 + gentamicin 4mg/kgX1 for 7.4 days (metronida-

zole 500mgX4 added to patients receiving combination in case of abdominal sepsis (15 patients overall)


Treatment failure (clinical and microbiological)


Adverse events


Notes Multicentre

Netherlands



Risk of bias



Klastersky 1973

Methods RCT

Sepsis

Participants 75 adult patients with disseminated cancer and life threatening infections, presumed Gram-negative.

Randomized to 3 arms, of which 2 are relevant for the review. 18% of patients leukopenic (leukopenia

not defined) - no information for neutropenia

Interventions Carbenicillin 10grX3 for 8.3 days vs. carbenicillin 10grX3 + gentamicin 160mgX3 (IM or IV) for 9 days

vs. gentamicin 160mgX3 (3rd arm, not included in review)



Colonization and Superinfection


Dropouts



Klastersky 1973 (Continued)

Notes Belgium



Bacteremia


Risk of bias



Kljucar 1990

Methods RCT

Sepsis

Participants 150 patients > 14yrs. hospitalized in the intensive care unit and ventilated, with nosocomially acquired

pneumonia. Randomized to 3 arms (2 combination and 1 monotherapy)

Interventions Ceftazidime 2grX3 vs.

ceftazidime 2grX3 + tobramycin 80mgX3 vs. azlocillin 5mgX3 + tobramycin 80mgX3, overall for 6.6

days



Notes Germany


Risk of bias



Koehler 1990

Methods RCT

Sepsis

Participants 144 patients > 18 yrs. with nosocomially acquired pneumonia



Koehler 1990 (Continued)

Interventions Ceftazidime 1grX3 vs. piperacillin 4grX3 + tobramycin 80mgX3



Bacterial and fungal colonization

Dropouts

Notes Multicentre

Germany


Gram negative and Pseudomonas sp. infections

Risk of bias



Korzeniowski 1982

Methods RCT

Partially semi-empirical


Participants 156 patients with clinically suspected infective endocarditis were randomized (prior antibiotic treatment of

< 48 hours permitted) 78 patients with Staphylococcus aureus bacteremia and endocarditis were analysed:

48 drug addicts and 30 non-addicts (14 patients randomized semi-empirically)

Interventions Nafcillin 1.5-6grX6 vs. nafcillin 1.5-6grX6 + gentamicin 1mg/kgX3 administered for the first 2 weeks of

a 4-week treatment protocol



Dropouts

Need for surgery

Adverse events

Duration of bacteremia and fever are other outcomes shown in the study, but these are shown by groups

of empirical treatment regimen which was not always randomly allocated

Notes Multicentre

USA


Bacteremia

Risk of bias



Korzeniowski 1982 (Continued)



Landau 1990

Methods Quasi-randomized


Participants 40 adult patients hospitalized with complicated urinary tract infection

Interventions Ceftriaxone 2grX1

vs. cefazolin 1grX3 + gentamicin 80mgX3


Treatment failure (bacteriological only)

Adverse events

Drop-outs after randomization

Duration of fever

Notes Israel (Hebrew) Outcomes in subgroups:

Urinary tract and


Risk of bias


Allocation concealment? No C - Inadequate

Limson 1988

Methods RCT

Sepsis

Participants 54 adult patients randomized, of which 40 patients with severe Gram-negative infections were evaluated


ticarcillin 3grX3-4 + amikacin 500mgX2 (or 15mg/kgX1)

Outcomes Treatment failure (clinical and microbiological)

Fungal superinfections

Adverse events



Limson 1988 (Continued)

Notes The Philippines Outcomes in subgroups:

Bacteremia

Gram negative, and Pseudomonas sp. infections

Risk of bias



Mandell 1987

Methods RCT

Sepsis

Participants 110 patients > 16yrs. evaluated with community acquired or nosocomial pneumonia (2/3 nosocomial)


cefazolin 1.5grX3 or ticarcillin 3grX4 + tobramycin 1.7mg/kgX3


Superinfections

Colonization (including resistant development)

Adverse events

Notes Multicentre

Canada


Bacteraemia

Gram-negative infections.

Cefazolin replaced by ticarcillin for combination group patients with documented Pseudomonas infections

Risk of bias



Martin 1991

Methods RCT


Participants 116 patients hospitalized with suspected pyelonephritis



Martin 1991 (Continued)

Interventions Ceftriaxone 2grX1 vs. ampicillin 1grX4 + gentamicin 1mg/kgX3


Superinfection (relapse and re-infections)

Dropouts

Adverse events

Notes Brussels (French)



Bacteremia

Risk of bias



McCormick 1997

Methods RCT

Sepsis

Participants 128 adult patients with chronic liver disease (cirrhosis) and suspected or proven sepsis

Interventions Ceftazidime 2grX2 for 5 days vs. mezlocillin 5grX3 + netilmicin 3mg/kgX2 for 4 days


Treatment failure

(clinical)

Adverse events

Duration of treatment and hospital stay

Notes Ireland


Bacteremia

Risk of bias





Mergoni 1987

Methods RCT

Sepsis

Participants Adult patients in ICU with severe infections

Interventions Azlocillin 13+-2.2gr for 6.5 days vs. azloclillin 14.1+-1gr + amikacin 1.16+-0.027gr for 7.2 days (all in

for daily doses)


Adverse events


Notes Italy



Risk of bias



Moreno 1997

Methods RCT

Sepsis

Participants Renal or (kidney-

pancreas) transplant patients with fever and suspected bacterial infection

Interventions Imipenem-cilastatin 500mgX4 vs. piperacillin 4grX3 + tobramycin 80mgX2


Notes Spain



Risk of bias





Mouton 1990

Methods RCT

Sepsis

Participants 211 adult patients hospitalized in intensive care unit with respiratory tract infections

Interventions Imipenem 500mgX4 for 11.1 days vs. cefotaxime 1grX4 + amikacin 5mg/kgX3 for 10.4 days



Superinfections

Colonization

Hospitalization duration


Notes Multicentre

France (French) Outcomes in subgroups:

Bacteremia

Risk of bias



Mouton 1995

Methods RCT

Sepsis

Participants 237 adult patients with community or hospital acquired serious infections, excluding intra-abdominal

sepsis (urinary tract infection included)

Interventions Meropenem 1grX3 for 8.8 days vs. ceftazidime 2grX3 + amikacin 5-7.5mg/kgX2-3 for 8.3 days



Superinfections

Adverse events

Dropouts


Notes Multicentre

Europe


Bacteremia



Mouton 1995 (Continued)

Gram negative and Pseudomonas sp. and urinary tract infections

Risk of bias



Muller 1987

Methods RCT

Abdominal

Participants Trial includes 3 arms (2 monotherapies, 1 combination treatment)

106 patients evaluated with acute cholecystitis or cholangitis

Interventions Piperacillin 3grX6 for 7.4 days vs. cefoperazone 2grX3 for 8.1 days vs.

ampicillin 2grX4 + tobramycin 1-1.5mg/kgX3 following 1.5mg/kg loading dose for 11.1 days


Adverse events


Notes Bi-centre

USA


Risk of bias



Naime Libien 1992

Methods RCT

Sepsis

Participants 30 children aged 1m - 11yr with severe lower respiratory tract infections

Interventions Ceftizoxime 20-50mg/kgX2-3 vs. penicillin 0.7-1.7 megaunit/kgX3 + gentamicin 1-1.5mg/kgX2



Naime Libien 1992 (Continued)



Adverse events

Duration of fever

Notes Mexico (Spanish)


Risk of bias



Piccart 1984

Methods RCT

Sepsis

Participants 105 adult, non-neutropenic, cancer patients with suspected Gram-negative infections. Study included

both neutropenic and non-neutropenic patients, but analysis was completely separated Patients with

Gram-positive bacteremia were excluded

Interventions Cefoperazone 6grX2 vs.

cefoperazone 2grX2 + amikacin 500mgX2


Superinfections (bacterial and fungal)


Notes Belgium



Bacteremia

Risk of bias





Rapp 1984

Methods RCT

Sepsis

Participants 35 adult patients hospitalized in a neurosurgical intensive care unit. All with nosocomial pneumonia


ticarcillin 3grX4 + tobramycin pharmacokinetically adjusted doses after 1.75mg/kd loading dose


Adverse events

Notes USA


Gram negative bacteremia

Pseudomonas sp. infections

Risk of bias



Rasmussen 1986

Methods RCT


Participants 62 adult patients hospitalized in a urosurgical department with urinary tract infections, mostly post-

operative

Interventions Cefotaxime 3grX3 for 5.4 days vs. ampicillin 1grX4 + netilmicin 150mgX3 for 7 days


Relapse

Duration of fever and treatment

Adverse events

Notes Denmark



Risk of bias




Rasmussen 1986 (Continued)


Ribera 1996

Methods RCT

Semi-empirical

Gram-positive infections

Participants Spain

90 intravenous drug users randomized, of which 74 had Staphylococcus aureus right-sided endocarditis.

90.5% of patients were HIV positive. Diagnostic criteria for possible (13% of study patients), probable

(34%) and definitive endocarditis (53%) are defined in study

Interventions Cloxacillin 2grX6 vs. cloxacillin 2grX6 + gentamicin 1mg/kgX3



Relapse, re-infection and need for surgery


Adverse events

Notes Spain

Journal publication.


Bacteremia

Risk of bias



Rubinstein 1995

Methods RCT

Sepsis

Participants 580 adult patients with serious hospital acquired infections and a diagnosis of sepsis, pneumonia or upper

urinary tract infection

Interventions Ceftazidime 2grX2 for 9 days vs. ceftriaxone 2grX1 + tobramycin 3-5mg/kgX1 following 2mg/kg loading

dose for 9 days



Rubinstein 1995 (Continued)



Superinfections


Adverse events

Notes Multicentre

Europe, Middle East, Asia, South America



Bacteremia


Risk of bias



Sage 1987

Methods RCT

Sepsis

Participants 93 patients > 14yrs. randomized to 3 arms, of which 2 are usable in the review. The 3rd arm is aminogly-

coside monotherapy. Patients were suspected of a life threatening sepsis, thought to be caused by Enter-

obacteriaceae or Staphylococci

Interventions Cefotaxime 1-2grX4 for 7.4 days vs. cefotaxime 1-2grX4 + netilmicin 2-3mg/kgX3 (3rd arm, not used -

netilmicin 2-3mg/kgX3) for 8.7 days


Bacterial and fungal superinfections

Dropouts

Adverse events


Notes UK


Bacteremia

Gram negative and urinary tract infections

Risk of bias



Sage 1987 (Continued)



Sandberg 1997

Methods RCT


Participants 73 adult female patients with suspected pyelonephritis

Interventions Cefotaxime 1grX2 for 2 days followed by oral cefadroxil 1grX2 vs.

cefotaxime 1grX2 + tobramycin 160mgX1 for 2 days, followed by oral cefadroxil 1 grX2


Superinfection and colonization (relapse, re-infections and asymptomatic bacteriuria recurrence)

Adverse events


Duration of fever

Notes Multicentre

Sweden

Outcomes in subgroups: Urinary tract infections

Risk of bias



Sanfilippo 1989

Methods RCT

Abdominal

Participants 26 female patients aged 16-19 years with acute pelvic inflammatory disease

Interventions Mezlocillin 62.5mg/kgX4 vs. penicillin 480,000U/kgX4 + tobramycin 1mg/kgX3


Notes USA




Sanfilippo 1989 (Continued)

Risk of bias



Sculier 1982

Methods RCT

Sepsis

Participants 20 adult, intubated, patients with Gram-negative pneumonia in the neurosurgical intensive-care unit

Patients were randomized when presenting with radiographic broncho-

pneumonia, purulent sputum and Gram-negative rods on sputum direct smear

Interventions Mezlocillin 10grX3 vs. mezlocillin 10grX3 + sisomicin 75mgX3.

In addition to allocated systemic treatment, all patients received intra-tracheal sisomycin 25mgX3/d



Bacterial colonization

Resistance development

Adverse events

Notes Belgium



Risk of bias



Sexton 1998

Methods RCT

Semi-empirical

Gram-positive infections

Participants 67 adult patients randomized, of which 51 with native valve endocarditis (defined by Duke criteria) caused

by penicillin-

susceptible Streptococci.



Sexton 1998 (Continued)

Interventions Ceftriaxone 2grX1 for 4 weeks vs. ceftriaxone 2grX1 + gentamicin 3mg/kgX1 for 2 weeks


Relapse and re-infection Adverse events

Dropouts

Duration of hospital stay

Need for surgery

Notes Multicentre

USA


Bacteremia

Risk of bias



Sieger 1997

Methods RCT

Sepsis

Participants 211 adults >18yrs. with hospital-

acquired lower respiratory tract infections. 70% intubated and 27% with severe pneumonia

Interventions Meropenem 1grX3 for 7.8 days vs. ceftazidime 2grX3 + tobramycin 1mg/kgX3 (following 1.5-2mg/kg

loading dose) for 7.4 days


Treatment failure (clinical and bacteriological) Superinfections

Adverse events


Notes Multicentre

USA


Gram-negative and Pseudomonas sp. infections.

Study performs both efficacy and ITT analysis, with a drop-out rate of 43% for the efficacy analysis.

Outcomes were extracted by ITT. Superinfections and subgroup analyses are given only by efficacy analysis

in study

Risk of bias



Sieger 1997 (Continued)



Smith 1984

Methods RCT

Sepsis

Participants 200 adult patients randomized with suspected or proven serious infections. 195 who actually received

study drugs were evaluated for efficacy

Interventions Cefotaxime 2grX6

+ placebo X3 for 5 days vs.

nafcillin 1.5grX6 + tobramycin 2mg/kgX3 for 5.3 days

(Addition of clindamycin 600mgX3 to both groups permitted for suspected anaerobic infections)


Treatment failure

(clinical and microbiological)


Colonization

Adverse events


Notes USA


Urinary tract and Gram negative infections.

Two additional references refer to the same trial: Moore 1986a (cost-effectiveness analysis), and Moore

1986b (nephrotoxicity analysis). Overall mortality, and treatment duration are taken from Moore 1986a

that analysed all patients given study drugs. Cost outcome not included in the review

Risk of bias



Speich 1998

Methods RCT

Sepsis

Participants 89 adults >16yrs. with severe pneumonia. Community acquired in 89%



Speich 1998 (Continued)

Interventions Piperacillin-tazobactam 4.5grX3 for 10.2 days vs.

amoxicllin-clavulonic acid 2.2grX3 + gentamicin or netilmicin 3-6mg/kgX1 for 10.1 days



Dropouts

Adverse events


Notes Multicentre

Switzerland


Risk of bias



Stille 1992

Methods RCT

Sepsis

Participants 337 adult patients randomized with non-life-

threatening infections, of abdominal, gynaecological or respiratory tract origin (UTI, skin, bone, and

CNS infections excluded)

Interventions Imipenem 500mgX3 for 8.4 days vs. cefotaxime 2grX3 + gentamicin 0.66-1mg/kgX3 for 8.2 days (metron-

idazile allowed in combination treatment group for suspected anaerobic infection)



Colonization and resistance development

Adverse events


Notes Multicentre

Germany and Austria



Risk of bias



Stille 1992 (Continued)



Sukoh 1994

Methods RCT

Sepsis

Participants 63 patients with respiratory tract infections and underlying respiratory disease

Interventions Cefoperazone/ sulbactam 1-4gr/d for 11.7 days vs. Cefoperazone/ sulbactam 2-6gr/d + one of several

aminoglycosides in low doses (amikacin 100-400 mg/d 16 patients, tobramycin 40-180 mg/d 15 patients,

isepamicin 400 mg/d 1 patient, netilmicin 200 mg/d 1 patient) for 11.1 days


Notes Japan (Japanese)



Risk of bias



Takamoto 1994

Methods RCT

Sepsis

Participants 171 adult patients with respiratory tract infections

Interventions Imipenem/cilastatin sodium vs.

imipenem/cilastatin sodium + amikacin sulfate



Adverse events

Notes Multicentre Japan (Japanese) Outcomes in subgroups:




Takamoto 1994 (Continued)

Risk of bias



Thompson 1990

Methods RCT

Abdominal

Participants 96 patients evaluated with acute cholangitis (cholecystitis not included)

Interventions Piperacillin 3grX6 for 8.4 days vs. ampicillin 2grX4 + tobramycin 1-1.5mg/kgX3 for 9.1 days (following

1.5mg/kg loading dose). In addition 35/96 patients were operated on



Adverse events

Treatment duration

Notes Multicentre

USA


Risk of bias



Thompson 1993

Methods RCT

Abdominal

Participants 120 patients evaluated with acute biliary tract infections (cholecystitis and cholangitis)

Interventions Cefepime 2grX2 for 7.5 days vs. mezlocillin 3grX6 + gentamicin 1.5mg/kgX3 for 7 days. In addition,

118/120 patients were operated on



Adverse events



Thompson 1993 (Continued)

Treatment and hospitalization duration

Notes Multicenter

USA


Risk of bias



Trujillo 1992

Methods RCT

Sepsis

Participants 30 adult patients with severe skin and soft tissue or respiratory tract infections

Interventions Ceftizoxime 1-2grX3 vs. ampicillin 1-3grX4 + gentamicin 3-5mg/kg/d, overall for 10 days



Adverse events

Fever duration

Notes Mexico (Spanish)


Risk of bias



Vergnon 1985

Methods RCT

Sepsis

Participants 30 adult patients wth severe broncho-

pulmonary infections



Vergnon 1985 (Continued)

Interventions Cefoperazone 2grX2 for 16.8 days vs. ampicillin 1.5grX4 + tobramycin 1mg/kgX3 for 11.8 days


Resistant colonization

Adverse events


Notes France (French)


Risk of bias



Verzasconi 1995

Methods RCT


Participants 93 adult patients with acute pyelonphritis or complicated urinary tract infections

Interventions Amoxicillin-clavulonate 2.2grX3 for 4.1 days vs. amoxicillin 2grX3 + gentamicin 1.5mg/kg loading fol-

lowed by maintenance for 4.2 days

Outcomes Treatment failure (bacteriological)

Superinfection

Dropouts

Treatment and fever duration

Adverse events

Notes Bi-centre

Switzerland (German)


Urinary tract infection

Risk of bias





Warren 1983

Methods RCT

Sepsis

Participants 120 adult patients with suspected or known life-threatening infections caused by Gram-negative bacilli

Interventions Cefoperazone 1.5grX4 for a median of 9 days vs.

cefamandole 2grX6 + tobramycin 1.7mg/kg loading dose, followed by drug- level-adjusted maintenance

dose for a median of 8 days



Superinfection


Adverse events


Notes USA


Bacteremia


Risk of bias



Wiecek 1986

Methods RCT


Participants 20 adult patient with acute pyelonphritis


cefotaxime 1grX2 + tobramycin 1mg/kgX3

Outcomes Treatment failure (bacteriological)

Re-infection

Adverse events

Notes Poland






Wiecek 1986 (Continued)

Bacteremia

Risk of bias



Wing 1998

Methods RCT


Participants 179 pregnant women <24 weeks gestation with pyelonephritis randomized to 2 monotherapy arms and

1 combination therapy arm

Interventions Cefazolin 1grX3 vs. ceftriaxone 1grX1 vs. ampicillin 2grX4 + gentamicin 1.75mg/kgX3 (after 2mg/kg

loading)



Re-infection

Fever and hospitalization duration

Notes Bi-centre

USA



Risk of bias



Yellin 1993

Methods RCT

Abdominal

Participants 179 patients with clinically suspected cholecystitisOnly those operated on while on allocated treatment

were evaluated (infection proven at surgery) Patients who were not evaluated because surgery was not

performed or incorrect diagnosis are not considered as drop-outs for the review



Yellin 1993 (Continued)

Interventions Cefepime 2grX2 for 7.3 days vs. mezlocillin 4grX4 + gentamicin 1.5mg/kgX3 for 7.2 days. In addition

to antibiotic treatment all patients operated



Fever, treatment and hospitalization duration

Notes USA


Risk of bias



RCT - randomized controlled trial

vs - versus

Semi-empirical - comparison of second-line antibiotic treatment, given following establishment of microbiological or clinical diagnosis.

Treatment duration represents means unless otherwise specified.

Characteristics of excluded studies [ordered by study ID]

Alvarez-Lerma 2001b Beta-lactam-aminoglycoside combination treatment versus beta-lactam-aminoglycoside combination

treatment.

Badaro 2002 Allocation to additional aminoglycoside treatment not randomized. Patients were randomized to treatment

with beta-lactam monotherapy versus ’standard’ antibiotic treatment, which was a beta-lactam with or

without an aminoglycoside.

Benlloch 1995 Antibiotic regimens incompatible with protocol. Randomization to 3 arms: 1) beta-lactam-aminogly-

coside-nitroimmidazole combination 2) beta-lactam-aminoglycoside combination 3) double beta-lactam

combination.

Blumer 2003 No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the

definition of exacerbation does answer the criteria for sepsis as defined in review.

Cetto 1983 Study includes 71% patients with neutropenia.



(Continued)

Ciftci 1997 Antibiotic regimens incompatible with protocol. Randomization to 4 arms: 1) beta-lactam-aminlgly-

coside-lincosamide combination 2) beta-lactam-aminoglycoside-imidazole combination 3) beta-lactam

monotherapy 4) beta-lactam-imidazole combination.

Crenshaw 1983 Prophylaxis study. Randomization to beta-lactam monotherapy versus beta-lactam aminoglycoside com-

bination therapy as preventive therapy for patients with penetrating abdominal wounds requiring surgical

intervention.

Croce 1993 Not a randomized trial. Monotherapy and combination therapy groups were studied consecutively.

De Louvois 1992 Included patients were newborns with suspected sepsis.

Extermann 1995 Randomization to beta-lactam monotherapy versus best-guess antibiotic treatment as chosen by physician.

The best guess treatment group includes monotherapy and various combinations.

Fainstein 1983 Study includes 62.5% neutropenic patients. The study randomized 321 episodes, of which 275 were

evaluable - 172 in neutropenic patients and 103 episodes in non-neutropenic patients. Although analysis

was intended to be separated, the number of evaluated patients in each group, is not separated to neutropenic

and non-neutropenic patients. Although outcomes (death and failures) are given for non-neutropenic

patients, the number of patients in the group is unknown. Information was unavailable from authors.

Fernandez 1991 Randomization to beta-lactam monotherapy versus

combination therapy commonly used in specific centre (multicentre trial). Combinations consisted of

different beta-lactams with aminoglycoside antibiotics in 211/273 patients evaluated in the combination

group, and other antibiotic combinations in 62/273 patients. Outcomes are given per specific combination

(failure), but the study is excluded since the decision as to which combination the patient received was left

to the care-taker.

Foord 1985 Not a randomized trial. Article describes all patients on Glaxo data files who have been administered

Ceftazidime monotherapy in comparative and non-comparative trials. No references in the article.

Gentry 1980 Not a randomized trial. Study describes centre’s experience with monotherapy versus combination therapy.

One study group was previously reported. All prospective, comparative, but no mention of randomization.

Gentry 1984 Prophylaxis study. Randomization to 3 arms (2 beta-lactam monotherapy arms and 1 beta-lactam-amino-

glycoside combination therapy arm), as perioperative prophylaxis for patients with penetrating injuries of

the abdomen.

Gentry 1985 Pooled analysis of patients with skin, soft-tissue and bone infections, comparing ceftazidime monotherapy

to control regimens, including ticalcillin and tobramycin combination therapy. However, randomized

patients cannot be separate from those who entered open comparative trials.

Gerber 1989 Prophylaxis study. Antibiotic treatment was administered as prophylaxis and patients did not fulfil the

criteria for sepsis when randomized.



(Continued)

Gilbert 1998 Study includes 18% neutropenic patients (32/175 evaluable patients). In addition neutropenic patients

were not randomized - all were allocated only to the combination regimen. Outcome data was unavailable

separating randomized from non randomized (neutropenic) patients.

Giraud 1989 Antibiotic regimens incompatible with protocol. Randomization to 2 arms: 1) beta-lactam monotherapy

versus 2) beta-lactam-aminoglycoside-nitroimidazole triple combination therapy.

Gold 1985 No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the


Gomez 1990b Observational study according to author correspondence.

Greco 1989 Non-randomized prospective comparative trial.

Gribble 1983 Study includes 60% neutropenic patients (30/50 evaluable episodes).

Haffejee 1984 Included patients were neonates and children.

Hall 1988 Included patients were neonates.

Hammerberg 1989 Included patients were premature neonates with risk factors for sepsis (31/72 patients between ages 0-1

months).

Hanson 1982 Antibiotic regimens incompatible with protocol. Combination therapy versus combination therapy.

Hoogkamp 1983 Not a randomizd trial. Study groups were studied sequentially. In addition study population consists of

cystic fibrosis patients with an exacerbation - sepsis not part of inclusion criteria.

Iakovlev 1997 Aminoglycoside was added only to patients that did not respond to the initial beta-lactam monotherapy

that was administered empirically.

Iakovlev 2000 Not a randomized trial.

Ker 1989 Prophylaxis study. Randomization to prophylactic antibiotic treatment, patients did not fulfil criteria for

sepsis when randomized.

Krumpe 1999 Patients first stratified by disease severity to monotherapy (severe disease) or combination therapy. Fol-

lowing stratification, the patients were randomized to 4 arms: 1) quinolone monotherapy 2) ’standard

monotherapy” from a defined choice of various beta-lactams, at investigator’s discretion 3) quinolone-

beta-lactam combination therapy 4) ’standard combination therapy’ which consisted of various possible

combinations of beta-lactams and aminoglycosides at investigators discretion.

Ludwig 1980 Description of two separate randomized trials: 1) beta-lactam versus aminoglycoside 2) beta-lactam versus

beta-lactam. All administered as monotherapies.



(Continued)

Maller 1991 Randomization to once daily aminoglycoside treatment versus twice daily aminoglycoside treatment. In

addition to the aminoglycoside, a beta-lactam was administered if considered necessary. Administration of

the beta-lactam not randomized (interim analysis of a multicentre study).

Mangi 1988 Randomization to beta-lactam monotherapy versus combination. The combination group consisted of

clindamycin-aminoglycoside or beta-lactam-aminoglycoside combinations. The decision as to which com-

bination treatment was administered was made on a case-by-case basis, according to the sputum’s Gram

stain. Patients with Gram-negative bacilli in the sputum were administered the beta-lactam based combina-

tion while all others received the clindamycin-based regimen. Outcomes for the two different combination

treatments are given together.

McArdle 1987 Prophylaxis study. Randomization to beta-lactam monotherapy versus beta-lactam aminoglycoside com-

bination therapy for prophylaxis prior to high-risk biliary tract surgery.

McCarty 1988 No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the


McLaughlin 1983 No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the


Mondorf 1987 Infection or sepsis not mentioned as part of inclusion criteria. Patients were randomized to receive beta-

lactam monotherapy versus beta-lactam-aminoglycoside combination therapy, and the only outcome given

is urinary enzyme excretion.

Mondorf 1989 No outcomes relevant for this review. The study randomized patients with severe infections to beta-lactam

monotherapy versus beta-lactam aminoglycoside combination therapy. The only outcomes given are renal

functions, mainly urinary enzyme levels, and mean serum creatinine per group. Author contacted to ask

number of patients per group developing nephrotoxicity and other outcomes - but did not respond.

Moreno-Martinez 1998 Comparison of oral cefixime versus oral amoxicillin and intramuscular netilmicin. By protocol only intra-

venously administered beta-lactams are included.

Mouton 1985 Study published as conference proceeding, comparative without mention on randomization. No further

details regarding the study were available.

Oblinger 1982 Randomization to beta-lactam monotherapy versus combination of antibiotics as deemed appropriate by

the attending physicians.

Odio 1987 Included patients were neonates with proven invasive bacterial infections.

Padoan 1987 Inclusion criteria did not mandate sepsis for all included patients. Study included patients with acute

exacerbation of cystic fibrosis, but the definition of exacerbation does answer the criteria for sepsis as

defined in review.



(Continued)

Paoletti 1989 Comparison between aminglycoside monotherapy (netimicin) to beta-lactam-aminoglycoside combina-

tion therapy (ampicillin + netilmicin).

Rodloff 1998 Study randomized patients to imipenem monotherapy versus various combination regimens: beta-lactam-

aminoglycoside, two beta-lactams, beta-lactam-beta-lactamsa inhibitor, beta-lactam-anaerobic agent and

quinolone-anaerobic agent. Patients allocated to the combination group were analysed as one group.

Romanelli 2002 Study randomized patients to beta-lactam monotherapy versus macrolide-aminogycoside or macrolide-

beta-lactam combination therapy.

Schoengut 1983 Non-randomized, prospective comparative trial.

Schuler 1995 Randomization to meropenem versus cefotaxime monotherapy. Aminoglycoside added to the cefotaxime

arm for urinary tract infections and metronidazole added to the cefotaxime arm when anaerobic infection

was suspected. These additions were performed non-randomly, by protocol.

Scott 1987 Randomization to 3 arms comparing beta-lactam monotherapy versus beta-lactam-metronidazole-amino-

glycoside triple combination therapy versus beta-lactam-metronidazole combination therapy.

Sexton 1984 ICAAC abstract. Twenty-two patients were enrolled in a prospective randomized trial, and 8 patients

received monotherapy in an open study. Results are shown for all 30 patients combined. Author contacted

and replied that original data are no longer available, and therefore randomized patients cannot be separated

from the non-randomized. However, results of these trials were pooled with other trials and are described

in Gentry 1985.

Sheftel 1986 No relevant outcomes for this review. The study randomized patients with osteomyelitis and provides

outcomes only for evaluated patients at a follow up range of 2-38 months (appropriate for the type of

infection). The number of randomised patients is unknown and outcomes at 30-days were unavailable.

Smith 1999 No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the


Solberg 1995 Article describes results from 4 separate trials. Randomization to meropenem versus ceftazidime monother-

apy. An aminoglycoside was added to patients allocated to ceftazidime when resistance to ceftazidime and

severe infections were suspected.

Solomkin 1986 Inadequate methodology. A publication stating that ’case report forms from an open multicentre study

were reviewed’: 69 patients assigned to ceftazidime and 66 patients assigned to ticarcillin and tobramycin

with soft tissue infections are reported. Information obtained through author contact: these were the only

arms of the trial, all patients included in the trial are reported in the publication, and this is the only report

of the trial. However, according to the author, the study was not well designed and considered more as a

collection of case reports, as stated in the publication.

Stack 1985 No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the




(Continued)

Tally 1986 Randomization to beta-lactam monotherapy (moxalactam) versus another beta-lactam (cefoxitime). An

aminoglycoside could be added to the cefoxitime arm by the attending physician’s decision, in consultation

with an infectious diseases consultant.

Thompson 1980 Oral versus intravenous antibiotic administration. Study randomized women with PID to monotherapy of

oral amoxicillin versus combination therapy consisting of IV penicillin + IV gentamicin. Inclusion criteria

for the review specify IV administration of the beta-lactam in both arms.

Vazquez 1994 Prophylaxis study. Antibiotic treatment administered for prophylaxis, without sepsis. In addition trial is

probably not randomized.

Vetter 1987 No sepsis in inclusion criteria. Study randomized patients with acute exacerbations of chronic bronchitis.

Only 19/102 included patients were febrile.

Vetter 1992 Comparison of monotherapy (meropenem) versus monotherapy (ceftazidime)

Watanakunakorn 1997 Non-randomized comparison of penicillin versus penicillin + gentamicin for Staphylococcus aureus endo-

carditis.



D A T A A N D A N A L Y S E S

Comparison 1. Monotherapy versus combination therapy

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 All cause fatality 43 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

1.1 Same BL 12 1381 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.75, 1.35]

1.2 Different BL 31 4146 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.71, 1.01]

2 All cause fatality by study groups 40 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

2.1 Same sepsis 6 789 Risk Ratio (M-H, Fixed, 95% CI) 1.15 [0.79, 1.67]

2.2 Same abdominal 2 331 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.54, 1.55]

2.3 Same UTI 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

2.4 Different sepsis 21 3298 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.69, 0.99]

2.5 Different abdominal 6 550 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.56, 2.15]

2.6 Different UTI 4 298 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.34, 5.21]

3 All cause fatality (Gram negative

infections)

8 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only



4 All cause fatality (Gram negative

bacteremia)




5 All cause fatality (non urinary

tract infections)






studies

No. of


1 Clinical failure 63 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only



2 Clinical failure by study groups 58 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

2.1 Same sepsis 12 1196 Risk Ratio (M-H, Fixed, 95% CI) 1.25 [1.01, 1.55]

2.2 Same abdominal 2 308 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.80, 1.32]

2.3 Same UTI 1 61 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.46, 2.09]

2.4 Different sepsis 29 3612 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.66, 0.84]

2.5 Different abdominal 9 675 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.59, 1.13]

2.6 Different UTI 5 459 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.65, 1.91]

3 Bacteriological failure - all 43 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only





4 UTI relapse or re-infection 6 458 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.61, 1.67]

5 Clinical failure (Gram negative

infections)




6 Clinical failure (Gram negative

bacteremia)




7 Clinical failure (Pseudomonas

aeruginosa infections)




8 Clinical failure (bacteremia) 22 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only



9 Clinical failure (urinary tract

infections)




10 Clinical failure (non urinary

tract infections)






studies

No. of


1 Bacterial superinfections 27 3085 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.57, 1.01]

2 Fungal superinfections 11 1119 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.42, 1.48]

3 Bacterial colonization 14 1635 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.65, 1.10]

4 Fungal colonization 7 1132 Risk Ratio (M-H, Fixed, 95% CI) 1.39 [0.93, 2.09]

5 Bacterial colonization -

surveillance cultures

6 751 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.60, 1.01]

6 Bacterial resistance development 9 1370 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.54, 1.45]



studies

No. of


1 Any adverse event 39 4945 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.83, 1.01]

2 Adverse events requiring

treatment discontinuation

19 3042 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.52, 1.52]

3 Any nephrotoxicity 45 5213 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.23, 0.39]



3.1 Once daily aminoglycoside 5 865 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.06, 0.53]

3.2 Twice daily

aminoglycoside


3.3 Thrice daily

aminoglycoside


3.4 Non specified

aminoglycoside regimen




studies

No. of


1 Drop-outs for all cause fatality 8 910 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.66, 1.49]



2 Drop-outs for clinical failure 24 3631 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.88, 1.23]





studies

No. of


1 All cause fatality (Gram positive

infections)


2 Clinical failure (Gram positive

infections)


3 Bacteriological failure (Gram

positive infections)


4 Need for operation (endocarditis) 4 243 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.41, 1.39]

Comparison 7. Monotherapy versus combination therapy (sensitivity analyses)


studies

No. of


1 All cause fatality by allocation

concealment


1.1 A same BL 6 1068 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.71, 1.31]

1.2 B same BL 6 313 Risk Ratio (M-H, Fixed, 95% CI) 1.56 [0.58, 4.18]

1.3 A different BL 12 2154 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.75, 1.19]

1.4 B different BL 18 1952 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.53, 0.93]



1.5 C different BL 1 40 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.34, 5.21]

2 All cause fatality by allocation

generation







3 All cause fatality by ITT vs. per-

protocol analysis


3.1 ITT - same BL (type 1

studies)


3.2 per-protocol - same BL

(type 2 and 3 studies)


3.3 unknown - same BL (type

4 studies)


3.4 ITT - different BL (type 1

studies)


3.5 per-protocol - different

BL (type 2 and 3 studies)


3.6 unknown - different BL

(type 4 studies)


4 Clinical failure by allocation

concealment







5 Clinical failure by allocation

generation







6 Clinical failure by blinding 63 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

6.1 Non-blinded - same BL 19 1666 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.93, 1.35]

6.2 Any blinding - same BL 1 204 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.82, 1.37]

6.3 Non-blinded - different

BL


6.4 Any blinding - different

BL


7 Clinical failure by ITT versus

per-protocol analysis


7.1 ITT - same BL (type 1) 2 110 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.43, 1.40]

7.2 ITT assuming failure for

drop-outs - same BL (type 2)


7.3 Per protocol - same BL

(type 3 studies)


7.4 Type 4 studies - same BL 5 278 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.56, 1.61]



7.5 ITT - different BL (type

1)


7.6 ITT assuming failure for

drop-outs - different BL (type

2)


7.7 Per protocol - different BL

(type 3 studies)


7.8 Type 4 studies - different

BL


Analysis 1.1. Comparison 1 Monotherapy versus combination therapy, Outcome 1 All cause fatality.

Review: Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis

Comparison: 1 Monotherapy versus combination therapy

Outcome: 1 All cause fatality

Study or subgroup Monotherapy Combination therapy Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Carbon 1987 1/25 1/22 1.4 % 0.88 [ 0.06, 13.25 ]

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Cometta 1994 24/148 19/144 25.8 % 1.23 [ 0.70, 2.14 ]

D’Antonio 1992 7/144 10/142 13.5 % 0.69 [ 0.27, 1.76 ]

Dupont 2000 21/111 24/116 31.5 % 0.91 [ 0.54, 1.55 ]

Klastersky 1973 7/22 3/23 3.9 % 2.44 [ 0.72, 8.26 ]

Kljucar 1990 11/49 9/50 11.9 % 1.25 [ 0.57, 2.74 ]

Korzeniowski 1982 2/33 6/41 7.2 % 0.41 [ 0.09, 1.92 ]

Ribera 1996 1/45 2/45 2.7 % 0.50 [ 0.05, 5.32 ]

Sandberg 1997 0/37 0/36 0.0 % 0.0 [ 0.0, 0.0 ]

Sculier 1982 0/10 1/10 2.0 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 692 689 100.0 % 1.01 [ 0.75, 1.35 ]

Total events: 74 (Monotherapy), 75 (Combination therapy)

Heterogeneity: Chi2 = 5.68, df = 8 (P = 0.68); I2 =0.0%

Test for overall effect: Z = 0.04 (P = 0.97)

2 Different BL

Alvarez-Lerma 2001a 16/69 20/71 8.7 % 0.82 [ 0.47, 1.45 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0

Favours monotherapy Favours combination

(Continued . . . )



(. . . Continued)Study or subgroup Monotherapy Combination therapy Risk Ratio Weight Risk Ratio


Arich 1987 8/25 5/22 2.3 % 1.41 [ 0.54, 3.67 ]

Bergeron 1988 0/37 1/29 0.7 % 0.26 [ 0.01, 6.23 ]

Brown 1984 11/18 9/16 4.2 % 1.09 [ 0.62, 1.92 ]

Cone 1985 1/21 2/19 0.9 % 0.45 [ 0.04, 4.60 ]

Duff 1982 0/31 0/43 0.0 % 0.0 [ 0.0, 0.0 ]

Felisart 1985 7/37 11/36 4.9 % 0.62 [ 0.27, 1.42 ]

Finer 1992 40/249 21/222 9.8 % 1.70 [ 1.03, 2.79 ]

Gomez 1990a 6/39 5/39 2.2 % 1.20 [ 0.40, 3.61 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

Hoepelman 1988 2/45 4/41 1.8 % 0.46 [ 0.09, 2.36 ]

Jaspers 1998 3/39 4/40 1.7 % 0.77 [ 0.18, 3.22 ]

Koehler 1990 5/73 2/71 0.9 % 2.43 [ 0.49, 12.13 ]

Landau 1990 4/20 3/20 1.3 % 1.33 [ 0.34, 5.21 ]

McCormick 1997 13/65 9/63 4.0 % 1.40 [ 0.64, 3.04 ]

Mouton 1990 14/105 19/106 8.4 % 0.74 [ 0.39, 1.40 ]

Mouton 1995 7/116 8/121 3.5 % 0.91 [ 0.34, 2.44 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Rubinstein 1995 31/306 33/274 15.4 % 0.84 [ 0.53, 1.34 ]

Sieger 1997 13/104 23/107 10.0 % 0.58 [ 0.31, 1.09 ]

Smith 1984 7/94 19/93 8.4 % 0.36 [ 0.16, 0.83 ]

Speich 1998 1/44 6/45 2.6 % 0.17 [ 0.02, 1.36 ]

Stille 1992 3/186 6/151 2.9 % 0.41 [ 0.10, 1.60 ]

Thompson 1990 2/49 3/47 1.4 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 3/56 9/64 3.7 % 0.38 [ 0.11, 1.34 ]

Wiecek 1986 0/10 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Wing 1998 0/117 0/62 0.0 % 0.0 [ 0.0, 0.0 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 2175 1971 100.0 % 0.85 [ 0.71, 1.01 ]


0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Heterogeneity: Chi2 = 26.06, df = 21 (P = 0.20); I2 =19%


0.1 0.2 0.5 1.0 2.0 5.0 10.0







1 Same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Carbon 1987 1/25 1/22 1.4 % 0.88 [ 0.06, 13.25 ]

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Cometta 1994 24/148 19/144 25.8 % 1.23 [ 0.70, 2.14 ]

D’Antonio 1992 7/144 10/142 13.5 % 0.69 [ 0.27, 1.76 ]

Dupont 2000 21/111 24/116 31.5 % 0.91 [ 0.54, 1.55 ]

Klastersky 1973 7/22 3/23 3.9 % 2.44 [ 0.72, 8.26 ]

Kljucar 1990 11/49 9/50 11.9 % 1.25 [ 0.57, 2.74 ]

Korzeniowski 1982 2/33 6/41 7.2 % 0.41 [ 0.09, 1.92 ]

Ribera 1996 1/45 2/45 2.7 % 0.50 [ 0.05, 5.32 ]

Sandberg 1997 0/37 0/36 0.0 % 0.0 [ 0.0, 0.0 ]

Sculier 1982 0/10 1/10 2.0 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 692 689 100.0 % 1.01 [ 0.75, 1.35 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 Different BL

Alvarez-Lerma 2001a 16/69 20/71 8.7 % 0.82 [ 0.47, 1.45 ]

Arich 1987 8/25 5/22 2.3 % 1.41 [ 0.54, 3.67 ]

Bergeron 1988 0/37 1/29 0.7 % 0.26 [ 0.01, 6.23 ]

Brown 1984 11/18 9/16 4.2 % 1.09 [ 0.62, 1.92 ]

Cone 1985 1/21 2/19 0.9 % 0.45 [ 0.04, 4.60 ]

Duff 1982 0/31 0/43 0.0 % 0.0 [ 0.0, 0.0 ]

Felisart 1985 7/37 11/36 4.9 % 0.62 [ 0.27, 1.42 ]

Finer 1992 40/249 21/222 9.8 % 1.70 [ 1.03, 2.79 ]

Gomez 1990a 6/39 5/39 2.2 % 1.20 [ 0.40, 3.61 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

Hoepelman 1988 2/45 4/41 1.8 % 0.46 [ 0.09, 2.36 ]

Jaspers 1998 3/39 4/40 1.7 % 0.77 [ 0.18, 3.22 ]

Koehler 1990 5/73 2/71 0.9 % 2.43 [ 0.49, 12.13 ]

Landau 1990 4/20 3/20 1.3 % 1.33 [ 0.34, 5.21 ]

McCormick 1997 13/65 9/63 4.0 % 1.40 [ 0.64, 3.04 ]

Mouton 1990 14/105 19/106 8.4 % 0.74 [ 0.39, 1.40 ]

Mouton 1995 7/116 8/121 3.5 % 0.91 [ 0.34, 2.44 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Rubinstein 1995 31/306 33/274 15.4 % 0.84 [ 0.53, 1.34 ]

Sieger 1997 13/104 23/107 10.0 % 0.58 [ 0.31, 1.09 ]

Smith 1984 7/94 19/93 8.4 % 0.36 [ 0.16, 0.83 ]

Speich 1998 1/44 6/45 2.6 % 0.17 [ 0.02, 1.36 ]

Stille 1992 3/186 6/151 2.9 % 0.41 [ 0.10, 1.60 ]

Thompson 1990 2/49 3/47 1.4 % 0.64 [ 0.11, 3.66 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 3/56 9/64 3.7 % 0.38 [ 0.11, 1.34 ]

Wiecek 1986 0/10 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Wing 1998 0/117 0/62 0.0 % 0.0 [ 0.0, 0.0 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 2175 1971 100.0 % 0.85 [ 0.71, 1.01 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0


Analysis 1.2. Comparison 1 Monotherapy versus combination therapy, Outcome 2 All cause fatality by

study groups.



Outcome: 2 All cause fatality by study groups



1 Same sepsis

Carbon 1987 1/25 1/22 2.4 % 0.88 [ 0.06, 13.25 ]

Cometta 1994 24/148 19/144 44.0 % 1.23 [ 0.70, 2.14 ]

D’Antonio 1992 7/144 10/142 23.0 % 0.69 [ 0.27, 1.76 ]

Klastersky 1973 7/22 3/23 6.7 % 2.44 [ 0.72, 8.26 ]

Kljucar 1990 11/49 9/50 20.4 % 1.25 [ 0.57, 2.74 ]

Sculier 1982 0/10 1/10 3.4 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 398 391 100.0 % 1.15 [ 0.79, 1.67 ]



0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )






2 Same abdominal

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Dupont 2000 21/111 24/116 100.0 % 0.91 [ 0.54, 1.55 ]

Subtotal (95% CI) 167 164 100.0 % 0.91 [ 0.54, 1.55 ]




3 Same UTI

Sandberg 1997 0/37 0/36 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 37 36 0.0 % 0.0 [ 0.0, 0.0 ]


Heterogeneity: not applicable

Test for overall effect: Z = 0.0 (P < 0.00001)

4 Different sepsis

Alvarez-Lerma 2001a 16/69 20/71 9.4 % 0.82 [ 0.47, 1.45 ]

Arich 1987 8/25 5/22 2.5 % 1.41 [ 0.54, 3.67 ]

Brown 1984 11/18 9/16 4.5 % 1.09 [ 0.62, 1.92 ]

Cone 1985 1/21 2/19 1.0 % 0.45 [ 0.04, 4.60 ]

Duff 1982 0/31 0/43 0.0 % 0.0 [ 0.0, 0.0 ]

Felisart 1985 7/37 11/36 5.3 % 0.62 [ 0.27, 1.42 ]

Finer 1992 40/249 21/222 10.6 % 1.70 [ 1.03, 2.79 ]

Gomez 1990a 6/39 5/39 2.4 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 2/45 4/41 2.0 % 0.46 [ 0.09, 2.36 ]

Jaspers 1998 3/39 4/40 1.9 % 0.77 [ 0.18, 3.22 ]

Koehler 1990 5/73 2/71 1.0 % 2.43 [ 0.49, 12.13 ]

Mouton 1990 14/105 19/106 9.0 % 0.74 [ 0.39, 1.40 ]

Mouton 1995 7/116 8/121 3.7 % 0.91 [ 0.34, 2.44 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rubinstein 1995 31/306 33/274 16.6 % 0.84 [ 0.53, 1.34 ]

Sieger 1997 13/104 23/107 10.8 % 0.58 [ 0.31, 1.09 ]

Smith 1984 7/94 19/93 9.1 % 0.36 [ 0.16, 0.83 ]

Speich 1998 1/44 6/45 2.8 % 0.17 [ 0.02, 1.36 ]

Stille 1992 3/186 6/151 3.2 % 0.41 [ 0.10, 1.60 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Warren 1983 3/56 9/64 4.0 % 0.38 [ 0.11, 1.34 ]

Subtotal (95% CI) 1688 1610 100.0 % 0.83 [ 0.69, 0.99 ]




5 Different abdominal

Bergeron 1988 0/37 1/29 12.1 % 0.26 [ 0.01, 6.23 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

McCormick 1997 13/65 9/63 65.9 % 1.40 [ 0.64, 3.04 ]

Thompson 1990 2/49 3/47 22.1 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 311 239 100.0 % 1.09 [ 0.56, 2.15 ]




6 Different UTI

Landau 1990 4/20 3/20 100.0 % 1.33 [ 0.34, 5.21 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Wiecek 1986 0/10 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Wing 1998 0/117 0/62 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 176 122 100.0 % 1.33 [ 0.34, 5.21 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Same sepsis

Carbon 1987 1/25 1/22 2.4 % 0.88 [ 0.06, 13.25 ]

Cometta 1994 24/148 19/144 44.0 % 1.23 [ 0.70, 2.14 ]

D’Antonio 1992 7/144 10/142 23.0 % 0.69 [ 0.27, 1.76 ]

Klastersky 1973 7/22 3/23 6.7 % 2.44 [ 0.72, 8.26 ]

Kljucar 1990 11/49 9/50 20.4 % 1.25 [ 0.57, 2.74 ]

Sculier 1982 0/10 1/10 3.4 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 398 391 100.0 % 1.15 [ 0.79, 1.67 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







2 Same abdominal

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Dupont 2000 21/111 24/116 100.0 % 0.91 [ 0.54, 1.55 ]

Subtotal (95% CI) 167 164 100.0 % 0.91 [ 0.54, 1.55 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









3 Same UTI

Sandberg 1997 0/37 0/36 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 37 36 0.0 % 0.0 [ 0.0, 0.0 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







4 Different sepsis

Alvarez-Lerma 2001a 16/69 20/71 9.4 % 0.82 [ 0.47, 1.45 ]

Arich 1987 8/25 5/22 2.5 % 1.41 [ 0.54, 3.67 ]

Brown 1984 11/18 9/16 4.5 % 1.09 [ 0.62, 1.92 ]

Cone 1985 1/21 2/19 1.0 % 0.45 [ 0.04, 4.60 ]

Duff 1982 0/31 0/43 0.0 % 0.0 [ 0.0, 0.0 ]

Felisart 1985 7/37 11/36 5.3 % 0.62 [ 0.27, 1.42 ]

Finer 1992 40/249 21/222 10.6 % 1.70 [ 1.03, 2.79 ]

Gomez 1990a 6/39 5/39 2.4 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 2/45 4/41 2.0 % 0.46 [ 0.09, 2.36 ]

Jaspers 1998 3/39 4/40 1.9 % 0.77 [ 0.18, 3.22 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Koehler 1990 5/73 2/71 1.0 % 2.43 [ 0.49, 12.13 ]

Mouton 1990 14/105 19/106 9.0 % 0.74 [ 0.39, 1.40 ]

Mouton 1995 7/116 8/121 3.7 % 0.91 [ 0.34, 2.44 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rubinstein 1995 31/306 33/274 16.6 % 0.84 [ 0.53, 1.34 ]

Sieger 1997 13/104 23/107 10.8 % 0.58 [ 0.31, 1.09 ]

Smith 1984 7/94 19/93 9.1 % 0.36 [ 0.16, 0.83 ]

Speich 1998 1/44 6/45 2.8 % 0.17 [ 0.02, 1.36 ]

Stille 1992 3/186 6/151 3.2 % 0.41 [ 0.10, 1.60 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 3/56 9/64 4.0 % 0.38 [ 0.11, 1.34 ]

Subtotal (95% CI) 1688 1610 100.0 % 0.83 [ 0.69, 0.99 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0










Bergeron 1988 0/37 1/29 12.1 % 0.26 [ 0.01, 6.23 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

McCormick 1997 13/65 9/63 65.9 % 1.40 [ 0.64, 3.04 ]

Thompson 1990 2/49 3/47 22.1 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 311 239 100.0 % 1.09 [ 0.56, 2.15 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







6 Different UTI

Landau 1990 4/20 3/20 100.0 % 1.33 [ 0.34, 5.21 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Wiecek 1986 0/10 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Wing 1998 0/117 0/62 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 176 122 100.0 % 1.33 [ 0.34, 5.21 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 1.3. Comparison 1 Monotherapy versus combination therapy, Outcome 3 All cause fatality (Gram

negative infections).



Outcome: 3 All cause fatality (Gram negative infections)



1 Same BL

Carbon 1987 1/25 1/22 41.5 % 0.88 [ 0.06, 13.25 ]

Sandberg 1997 0/22 0/28 0.0 % 0.0 [ 0.0, 0.0 ]

Sculier 1982 0/10 1/10 58.5 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 57 60 100.0 % 0.56 [ 0.08, 4.07 ]




2 Different BL

Arich 1987 8/25 5/22 22.7 % 1.41 [ 0.54, 3.67 ]

Brown 1984 11/18 9/16 40.8 % 1.09 [ 0.62, 1.92 ]

Gomez 1990a 6/39 5/39 21.4 % 1.20 [ 0.40, 3.61 ]

Landau 1990 4/20 3/20 12.8 % 1.33 [ 0.34, 5.21 ]

Stille 1992 1/61 0/53 2.3 % 2.61 [ 0.11, 62.82 ]

Subtotal (95% CI) 163 150 100.0 % 1.25 [ 0.80, 1.95 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Same BL

Carbon 1987 1/25 1/22 41.5 % 0.88 [ 0.06, 13.25 ]

Sandberg 1997 0/22 0/28 0.0 % 0.0 [ 0.0, 0.0 ]

Sculier 1982 0/10 1/10 58.5 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 57 60 100.0 % 0.56 [ 0.08, 4.07 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







2 Different BL

Arich 1987 8/25 5/22 22.7 % 1.41 [ 0.54, 3.67 ]

Brown 1984 11/18 9/16 40.8 % 1.09 [ 0.62, 1.92 ]

Gomez 1990a 6/39 5/39 21.4 % 1.20 [ 0.40, 3.61 ]

Landau 1990 4/20 3/20 12.8 % 1.33 [ 0.34, 5.21 ]

Stille 1992 1/61 0/53 2.3 % 2.61 [ 0.11, 62.82 ]

Subtotal (95% CI) 163 150 100.0 % 1.25 [ 0.80, 1.95 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0





negative bacteremia).



Outcome: 4 All cause fatality (Gram negative bacteremia)



1 Same BL

Carbon 1987 1/25 1/22 54.5 % 0.88 [ 0.06, 13.25 ]

Piccart 1984 2/12 1/15 45.5 % 2.50 [ 0.26, 24.38 ]

Sandberg 1997 0/2 0/9 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 39 46 100.0 % 1.62 [ 0.30, 8.75 ]




2 Different BL

Arich 1987 8/25 5/22 51.5 % 1.41 [ 0.54, 3.67 ]

Gomez 1990a 6/39 5/39 48.5 % 1.20 [ 0.40, 3.61 ]

Subtotal (95% CI) 64 61 100.0 % 1.31 [ 0.63, 2.70 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Same BL

Carbon 1987 1/25 1/22 54.5 % 0.88 [ 0.06, 13.25 ]

Piccart 1984 2/12 1/15 45.5 % 2.50 [ 0.26, 24.38 ]

Sandberg 1997 0/2 0/9 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 39 46 100.0 % 1.62 [ 0.30, 8.75 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







2 Different BL

Arich 1987 8/25 5/22 51.5 % 1.41 [ 0.54, 3.67 ]

Gomez 1990a 6/39 5/39 48.5 % 1.20 [ 0.40, 3.61 ]

Subtotal (95% CI) 64 61 100.0 % 1.31 [ 0.63, 2.70 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 1.5. Comparison 1 Monotherapy versus combination therapy, Outcome 5 All cause fatality (non

urinary tract infections).



Outcome: 5 All cause fatality (non urinary tract infections)



1 Same BL

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Dupont 2000 21/111 24/116 94.0 % 0.91 [ 0.54, 1.55 ]

Sculier 1982 0/10 1/10 6.0 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 177 174 100.0 % 0.88 [ 0.53, 1.47 ]




2 Different BL

Alvarez-Lerma 2001a 16/69 20/71 24.5 % 0.82 [ 0.47, 1.45 ]

Bergeron 1988 0/37 1/30 2.1 % 0.27 [ 0.01, 6.44 ]

Brown 1984 11/18 9/16 11.8 % 1.09 [ 0.62, 1.92 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

Koehler 1990 5/73 2/71 2.5 % 2.43 [ 0.49, 12.13 ]

Mouton 1990 3/44 5/45 6.1 % 0.61 [ 0.16, 2.41 ]

Sieger 1997 13/104 23/107 28.1 % 0.58 [ 0.31, 1.09 ]

Smith 1984 4/34 5/26 7.0 % 0.61 [ 0.18, 2.05 ]

Speich 1998 1/44 6/45 7.4 % 0.17 [ 0.02, 1.36 ]

Stille 1992 2/144 5/124 6.7 % 0.34 [ 0.07, 1.74 ]

Thompson 1990 2/49 3/47 3.8 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 776 682 100.0 % 0.70 [ 0.52, 0.95 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Same BL

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Dupont 2000 21/111 24/116 94.0 % 0.91 [ 0.54, 1.55 ]

Sculier 1982 0/10 1/10 6.0 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 177 174 100.0 % 0.88 [ 0.53, 1.47 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







2 Different BL

Alvarez-Lerma 2001a 16/69 20/71 24.5 % 0.82 [ 0.47, 1.45 ]

Bergeron 1988 0/37 1/30 2.1 % 0.27 [ 0.01, 6.44 ]

Brown 1984 11/18 9/16 11.8 % 1.09 [ 0.62, 1.92 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

Koehler 1990 5/73 2/71 2.5 % 2.43 [ 0.49, 12.13 ]

Mouton 1990 3/44 5/45 6.1 % 0.61 [ 0.16, 2.41 ]

Sieger 1997 13/104 23/107 28.1 % 0.58 [ 0.31, 1.09 ]

Smith 1984 4/34 5/26 7.0 % 0.61 [ 0.18, 2.05 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Speich 1998 1/44 6/45 7.4 % 0.17 [ 0.02, 1.36 ]

Stille 1992 2/144 5/124 6.7 % 0.34 [ 0.07, 1.74 ]

Thompson 1990 2/49 3/47 3.8 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 776 682 100.0 % 0.70 [ 0.52, 0.95 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0


Analysis 2.1. Comparison 2 Monotherapy versus combination therapy, Outcome 1 Clinical failure.



Outcome: 1 Clinical failure



1 Same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Biglino 1991 1/12 1/10 0.5 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 2.0 % 0.66 [ 0.17, 2.63 ]

Cardozo 2001 9/56 9/48 4.5 % 0.86 [ 0.37, 1.98 ]

Cometta 1994 35/148 25/144 11.8 % 1.36 [ 0.86, 2.16 ]

Coppens 1983 2/22 7/44 2.2 % 0.57 [ 0.13, 2.52 ]

D’Antonio 1992 43/144 35/142 16.4 % 1.21 [ 0.83, 1.77 ]

Dupont 2000 55/99 55/105 24.8 % 1.06 [ 0.82, 1.37 ]

Klastersky 1973 11/22 4/23 1.8 % 2.88 [ 1.07, 7.69 ]

Kljucar 1990 12/44 9/45 4.1 % 1.36 [ 0.64, 2.91 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Korzeniowski 1982 3/33 7/41 2.9 % 0.53 [ 0.15, 1.90 ]

Mergoni 1987 4/20 4/22 1.8 % 1.10 [ 0.32, 3.83 ]

Piccart 1984 7/42 11/43 5.0 % 0.65 [ 0.28, 1.52 ]

Ribera 1996 11/45 14/45 6.5 % 0.79 [ 0.40, 1.54 ]

Sage 1987 10/26 2/22 1.0 % 4.23 [ 1.03, 17.29 ]

Sandberg 1997 8/26 11/35 4.4 % 0.98 [ 0.46, 2.09 ]

Sculier 1982 3/10 4/10 1.9 % 0.75 [ 0.22, 2.52 ]

Sexton 1998 1/26 1/25 0.5 % 0.96 [ 0.06, 14.55 ]

Sukoh 1994 6/30 5/33 2.2 % 1.32 [ 0.45, 3.88 ]

Takamoto 1994 12/77 13/80 5.9 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 919 951 100.0 % 1.11 [ 0.95, 1.29 ]




2 Different BL

Aguilar 1992 0/19 3/17 0.7 % 0.13 [ 0.01, 2.32 ]

Alvarez-Lerma 2001a 10/57 20/59 3.8 % 0.52 [ 0.27, 1.01 ]

Arich 1987 3/25 5/22 1.0 % 0.53 [ 0.14, 1.96 ]

Bergeron 1988 2/37 5/30 1.1 % 0.32 [ 0.07, 1.56 ]

Brown 1984 7/18 9/16 1.8 % 0.69 [ 0.34, 1.42 ]

Cone 1985 3/21 4/19 0.8 % 0.68 [ 0.17, 2.65 ]

Duff 1982 12/31 16/43 2.6 % 1.04 [ 0.58, 1.87 ]

Felisart 1985 9/37 18/36 3.5 % 0.49 [ 0.25, 0.94 ]

Finer 1992 24/220 22/195 4.5 % 0.97 [ 0.56, 1.67 ]

Gerecht 1989 4/24 13/22 2.6 % 0.28 [ 0.11, 0.74 ]

Gomez 1990a 6/39 5/39 1.0 % 1.20 [ 0.40, 3.61 ]

Havig 1973 1/24 2/26 0.4 % 0.54 [ 0.05, 5.60 ]

Hoepelman 1988 8/45 13/41 2.6 % 0.56 [ 0.26, 1.21 ]

Holloway 1985 2/15 3/18 0.5 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 4/48 10/47 1.9 % 0.39 [ 0.13, 1.16 ]

Jaspers 1998 12/39 15/40 2.9 % 0.82 [ 0.44, 1.52 ]

Koehler 1990 13/63 6/64 1.1 % 2.20 [ 0.89, 5.43 ]

Landau 1990 4/20 3/20 0.6 % 1.33 [ 0.34, 5.21 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Limson 1988 2/20 3/20 0.6 % 0.67 [ 0.12, 3.57 ]

Mandell 1987 7/52 9/58 1.6 % 0.87 [ 0.35, 2.16 ]

Martin 1991 10/52 8/42 1.7 % 1.01 [ 0.44, 2.33 ]

McCormick 1997 13/65 8/63 1.6 % 1.58 [ 0.70, 3.54 ]

Moreno 1997 1/30 0/28 0.1 % 2.81 [ 0.12, 66.17 ]

Mouton 1990 39/105 43/106 8.3 % 0.92 [ 0.65, 1.29 ]

Mouton 1995 14/111 20/118 3.7 % 0.74 [ 0.40, 1.40 ]

Muller 1987 16/73 5/33 1.3 % 1.45 [ 0.58, 3.62 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 2/17 3/18 0.6 % 0.71 [ 0.13, 3.72 ]

Rasmussen 1986 1/29 1/30 0.2 % 1.03 [ 0.07, 15.77 ]

Rubinstein 1995 40/267 59/238 12.0 % 0.60 [ 0.42, 0.87 ]

Sanfilippo 1989 0/13 1/13 0.3 % 0.33 [ 0.01, 7.50 ]

Sieger 1997 30/106 43/105 8.3 % 0.69 [ 0.47, 1.01 ]

Smith 1984 35/96 58/99 11.0 % 0.62 [ 0.46, 0.85 ]

Speich 1998 4/41 7/43 1.3 % 0.60 [ 0.19, 1.90 ]

Stille 1992 22/186 26/151 5.5 % 0.69 [ 0.41, 1.16 ]

Thompson 1990 15/49 14/47 2.8 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 0.1 % 2.53 [ 0.12, 51.50 ]

Trujillo 1992 0/16 2/14 0.5 % 0.18 [ 0.01, 3.39 ]

Vergnon 1985 7/16 4/14 0.8 % 1.53 [ 0.56, 4.15 ]

Verzasconi 1995 6/45 8/42 1.6 % 0.70 [ 0.26, 1.85 ]

Warren 1983 13/56 12/64 2.2 % 1.24 [ 0.62, 2.49 ]

Wing 1998 6/117 0/62 0.1 % 6.94 [ 0.40, 121.21 ]

Yellin 1993 1/56 1/34 0.2 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 2495 2251 100.0 % 0.77 [ 0.69, 0.86 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Biglino 1991 1/12 1/10 0.5 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 2.0 % 0.66 [ 0.17, 2.63 ]

Cardozo 2001 9/56 9/48 4.5 % 0.86 [ 0.37, 1.98 ]

Cometta 1994 35/148 25/144 11.8 % 1.36 [ 0.86, 2.16 ]

Coppens 1983 2/22 7/44 2.2 % 0.57 [ 0.13, 2.52 ]

D’Antonio 1992 43/144 35/142 16.4 % 1.21 [ 0.83, 1.77 ]

Dupont 2000 55/99 55/105 24.8 % 1.06 [ 0.82, 1.37 ]

Klastersky 1973 11/22 4/23 1.8 % 2.88 [ 1.07, 7.69 ]

Kljucar 1990 12/44 9/45 4.1 % 1.36 [ 0.64, 2.91 ]

Korzeniowski 1982 3/33 7/41 2.9 % 0.53 [ 0.15, 1.90 ]

Mergoni 1987 4/20 4/22 1.8 % 1.10 [ 0.32, 3.83 ]

Piccart 1984 7/42 11/43 5.0 % 0.65 [ 0.28, 1.52 ]

Ribera 1996 11/45 14/45 6.5 % 0.79 [ 0.40, 1.54 ]

Sage 1987 10/26 2/22 1.0 % 4.23 [ 1.03, 17.29 ]

Sandberg 1997 8/26 11/35 4.4 % 0.98 [ 0.46, 2.09 ]

Sculier 1982 3/10 4/10 1.9 % 0.75 [ 0.22, 2.52 ]

Sexton 1998 1/26 1/25 0.5 % 0.96 [ 0.06, 14.55 ]

Sukoh 1994 6/30 5/33 2.2 % 1.32 [ 0.45, 3.88 ]

Takamoto 1994 12/77 13/80 5.9 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 919 951 100.0 % 1.11 [ 0.95, 1.29 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 Different BL

Aguilar 1992 0/19 3/17 0.7 % 0.13 [ 0.01, 2.32 ]

Alvarez-Lerma 2001a 10/57 20/59 3.8 % 0.52 [ 0.27, 1.01 ]

Arich 1987 3/25 5/22 1.0 % 0.53 [ 0.14, 1.96 ]

Bergeron 1988 2/37 5/30 1.1 % 0.32 [ 0.07, 1.56 ]

Brown 1984 7/18 9/16 1.8 % 0.69 [ 0.34, 1.42 ]

Cone 1985 3/21 4/19 0.8 % 0.68 [ 0.17, 2.65 ]

Duff 1982 12/31 16/43 2.6 % 1.04 [ 0.58, 1.87 ]

Felisart 1985 9/37 18/36 3.5 % 0.49 [ 0.25, 0.94 ]

Finer 1992 24/220 22/195 4.5 % 0.97 [ 0.56, 1.67 ]

Gerecht 1989 4/24 13/22 2.6 % 0.28 [ 0.11, 0.74 ]

Gomez 1990a 6/39 5/39 1.0 % 1.20 [ 0.40, 3.61 ]

Havig 1973 1/24 2/26 0.4 % 0.54 [ 0.05, 5.60 ]

Hoepelman 1988 8/45 13/41 2.6 % 0.56 [ 0.26, 1.21 ]

Holloway 1985 2/15 3/18 0.5 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 4/48 10/47 1.9 % 0.39 [ 0.13, 1.16 ]

Jaspers 1998 12/39 15/40 2.9 % 0.82 [ 0.44, 1.52 ]

Koehler 1990 13/63 6/64 1.1 % 2.20 [ 0.89, 5.43 ]

Landau 1990 4/20 3/20 0.6 % 1.33 [ 0.34, 5.21 ]

Limson 1988 2/20 3/20 0.6 % 0.67 [ 0.12, 3.57 ]

Mandell 1987 7/52 9/58 1.6 % 0.87 [ 0.35, 2.16 ]

Martin 1991 10/52 8/42 1.7 % 1.01 [ 0.44, 2.33 ]

McCormick 1997 13/65 8/63 1.6 % 1.58 [ 0.70, 3.54 ]

Moreno 1997 1/30 0/28 0.1 % 2.81 [ 0.12, 66.17 ]

Mouton 1990 39/105 43/106 8.3 % 0.92 [ 0.65, 1.29 ]

Mouton 1995 14/111 20/118 3.7 % 0.74 [ 0.40, 1.40 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Muller 1987 16/73 5/33 1.3 % 1.45 [ 0.58, 3.62 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 2/17 3/18 0.6 % 0.71 [ 0.13, 3.72 ]

Rasmussen 1986 1/29 1/30 0.2 % 1.03 [ 0.07, 15.77 ]

Rubinstein 1995 40/267 59/238 12.0 % 0.60 [ 0.42, 0.87 ]

Sanfilippo 1989 0/13 1/13 0.3 % 0.33 [ 0.01, 7.50 ]

Sieger 1997 30/106 43/105 8.3 % 0.69 [ 0.47, 1.01 ]

Smith 1984 35/96 58/99 11.0 % 0.62 [ 0.46, 0.85 ]

Speich 1998 4/41 7/43 1.3 % 0.60 [ 0.19, 1.90 ]

Stille 1992 22/186 26/151 5.5 % 0.69 [ 0.41, 1.16 ]

Thompson 1990 15/49 14/47 2.8 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 0.1 % 2.53 [ 0.12, 51.50 ]

Trujillo 1992 0/16 2/14 0.5 % 0.18 [ 0.01, 3.39 ]

Vergnon 1985 7/16 4/14 0.8 % 1.53 [ 0.56, 4.15 ]

Verzasconi 1995 6/45 8/42 1.6 % 0.70 [ 0.26, 1.85 ]

Warren 1983 13/56 12/64 2.2 % 1.24 [ 0.62, 2.49 ]

Wing 1998 6/117 0/62 0.1 % 6.94 [ 0.40, 121.21 ]

Yellin 1993 1/56 1/34 0.2 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 2495 2251 100.0 % 0.77 [ 0.69, 0.86 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 2.2. Comparison 2 Monotherapy versus combination therapy, Outcome 2 Clinical failure by study

groups.



Outcome: 2 Clinical failure by study groups



1 Same sepsis

Biglino 1991 1/12 1/10 0.9 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 3.6 % 0.66 [ 0.17, 2.63 ]

Cometta 1994 35/148 25/144 21.6 % 1.36 [ 0.86, 2.16 ]

D’Antonio 1992 43/144 35/142 30.1 % 1.21 [ 0.83, 1.77 ]

Klastersky 1973 11/22 4/23 3.3 % 2.88 [ 1.07, 7.69 ]

Kljucar 1990 12/44 9/45 7.6 % 1.36 [ 0.64, 2.91 ]

Mergoni 1987 4/20 4/22 3.3 % 1.10 [ 0.32, 3.83 ]

Piccart 1984 7/42 11/43 9.3 % 0.65 [ 0.28, 1.52 ]

Sage 1987 10/26 2/22 1.9 % 4.23 [ 1.03, 17.29 ]

Sculier 1982 3/10 4/10 3.4 % 0.75 [ 0.22, 2.52 ]

Sukoh 1994 6/30 5/33 4.1 % 1.32 [ 0.45, 3.88 ]

Takamoto 1994 12/77 13/80 10.9 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 600 596 100.0 % 1.25 [ 1.01, 1.55 ]




2 Same abdominal

Cardozo 2001 9/56 9/48 15.4 % 0.86 [ 0.37, 1.98 ]

Dupont 2000 55/99 55/105 84.6 % 1.06 [ 0.82, 1.37 ]

Subtotal (95% CI) 155 153 100.0 % 1.03 [ 0.80, 1.32 ]




3 Same UTI

Sandberg 1997 8/26 11/35 100.0 % 0.98 [ 0.46, 2.09 ]

Subtotal (95% CI) 26 35 100.0 % 0.98 [ 0.46, 2.09 ]



0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )






4 Different sepsis

Aguilar 1992 0/19 3/17 0.8 % 0.13 [ 0.01, 2.32 ]

Alvarez-Lerma 2001a 10/57 20/59 4.5 % 0.52 [ 0.27, 1.01 ]

Arich 1987 3/25 5/22 1.2 % 0.53 [ 0.14, 1.96 ]

Brown 1984 7/18 9/16 2.2 % 0.69 [ 0.34, 1.42 ]

Cone 1985 3/21 4/19 1.0 % 0.68 [ 0.17, 2.65 ]

Felisart 1985 9/37 18/36 4.2 % 0.49 [ 0.25, 0.94 ]

Finer 1992 24/220 22/195 5.3 % 0.97 [ 0.56, 1.67 ]

Gomez 1990a 6/39 5/39 1.1 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 8/45 13/41 3.1 % 0.56 [ 0.26, 1.21 ]

Holloway 1985 2/15 3/18 0.6 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 4/48 10/47 2.3 % 0.39 [ 0.13, 1.16 ]

Jaspers 1998 12/39 15/40 3.4 % 0.82 [ 0.44, 1.52 ]

Koehler 1990 13/63 6/64 1.4 % 2.20 [ 0.89, 5.43 ]

Limson 1988 2/20 3/20 0.7 % 0.67 [ 0.12, 3.57 ]

Mandell 1987 7/52 9/58 1.9 % 0.87 [ 0.35, 2.16 ]

McCormick 1997 13/65 8/63 1.9 % 1.58 [ 0.70, 3.54 ]

Moreno 1997 1/30 0/28 0.1 % 2.81 [ 0.12, 66.17 ]

Mouton 1990 39/105 43/106 9.8 % 0.92 [ 0.65, 1.29 ]

Mouton 1995 14/111 20/118 4.4 % 0.74 [ 0.40, 1.40 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 2/17 3/18 0.7 % 0.71 [ 0.13, 3.72 ]

Rubinstein 1995 40/267 59/238 14.3 % 0.60 [ 0.42, 0.87 ]

Sieger 1997 30/106 43/105 9.9 % 0.69 [ 0.47, 1.01 ]

Smith 1984 35/96 58/99 13.0 % 0.62 [ 0.46, 0.85 ]

Speich 1998 4/41 7/43 1.6 % 0.60 [ 0.19, 1.90 ]

Stille 1992 22/186 26/151 6.6 % 0.69 [ 0.41, 1.16 ]

Trujillo 1992 0/16 2/14 0.6 % 0.18 [ 0.01, 3.39 ]

Vergnon 1985 7/16 4/14 1.0 % 1.53 [ 0.56, 4.15 ]

Warren 1983 13/56 12/64 2.6 % 1.24 [ 0.62, 2.49 ]

Subtotal (95% CI) 1845 1767 100.0 % 0.75 [ 0.66, 0.84 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )









Bergeron 1988 2/37 5/30 9.4 % 0.32 [ 0.07, 1.56 ]

Duff 1982 12/31 16/43 22.7 % 1.04 [ 0.58, 1.87 ]

Gerecht 1989 4/24 13/22 23.0 % 0.28 [ 0.11, 0.74 ]

Havig 1973 1/24 2/26 3.3 % 0.54 [ 0.05, 5.60 ]

Muller 1987 16/73 5/33 11.7 % 1.45 [ 0.58, 3.62 ]

Sanfilippo 1989 0/13 1/13 2.5 % 0.33 [ 0.01, 7.50 ]

Thompson 1990 15/49 14/47 24.2 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 1.1 % 2.53 [ 0.12, 51.50 ]

Yellin 1993 1/56 1/34 2.1 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 387 288 100.0 % 0.82 [ 0.59, 1.13 ]




6 Different UTI

Landau 1990 4/20 3/20 13.8 % 1.33 [ 0.34, 5.21 ]

Martin 1991 10/52 8/42 40.7 % 1.01 [ 0.44, 2.33 ]

Rasmussen 1986 1/29 1/30 4.5 % 1.03 [ 0.07, 15.77 ]

Verzasconi 1995 6/45 8/42 38.0 % 0.70 [ 0.26, 1.85 ]

Wing 1998 6/117 0/62 3.0 % 6.94 [ 0.40, 121.21 ]

Subtotal (95% CI) 263 196 100.0 % 1.12 [ 0.65, 1.91 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Same sepsis

Biglino 1991 1/12 1/10 0.9 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 3.6 % 0.66 [ 0.17, 2.63 ]

Cometta 1994 35/148 25/144 21.6 % 1.36 [ 0.86, 2.16 ]

D’Antonio 1992 43/144 35/142 30.1 % 1.21 [ 0.83, 1.77 ]

Klastersky 1973 11/22 4/23 3.3 % 2.88 [ 1.07, 7.69 ]

Kljucar 1990 12/44 9/45 7.6 % 1.36 [ 0.64, 2.91 ]

Mergoni 1987 4/20 4/22 3.3 % 1.10 [ 0.32, 3.83 ]

Piccart 1984 7/42 11/43 9.3 % 0.65 [ 0.28, 1.52 ]

Sage 1987 10/26 2/22 1.9 % 4.23 [ 1.03, 17.29 ]

Sculier 1982 3/10 4/10 3.4 % 0.75 [ 0.22, 2.52 ]

Sukoh 1994 6/30 5/33 4.1 % 1.32 [ 0.45, 3.88 ]

Takamoto 1994 12/77 13/80 10.9 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 600 596 100.0 % 1.25 [ 1.01, 1.55 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 Same abdominal

Cardozo 2001 9/56 9/48 15.4 % 0.86 [ 0.37, 1.98 ]

Dupont 2000 55/99 55/105 84.6 % 1.06 [ 0.82, 1.37 ]

Subtotal (95% CI) 155 153 100.0 % 1.03 [ 0.80, 1.32 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







3 Same UTI

Sandberg 1997 8/26 11/35 100.0 % 0.98 [ 0.46, 2.09 ]

Subtotal (95% CI) 26 35 100.0 % 0.98 [ 0.46, 2.09 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









4 Different sepsis

Aguilar 1992 0/19 3/17 0.8 % 0.13 [ 0.01, 2.32 ]

Alvarez-Lerma 2001a 10/57 20/59 4.5 % 0.52 [ 0.27, 1.01 ]

Arich 1987 3/25 5/22 1.2 % 0.53 [ 0.14, 1.96 ]

Brown 1984 7/18 9/16 2.2 % 0.69 [ 0.34, 1.42 ]

Cone 1985 3/21 4/19 1.0 % 0.68 [ 0.17, 2.65 ]

Felisart 1985 9/37 18/36 4.2 % 0.49 [ 0.25, 0.94 ]

Finer 1992 24/220 22/195 5.3 % 0.97 [ 0.56, 1.67 ]

Gomez 1990a 6/39 5/39 1.1 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 8/45 13/41 3.1 % 0.56 [ 0.26, 1.21 ]

Holloway 1985 2/15 3/18 0.6 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 4/48 10/47 2.3 % 0.39 [ 0.13, 1.16 ]

Jaspers 1998 12/39 15/40 3.4 % 0.82 [ 0.44, 1.52 ]

Koehler 1990 13/63 6/64 1.4 % 2.20 [ 0.89, 5.43 ]

Limson 1988 2/20 3/20 0.7 % 0.67 [ 0.12, 3.57 ]

Mandell 1987 7/52 9/58 1.9 % 0.87 [ 0.35, 2.16 ]

McCormick 1997 13/65 8/63 1.9 % 1.58 [ 0.70, 3.54 ]

Moreno 1997 1/30 0/28 0.1 % 2.81 [ 0.12, 66.17 ]

Mouton 1990 39/105 43/106 9.8 % 0.92 [ 0.65, 1.29 ]

Mouton 1995 14/111 20/118 4.4 % 0.74 [ 0.40, 1.40 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 2/17 3/18 0.7 % 0.71 [ 0.13, 3.72 ]

Rubinstein 1995 40/267 59/238 14.3 % 0.60 [ 0.42, 0.87 ]

Sieger 1997 30/106 43/105 9.9 % 0.69 [ 0.47, 1.01 ]

Smith 1984 35/96 58/99 13.0 % 0.62 [ 0.46, 0.85 ]

Speich 1998 4/41 7/43 1.6 % 0.60 [ 0.19, 1.90 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Stille 1992 22/186 26/151 6.6 % 0.69 [ 0.41, 1.16 ]

Trujillo 1992 0/16 2/14 0.6 % 0.18 [ 0.01, 3.39 ]

Vergnon 1985 7/16 4/14 1.0 % 1.53 [ 0.56, 4.15 ]

Warren 1983 13/56 12/64 2.6 % 1.24 [ 0.62, 2.49 ]

Subtotal (95% CI) 1845 1767 100.0 % 0.75 [ 0.66, 0.84 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0








Bergeron 1988 2/37 5/30 9.4 % 0.32 [ 0.07, 1.56 ]

Duff 1982 12/31 16/43 22.7 % 1.04 [ 0.58, 1.87 ]

Gerecht 1989 4/24 13/22 23.0 % 0.28 [ 0.11, 0.74 ]

Havig 1973 1/24 2/26 3.3 % 0.54 [ 0.05, 5.60 ]

Muller 1987 16/73 5/33 11.7 % 1.45 [ 0.58, 3.62 ]

Sanfilippo 1989 0/13 1/13 2.5 % 0.33 [ 0.01, 7.50 ]

Thompson 1990 15/49 14/47 24.2 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 1.1 % 2.53 [ 0.12, 51.50 ]

Yellin 1993 1/56 1/34 2.1 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 387 288 100.0 % 0.82 [ 0.59, 1.13 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









6 Different UTI

Landau 1990 4/20 3/20 13.8 % 1.33 [ 0.34, 5.21 ]

Martin 1991 10/52 8/42 40.7 % 1.01 [ 0.44, 2.33 ]

Rasmussen 1986 1/29 1/30 4.5 % 1.03 [ 0.07, 15.77 ]

Verzasconi 1995 6/45 8/42 38.0 % 0.70 [ 0.26, 1.85 ]

Wing 1998 6/117 0/62 3.0 % 6.94 [ 0.40, 121.21 ]

Subtotal (95% CI) 263 196 100.0 % 1.12 [ 0.65, 1.91 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 2.3. Comparison 2 Monotherapy versus combination therapy, Outcome 3 Bacteriological failure -

all.



Outcome: 3 Bacteriological failure - all



1 Same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Coppens 1983 8/22 17/44 15.6 % 0.94 [ 0.48, 1.83 ]

D’Antonio 1992 17/60 7/32 12.5 % 1.30 [ 0.60, 2.79 ]

Klastersky 1973 10/22 3/23 4.0 % 3.48 [ 1.10, 11.01 ]

Korzeniowski 1982 1/33 1/41 1.2 % 1.24 [ 0.08, 19.12 ]

Mergoni 1987 8/26 16/33 19.4 % 0.63 [ 0.32, 1.25 ]

Piccart 1984 5/24 8/19 12.3 % 0.49 [ 0.19, 1.27 ]

Ribera 1996 0/45 0/45 0.0 % 0.0 [ 0.0, 0.0 ]

Sage 1987 13/28 0/17 0.8 % 16.76 [ 1.06, 264.98 ]

Sandberg 1997 9/22 10/28 12.1 % 1.15 [ 0.57, 2.32 ]

Sculier 1982 4/10 0/10 0.7 % 9.00 [ 0.55, 147.95 ]

Sexton 1998 0/23 1/23 2.1 % 0.33 [ 0.01, 7.78 ]

Sukoh 1994 3/11 2/16 2.2 % 2.18 [ 0.43, 10.98 ]

Takamoto 1994 7/31 14/39 17.0 % 0.63 [ 0.29, 1.37 ]

Subtotal (95% CI) 369 382 100.0 % 1.15 [ 0.88, 1.51 ]




2 Different BL

Aguilar 1992 3/19 7/17 2.8 % 0.38 [ 0.12, 1.25 ]

Alvarez-Lerma 2001a 13/51 21/45 8.5 % 0.55 [ 0.31, 0.96 ]

Arich 1987 0/25 1/22 0.6 % 0.29 [ 0.01, 6.89 ]

Bergeron 1988 1/19 5/13 2.3 % 0.14 [ 0.02, 1.04 ]

Finer 1992 7/87 8/59 3.6 % 0.59 [ 0.23, 1.55 ]

Gerecht 1989 4/24 7/22 2.8 % 0.52 [ 0.18, 1.55 ]

Gomez 1990a 9/39 6/39 2.3 % 1.50 [ 0.59, 3.81 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Holloway 1985 2/15 3/18 1.0 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 6/44 7/43 2.7 % 0.84 [ 0.31, 2.29 ]

Jaspers 1998 7/22 7/19 2.9 % 0.86 [ 0.37, 2.02 ]

Koehler 1990 5/43 2/43 0.8 % 2.50 [ 0.51, 12.19 ]

Landau 1990 0/19 0/20 0.0 % 0.0 [ 0.0, 0.0 ]

Limson 1988 3/21 3/20 1.2 % 0.95 [ 0.22, 4.18 ]

Mandell 1987 12/57 14/64 5.0 % 0.96 [ 0.49, 1.91 ]

Moreno 1997 1/20 0/21 0.2 % 3.14 [ 0.14, 72.92 ]

Mouton 1990 32/105 27/106 10.3 % 1.20 [ 0.77, 1.85 ]

Mouton 1995 11/76 11/80 4.1 % 1.05 [ 0.49, 2.28 ]

Naime Libien 1992 0/6 0/1 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 7/17 12/18 4.5 % 0.62 [ 0.32, 1.19 ]

Rubinstein 1995 15/217 15/219 5.7 % 1.01 [ 0.51, 2.01 ]

Sieger 1997 48/106 67/105 25.8 % 0.71 [ 0.55, 0.91 ]

Smith 1984 3/33 8/37 2.9 % 0.42 [ 0.12, 1.45 ]

Speich 1998 0/14 1/14 0.6 % 0.33 [ 0.01, 7.55 ]

Stille 1992 5/152 7/113 3.1 % 0.53 [ 0.17, 1.63 ]

Trujillo 1992 0/16 5/14 2.2 % 0.08 [ 0.00, 1.33 ]

Verzasconi 1995 6/39 0/34 0.2 % 11.38 [ 0.66, 194.78 ]

Warren 1983 8/49 4/50 1.5 % 2.04 [ 0.66, 6.34 ]

Wiecek 1986 1/10 1/10 0.4 % 1.00 [ 0.07, 13.87 ]

Wing 1998 4/100 4/49 2.1 % 0.49 [ 0.13, 1.88 ]

Subtotal (95% CI) 1445 1315 100.0 % 0.81 [ 0.69, 0.94 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Coppens 1983 8/22 17/44 15.6 % 0.94 [ 0.48, 1.83 ]

D’Antonio 1992 17/60 7/32 12.5 % 1.30 [ 0.60, 2.79 ]

Klastersky 1973 10/22 3/23 4.0 % 3.48 [ 1.10, 11.01 ]

Korzeniowski 1982 1/33 1/41 1.2 % 1.24 [ 0.08, 19.12 ]

Mergoni 1987 8/26 16/33 19.4 % 0.63 [ 0.32, 1.25 ]

Piccart 1984 5/24 8/19 12.3 % 0.49 [ 0.19, 1.27 ]

Ribera 1996 0/45 0/45 0.0 % 0.0 [ 0.0, 0.0 ]

Sage 1987 13/28 0/17 0.8 % 16.76 [ 1.06, 264.98 ]

Sandberg 1997 9/22 10/28 12.1 % 1.15 [ 0.57, 2.32 ]

Sculier 1982 4/10 0/10 0.7 % 9.00 [ 0.55, 147.95 ]

Sexton 1998 0/23 1/23 2.1 % 0.33 [ 0.01, 7.78 ]

Sukoh 1994 3/11 2/16 2.2 % 2.18 [ 0.43, 10.98 ]

Takamoto 1994 7/31 14/39 17.0 % 0.63 [ 0.29, 1.37 ]

Subtotal (95% CI) 369 382 100.0 % 1.15 [ 0.88, 1.51 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 Different BL

Aguilar 1992 3/19 7/17 2.8 % 0.38 [ 0.12, 1.25 ]

Alvarez-Lerma 2001a 13/51 21/45 8.5 % 0.55 [ 0.31, 0.96 ]

Arich 1987 0/25 1/22 0.6 % 0.29 [ 0.01, 6.89 ]

Bergeron 1988 1/19 5/13 2.3 % 0.14 [ 0.02, 1.04 ]

Finer 1992 7/87 8/59 3.6 % 0.59 [ 0.23, 1.55 ]

Gerecht 1989 4/24 7/22 2.8 % 0.52 [ 0.18, 1.55 ]

Gomez 1990a 9/39 6/39 2.3 % 1.50 [ 0.59, 3.81 ]

Holloway 1985 2/15 3/18 1.0 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 6/44 7/43 2.7 % 0.84 [ 0.31, 2.29 ]

Jaspers 1998 7/22 7/19 2.9 % 0.86 [ 0.37, 2.02 ]

Koehler 1990 5/43 2/43 0.8 % 2.50 [ 0.51, 12.19 ]

Landau 1990 0/19 0/20 0.0 % 0.0 [ 0.0, 0.0 ]

Limson 1988 3/21 3/20 1.2 % 0.95 [ 0.22, 4.18 ]

Mandell 1987 12/57 14/64 5.0 % 0.96 [ 0.49, 1.91 ]

Moreno 1997 1/20 0/21 0.2 % 3.14 [ 0.14, 72.92 ]

Mouton 1990 32/105 27/106 10.3 % 1.20 [ 0.77, 1.85 ]

Mouton 1995 11/76 11/80 4.1 % 1.05 [ 0.49, 2.28 ]

Naime Libien 1992 0/6 0/1 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 7/17 12/18 4.5 % 0.62 [ 0.32, 1.19 ]

Rubinstein 1995 15/217 15/219 5.7 % 1.01 [ 0.51, 2.01 ]

Sieger 1997 48/106 67/105 25.8 % 0.71 [ 0.55, 0.91 ]

Smith 1984 3/33 8/37 2.9 % 0.42 [ 0.12, 1.45 ]

Speich 1998 0/14 1/14 0.6 % 0.33 [ 0.01, 7.55 ]

Stille 1992 5/152 7/113 3.1 % 0.53 [ 0.17, 1.63 ]

Trujillo 1992 0/16 5/14 2.2 % 0.08 [ 0.00, 1.33 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Verzasconi 1995 6/39 0/34 0.2 % 11.38 [ 0.66, 194.78 ]

Warren 1983 8/49 4/50 1.5 % 2.04 [ 0.66, 6.34 ]

Wiecek 1986 1/10 1/10 0.4 % 1.00 [ 0.07, 13.87 ]

Wing 1998 4/100 4/49 2.1 % 0.49 [ 0.13, 1.88 ]

Subtotal (95% CI) 1445 1315 100.0 % 0.81 [ 0.69, 0.94 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0


Analysis 2.4. Comparison 2 Monotherapy versus combination therapy, Outcome 4 UTI relapse or re-

infection.



Outcome: 4 UTI relapse or re-infection



Gomez 1990a 5/39 4/39 15.9 % 1.25 [ 0.36, 4.31 ]

Martin 1991 3/52 4/42 17.5 % 0.61 [ 0.14, 2.56 ]

Rasmussen 1986 2/12 2/14 7.3 % 1.17 [ 0.19, 7.07 ]

Sandberg 1997 9/26 10/35 33.8 % 1.21 [ 0.58, 2.55 ]

Wiecek 1986 0/10 2/10 9.9 % 0.20 [ 0.01, 3.70 ]

Wing 1998 7/117 3/62 15.6 % 1.24 [ 0.33, 4.61 ]

Total (95% CI) 256 202 100.0 % 1.01 [ 0.61, 1.67 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 2.5. Comparison 2 Monotherapy versus combination therapy, Outcome 5 Clinical failure (Gram

negative infections).



Outcome: 5 Clinical failure (Gram negative infections)



1 Same BL

Carbon 1987 3/25 4/22 8.2 % 0.66 [ 0.17, 2.63 ]

Cometta 1994 8/37 8/44 14.0 % 1.19 [ 0.49, 2.86 ]

D’Antonio 1992 5/26 3/16 7.1 % 1.03 [ 0.28, 3.72 ]

Klastersky 1973 11/22 4/23 7.5 % 2.88 [ 1.07, 7.69 ]

Mergoni 1987 8/24 14/30 23.8 % 0.71 [ 0.36, 1.41 ]

Piccart 1984 5/22 5/26 8.8 % 1.18 [ 0.39, 3.56 ]

Sage 1987 7/16 0/10 1.2 % 9.71 [ 0.61, 153.42 ]

Sculier 1982 3/10 4/10 7.7 % 0.75 [ 0.22, 2.52 ]

Sukoh 1994 3/7 2/10 3.2 % 2.14 [ 0.48, 9.66 ]

Takamoto 1994 10/23 11/29 18.6 % 1.15 [ 0.59, 2.21 ]

Subtotal (95% CI) 212 220 100.0 % 1.23 [ 0.90, 1.68 ]




2 Different BL

Alvarez-Lerma 2001a 11/55 17/51 16.1 % 0.60 [ 0.31, 1.16 ]

Arich 1987 3/25 5/22 4.9 % 0.53 [ 0.14, 1.96 ]

Brown 1984 7/18 9/16 8.7 % 0.69 [ 0.34, 1.42 ]

Duff 1982 4/7 7/17 3.7 % 1.39 [ 0.59, 3.27 ]

Gomez 1990a 6/39 5/39 4.6 % 1.20 [ 0.40, 3.61 ]

Holloway 1985 1/8 1/13 0.7 % 1.63 [ 0.12, 22.50 ]

Koehler 1990 2/16 1/16 0.9 % 2.00 [ 0.20, 19.91 ]

Landau 1990 4/20 3/20 2.7 % 1.33 [ 0.34, 5.21 ]

Limson 1988 2/21 3/20 2.8 % 0.63 [ 0.12, 3.41 ]

Moreno 1997 1/17 0/15 0.5 % 2.67 [ 0.12, 60.93 ]

Mouton 1995 12/58 9/65 7.8 % 1.49 [ 0.68, 3.29 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Rubinstein 1995 12/205 6/172 6.0 % 1.68 [ 0.64, 4.38 ]

Sieger 1997 6/80 16/78 14.8 % 0.37 [ 0.15, 0.89 ]

Smith 1984 3/29 16/40 12.3 % 0.26 [ 0.08, 0.81 ]

Stille 1992 6/61 6/53 5.9 % 0.87 [ 0.30, 2.53 ]

Trujillo 1992 0/5 0/1 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 10/38 8/44 6.8 % 1.45 [ 0.64, 3.29 ]

Wiecek 1986 1/9 1/10 0.9 % 1.11 [ 0.08, 15.28 ]

Subtotal (95% CI) 711 692 100.0 % 0.85 [ 0.66, 1.09 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







1 Same BL

Carbon 1987 3/25 4/22 8.2 % 0.66 [ 0.17, 2.63 ]

Cometta 1994 8/37 8/44 14.0 % 1.19 [ 0.49, 2.86 ]

D’Antonio 1992 5/26 3/16 7.1 % 1.03 [ 0.28, 3.72 ]

Klastersky 1973 11/22 4/23 7.5 % 2.88 [ 1.07, 7.69 ]

Mergoni 1987 8/24 14/30 23.8 % 0.71 [ 0.36, 1.41 ]

Piccart 1984 5/22 5/26 8.8 % 1.18 [ 0.39, 3.56 ]

Sage 1987 7/16 0/10 1.2 % 9.71 [ 0.61, 153.42 ]

Sculier 1982 3/10 4/10 7.7 % 0.75 [ 0.22, 2.52 ]

Sukoh 1994 3/7 2/10 3.2 % 2.14 [ 0.48, 9.66 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Takamoto 1994 10/23 11/29 18.6 % 1.15 [ 0.59, 2.21 ]

Subtotal (95% CI) 212 220 100.0 % 1.23 [ 0.90, 1.68 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







2 Different BL

Alvarez-Lerma 2001a 11/55 17/51 16.1 % 0.60 [ 0.31, 1.16 ]

Arich 1987 3/25 5/22 4.9 % 0.53 [ 0.14, 1.96 ]

Brown 1984 7/18 9/16 8.7 % 0.69 [ 0.34, 1.42 ]

Duff 1982 4/7 7/17 3.7 % 1.39 [ 0.59, 3.27 ]

Gomez 1990a 6/39 5/39 4.6 % 1.20 [ 0.40, 3.61 ]

Holloway 1985 1/8 1/13 0.7 % 1.63 [ 0.12, 22.50 ]

Koehler 1990 2/16 1/16 0.9 % 2.00 [ 0.20, 19.91 ]

Landau 1990 4/20 3/20 2.7 % 1.33 [ 0.34, 5.21 ]

Limson 1988 2/21 3/20 2.8 % 0.63 [ 0.12, 3.41 ]

Moreno 1997 1/17 0/15 0.5 % 2.67 [ 0.12, 60.93 ]

Mouton 1995 12/58 9/65 7.8 % 1.49 [ 0.68, 3.29 ]

Rubinstein 1995 12/205 6/172 6.0 % 1.68 [ 0.64, 4.38 ]

Sieger 1997 6/80 16/78 14.8 % 0.37 [ 0.15, 0.89 ]

Smith 1984 3/29 16/40 12.3 % 0.26 [ 0.08, 0.81 ]

Stille 1992 6/61 6/53 5.9 % 0.87 [ 0.30, 2.53 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Trujillo 1992 0/5 0/1 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 10/38 8/44 6.8 % 1.45 [ 0.64, 3.29 ]

Wiecek 1986 1/9 1/10 0.9 % 1.11 [ 0.08, 15.28 ]

Subtotal (95% CI) 711 692 100.0 % 0.85 [ 0.66, 1.09 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0



negative bacteremia).



Outcome: 6 Clinical failure (Gram negative bacteremia)



1 Same BL

Carbon 1987 3/25 4/22 54.5 % 0.66 [ 0.17, 2.63 ]

Cometta 1994 2/8 2/10 22.8 % 1.25 [ 0.22, 7.02 ]

Klastersky 1973 2/4 1/5 11.4 % 2.50 [ 0.34, 18.63 ]

Piccart 1984 1/12 1/15 11.4 % 1.25 [ 0.09, 17.98 ]

Subtotal (95% CI) 49 52 100.0 % 1.07 [ 0.45, 2.56 ]




2 Different BL

Arich 1987 3/25 5/22 33.1 % 0.53 [ 0.14, 1.96 ]

Gomez 1990a 6/39 5/39 31.1 % 1.20 [ 0.40, 3.61 ]

Holloway 1985 1/8 1/13 4.7 % 1.63 [ 0.12, 22.50 ]

Limson 1988 1/10 2/11 11.9 % 0.55 [ 0.06, 5.18 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Mandell 1987 0/4 1/2 11.7 % 0.20 [ 0.01, 3.50 ]

Mouton 1995 0/9 0/13 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 0/1 1/2 7.5 % 0.50 [ 0.04, 7.10 ]

Subtotal (95% CI) 96 102 100.0 % 0.75 [ 0.38, 1.48 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







1 Same BL

Carbon 1987 3/25 4/22 54.5 % 0.66 [ 0.17, 2.63 ]

Cometta 1994 2/8 2/10 22.8 % 1.25 [ 0.22, 7.02 ]

Klastersky 1973 2/4 1/5 11.4 % 2.50 [ 0.34, 18.63 ]

Piccart 1984 1/12 1/15 11.4 % 1.25 [ 0.09, 17.98 ]

Subtotal (95% CI) 49 52 100.0 % 1.07 [ 0.45, 2.56 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 Different BL

Arich 1987 3/25 5/22 33.1 % 0.53 [ 0.14, 1.96 ]

Gomez 1990a 6/39 5/39 31.1 % 1.20 [ 0.40, 3.61 ]

Holloway 1985 1/8 1/13 4.7 % 1.63 [ 0.12, 22.50 ]

Limson 1988 1/10 2/11 11.9 % 0.55 [ 0.06, 5.18 ]

Mandell 1987 0/4 1/2 11.7 % 0.20 [ 0.01, 3.50 ]

Mouton 1995 0/9 0/13 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 0/1 1/2 7.5 % 0.50 [ 0.04, 7.10 ]

Subtotal (95% CI) 96 102 100.0 % 0.75 [ 0.38, 1.48 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 2.7. Comparison 2 Monotherapy versus combination therapy, Outcome 7 Clinical failure

(Pseudomonas aeruginosa infections).



Outcome: 7 Clinical failure (Pseudomonas aeruginosa infections)



1 Same BL

Cometta 1994 4/9 6/12 19.6 % 0.89 [ 0.35, 2.24 ]

D’Antonio 1992 2/10 1/8 4.2 % 1.60 [ 0.17, 14.63 ]

Mergoni 1987 8/16 10/19 34.9 % 0.95 [ 0.50, 1.82 ]

Sculier 1982 1/4 2/5 6.8 % 0.63 [ 0.08, 4.66 ]

Sukoh 1994 3/5 2/6 6.9 % 1.80 [ 0.47, 6.87 ]

Takamoto 1994 6/12 9/18 27.5 % 1.00 [ 0.48, 2.08 ]

Subtotal (95% CI) 56 68 100.0 % 1.02 [ 0.68, 1.51 ]




2 Different BL

Alvarez-Lerma 2001a 6/14 6/13 25.4 % 0.93 [ 0.40, 2.16 ]

Brown 1984 4/4 3/3 0.0 % 0.0 [ 0.0, 0.0 ]

Iakovlev 1998 2/15 2/10 9.8 % 0.67 [ 0.11, 3.99 ]

Klastersky 1973 6/12 1/10 4.4 % 5.00 [ 0.72, 34.92 ]

Koehler 1990 0/6 0/4 0.0 % 0.0 [ 0.0, 0.0 ]

Limson 1988 1/7 1/7 4.1 % 1.00 [ 0.08, 13.02 ]

Moreno 1997 0/4 0/8 0.0 % 0.0 [ 0.0, 0.0 ]

Mouton 1995 6/13 1/9 4.8 % 4.15 [ 0.60, 28.87 ]

Rapp 1984 1/5 1/3 5.1 % 0.60 [ 0.06, 6.44 ]

Rubinstein 1995 8/56 4/50 17.2 % 1.79 [ 0.57, 5.57 ]

Sieger 1997 3/15 4/12 18.1 % 0.60 [ 0.17, 2.18 ]

Stille 1992 1/15 2/7 11.1 % 0.23 [ 0.03, 2.16 ]

Subtotal (95% CI) 166 136 100.0 % 1.24 [ 0.77, 1.98 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Same BL

Cometta 1994 4/9 6/12 19.6 % 0.89 [ 0.35, 2.24 ]

D’Antonio 1992 2/10 1/8 4.2 % 1.60 [ 0.17, 14.63 ]

Mergoni 1987 8/16 10/19 34.9 % 0.95 [ 0.50, 1.82 ]

Sculier 1982 1/4 2/5 6.8 % 0.63 [ 0.08, 4.66 ]

Sukoh 1994 3/5 2/6 6.9 % 1.80 [ 0.47, 6.87 ]

Takamoto 1994 6/12 9/18 27.5 % 1.00 [ 0.48, 2.08 ]

Subtotal (95% CI) 56 68 100.0 % 1.02 [ 0.68, 1.51 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 Different BL

Alvarez-Lerma 2001a 6/14 6/13 25.4 % 0.93 [ 0.40, 2.16 ]

Brown 1984 4/4 3/3 0.0 % 0.0 [ 0.0, 0.0 ]

Iakovlev 1998 2/15 2/10 9.8 % 0.67 [ 0.11, 3.99 ]

Klastersky 1973 6/12 1/10 4.4 % 5.00 [ 0.72, 34.92 ]

Koehler 1990 0/6 0/4 0.0 % 0.0 [ 0.0, 0.0 ]

Limson 1988 1/7 1/7 4.1 % 1.00 [ 0.08, 13.02 ]

Moreno 1997 0/4 0/8 0.0 % 0.0 [ 0.0, 0.0 ]

Mouton 1995 6/13 1/9 4.8 % 4.15 [ 0.60, 28.87 ]

Rapp 1984 1/5 1/3 5.1 % 0.60 [ 0.06, 6.44 ]

Rubinstein 1995 8/56 4/50 17.2 % 1.79 [ 0.57, 5.57 ]

Sieger 1997 3/15 4/12 18.1 % 0.60 [ 0.17, 2.18 ]

Stille 1992 1/15 2/7 11.1 % 0.23 [ 0.03, 2.16 ]

Subtotal (95% CI) 166 136 100.0 % 1.24 [ 0.77, 1.98 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 2.8. Comparison 2 Monotherapy versus combination therapy, Outcome 8 Clinical failure

(bacteremia).



Outcome: 8 Clinical failure (bacteremia)



1 Same BL

Carbon 1987 3/25 4/22 31.4 % 0.66 [ 0.17, 2.63 ]

D’Antonio 1992 7/20 4/14 34.7 % 1.23 [ 0.44, 3.40 ]

Klastersky 1973 2/4 1/5 6.5 % 2.50 [ 0.34, 18.63 ]

Piccart 1984 2/12 4/18 23.6 % 0.75 [ 0.16, 3.47 ]

Sage 1987 6/11 0/10 3.8 % 11.92 [ 0.76, 187.84 ]

Subtotal (95% CI) 72 69 100.0 % 1.43 [ 0.77, 2.66 ]




2 Different BL

Arich 1987 3/25 5/22 7.5 % 0.53 [ 0.14, 1.96 ]

Bergeron 1988 0/8 2/5 4.2 % 0.13 [ 0.01, 2.32 ]

Cone 1985 1/8 2/8 2.8 % 0.50 [ 0.06, 4.47 ]

Felisart 1985 4/13 10/13 14.1 % 0.40 [ 0.17, 0.95 ]

Finer 1992 3/36 4/21 7.1 % 0.44 [ 0.11, 1.77 ]

Gomez 1990a 6/39 5/39 7.0 % 1.20 [ 0.40, 3.61 ]

Holloway 1985 2/11 3/16 3.4 % 0.97 [ 0.19, 4.88 ]

Limson 1988 1/10 2/11 2.7 % 0.55 [ 0.06, 5.18 ]

Mandell 1987 0/4 1/2 2.6 % 0.20 [ 0.01, 3.50 ]

Martin 1991 1/10 2/12 2.6 % 0.60 [ 0.06, 5.69 ]

McCormick 1997 1/4 2/12 1.4 % 1.50 [ 0.18, 12.46 ]

Mouton 1990 6/26 5/25 7.2 % 1.15 [ 0.40, 3.30 ]

Mouton 1995 2/12 1/17 1.2 % 2.83 [ 0.29, 27.81 ]

Rapp 1984 0/2 1/4 1.6 % 0.56 [ 0.03, 9.73 ]

Rubinstein 1995 5/67 15/69 20.8 % 0.34 [ 0.13, 0.89 ]

Stille 1992 0/13 2/18 3.0 % 0.27 [ 0.01, 5.22 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Warren 1983 9/23 7/19 10.8 % 1.06 [ 0.49, 2.31 ]

Subtotal (95% CI) 311 313 100.0 % 0.64 [ 0.46, 0.89 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







1 Same BL

Carbon 1987 3/25 4/22 31.4 % 0.66 [ 0.17, 2.63 ]

D’Antonio 1992 7/20 4/14 34.7 % 1.23 [ 0.44, 3.40 ]

Klastersky 1973 2/4 1/5 6.5 % 2.50 [ 0.34, 18.63 ]

Piccart 1984 2/12 4/18 23.6 % 0.75 [ 0.16, 3.47 ]

Sage 1987 6/11 0/10 3.8 % 11.92 [ 0.76, 187.84 ]

Subtotal (95% CI) 72 69 100.0 % 1.43 [ 0.77, 2.66 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 Different BL

Arich 1987 3/25 5/22 7.5 % 0.53 [ 0.14, 1.96 ]

Bergeron 1988 0/8 2/5 4.2 % 0.13 [ 0.01, 2.32 ]

Cone 1985 1/8 2/8 2.8 % 0.50 [ 0.06, 4.47 ]

Felisart 1985 4/13 10/13 14.1 % 0.40 [ 0.17, 0.95 ]

Finer 1992 3/36 4/21 7.1 % 0.44 [ 0.11, 1.77 ]

Gomez 1990a 6/39 5/39 7.0 % 1.20 [ 0.40, 3.61 ]

Holloway 1985 2/11 3/16 3.4 % 0.97 [ 0.19, 4.88 ]

Limson 1988 1/10 2/11 2.7 % 0.55 [ 0.06, 5.18 ]

Mandell 1987 0/4 1/2 2.6 % 0.20 [ 0.01, 3.50 ]

Martin 1991 1/10 2/12 2.6 % 0.60 [ 0.06, 5.69 ]

McCormick 1997 1/4 2/12 1.4 % 1.50 [ 0.18, 12.46 ]

Mouton 1990 6/26 5/25 7.2 % 1.15 [ 0.40, 3.30 ]

Mouton 1995 2/12 1/17 1.2 % 2.83 [ 0.29, 27.81 ]

Rapp 1984 0/2 1/4 1.6 % 0.56 [ 0.03, 9.73 ]

Rubinstein 1995 5/67 15/69 20.8 % 0.34 [ 0.13, 0.89 ]

Stille 1992 0/13 2/18 3.0 % 0.27 [ 0.01, 5.22 ]

Warren 1983 9/23 7/19 10.8 % 1.06 [ 0.49, 2.31 ]

Subtotal (95% CI) 311 313 100.0 % 0.64 [ 0.46, 0.89 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 2.9. Comparison 2 Monotherapy versus combination therapy, Outcome 9 Clinical failure (urinary

tract infections).



Outcome: 9 Clinical failure (urinary tract infections)



1 Same BL

D’Antonio 1992 4/7 1/4 10.6 % 2.29 [ 0.37, 14.03 ]

Klastersky 1973 2/4 1/2 11.1 % 1.00 [ 0.18, 5.46 ]

Sage 1987 0/3 0/3 0.0 % 0.0 [ 0.0, 0.0 ]

Sandberg 1997 8/26 11/35 78.3 % 0.98 [ 0.46, 2.09 ]

Subtotal (95% CI) 40 44 100.0 % 1.12 [ 0.59, 2.13 ]




2 Different BL

Felisart 1985 2/4 1/1 6.7 % 0.67 [ 0.20, 2.18 ]

Iakovlev 1998 3/10 2/10 6.3 % 1.50 [ 0.32, 7.14 ]

Jaspers 1998 3/6 2/5 6.8 % 1.25 [ 0.33, 4.77 ]

Landau 1990 4/20 3/20 9.4 % 1.33 [ 0.34, 5.21 ]

Martin 1991 10/50 8/42 27.3 % 1.05 [ 0.46, 2.42 ]

Moreno 1997 0/16 0/17 0.0 % 0.0 [ 0.0, 0.0 ]

Mouton 1995 2/16 0/25 1.2 % 7.65 [ 0.39, 149.68 ]

Rasmussen 1986 1/29 1/30 3.1 % 1.03 [ 0.07, 15.77 ]

Rubinstein 1995 1/38 1/41 3.0 % 1.08 [ 0.07, 16.65 ]

Smith 1984 2/17 2/25 5.1 % 1.47 [ 0.23, 9.45 ]

Verzasconi 1995 6/45 8/42 25.9 % 0.70 [ 0.26, 1.85 ]

Wiecek 1986 1/10 1/10 3.1 % 1.00 [ 0.07, 13.87 ]

Wing 1998 6/117 0/62 2.0 % 6.94 [ 0.40, 121.21 ]

Subtotal (95% CI) 378 330 100.0 % 1.22 [ 0.80, 1.87 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Same BL

D’Antonio 1992 4/7 1/4 10.6 % 2.29 [ 0.37, 14.03 ]

Klastersky 1973 2/4 1/2 11.1 % 1.00 [ 0.18, 5.46 ]

Sage 1987 0/3 0/3 0.0 % 0.0 [ 0.0, 0.0 ]

Sandberg 1997 8/26 11/35 78.3 % 0.98 [ 0.46, 2.09 ]

Subtotal (95% CI) 40 44 100.0 % 1.12 [ 0.59, 2.13 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







2 Different BL

Felisart 1985 2/4 1/1 6.7 % 0.67 [ 0.20, 2.18 ]

Iakovlev 1998 3/10 2/10 6.3 % 1.50 [ 0.32, 7.14 ]

Jaspers 1998 3/6 2/5 6.8 % 1.25 [ 0.33, 4.77 ]

Landau 1990 4/20 3/20 9.4 % 1.33 [ 0.34, 5.21 ]

Martin 1991 10/50 8/42 27.3 % 1.05 [ 0.46, 2.42 ]

Moreno 1997 0/16 0/17 0.0 % 0.0 [ 0.0, 0.0 ]

Mouton 1995 2/16 0/25 1.2 % 7.65 [ 0.39, 149.68 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Rasmussen 1986 1/29 1/30 3.1 % 1.03 [ 0.07, 15.77 ]

Rubinstein 1995 1/38 1/41 3.0 % 1.08 [ 0.07, 16.65 ]

Smith 1984 2/17 2/25 5.1 % 1.47 [ 0.23, 9.45 ]

Verzasconi 1995 6/45 8/42 25.9 % 0.70 [ 0.26, 1.85 ]

Wiecek 1986 1/10 1/10 3.1 % 1.00 [ 0.07, 13.87 ]

Wing 1998 6/117 0/62 2.0 % 6.94 [ 0.40, 121.21 ]

Subtotal (95% CI) 378 330 100.0 % 1.22 [ 0.80, 1.87 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0


Analysis 2.10. Comparison 2 Monotherapy versus combination therapy, Outcome 10 Clinical failure (non

urinary tract infections).



Outcome: 10 Clinical failure (non urinary tract infections)



1 Same BL

Cardozo 2001 9/56 9/48 6.5 % 0.86 [ 0.37, 1.98 ]

Cometta 1994 24/130 17/125 11.7 % 1.36 [ 0.77, 2.40 ]

D’Antonio 1992 35/136 32/136 21.6 % 1.09 [ 0.72, 1.66 ]

Dupont 2000 55/99 55/105 36.1 % 1.06 [ 0.82, 1.37 ]

Klastersky 1973 9/21 3/21 2.0 % 3.00 [ 0.94, 9.55 ]

Kljucar 1990 12/44 9/45 6.0 % 1.36 [ 0.64, 2.91 ]

Sage 1987 10/23 2/19 1.5 % 4.13 [ 1.03, 16.60 ]

Sculier 1982 3/10 4/10 2.7 % 0.75 [ 0.22, 2.52 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Sukoh 1994 6/30 5/33 3.2 % 1.32 [ 0.45, 3.88 ]

Takamoto 1994 12/77 13/80 8.6 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 626 622 100.0 % 1.18 [ 0.99, 1.42 ]




2 Different BL

Alvarez-Lerma 2001a 22/69 32/71 9.2 % 0.71 [ 0.46, 1.09 ]

Bergeron 1988 2/37 5/30 1.6 % 0.32 [ 0.07, 1.56 ]

Brown 1984 7/18 9/16 2.8 % 0.69 [ 0.34, 1.42 ]

Cone 1985 1/13 2/11 0.6 % 0.42 [ 0.04, 4.06 ]

Duff 1982 12/31 16/43 3.9 % 1.04 [ 0.58, 1.87 ]

Felisart 1985 7/33 17/35 4.8 % 0.44 [ 0.21, 0.92 ]

Finer 1992 14/98 11/81 3.5 % 1.05 [ 0.51, 2.19 ]

Gerecht 1989 4/24 13/22 4.0 % 0.28 [ 0.11, 0.74 ]

Havig 1973 1/24 2/26 0.6 % 0.54 [ 0.05, 5.60 ]

Holloway 1985 0/4 0/2 0.0 % 0.0 [ 0.0, 0.0 ]

Iakovlev 1998 1/38 6/37 1.8 % 0.16 [ 0.02, 1.28 ]

Jaspers 1998 8/30 7/25 2.2 % 0.95 [ 0.40, 2.26 ]

Koehler 1990 13/73 6/71 1.8 % 2.11 [ 0.85, 5.24 ]

Limson 1988 0/6 1/8 0.4 % 0.43 [ 0.02, 9.00 ]

Mandell 1987 7/52 9/58 2.5 % 0.87 [ 0.35, 2.16 ]

McCormick 1997 6/18 4/16 1.2 % 1.33 [ 0.46, 3.89 ]

Moreno 1997 0/3 0/2 0.0 % 0.0 [ 0.0, 0.0 ]

Mouton 1990 6/44 11/45 3.2 % 0.56 [ 0.23, 1.38 ]

Mouton 1995 12/95 20/93 5.9 % 0.59 [ 0.30, 1.13 ]

Muller 1987 13/73 4/33 1.6 % 1.47 [ 0.52, 4.17 ]

Rapp 1984 2/17 3/18 0.9 % 0.71 [ 0.13, 3.72 ]

Rubinstein 1995 33/223 50/189 15.8 % 0.56 [ 0.38, 0.83 ]

Sanfilippo 1989 0/13 1/13 0.4 % 0.33 [ 0.01, 7.50 ]

Sieger 1997 30/104 43/107 12.4 % 0.72 [ 0.49, 1.05 ]

Smith 1984 10/34 18/26 6.0 % 0.42 [ 0.24, 0.76 ]

Speich 1998 4/44 7/45 2.0 % 0.58 [ 0.18, 1.86 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Stille 1992 13/144 17/124 5.3 % 0.66 [ 0.33, 1.30 ]

Thompson 1990 12/49 12/47 3.6 % 0.96 [ 0.48, 1.92 ]

Thompson 1993 2/80 0/40 0.2 % 2.53 [ 0.12, 51.50 ]

Vergnon 1985 7/16 4/14 1.2 % 1.53 [ 0.56, 4.15 ]

Yellin 1993 1/56 1/34 0.4 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 1563 1382 100.0 % 0.70 [ 0.61, 0.81 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







1 Same BL

Cardozo 2001 9/56 9/48 6.5 % 0.86 [ 0.37, 1.98 ]

Cometta 1994 24/130 17/125 11.7 % 1.36 [ 0.77, 2.40 ]

D’Antonio 1992 35/136 32/136 21.6 % 1.09 [ 0.72, 1.66 ]

Dupont 2000 55/99 55/105 36.1 % 1.06 [ 0.82, 1.37 ]

Klastersky 1973 9/21 3/21 2.0 % 3.00 [ 0.94, 9.55 ]

Kljucar 1990 12/44 9/45 6.0 % 1.36 [ 0.64, 2.91 ]

Sage 1987 10/23 2/19 1.5 % 4.13 [ 1.03, 16.60 ]

Sculier 1982 3/10 4/10 2.7 % 0.75 [ 0.22, 2.52 ]

Sukoh 1994 6/30 5/33 3.2 % 1.32 [ 0.45, 3.88 ]

Takamoto 1994 12/77 13/80 8.6 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 626 622 100.0 % 1.18 [ 0.99, 1.42 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )








0.1 0.2 0.5 1.0 2.0 5.0 10.0







2 Different BL

Alvarez-Lerma 2001a 22/69 32/71 9.2 % 0.71 [ 0.46, 1.09 ]

Bergeron 1988 2/37 5/30 1.6 % 0.32 [ 0.07, 1.56 ]

Brown 1984 7/18 9/16 2.8 % 0.69 [ 0.34, 1.42 ]

Cone 1985 1/13 2/11 0.6 % 0.42 [ 0.04, 4.06 ]

Duff 1982 12/31 16/43 3.9 % 1.04 [ 0.58, 1.87 ]

Felisart 1985 7/33 17/35 4.8 % 0.44 [ 0.21, 0.92 ]

Finer 1992 14/98 11/81 3.5 % 1.05 [ 0.51, 2.19 ]

Gerecht 1989 4/24 13/22 4.0 % 0.28 [ 0.11, 0.74 ]

Havig 1973 1/24 2/26 0.6 % 0.54 [ 0.05, 5.60 ]

Holloway 1985 0/4 0/2 0.0 % 0.0 [ 0.0, 0.0 ]

Iakovlev 1998 1/38 6/37 1.8 % 0.16 [ 0.02, 1.28 ]

Jaspers 1998 8/30 7/25 2.2 % 0.95 [ 0.40, 2.26 ]

Koehler 1990 13/73 6/71 1.8 % 2.11 [ 0.85, 5.24 ]

Limson 1988 0/6 1/8 0.4 % 0.43 [ 0.02, 9.00 ]

Mandell 1987 7/52 9/58 2.5 % 0.87 [ 0.35, 2.16 ]

McCormick 1997 6/18 4/16 1.2 % 1.33 [ 0.46, 3.89 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Moreno 1997 0/3 0/2 0.0 % 0.0 [ 0.0, 0.0 ]

Mouton 1990 6/44 11/45 3.2 % 0.56 [ 0.23, 1.38 ]

Mouton 1995 12/95 20/93 5.9 % 0.59 [ 0.30, 1.13 ]

Muller 1987 13/73 4/33 1.6 % 1.47 [ 0.52, 4.17 ]

Rapp 1984 2/17 3/18 0.9 % 0.71 [ 0.13, 3.72 ]

Rubinstein 1995 33/223 50/189 15.8 % 0.56 [ 0.38, 0.83 ]

Sanfilippo 1989 0/13 1/13 0.4 % 0.33 [ 0.01, 7.50 ]

Sieger 1997 30/104 43/107 12.4 % 0.72 [ 0.49, 1.05 ]

Smith 1984 10/34 18/26 6.0 % 0.42 [ 0.24, 0.76 ]

Speich 1998 4/44 7/45 2.0 % 0.58 [ 0.18, 1.86 ]

Stille 1992 13/144 17/124 5.3 % 0.66 [ 0.33, 1.30 ]

Thompson 1990 12/49 12/47 3.6 % 0.96 [ 0.48, 1.92 ]

Thompson 1993 2/80 0/40 0.2 % 2.53 [ 0.12, 51.50 ]

Vergnon 1985 7/16 4/14 1.2 % 1.53 [ 0.56, 4.15 ]

Yellin 1993 1/56 1/34 0.4 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 1563 1382 100.0 % 0.70 [ 0.61, 0.81 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 3.1. Comparison 3 Monotherapy versus combination therapy, Outcome 1 Bacterial superinfections.



Outcome: 1 Bacterial superinfections



Abrams 1979 0/1 0/1 0.0 % 0.0 [ 0.0, 0.0 ]

Alvarez-Lerma 2001a 5/57 3/59 2.8 % 1.73 [ 0.43, 6.89 ]

Arich 1987 1/25 0/22 0.5 % 2.65 [ 0.11, 62.00 ]

Brown 1984 2/18 0/16 0.5 % 4.47 [ 0.23, 86.77 ]

Carbon 1987 5/25 3/22 3.0 % 1.47 [ 0.40, 5.44 ]

Cometta 1994 5/142 5/138 4.8 % 0.97 [ 0.29, 3.28 ]

Cone 1985 3/21 0/19 0.5 % 6.36 [ 0.35, 115.73 ]

Coppens 1983 3/14 3/26 2.0 % 1.86 [ 0.43, 8.02 ]

D’Antonio 1992 9/143 17/140 16.3 % 0.52 [ 0.24, 1.12 ]

Felisart 1985 0/37 5/36 5.3 % 0.09 [ 0.01, 1.54 ]

Finer 1992 3/87 2/59 2.3 % 1.02 [ 0.18, 5.90 ]

Gerecht 1989 0/24 2/22 2.5 % 0.18 [ 0.01, 3.63 ]

Hoepelman 1988 0/13 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Jaspers 1998 2/39 1/40 0.9 % 2.05 [ 0.19, 21.72 ]

Klastersky 1973 2/22 1/23 0.9 % 2.09 [ 0.20, 21.45 ]

Mandell 1987 2/52 5/58 4.5 % 0.45 [ 0.09, 2.20 ]

Mouton 1990 5/105 8/106 7.6 % 0.63 [ 0.21, 1.87 ]

Mouton 1995 0/76 3/80 3.2 % 0.15 [ 0.01, 2.86 ]

Piccart 1984 2/42 3/43 2.8 % 0.68 [ 0.12, 3.88 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Rubinstein 1995 14/306 20/274 20.0 % 0.63 [ 0.32, 1.22 ]

Sage 1987 1/30 3/24 3.2 % 0.27 [ 0.03, 2.40 ]

Sieger 1997 3/63 2/58 2.0 % 1.38 [ 0.24, 7.97 ]

Smith 1984 0/89 4/92 4.2 % 0.11 [ 0.01, 2.10 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Verzasconi 1995 2/39 0/34 0.5 % 4.38 [ 0.22, 88.08 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Warren 1983 8/56 11/64 9.7 % 0.83 [ 0.36, 1.92 ]

Total (95% CI) 1571 1514 100.0 % 0.76 [ 0.57, 1.01 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0


Analysis 3.2. Comparison 3 Monotherapy versus combination therapy, Outcome 2 Fungal superinfections.



Outcome: 2 Fungal superinfections



Brown 1984 0/18 1/16 7.5 % 0.30 [ 0.01, 6.84 ]

Cometta 1994 3/142 6/138 28.9 % 0.49 [ 0.12, 1.90 ]

Cone 1985 0/21 0/19 0.0 % 0.0 [ 0.0, 0.0 ]

D’Antonio 1992 3/143 2/140 9.6 % 1.47 [ 0.25, 8.66 ]

Gerecht 1989 0/24 1/22 7.4 % 0.31 [ 0.01, 7.16 ]

Hoepelman 1988 0/13 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Limson 1988 1/20 0/20 2.4 % 3.00 [ 0.13, 69.52 ]

Mandell 1987 2/52 1/58 4.5 % 2.23 [ 0.21, 23.89 ]

Piccart 1984 1/42 3/43 14.1 % 0.34 [ 0.04, 3.15 ]

Sage 1987 1/30 4/24 21.1 % 0.20 [ 0.02, 1.67 ]

Warren 1983 4/56 1/64 4.4 % 4.57 [ 0.53, 39.71 ]

Total (95% CI) 561 558 100.0 % 0.79 [ 0.42, 1.48 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 3.3. Comparison 3 Monotherapy versus combination therapy, Outcome 3 Bacterial colonization.



Outcome: 3 Bacterial colonization



Bergeron 1988 2/36 2/28 2.3 % 0.78 [ 0.12, 5.18 ]

Cometta 1994 8/142 13/138 13.8 % 0.60 [ 0.26, 1.40 ]

Coppens 1983 9/14 8/26 5.8 % 2.09 [ 1.04, 4.19 ]

D’Antonio 1992 10/143 4/140 4.2 % 2.45 [ 0.79, 7.62 ]

Finer 1992 2/87 2/59 2.5 % 0.68 [ 0.10, 4.68 ]

Gomez 1990a 2/39 0/39 0.5 % 5.00 [ 0.25, 100.89 ]

Klastersky 1973 5/22 5/23 5.1 % 1.05 [ 0.35, 3.12 ]

Koehler 1990 1/43 4/43 4.2 % 0.25 [ 0.03, 2.15 ]

Mandell 1987 13/52 20/58 19.7 % 0.73 [ 0.40, 1.31 ]

Mouton 1990 6/105 7/106 7.3 % 0.87 [ 0.30, 2.49 ]

Sandberg 1997 6/26 12/35 10.7 % 0.67 [ 0.29, 1.56 ]

Sculier 1982 4/10 8/10 8.4 % 0.50 [ 0.22, 1.14 ]

Smith 1984 8/89 14/92 14.4 % 0.59 [ 0.26, 1.34 ]

Vergnon 1985 1/16 1/14 1.1 % 0.88 [ 0.06, 12.73 ]

Total (95% CI) 824 811 100.0 % 0.85 [ 0.65, 1.10 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 3.4. Comparison 3 Monotherapy versus combination therapy, Outcome 4 Fungal colonization.



Outcome: 4 Fungal colonization



D’Antonio 1992 2/143 1/140 3.3 % 1.96 [ 0.18, 21.35 ]

Gomez 1990a 2/39 0/39 1.6 % 5.00 [ 0.25, 100.89 ]

Hoepelman 1988 13/13 6/14 20.3 % 2.23 [ 1.24, 4.00 ]

Koehler 1990 4/43 1/43 3.2 % 4.00 [ 0.47, 34.34 ]

Mandell 1987 5/52 5/58 15.3 % 1.12 [ 0.34, 3.64 ]

Mouton 1990 1/105 2/106 6.4 % 0.50 [ 0.05, 5.48 ]

Stille 1992 16/186 14/151 49.9 % 0.93 [ 0.47, 1.84 ]

Total (95% CI) 581 551 100.0 % 1.39 [ 0.93, 2.09 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 3.5. Comparison 3 Monotherapy versus combination therapy, Outcome 5 Bacterial colonization -

surveillance cultures.



Outcome: 5 Bacterial colonization - surveillance cultures



Cometta 1994 21/31 33/40 37.2 % 0.82 [ 0.62, 1.09 ]

D’Antonio 1992 10/143 4/140 5.2 % 2.45 [ 0.79, 7.62 ]

Koehler 1990 1/43 4/43 5.2 % 0.25 [ 0.03, 2.15 ]

Mandell 1987 13/52 20/58 24.4 % 0.73 [ 0.40, 1.31 ]

Sculier 1982 4/10 8/10 10.3 % 0.50 [ 0.22, 1.14 ]

Smith 1984 8/89 14/92 17.8 % 0.59 [ 0.26, 1.34 ]

Total (95% CI) 368 383 100.0 % 0.78 [ 0.60, 1.01 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 3.6. Comparison 3 Monotherapy versus combination therapy, Outcome 6 Bacterial resistance

development.



Outcome: 6 Bacterial resistance development



Carbon 1987 0/25 0/22 0.0 % 0.0 [ 0.0, 0.0 ]

Cometta 1994 6/142 9/138 29.1 % 0.65 [ 0.24, 1.77 ]

Hoepelman 1988 2/10 1/6 4.0 % 1.20 [ 0.14, 10.58 ]

Iakovlev 1998 2/44 2/43 6.5 % 0.98 [ 0.14, 6.63 ]

Klastersky 1973 2/22 0/23 1.6 % 5.22 [ 0.26, 102.93 ]

Mandell 1987 2/58 0/58 1.6 % 5.00 [ 0.25, 101.93 ]

Rubinstein 1995 12/261 14/230 47.5 % 0.76 [ 0.36, 1.60 ]

Sculier 1982 1/10 2/10 6.4 % 0.50 [ 0.05, 4.67 ]

Stille 1992 1/144 1/124 3.4 % 0.86 [ 0.05, 13.62 ]

Total (95% CI) 716 654 100.0 % 0.88 [ 0.54, 1.45 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 4.1. Comparison 4 Monotherapy versus combination therapy, Outcome 1 Any adverse event.



Outcome: 1 Any adverse event



Abrams 1979 1/12 3/12 0.5 % 0.33 [ 0.04, 2.77 ]

Alvarez-Lerma 2001a 31/69 35/71 5.7 % 0.91 [ 0.64, 1.30 ]

Arich 1987 1/25 3/22 0.5 % 0.29 [ 0.03, 2.62 ]

Bergeron 1988 7/36 5/28 0.9 % 1.09 [ 0.39, 3.07 ]

Biglino 1991 0/12 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Brown 1984 5/18 2/16 0.4 % 2.22 [ 0.50, 9.91 ]

Cometta 1994 41/158 64/155 10.7 % 0.63 [ 0.45, 0.87 ]

D’Antonio 1992 6/143 24/140 4.0 % 0.24 [ 0.10, 0.58 ]

Duff 1982 1/31 0/43 0.1 % 4.13 [ 0.17, 98.01 ]

Dupont 2000 58/111 66/116 10.7 % 0.92 [ 0.72, 1.17 ]

Felisart 1985 6/37 7/36 1.2 % 0.83 [ 0.31, 2.24 ]

Finer 1992 56/249 33/222 5.8 % 1.51 [ 1.02, 2.24 ]

Gerecht 1989 2/24 8/22 1.4 % 0.23 [ 0.05, 0.96 ]

Gomez 1990a 4/39 8/39 1.3 % 0.50 [ 0.16, 1.53 ]

Iakovlev 1998 4/48 5/47 0.8 % 0.78 [ 0.22, 2.74 ]

Jaspers 1998 19/39 18/40 2.9 % 1.08 [ 0.68, 1.73 ]

Limson 1988 1/20 2/20 0.3 % 0.50 [ 0.05, 5.08 ]

Martin 1991 9/52 11/42 2.0 % 0.66 [ 0.30, 1.44 ]

Mergoni 1987 4/20 5/22 0.8 % 0.88 [ 0.27, 2.83 ]

Mouton 1990 41/105 27/106 4.4 % 1.53 [ 1.02, 2.30 ]

Mouton 1995 49/116 45/121 7.3 % 1.14 [ 0.83, 1.56 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rasmussen 1986 3/29 2/30 0.3 % 1.55 [ 0.28, 8.62 ]

Rubinstein 1995 46/306 44/274 7.7 % 0.94 [ 0.64, 1.37 ]

Sage 1987 2/30 4/24 0.7 % 0.40 [ 0.08, 2.00 ]

Sandberg 1997 10/36 10/33 1.7 % 0.92 [ 0.44, 1.92 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Sculier 1982 1/10 1/10 0.2 % 1.00 [ 0.07, 13.87 ]

Sexton 1998 5/26 3/25 0.5 % 1.60 [ 0.43, 6.01 ]

Sieger 1997 23/104 20/107 3.3 % 1.18 [ 0.69, 2.02 ]

Speich 1998 1/44 3/45 0.5 % 0.34 [ 0.04, 3.15 ]

Stille 1992 62/186 54/151 9.9 % 0.93 [ 0.69, 1.25 ]

Sukoh 1994 6/30 4/33 0.6 % 1.65 [ 0.51, 5.29 ]

Takamoto 1994 11/83 12/88 1.9 % 0.97 [ 0.45, 2.08 ]

Thompson 1990 5/49 6/47 1.0 % 0.80 [ 0.26, 2.44 ]

Thompson 1993 7/80 4/70 0.7 % 1.53 [ 0.47, 5.01 ]

Trujillo 1992 1/16 5/14 0.9 % 0.18 [ 0.02, 1.32 ]

Vergnon 1985 1/16 2/14 0.4 % 0.44 [ 0.04, 4.32 ]

Warren 1983 18/56 25/64 3.9 % 0.82 [ 0.50, 1.34 ]

Yellin 1993 21/56 20/35 4.1 % 0.66 [ 0.42, 1.02 ]

Total (95% CI) 2536 2409 100.0 % 0.92 [ 0.83, 1.01 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 4.2. Comparison 4 Monotherapy versus combination therapy, Outcome 2 Adverse events requiring

treatment discontinuation.



Outcome: 2 Adverse events requiring treatment discontinuation


n/N n/N M-H,Random,95% CI M-H,Random,95% CI

Alvarez-Lerma 2001a 3/69 4/71 13.5 % 0.77 [ 0.18, 3.32 ]

Bergeron 1988 0/36 0/28 0.0 % 0.0 [ 0.0, 0.0 ]

Cometta 1994 2/158 1/155 5.0 % 1.96 [ 0.18, 21.42 ]

Holloway 1985 1/15 1/18 4.0 % 1.20 [ 0.08, 17.60 ]

Iakovlev 1998 0/48 2/47 3.2 % 0.20 [ 0.01, 3.98 ]

Landau 1990 0/20 0/20 0.0 % 0.0 [ 0.0, 0.0 ]

Martin 1991 1/52 3/42 5.8 % 0.27 [ 0.03, 2.49 ]

Mouton 1990 2/105 0/106 3.1 % 5.05 [ 0.25, 103.89 ]

Mouton 1995 5/116 2/121 11.0 % 2.61 [ 0.52, 13.18 ]

Muller 1987 3/73 0/33 3.3 % 3.22 [ 0.17, 60.55 ]

Rasmussen 1986 0/29 1/30 2.9 % 0.34 [ 0.01, 8.13 ]

Rubinstein 1995 1/306 3/274 5.7 % 0.30 [ 0.03, 2.85 ]

Sexton 1998 0/26 0/25 0.0 % 0.0 [ 0.0, 0.0 ]

Sieger 1997 6/104 3/107 15.6 % 2.06 [ 0.53, 8.01 ]

Smith 1984 2/96 7/99 12.0 % 0.29 [ 0.06, 1.38 ]

Speich 1998 0/44 0/45 0.0 % 0.0 [ 0.0, 0.0 ]

Stille 1992 3/186 2/151 9.1 % 1.22 [ 0.21, 7.19 ]

Thompson 1990 0/49 1/47 2.9 % 0.32 [ 0.01, 7.66 ]

Yellin 1993 0/56 1/35 2.9 % 0.21 [ 0.01, 5.03 ]

Total (95% CI) 1588 1454 100.0 % 0.89 [ 0.52, 1.52 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 12.26, df = 14 (P = 0.59); I2 =0.0%


0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 4.3. Comparison 4 Monotherapy versus combination therapy, Outcome 3 Any nephrotoxicity.



Outcome: 3 Any nephrotoxicity



1 Once daily aminoglycoside

Jaspers 1998 2/39 5/40 2.1 % 0.41 [ 0.08, 1.99 ]

Rubinstein 1995 0/306 9/274 4.2 % 0.05 [ 0.00, 0.81 ]

Sandberg 1997 0/33 0/33 0.0 % 0.0 [ 0.0, 0.0 ]

Sexton 1998 0/26 2/25 1.1 % 0.19 [ 0.01, 3.82 ]

Speich 1998 0/44 2/45 1.0 % 0.20 [ 0.01, 4.14 ]

Subtotal (95% CI) 448 417 8.3 % 0.17 [ 0.06, 0.53 ]




2 Twice daily aminoglycoside

Alvarez-Lerma 2001a 0/69 2/71 1.0 % 0.21 [ 0.01, 4.21 ]

Cometta 1994 8/158 14/155 5.9 % 0.56 [ 0.24, 1.30 ]

Dupont 2000 3/111 3/116 1.2 % 1.05 [ 0.22, 5.07 ]

Gomez 1990a 0/39 3/39 1.5 % 0.14 [ 0.01, 2.68 ]

McCormick 1997 2/65 8/63 3.4 % 0.24 [ 0.05, 1.10 ]

Mouton 1990 1/105 4/106 1.7 % 0.25 [ 0.03, 2.22 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 562 565 14.7 % 0.43 [ 0.24, 0.77 ]




3 Thrice daily aminoglycoside

Arich 1987 0/25 3/22 1.6 % 0.13 [ 0.01, 2.32 ]

Bergeron 1988 1/36 3/28 1.4 % 0.26 [ 0.03, 2.36 ]

Cone 1985 0/21 1/19 0.7 % 0.30 [ 0.01, 7.02 ]

Coppens 1983 0/22 4/34 1.5 % 0.17 [ 0.01, 2.99 ]

D’Antonio 1992 1/143 10/140 4.2 % 0.10 [ 0.01, 0.75 ]

Gerecht 1989 0/24 8/22 3.7 % 0.05 [ 0.00, 0.89 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Hoepelman 1988 1/45 4/41 1.7 % 0.23 [ 0.03, 1.96 ]

Korzeniowski 1982 6/35 16/43 6.0 % 0.46 [ 0.20, 1.05 ]

Landau 1990 0/20 0/20 0.0 % 0.0 [ 0.0, 0.0 ]

Mandell 1987 0/52 7/58 3.0 % 0.07 [ 0.00, 1.27 ]

Martin 1991 0/52 3/42 1.6 % 0.12 [ 0.01, 2.18 ]

Muller 1987 1/73 2/33 1.1 % 0.23 [ 0.02, 2.41 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Ribera 1996 3/38 5/36 2.1 % 0.57 [ 0.15, 2.21 ]

Sage 1987 2/30 3/24 1.4 % 0.53 [ 0.10, 2.94 ]

Sculier 1982 0/10 1/10 0.6 % 0.33 [ 0.02, 7.32 ]

Sieger 1997 0/23 2/20 1.1 % 0.18 [ 0.01, 3.44 ]

Smith 1984 7/88 37/91 15.2 % 0.20 [ 0.09, 0.42 ]

Stille 1992 9/186 18/151 8.3 % 0.41 [ 0.19, 0.88 ]

Thompson 1990 3/49 4/47 1.7 % 0.72 [ 0.17, 3.04 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Vergnon 1985 0/16 1/14 0.7 % 0.29 [ 0.01, 6.69 ]

Wiecek 1986 1/10 1/10 0.4 % 1.00 [ 0.07, 13.87 ]

Subtotal (95% CI) 1107 975 58.0 % 0.28 [ 0.20, 0.39 ]




4 Non specified aminoglycoside regimen

Carbon 1987 0/25 7/22 3.3 % 0.06 [ 0.00, 0.98 ]

Felisart 1985 6/37 7/36 3.0 % 0.83 [ 0.31, 2.24 ]

Finer 1992 0/249 12/222 5.5 % 0.04 [ 0.00, 0.60 ]

Mergoni 1987 3/20 4/22 1.6 % 0.83 [ 0.21, 3.24 ]

Rapp 1984 0/17 0/18 0.0 % 0.0 [ 0.0, 0.0 ]

Sukoh 1994 0/30 0/33 0.0 % 0.0 [ 0.0, 0.0 ]

Takamoto 1994 0/83 3/88 1.4 % 0.15 [ 0.01, 2.89 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Verzasconi 1995 0/45 1/42 0.6 % 0.31 [ 0.01, 7.44 ]

Warren 1983 4/56 9/64 3.5 % 0.51 [ 0.17, 1.56 ]

Subtotal (95% CI) 578 561 19.0 % 0.34 [ 0.19, 0.58 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )








Total (95% CI) 2695 2518 100.0 % 0.30 [ 0.23, 0.39 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







1 Once daily aminoglycoside

Jaspers 1998 2/39 5/40 2.1 % 0.41 [ 0.08, 1.99 ]

Rubinstein 1995 0/306 9/274 4.2 % 0.05 [ 0.00, 0.81 ]

Sandberg 1997 0/33 0/33 0.0 % 0.0 [ 0.0, 0.0 ]

Sexton 1998 0/26 2/25 1.1 % 0.19 [ 0.01, 3.82 ]

Speich 1998 0/44 2/45 1.0 % 0.20 [ 0.01, 4.14 ]

Subtotal (95% CI) 448 417 8.3 % 0.17 [ 0.06, 0.53 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 Twice daily aminoglycoside

Alvarez-Lerma 2001a 0/69 2/71 1.0 % 0.21 [ 0.01, 4.21 ]

Cometta 1994 8/158 14/155 5.9 % 0.56 [ 0.24, 1.30 ]

Dupont 2000 3/111 3/116 1.2 % 1.05 [ 0.22, 5.07 ]

Gomez 1990a 0/39 3/39 1.5 % 0.14 [ 0.01, 2.68 ]

McCormick 1997 2/65 8/63 3.4 % 0.24 [ 0.05, 1.10 ]

Mouton 1990 1/105 4/106 1.7 % 0.25 [ 0.03, 2.22 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 562 565 14.7 % 0.43 [ 0.24, 0.77 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









3 Thrice daily aminoglycoside

Arich 1987 0/25 3/22 1.6 % 0.13 [ 0.01, 2.32 ]

Bergeron 1988 1/36 3/28 1.4 % 0.26 [ 0.03, 2.36 ]

Cone 1985 0/21 1/19 0.7 % 0.30 [ 0.01, 7.02 ]

Coppens 1983 0/22 4/34 1.5 % 0.17 [ 0.01, 2.99 ]

D’Antonio 1992 1/143 10/140 4.2 % 0.10 [ 0.01, 0.75 ]

Gerecht 1989 0/24 8/22 3.7 % 0.05 [ 0.00, 0.89 ]

Hoepelman 1988 1/45 4/41 1.7 % 0.23 [ 0.03, 1.96 ]

Korzeniowski 1982 6/35 16/43 6.0 % 0.46 [ 0.20, 1.05 ]

Landau 1990 0/20 0/20 0.0 % 0.0 [ 0.0, 0.0 ]

Mandell 1987 0/52 7/58 3.0 % 0.07 [ 0.00, 1.27 ]

Martin 1991 0/52 3/42 1.6 % 0.12 [ 0.01, 2.18 ]

Muller 1987 1/73 2/33 1.1 % 0.23 [ 0.02, 2.41 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Ribera 1996 3/38 5/36 2.1 % 0.57 [ 0.15, 2.21 ]

Sage 1987 2/30 3/24 1.4 % 0.53 [ 0.10, 2.94 ]

Sculier 1982 0/10 1/10 0.6 % 0.33 [ 0.02, 7.32 ]

Sieger 1997 0/23 2/20 1.1 % 0.18 [ 0.01, 3.44 ]

Smith 1984 7/88 37/91 15.2 % 0.20 [ 0.09, 0.42 ]

Stille 1992 9/186 18/151 8.3 % 0.41 [ 0.19, 0.88 ]

Thompson 1990 3/49 4/47 1.7 % 0.72 [ 0.17, 3.04 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Vergnon 1985 0/16 1/14 0.7 % 0.29 [ 0.01, 6.69 ]

Wiecek 1986 1/10 1/10 0.4 % 1.00 [ 0.07, 13.87 ]

Subtotal (95% CI) 1107 975 58.0 % 0.28 [ 0.20, 0.39 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









4 Non specified aminoglycoside regimen

Carbon 1987 0/25 7/22 3.3 % 0.06 [ 0.00, 0.98 ]

Felisart 1985 6/37 7/36 3.0 % 0.83 [ 0.31, 2.24 ]

Finer 1992 0/249 12/222 5.5 % 0.04 [ 0.00, 0.60 ]

Mergoni 1987 3/20 4/22 1.6 % 0.83 [ 0.21, 3.24 ]

Rapp 1984 0/17 0/18 0.0 % 0.0 [ 0.0, 0.0 ]

Sukoh 1994 0/30 0/33 0.0 % 0.0 [ 0.0, 0.0 ]

Takamoto 1994 0/83 3/88 1.4 % 0.15 [ 0.01, 2.89 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Verzasconi 1995 0/45 1/42 0.6 % 0.31 [ 0.01, 7.44 ]

Warren 1983 4/56 9/64 3.5 % 0.51 [ 0.17, 1.56 ]

Subtotal (95% CI) 578 561 19.0 % 0.34 [ 0.19, 0.58 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 5.1. Comparison 5 Monotherapy versus combination therapy, Outcome 1 Drop-outs for all cause

fatality.



Outcome: 1 Drop-outs for all cause fatality



1 Same BL

Cometta 1994 10/158 11/155 26.9 % 0.89 [ 0.39, 2.04 ]

Klastersky 1973 3/25 2/25 4.8 % 1.50 [ 0.27, 8.22 ]

Kljucar 1990 1/50 0/50 1.2 % 3.00 [ 0.13, 71.92 ]

Korzeniowski 1982 2/35 2/43 4.3 % 1.23 [ 0.18, 8.28 ]

Subtotal (95% CI) 268 273 37.3 % 1.08 [ 0.55, 2.11 ]




2 Different BL

Bergeron 1988 2/39 9/38 22.1 % 0.22 [ 0.05, 0.94 ]

Cone 1985 7/28 10/29 23.8 % 0.73 [ 0.32, 1.64 ]

Warren 1983 3/59 0/64 1.2 % 7.58 [ 0.40, 143.78 ]

Yellin 1993 17/73 5/39 15.8 % 1.82 [ 0.73, 4.55 ]

Subtotal (95% CI) 199 170 62.7 % 0.95 [ 0.57, 1.58 ]




Total (95% CI) 467 443 100.0 % 1.00 [ 0.66, 1.49 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Same BL

Cometta 1994 10/158 11/155 26.9 % 0.89 [ 0.39, 2.04 ]

Klastersky 1973 3/25 2/25 4.8 % 1.50 [ 0.27, 8.22 ]

Kljucar 1990 1/50 0/50 1.2 % 3.00 [ 0.13, 71.92 ]

Korzeniowski 1982 2/35 2/43 4.3 % 1.23 [ 0.18, 8.28 ]

Subtotal (95% CI) 268 273 37.3 % 1.08 [ 0.55, 2.11 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







2 Different BL

Bergeron 1988 2/39 9/38 22.1 % 0.22 [ 0.05, 0.94 ]

Cone 1985 7/28 10/29 23.8 % 0.73 [ 0.32, 1.64 ]

Warren 1983 3/59 0/64 1.2 % 7.58 [ 0.40, 143.78 ]

Yellin 1993 17/73 5/39 15.8 % 1.82 [ 0.73, 4.55 ]

Subtotal (95% CI) 199 170 62.7 % 0.95 [ 0.57, 1.58 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 5.2. Comparison 5 Monotherapy versus combination therapy, Outcome 2 Drop-outs for clinical

failure.



Outcome: 2 Drop-outs for clinical failure



1 Same BL

Cometta 1994 10/158 11/155 5.0 % 0.89 [ 0.39, 2.04 ]

Dupont 2000 12/111 11/115 4.8 % 1.13 [ 0.52, 2.45 ]

Klastersky 1973 3/25 2/25 0.9 % 1.50 [ 0.27, 8.22 ]

Kljucar 1990 6/50 5/50 2.2 % 1.20 [ 0.39, 3.68 ]

Korzeniowski 1982 2/35 2/43 0.8 % 1.23 [ 0.18, 8.28 ]

Piccart 1984 13/55 7/50 3.3 % 1.69 [ 0.73, 3.89 ]

Sage 1987 8/34 5/27 2.5 % 1.27 [ 0.47, 3.44 ]

Sandberg 1997 11/37 1/36 0.5 % 10.70 [ 1.46, 78.69 ]

Sexton 1998 7/33 9/34 4.0 % 0.80 [ 0.34, 1.90 ]

Takamoto 1994 6/83 8/88 3.5 % 0.80 [ 0.29, 2.19 ]

Subtotal (95% CI) 621 623 27.3 % 1.26 [ 0.92, 1.72 ]




2 Different BL

Alvarez-Lerma 2001a 12/69 12/71 5.3 % 1.03 [ 0.50, 2.13 ]

Bergeron 1988 2/39 8/38 3.6 % 0.24 [ 0.06, 1.07 ]

Cone 1985 7/28 10/29 4.4 % 0.73 [ 0.32, 1.64 ]

Finer 1992 29/249 27/222 12.7 % 0.96 [ 0.59, 1.57 ]

Holloway 1985 6/21 4/22 1.7 % 1.57 [ 0.52, 4.79 ]

Koehler 1990 10/73 7/71 3.2 % 1.39 [ 0.56, 3.45 ]

Martin 1991 10/62 12/54 5.7 % 0.73 [ 0.34, 1.55 ]

Moreno 1997 6/36 6/34 2.8 % 0.94 [ 0.34, 2.65 ]

Mouton 1995 17/128 26/144 10.9 % 0.74 [ 0.42, 1.29 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Rubinstein 1995 39/306 36/274 17.0 % 0.97 [ 0.64, 1.48 ]

Speich 1998 3/44 2/45 0.9 % 1.53 [ 0.27, 8.74 ]

Verzasconi 1995 3/48 3/45 1.4 % 0.94 [ 0.20, 4.41 ]

Warren 1983 3/59 0/64 0.2 % 7.58 [ 0.40, 143.78 ]

Yellin 1993 17/73 5/39 2.9 % 1.82 [ 0.73, 4.55 ]

Subtotal (95% CI) 1235 1152 72.7 % 0.96 [ 0.78, 1.17 ]




Total (95% CI) 1856 1775 100.0 % 1.04 [ 0.88, 1.23 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







1 Same BL

Cometta 1994 10/158 11/155 5.0 % 0.89 [ 0.39, 2.04 ]

Dupont 2000 12/111 11/115 4.8 % 1.13 [ 0.52, 2.45 ]

Klastersky 1973 3/25 2/25 0.9 % 1.50 [ 0.27, 8.22 ]

Kljucar 1990 6/50 5/50 2.2 % 1.20 [ 0.39, 3.68 ]

Korzeniowski 1982 2/35 2/43 0.8 % 1.23 [ 0.18, 8.28 ]

Piccart 1984 13/55 7/50 3.3 % 1.69 [ 0.73, 3.89 ]

Sage 1987 8/34 5/27 2.5 % 1.27 [ 0.47, 3.44 ]

Sandberg 1997 11/37 1/36 0.5 % 10.70 [ 1.46, 78.69 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Sexton 1998 7/33 9/34 4.0 % 0.80 [ 0.34, 1.90 ]

Takamoto 1994 6/83 8/88 3.5 % 0.80 [ 0.29, 2.19 ]

Subtotal (95% CI) 621 623 27.3 % 1.26 [ 0.92, 1.72 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







2 Different BL

Alvarez-Lerma 2001a 12/69 12/71 5.3 % 1.03 [ 0.50, 2.13 ]

Bergeron 1988 2/39 8/38 3.6 % 0.24 [ 0.06, 1.07 ]

Cone 1985 7/28 10/29 4.4 % 0.73 [ 0.32, 1.64 ]

Finer 1992 29/249 27/222 12.7 % 0.96 [ 0.59, 1.57 ]

Holloway 1985 6/21 4/22 1.7 % 1.57 [ 0.52, 4.79 ]

Koehler 1990 10/73 7/71 3.2 % 1.39 [ 0.56, 3.45 ]

Martin 1991 10/62 12/54 5.7 % 0.73 [ 0.34, 1.55 ]

Moreno 1997 6/36 6/34 2.8 % 0.94 [ 0.34, 2.65 ]

Mouton 1995 17/128 26/144 10.9 % 0.74 [ 0.42, 1.29 ]

Rubinstein 1995 39/306 36/274 17.0 % 0.97 [ 0.64, 1.48 ]

Speich 1998 3/44 2/45 0.9 % 1.53 [ 0.27, 8.74 ]

Verzasconi 1995 3/48 3/45 1.4 % 0.94 [ 0.20, 4.41 ]

Warren 1983 3/59 0/64 0.2 % 7.58 [ 0.40, 143.78 ]

Yellin 1993 17/73 5/39 2.9 % 1.82 [ 0.73, 4.55 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Subtotal (95% CI) 1235 1152 72.7 % 0.96 [ 0.78, 1.17 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0



positive infections).



Outcome: 1 All cause fatality (Gram positive infections)



Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Korzeniowski 1982 2/33 6/41 72.8 % 0.41 [ 0.09, 1.92 ]

Ribera 1996 1/45 2/45 27.2 % 0.50 [ 0.05, 5.32 ]

Total (95% CI) 90 98 100.0 % 0.44 [ 0.12, 1.58 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0

Favours treatment Favours control




positive infections).



Outcome: 2 Clinical failure (Gram positive infections)



Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Coppens 1983 2/22 7/44 18.0 % 0.57 [ 0.13, 2.52 ]

Korzeniowski 1982 3/33 7/41 24.1 % 0.53 [ 0.15, 1.90 ]

Ribera 1996 11/45 14/45 54.0 % 0.79 [ 0.40, 1.54 ]

Sexton 1998 1/26 1/25 3.9 % 0.96 [ 0.06, 14.55 ]

Total (95% CI) 138 167 100.0 % 0.69 [ 0.40, 1.19 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 6.3. Comparison 6 Monotherapy versus combination therapy, Outcome 3 Bacteriological failure

(Gram positive infections).



Outcome: 3 Bacteriological failure (Gram positive infections)



Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Coppens 1983 8/22 17/44 82.6 % 0.94 [ 0.48, 1.83 ]

Korzeniowski 1982 1/33 1/41 6.5 % 1.24 [ 0.08, 19.12 ]

Ribera 1996 0/45 0/45 0.0 % 0.0 [ 0.0, 0.0 ]

Sexton 1998 0/23 1/23 10.9 % 0.33 [ 0.01, 7.78 ]

Total (95% CI) 135 165 100.0 % 0.89 [ 0.47, 1.69 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0


Analysis 6.4. Comparison 6 Monotherapy versus combination therapy, Outcome 4 Need for operation

(endocarditis).



Outcome: 4 Need for operation (endocarditis)



Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Korzeniowski 1982 8/35 10/43 49.4 % 0.98 [ 0.43, 2.22 ]

Ribera 1996 0/45 0/45 0.0 % 0.0 [ 0.0, 0.0 ]

Sexton 1998 5/26 9/25 50.6 % 0.53 [ 0.21, 1.37 ]

Total (95% CI) 118 125 100.0 % 0.76 [ 0.41, 1.39 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 7.1. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 1 All

cause fatality by allocation concealment.


Comparison: 7 Monotherapy versus combination therapy (sensitivity analyses)

Outcome: 1 All cause fatality by allocation concealment



1 A same BL

Cometta 1994 24/148 19/144 27.9 % 1.23 [ 0.70, 2.14 ]

D’Antonio 1992 7/144 10/142 14.6 % 0.69 [ 0.27, 1.76 ]

Dupont 2000 21/111 24/116 34.0 % 0.91 [ 0.54, 1.55 ]

Kljucar 1990 11/49 9/50 12.9 % 1.25 [ 0.57, 2.74 ]

Korzeniowski 1982 2/33 6/41 7.7 % 0.41 [ 0.09, 1.92 ]

Ribera 1996 1/45 2/45 2.9 % 0.50 [ 0.05, 5.32 ]

Subtotal (95% CI) 530 538 100.0 % 0.96 [ 0.71, 1.31 ]




2 B same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Carbon 1987 1/25 1/22 19.4 % 0.88 [ 0.06, 13.25 ]

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Klastersky 1973 7/22 3/23 53.4 % 2.44 [ 0.72, 8.26 ]

Sandberg 1997 0/37 0/36 0.0 % 0.0 [ 0.0, 0.0 ]

Sculier 1982 0/10 1/10 27.3 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 162 151 100.0 % 1.56 [ 0.58, 4.18 ]




3 A different BL

Alvarez-Lerma 2001a 16/69 20/71 15.2 % 0.82 [ 0.47, 1.45 ]

Arich 1987 8/25 5/22 4.1 % 1.41 [ 0.54, 3.67 ]

Finer 1992 40/249 21/222 17.2 % 1.70 [ 1.03, 2.79 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Gomez 1990a 6/39 5/39 3.9 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 2/45 4/41 3.2 % 0.46 [ 0.09, 2.36 ]

Jaspers 1998 3/39 4/40 3.1 % 0.77 [ 0.18, 3.22 ]

McCormick 1997 13/65 9/63 7.1 % 1.40 [ 0.64, 3.04 ]

Rubinstein 1995 31/306 33/274 26.9 % 0.84 [ 0.53, 1.34 ]

Smith 1984 7/94 19/93 14.8 % 0.36 [ 0.16, 0.83 ]

Speich 1998 1/44 6/45 4.6 % 0.17 [ 0.02, 1.36 ]

Wing 1998 0/117 0/62 0.0 % 0.0 [ 0.0, 0.0 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 1148 1006 100.0 % 0.95 [ 0.75, 1.19 ]




4 B different BL

Bergeron 1988 0/37 1/29 1.8 % 0.26 [ 0.01, 6.23 ]

Brown 1984 11/18 9/16 10.1 % 1.09 [ 0.62, 1.92 ]

Cone 1985 1/21 2/19 2.2 % 0.45 [ 0.04, 4.60 ]

Duff 1982 0/31 0/43 0.0 % 0.0 [ 0.0, 0.0 ]

Felisart 1985 7/37 11/36 11.9 % 0.62 [ 0.27, 1.42 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

Koehler 1990 5/73 2/71 2.2 % 2.43 [ 0.49, 12.13 ]

Mouton 1990 14/105 19/106 20.1 % 0.74 [ 0.39, 1.40 ]

Mouton 1995 7/116 8/121 8.3 % 0.91 [ 0.34, 2.44 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Sieger 1997 13/104 23/107 24.1 % 0.58 [ 0.31, 1.09 ]

Stille 1992 3/186 6/151 7.0 % 0.41 [ 0.10, 1.60 ]

Thompson 1990 2/49 3/47 3.3 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 3/56 9/64 8.9 % 0.38 [ 0.11, 1.34 ]

Wiecek 1986 0/10 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 1007 945 100.0 % 0.70 [ 0.53, 0.93 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )








5 C different BL

Landau 1990 4/20 3/20 100.0 % 1.33 [ 0.34, 5.21 ]

Subtotal (95% CI) 20 20 100.0 % 1.33 [ 0.34, 5.21 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







1 A same BL

Cometta 1994 24/148 19/144 27.9 % 1.23 [ 0.70, 2.14 ]

D’Antonio 1992 7/144 10/142 14.6 % 0.69 [ 0.27, 1.76 ]

Dupont 2000 21/111 24/116 34.0 % 0.91 [ 0.54, 1.55 ]

Kljucar 1990 11/49 9/50 12.9 % 1.25 [ 0.57, 2.74 ]

Korzeniowski 1982 2/33 6/41 7.7 % 0.41 [ 0.09, 1.92 ]

Ribera 1996 1/45 2/45 2.9 % 0.50 [ 0.05, 5.32 ]

Subtotal (95% CI) 530 538 100.0 % 0.96 [ 0.71, 1.31 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 B same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Carbon 1987 1/25 1/22 19.4 % 0.88 [ 0.06, 13.25 ]

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Klastersky 1973 7/22 3/23 53.4 % 2.44 [ 0.72, 8.26 ]

Sandberg 1997 0/37 0/36 0.0 % 0.0 [ 0.0, 0.0 ]

Sculier 1982 0/10 1/10 27.3 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 162 151 100.0 % 1.56 [ 0.58, 4.18 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









3 A different BL

Alvarez-Lerma 2001a 16/69 20/71 15.2 % 0.82 [ 0.47, 1.45 ]

Arich 1987 8/25 5/22 4.1 % 1.41 [ 0.54, 3.67 ]

Finer 1992 40/249 21/222 17.2 % 1.70 [ 1.03, 2.79 ]

Gomez 1990a 6/39 5/39 3.9 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 2/45 4/41 3.2 % 0.46 [ 0.09, 2.36 ]

Jaspers 1998 3/39 4/40 3.1 % 0.77 [ 0.18, 3.22 ]

McCormick 1997 13/65 9/63 7.1 % 1.40 [ 0.64, 3.04 ]

Rubinstein 1995 31/306 33/274 26.9 % 0.84 [ 0.53, 1.34 ]

Smith 1984 7/94 19/93 14.8 % 0.36 [ 0.16, 0.83 ]

Speich 1998 1/44 6/45 4.6 % 0.17 [ 0.02, 1.36 ]

Wing 1998 0/117 0/62 0.0 % 0.0 [ 0.0, 0.0 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 1148 1006 100.0 % 0.95 [ 0.75, 1.19 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









4 B different BL

Bergeron 1988 0/37 1/29 1.8 % 0.26 [ 0.01, 6.23 ]

Brown 1984 11/18 9/16 10.1 % 1.09 [ 0.62, 1.92 ]

Cone 1985 1/21 2/19 2.2 % 0.45 [ 0.04, 4.60 ]

Duff 1982 0/31 0/43 0.0 % 0.0 [ 0.0, 0.0 ]

Felisart 1985 7/37 11/36 11.9 % 0.62 [ 0.27, 1.42 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

Koehler 1990 5/73 2/71 2.2 % 2.43 [ 0.49, 12.13 ]

Mouton 1990 14/105 19/106 20.1 % 0.74 [ 0.39, 1.40 ]

Mouton 1995 7/116 8/121 8.3 % 0.91 [ 0.34, 2.44 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Sieger 1997 13/104 23/107 24.1 % 0.58 [ 0.31, 1.09 ]

Stille 1992 3/186 6/151 7.0 % 0.41 [ 0.10, 1.60 ]

Thompson 1990 2/49 3/47 3.3 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 3/56 9/64 8.9 % 0.38 [ 0.11, 1.34 ]

Wiecek 1986 0/10 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 1007 945 100.0 % 0.70 [ 0.53, 0.93 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









5 C different BL

Landau 1990 4/20 3/20 100.0 % 1.33 [ 0.34, 5.21 ]

Subtotal (95% CI) 20 20 100.0 % 1.33 [ 0.34, 5.21 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0



cause fatality by allocation generation.



Outcome: 2 All cause fatality by allocation generation



1 A same BL

Cometta 1994 24/148 19/144 27.9 % 1.23 [ 0.70, 2.14 ]

D’Antonio 1992 7/144 10/142 14.6 % 0.69 [ 0.27, 1.76 ]

Dupont 2000 21/111 24/116 34.0 % 0.91 [ 0.54, 1.55 ]

Kljucar 1990 11/49 9/50 12.9 % 1.25 [ 0.57, 2.74 ]

Korzeniowski 1982 2/33 6/41 7.7 % 0.41 [ 0.09, 1.92 ]

Ribera 1996 1/45 2/45 2.9 % 0.50 [ 0.05, 5.32 ]

Subtotal (95% CI) 530 538 100.0 % 0.96 [ 0.71, 1.31 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





2 B same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Carbon 1987 1/25 1/22 19.4 % 0.88 [ 0.06, 13.25 ]

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Klastersky 1973 7/22 3/23 53.4 % 2.44 [ 0.72, 8.26 ]

Sandberg 1997 0/37 0/36 0.0 % 0.0 [ 0.0, 0.0 ]

Sculier 1982 0/10 1/10 27.3 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 162 151 100.0 % 1.56 [ 0.58, 4.18 ]




3 A different BL

Alvarez-Lerma 2001a 16/69 20/71 12.0 % 0.82 [ 0.47, 1.45 ]

Arich 1987 8/25 5/22 3.2 % 1.41 [ 0.54, 3.67 ]

Brown 1984 11/18 9/16 5.8 % 1.09 [ 0.62, 1.92 ]

Felisart 1985 7/37 11/36 6.8 % 0.62 [ 0.27, 1.42 ]

Finer 1992 40/249 21/222 13.5 % 1.70 [ 1.03, 2.79 ]

Gomez 1990a 6/39 5/39 3.0 % 1.20 [ 0.40, 3.61 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

Jaspers 1998 3/39 4/40 2.4 % 0.77 [ 0.18, 3.22 ]

McCormick 1997 13/65 9/63 5.6 % 1.40 [ 0.64, 3.04 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Rubinstein 1995 31/306 33/274 21.2 % 0.84 [ 0.53, 1.34 ]

Smith 1984 7/94 19/93 11.7 % 0.36 [ 0.16, 0.83 ]

Speich 1998 1/44 6/45 3.6 % 0.17 [ 0.02, 1.36 ]

Stille 1992 3/186 6/151 4.0 % 0.41 [ 0.10, 1.60 ]

Thompson 1990 2/49 3/47 1.9 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 3/56 9/64 5.1 % 0.38 [ 0.11, 1.34 ]

Wing 1998 0/117 0/62 0.0 % 0.0 [ 0.0, 0.0 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 1582 1375 100.0 % 0.89 [ 0.72, 1.09 ]



0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )






4 B different BL

Bergeron 1988 0/37 1/29 2.8 % 0.26 [ 0.01, 6.23 ]

Cone 1985 1/21 2/19 3.5 % 0.45 [ 0.04, 4.60 ]

Duff 1982 0/31 0/43 0.0 % 0.0 [ 0.0, 0.0 ]

Hoepelman 1988 2/45 4/41 7.0 % 0.46 [ 0.09, 2.36 ]

Koehler 1990 5/73 2/71 3.4 % 2.43 [ 0.49, 12.13 ]

Mouton 1990 14/105 19/106 31.8 % 0.74 [ 0.39, 1.40 ]

Mouton 1995 7/116 8/121 13.2 % 0.91 [ 0.34, 2.44 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Sieger 1997 13/104 23/107 38.2 % 0.58 [ 0.31, 1.09 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Wiecek 1986 0/10 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 573 576 100.0 % 0.72 [ 0.50, 1.04 ]




5 C different BL

Landau 1990 4/20 3/20 100.0 % 1.33 [ 0.34, 5.21 ]

Subtotal (95% CI) 20 20 100.0 % 1.33 [ 0.34, 5.21 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 A same BL

Cometta 1994 24/148 19/144 27.9 % 1.23 [ 0.70, 2.14 ]

D’Antonio 1992 7/144 10/142 14.6 % 0.69 [ 0.27, 1.76 ]

Dupont 2000 21/111 24/116 34.0 % 0.91 [ 0.54, 1.55 ]

Kljucar 1990 11/49 9/50 12.9 % 1.25 [ 0.57, 2.74 ]

Korzeniowski 1982 2/33 6/41 7.7 % 0.41 [ 0.09, 1.92 ]

Ribera 1996 1/45 2/45 2.9 % 0.50 [ 0.05, 5.32 ]

Subtotal (95% CI) 530 538 100.0 % 0.96 [ 0.71, 1.31 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 B same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Carbon 1987 1/25 1/22 19.4 % 0.88 [ 0.06, 13.25 ]

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Klastersky 1973 7/22 3/23 53.4 % 2.44 [ 0.72, 8.26 ]

Sandberg 1997 0/37 0/36 0.0 % 0.0 [ 0.0, 0.0 ]

Sculier 1982 0/10 1/10 27.3 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 162 151 100.0 % 1.56 [ 0.58, 4.18 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









3 A different BL

Alvarez-Lerma 2001a 16/69 20/71 12.0 % 0.82 [ 0.47, 1.45 ]

Arich 1987 8/25 5/22 3.2 % 1.41 [ 0.54, 3.67 ]

Brown 1984 11/18 9/16 5.8 % 1.09 [ 0.62, 1.92 ]

Felisart 1985 7/37 11/36 6.8 % 0.62 [ 0.27, 1.42 ]

Finer 1992 40/249 21/222 13.5 % 1.70 [ 1.03, 2.79 ]

Gomez 1990a 6/39 5/39 3.0 % 1.20 [ 0.40, 3.61 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

Jaspers 1998 3/39 4/40 2.4 % 0.77 [ 0.18, 3.22 ]

McCormick 1997 13/65 9/63 5.6 % 1.40 [ 0.64, 3.04 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Rubinstein 1995 31/306 33/274 21.2 % 0.84 [ 0.53, 1.34 ]

Smith 1984 7/94 19/93 11.7 % 0.36 [ 0.16, 0.83 ]

Speich 1998 1/44 6/45 3.6 % 0.17 [ 0.02, 1.36 ]

Stille 1992 3/186 6/151 4.0 % 0.41 [ 0.10, 1.60 ]

Thompson 1990 2/49 3/47 1.9 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 3/56 9/64 5.1 % 0.38 [ 0.11, 1.34 ]

Wing 1998 0/117 0/62 0.0 % 0.0 [ 0.0, 0.0 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 1582 1375 100.0 % 0.89 [ 0.72, 1.09 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









4 B different BL

Bergeron 1988 0/37 1/29 2.8 % 0.26 [ 0.01, 6.23 ]

Cone 1985 1/21 2/19 3.5 % 0.45 [ 0.04, 4.60 ]

Duff 1982 0/31 0/43 0.0 % 0.0 [ 0.0, 0.0 ]

Hoepelman 1988 2/45 4/41 7.0 % 0.46 [ 0.09, 2.36 ]

Koehler 1990 5/73 2/71 3.4 % 2.43 [ 0.49, 12.13 ]

Mouton 1990 14/105 19/106 31.8 % 0.74 [ 0.39, 1.40 ]

Mouton 1995 7/116 8/121 13.2 % 0.91 [ 0.34, 2.44 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Sieger 1997 13/104 23/107 38.2 % 0.58 [ 0.31, 1.09 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Wiecek 1986 0/10 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 573 576 100.0 % 0.72 [ 0.50, 1.04 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









5 C different BL

Landau 1990 4/20 3/20 100.0 % 1.33 [ 0.34, 5.21 ]

Subtotal (95% CI) 20 20 100.0 % 1.33 [ 0.34, 5.21 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0



cause fatality by ITT vs. per-protocol analysis.



Outcome: 3 All cause fatality by ITT vs. per-protocol analysis



1 ITT - same BL (type 1 studies)

D’Antonio 1992 7/144 10/142 74.2 % 0.69 [ 0.27, 1.76 ]

Ribera 1996 1/45 2/45 14.7 % 0.50 [ 0.05, 5.32 ]

Sandberg 1997 0/37 0/36 0.0 % 0.0 [ 0.0, 0.0 ]

Sculier 1982 0/10 1/10 11.1 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 236 233 100.0 % 0.62 [ 0.27, 1.43 ]




2 per-protocol - same BL (type 2 and 3 studies)

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Cometta 1994 24/148 19/144 32.1 % 1.23 [ 0.70, 2.14 ]

Dupont 2000 21/111 24/116 39.2 % 0.91 [ 0.54, 1.55 ]

Klastersky 1973 7/22 3/23 4.9 % 2.44 [ 0.72, 8.26 ]

Kljucar 1990 11/49 9/50 14.9 % 1.25 [ 0.57, 2.74 ]

Korzeniowski 1982 2/33 6/41 8.9 % 0.41 [ 0.09, 1.92 ]

Subtotal (95% CI) 375 386 100.0 % 1.09 [ 0.80, 1.51 ]




3 unknown - same BL (type 4 studies)

Carbon 1987 1/25 1/22 100.0 % 0.88 [ 0.06, 13.25 ]

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 81 70 100.0 % 0.88 [ 0.06, 13.25 ]




4 ITT - different BL (type 1 studies)

Alvarez-Lerma 2001a 16/69 20/71 11.9 % 0.82 [ 0.47, 1.45 ]

Duff 1982 0/31 0/43 0.0 % 0.0 [ 0.0, 0.0 ]

Felisart 1985 7/37 11/36 6.8 % 0.62 [ 0.27, 1.42 ]

Finer 1992 40/249 21/222 13.5 % 1.70 [ 1.03, 2.79 ]

Gomez 1990a 6/39 5/39 3.0 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 2/45 4/41 2.5 % 0.46 [ 0.09, 2.36 ]

Jaspers 1998 3/39 4/40 2.4 % 0.77 [ 0.18, 3.22 ]

Koehler 1990 5/73 2/71 1.2 % 2.43 [ 0.49, 12.13 ]

Mouton 1990 14/105 19/106 11.5 % 0.74 [ 0.39, 1.40 ]

Mouton 1995 7/116 8/121 4.7 % 0.91 [ 0.34, 2.44 ]

Rubinstein 1995 31/306 33/274 21.1 % 0.84 [ 0.53, 1.34 ]

Sieger 1997 13/104 23/107 13.7 % 0.58 [ 0.31, 1.09 ]

Speich 1998 1/44 6/45 3.6 % 0.17 [ 0.02, 1.36 ]

Stille 1992 3/186 6/151 4.0 % 0.41 [ 0.10, 1.60 ]

Wing 1998 0/117 0/62 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 1560 1429 100.0 % 0.87 [ 0.71, 1.07 ]



0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )






5 per-protocol - different BL (type 2 and 3 studies)

Arich 1987 8/25 5/22 9.1 % 1.41 [ 0.54, 3.67 ]

Bergeron 1988 0/37 1/29 2.9 % 0.26 [ 0.01, 6.23 ]

Brown 1984 11/18 9/16 16.3 % 1.09 [ 0.62, 1.92 ]

Cone 1985 1/21 2/19 3.6 % 0.45 [ 0.04, 4.60 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

McCormick 1997 13/65 9/63 15.7 % 1.40 [ 0.64, 3.04 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Smith 1984 7/94 19/93 32.7 % 0.36 [ 0.16, 0.83 ]

Thompson 1990 2/49 3/47 5.3 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 3/56 9/64 14.4 % 0.38 [ 0.11, 1.34 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 554 483 100.0 % 0.76 [ 0.54, 1.07 ]




6 unknown - different BL (type 4 studies)

Landau 1990 4/20 3/20 100.0 % 1.33 [ 0.34, 5.21 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Wiecek 1986 0/10 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 61 59 100.0 % 1.33 [ 0.34, 5.21 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 ITT - same BL (type 1 studies)

D’Antonio 1992 7/144 10/142 74.2 % 0.69 [ 0.27, 1.76 ]

Ribera 1996 1/45 2/45 14.7 % 0.50 [ 0.05, 5.32 ]

Sandberg 1997 0/37 0/36 0.0 % 0.0 [ 0.0, 0.0 ]

Sculier 1982 0/10 1/10 11.1 % 0.33 [ 0.02, 7.32 ]

Subtotal (95% CI) 236 233 100.0 % 0.62 [ 0.27, 1.43 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 per-protocol - same BL (type 2 and 3 studies)

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Cometta 1994 24/148 19/144 32.1 % 1.23 [ 0.70, 2.14 ]

Dupont 2000 21/111 24/116 39.2 % 0.91 [ 0.54, 1.55 ]

Klastersky 1973 7/22 3/23 4.9 % 2.44 [ 0.72, 8.26 ]

Kljucar 1990 11/49 9/50 14.9 % 1.25 [ 0.57, 2.74 ]

Korzeniowski 1982 2/33 6/41 8.9 % 0.41 [ 0.09, 1.92 ]

Subtotal (95% CI) 375 386 100.0 % 1.09 [ 0.80, 1.51 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







3 unknown - same BL (type 4 studies)

Carbon 1987 1/25 1/22 100.0 % 0.88 [ 0.06, 13.25 ]

Cardozo 2001 0/56 0/48 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 81 70 100.0 % 0.88 [ 0.06, 13.25 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









4 ITT - different BL (type 1 studies)

Alvarez-Lerma 2001a 16/69 20/71 11.9 % 0.82 [ 0.47, 1.45 ]

Duff 1982 0/31 0/43 0.0 % 0.0 [ 0.0, 0.0 ]

Felisart 1985 7/37 11/36 6.8 % 0.62 [ 0.27, 1.42 ]

Finer 1992 40/249 21/222 13.5 % 1.70 [ 1.03, 2.79 ]

Gomez 1990a 6/39 5/39 3.0 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 2/45 4/41 2.5 % 0.46 [ 0.09, 2.36 ]

Jaspers 1998 3/39 4/40 2.4 % 0.77 [ 0.18, 3.22 ]

Koehler 1990 5/73 2/71 1.2 % 2.43 [ 0.49, 12.13 ]

Mouton 1990 14/105 19/106 11.5 % 0.74 [ 0.39, 1.40 ]

Mouton 1995 7/116 8/121 4.7 % 0.91 [ 0.34, 2.44 ]

Rubinstein 1995 31/306 33/274 21.1 % 0.84 [ 0.53, 1.34 ]

Sieger 1997 13/104 23/107 13.7 % 0.58 [ 0.31, 1.09 ]

Speich 1998 1/44 6/45 3.6 % 0.17 [ 0.02, 1.36 ]

Stille 1992 3/186 6/151 4.0 % 0.41 [ 0.10, 1.60 ]

Wing 1998 0/117 0/62 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 1560 1429 100.0 % 0.87 [ 0.71, 1.07 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









5 per-protocol - different BL (type 2 and 3 studies)

Arich 1987 8/25 5/22 9.1 % 1.41 [ 0.54, 3.67 ]

Bergeron 1988 0/37 1/29 2.9 % 0.26 [ 0.01, 6.23 ]

Brown 1984 11/18 9/16 16.3 % 1.09 [ 0.62, 1.92 ]

Cone 1985 1/21 2/19 3.6 % 0.45 [ 0.04, 4.60 ]

Havig 1973 0/24 0/26 0.0 % 0.0 [ 0.0, 0.0 ]

McCormick 1997 13/65 9/63 15.7 % 1.40 [ 0.64, 3.04 ]

Rasmussen 1986 0/29 0/30 0.0 % 0.0 [ 0.0, 0.0 ]

Smith 1984 7/94 19/93 32.7 % 0.36 [ 0.16, 0.83 ]

Thompson 1990 2/49 3/47 5.3 % 0.64 [ 0.11, 3.66 ]

Thompson 1993 0/80 0/40 0.0 % 0.0 [ 0.0, 0.0 ]

Warren 1983 3/56 9/64 14.4 % 0.38 [ 0.11, 1.34 ]

Yellin 1993 0/56 0/34 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 554 483 100.0 % 0.76 [ 0.54, 1.07 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









6 unknown - different BL (type 4 studies)

Landau 1990 4/20 3/20 100.0 % 1.33 [ 0.34, 5.21 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Trujillo 1992 0/16 0/14 0.0 % 0.0 [ 0.0, 0.0 ]

Wiecek 1986 0/10 0/10 0.0 % 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 61 59 100.0 % 1.33 [ 0.34, 5.21 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0




Analysis 7.4. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 4

Clinical failure by allocation concealment.



Outcome: 4 Clinical failure by allocation concealment



1 A same BL

Cometta 1994 35/148 25/144 16.2 % 1.36 [ 0.86, 2.16 ]

D’Antonio 1992 43/144 35/142 22.5 % 1.21 [ 0.83, 1.77 ]

Dupont 2000 55/99 55/105 34.2 % 1.06 [ 0.82, 1.37 ]

Kljucar 1990 12/44 9/45 5.7 % 1.36 [ 0.64, 2.91 ]

Korzeniowski 1982 3/33 7/41 4.0 % 0.53 [ 0.15, 1.90 ]

Mergoni 1987 4/20 4/22 2.4 % 1.10 [ 0.32, 3.83 ]

Ribera 1996 11/45 14/45 9.0 % 0.79 [ 0.40, 1.54 ]

Sandberg 1997 8/26 11/35 6.0 % 0.98 [ 0.46, 2.09 ]

Subtotal (95% CI) 559 579 100.0 % 1.11 [ 0.93, 1.32 ]




2 B same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Biglino 1991 1/12 1/10 1.8 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 7.2 % 0.66 [ 0.17, 2.63 ]

Cardozo 2001 9/56 9/48 16.4 % 0.86 [ 0.37, 1.98 ]

Coppens 1983 2/22 7/44 7.9 % 0.57 [ 0.13, 2.52 ]

Klastersky 1973 11/22 4/23 6.6 % 2.88 [ 1.07, 7.69 ]

Piccart 1984 7/42 11/43 18.4 % 0.65 [ 0.28, 1.52 ]

Sage 1987 10/26 2/22 3.7 % 4.23 [ 1.03, 17.29 ]

Sculier 1982 3/10 4/10 6.8 % 0.75 [ 0.22, 2.52 ]

Sexton 1998 1/26 1/25 1.7 % 0.96 [ 0.06, 14.55 ]

Sukoh 1994 6/30 5/33 8.0 % 1.32 [ 0.45, 3.88 ]

Takamoto 1994 12/77 13/80 21.5 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 360 372 100.0 % 1.09 [ 0.79, 1.50 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )








3 A different BL

Alvarez-Lerma 2001a 10/57 20/59 9.0 % 0.52 [ 0.27, 1.01 ]

Arich 1987 3/25 5/22 2.4 % 0.53 [ 0.14, 1.96 ]

Finer 1992 24/220 22/195 10.6 % 0.97 [ 0.56, 1.67 ]

Gomez 1990a 6/39 5/39 2.3 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 8/45 13/41 6.2 % 0.56 [ 0.26, 1.21 ]

Jaspers 1998 12/39 15/40 6.7 % 0.82 [ 0.44, 1.52 ]

McCormick 1997 13/65 8/63 3.7 % 1.58 [ 0.70, 3.54 ]

Rubinstein 1995 40/267 59/238 28.4 % 0.60 [ 0.42, 0.87 ]

Sanfilippo 1989 0/13 1/13 0.7 % 0.33 [ 0.01, 7.50 ]

Smith 1984 35/96 58/99 26.0 % 0.62 [ 0.46, 0.85 ]

Speich 1998 4/41 7/43 3.1 % 0.60 [ 0.19, 1.90 ]

Wing 1998 6/117 0/62 0.3 % 6.94 [ 0.40, 121.21 ]

Yellin 1993 1/56 1/34 0.6 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 1080 948 100.0 % 0.72 [ 0.60, 0.86 ]




4 B different BL

Aguilar 1992 0/19 3/17 1.3 % 0.13 [ 0.01, 2.32 ]

Bergeron 1988 2/37 5/30 2.0 % 0.32 [ 0.07, 1.56 ]

Brown 1984 7/18 9/16 3.4 % 0.69 [ 0.34, 1.42 ]

Cone 1985 3/21 4/19 1.5 % 0.68 [ 0.17, 2.65 ]

Felisart 1985 9/37 18/36 6.5 % 0.49 [ 0.25, 0.94 ]

Gerecht 1989 4/24 13/22 4.8 % 0.28 [ 0.11, 0.74 ]

Havig 1973 1/24 2/26 0.7 % 0.54 [ 0.05, 5.60 ]

Holloway 1985 2/15 3/18 1.0 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 4/48 10/47 3.6 % 0.39 [ 0.13, 1.16 ]

Koehler 1990 13/63 6/64 2.1 % 2.20 [ 0.89, 5.43 ]

Limson 1988 2/20 3/20 1.1 % 0.67 [ 0.12, 3.57 ]

Mandell 1987 7/52 9/58 3.0 % 0.87 [ 0.35, 2.16 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Martin 1991 10/52 8/42 3.1 % 1.01 [ 0.44, 2.33 ]

Moreno 1997 1/30 0/28 0.2 % 2.81 [ 0.12, 66.17 ]

Mouton 1990 39/105 43/106 15.1 % 0.92 [ 0.65, 1.29 ]

Mouton 1995 14/111 20/118 6.9 % 0.74 [ 0.40, 1.40 ]

Muller 1987 16/73 5/33 2.4 % 1.45 [ 0.58, 3.62 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 2/17 3/18 1.0 % 0.71 [ 0.13, 3.72 ]

Rasmussen 1986 1/29 1/30 0.3 % 1.03 [ 0.07, 15.77 ]

Sieger 1997 30/106 43/105 15.3 % 0.69 [ 0.47, 1.01 ]

Stille 1992 22/186 26/151 10.2 % 0.69 [ 0.41, 1.16 ]

Thompson 1990 15/49 14/47 5.1 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 0.2 % 2.53 [ 0.12, 51.50 ]

Trujillo 1992 0/16 2/14 0.9 % 0.18 [ 0.01, 3.39 ]

Vergnon 1985 7/16 4/14 1.5 % 1.53 [ 0.56, 4.15 ]

Verzasconi 1995 6/45 8/42 2.9 % 0.70 [ 0.26, 1.85 ]

Warren 1983 13/56 12/64 4.0 % 1.24 [ 0.62, 2.49 ]

Subtotal (95% CI) 1364 1240 100.0 % 0.79 [ 0.68, 0.92 ]




5 C different BL

Duff 1982 12/31 16/43 81.7 % 1.04 [ 0.58, 1.87 ]

Landau 1990 4/20 3/20 18.3 % 1.33 [ 0.34, 5.21 ]

Subtotal (95% CI) 51 63 100.0 % 1.09 [ 0.63, 1.88 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 A same BL

Cometta 1994 35/148 25/144 16.2 % 1.36 [ 0.86, 2.16 ]

D’Antonio 1992 43/144 35/142 22.5 % 1.21 [ 0.83, 1.77 ]

Dupont 2000 55/99 55/105 34.2 % 1.06 [ 0.82, 1.37 ]

Kljucar 1990 12/44 9/45 5.7 % 1.36 [ 0.64, 2.91 ]

Korzeniowski 1982 3/33 7/41 4.0 % 0.53 [ 0.15, 1.90 ]

Mergoni 1987 4/20 4/22 2.4 % 1.10 [ 0.32, 3.83 ]

Ribera 1996 11/45 14/45 9.0 % 0.79 [ 0.40, 1.54 ]

Sandberg 1997 8/26 11/35 6.0 % 0.98 [ 0.46, 2.09 ]

Subtotal (95% CI) 559 579 100.0 % 1.11 [ 0.93, 1.32 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 B same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Biglino 1991 1/12 1/10 1.8 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 7.2 % 0.66 [ 0.17, 2.63 ]

Cardozo 2001 9/56 9/48 16.4 % 0.86 [ 0.37, 1.98 ]

Coppens 1983 2/22 7/44 7.9 % 0.57 [ 0.13, 2.52 ]

Klastersky 1973 11/22 4/23 6.6 % 2.88 [ 1.07, 7.69 ]

Piccart 1984 7/42 11/43 18.4 % 0.65 [ 0.28, 1.52 ]

Sage 1987 10/26 2/22 3.7 % 4.23 [ 1.03, 17.29 ]

Sculier 1982 3/10 4/10 6.8 % 0.75 [ 0.22, 2.52 ]

Sexton 1998 1/26 1/25 1.7 % 0.96 [ 0.06, 14.55 ]

Sukoh 1994 6/30 5/33 8.0 % 1.32 [ 0.45, 3.88 ]

Takamoto 1994 12/77 13/80 21.5 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 360 372 100.0 % 1.09 [ 0.79, 1.50 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









3 A different BL

Alvarez-Lerma 2001a 10/57 20/59 9.0 % 0.52 [ 0.27, 1.01 ]

Arich 1987 3/25 5/22 2.4 % 0.53 [ 0.14, 1.96 ]

Finer 1992 24/220 22/195 10.6 % 0.97 [ 0.56, 1.67 ]

Gomez 1990a 6/39 5/39 2.3 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 8/45 13/41 6.2 % 0.56 [ 0.26, 1.21 ]

Jaspers 1998 12/39 15/40 6.7 % 0.82 [ 0.44, 1.52 ]

McCormick 1997 13/65 8/63 3.7 % 1.58 [ 0.70, 3.54 ]

Rubinstein 1995 40/267 59/238 28.4 % 0.60 [ 0.42, 0.87 ]

Sanfilippo 1989 0/13 1/13 0.7 % 0.33 [ 0.01, 7.50 ]

Smith 1984 35/96 58/99 26.0 % 0.62 [ 0.46, 0.85 ]

Speich 1998 4/41 7/43 3.1 % 0.60 [ 0.19, 1.90 ]

Wing 1998 6/117 0/62 0.3 % 6.94 [ 0.40, 121.21 ]

Yellin 1993 1/56 1/34 0.6 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 1080 948 100.0 % 0.72 [ 0.60, 0.86 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









4 B different BL

Aguilar 1992 0/19 3/17 1.3 % 0.13 [ 0.01, 2.32 ]

Bergeron 1988 2/37 5/30 2.0 % 0.32 [ 0.07, 1.56 ]

Brown 1984 7/18 9/16 3.4 % 0.69 [ 0.34, 1.42 ]

Cone 1985 3/21 4/19 1.5 % 0.68 [ 0.17, 2.65 ]

Felisart 1985 9/37 18/36 6.5 % 0.49 [ 0.25, 0.94 ]

Gerecht 1989 4/24 13/22 4.8 % 0.28 [ 0.11, 0.74 ]

Havig 1973 1/24 2/26 0.7 % 0.54 [ 0.05, 5.60 ]

Holloway 1985 2/15 3/18 1.0 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 4/48 10/47 3.6 % 0.39 [ 0.13, 1.16 ]

Koehler 1990 13/63 6/64 2.1 % 2.20 [ 0.89, 5.43 ]

Limson 1988 2/20 3/20 1.1 % 0.67 [ 0.12, 3.57 ]

Mandell 1987 7/52 9/58 3.0 % 0.87 [ 0.35, 2.16 ]

Martin 1991 10/52 8/42 3.1 % 1.01 [ 0.44, 2.33 ]

Moreno 1997 1/30 0/28 0.2 % 2.81 [ 0.12, 66.17 ]

Mouton 1990 39/105 43/106 15.1 % 0.92 [ 0.65, 1.29 ]

Mouton 1995 14/111 20/118 6.9 % 0.74 [ 0.40, 1.40 ]

Muller 1987 16/73 5/33 2.4 % 1.45 [ 0.58, 3.62 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 2/17 3/18 1.0 % 0.71 [ 0.13, 3.72 ]

Rasmussen 1986 1/29 1/30 0.3 % 1.03 [ 0.07, 15.77 ]

Sieger 1997 30/106 43/105 15.3 % 0.69 [ 0.47, 1.01 ]

Stille 1992 22/186 26/151 10.2 % 0.69 [ 0.41, 1.16 ]

Thompson 1990 15/49 14/47 5.1 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 0.2 % 2.53 [ 0.12, 51.50 ]

Trujillo 1992 0/16 2/14 0.9 % 0.18 [ 0.01, 3.39 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Vergnon 1985 7/16 4/14 1.5 % 1.53 [ 0.56, 4.15 ]

Verzasconi 1995 6/45 8/42 2.9 % 0.70 [ 0.26, 1.85 ]

Warren 1983 13/56 12/64 4.0 % 1.24 [ 0.62, 2.49 ]

Subtotal (95% CI) 1364 1240 100.0 % 0.79 [ 0.68, 0.92 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







5 C different BL

Duff 1982 12/31 16/43 81.7 % 1.04 [ 0.58, 1.87 ]

Landau 1990 4/20 3/20 18.3 % 1.33 [ 0.34, 5.21 ]

Subtotal (95% CI) 51 63 100.0 % 1.09 [ 0.63, 1.88 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0





Clinical failure by allocation generation.



Outcome: 5 Clinical failure by allocation generation



1 A same BL

Cometta 1994 35/148 25/144 14.9 % 1.36 [ 0.86, 2.16 ]

Coppens 1983 2/22 7/44 2.7 % 0.57 [ 0.13, 2.52 ]

D’Antonio 1992 43/144 35/142 20.7 % 1.21 [ 0.83, 1.77 ]

Dupont 2000 55/99 55/105 31.4 % 1.06 [ 0.82, 1.37 ]

Kljucar 1990 12/44 9/45 5.2 % 1.36 [ 0.64, 2.91 ]

Korzeniowski 1982 3/33 7/41 3.7 % 0.53 [ 0.15, 1.90 ]

Ribera 1996 11/45 14/45 8.2 % 0.79 [ 0.40, 1.54 ]

Sandberg 1997 8/26 11/35 5.5 % 0.98 [ 0.46, 2.09 ]

Takamoto 1994 12/77 13/80 7.5 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 638 681 100.0 % 1.09 [ 0.91, 1.29 ]




2 B same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Biglino 1991 1/12 1/10 2.4 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 9.3 % 0.66 [ 0.17, 2.63 ]

Cardozo 2001 9/56 9/48 21.3 % 0.86 [ 0.37, 1.98 ]

Klastersky 1973 11/22 4/23 8.6 % 2.88 [ 1.07, 7.69 ]

Mergoni 1987 4/20 4/22 8.4 % 1.10 [ 0.32, 3.83 ]

Piccart 1984 7/42 11/43 23.9 % 0.65 [ 0.28, 1.52 ]

Sage 1987 10/26 2/22 4.8 % 4.23 [ 1.03, 17.29 ]

Sculier 1982 3/10 4/10 8.8 % 0.75 [ 0.22, 2.52 ]

Sexton 1998 1/26 1/25 2.2 % 0.96 [ 0.06, 14.55 ]

Sukoh 1994 6/30 5/33 10.4 % 1.32 [ 0.45, 3.88 ]

Subtotal (95% CI) 281 270 100.0 % 1.18 [ 0.83, 1.69 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )








3 A different BL

Alvarez-Lerma 2001a 10/57 20/59 5.9 % 0.52 [ 0.27, 1.01 ]

Arich 1987 3/25 5/22 1.6 % 0.53 [ 0.14, 1.96 ]

Brown 1984 7/18 9/16 2.9 % 0.69 [ 0.34, 1.42 ]

Felisart 1985 9/37 18/36 5.5 % 0.49 [ 0.25, 0.94 ]

Finer 1992 24/220 22/195 7.0 % 0.97 [ 0.56, 1.67 ]

Gerecht 1989 4/24 13/22 4.1 % 0.28 [ 0.11, 0.74 ]

Gomez 1990a 6/39 5/39 1.5 % 1.20 [ 0.40, 3.61 ]

Havig 1973 1/24 2/26 0.6 % 0.54 [ 0.05, 5.60 ]

Jaspers 1998 12/39 15/40 4.4 % 0.82 [ 0.44, 1.52 ]

Mandell 1987 7/52 9/58 2.6 % 0.87 [ 0.35, 2.16 ]

Martin 1991 10/52 8/42 2.7 % 1.01 [ 0.44, 2.33 ]

McCormick 1997 13/65 8/63 2.4 % 1.58 [ 0.70, 3.54 ]

Muller 1987 16/73 5/33 2.1 % 1.45 [ 0.58, 3.62 ]

Rasmussen 1986 1/29 1/30 0.3 % 1.03 [ 0.07, 15.77 ]

Rubinstein 1995 40/267 59/238 18.7 % 0.60 [ 0.42, 0.87 ]

Sanfilippo 1989 0/13 1/13 0.4 % 0.33 [ 0.01, 7.50 ]

Smith 1984 35/96 58/99 17.1 % 0.62 [ 0.46, 0.85 ]

Speich 1998 4/41 7/43 2.0 % 0.60 [ 0.19, 1.90 ]

Stille 1992 22/186 26/151 8.6 % 0.69 [ 0.41, 1.16 ]

Thompson 1990 15/49 14/47 4.3 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 0.2 % 2.53 [ 0.12, 51.50 ]

Vergnon 1985 7/16 4/14 1.3 % 1.53 [ 0.56, 4.15 ]

Warren 1983 13/56 12/64 3.4 % 1.24 [ 0.62, 2.49 ]

Wing 1998 6/117 0/62 0.2 % 6.94 [ 0.40, 121.21 ]

Yellin 1993 1/56 1/34 0.4 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 1731 1486 100.0 % 0.76 [ 0.66, 0.88 ]




4 B different BL

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Aguilar 1992 0/19 3/17 2.2 % 0.13 [ 0.01, 2.32 ]

Bergeron 1988 2/37 5/30 3.3 % 0.32 [ 0.07, 1.56 ]

Cone 1985 3/21 4/19 2.5 % 0.68 [ 0.17, 2.65 ]

Hoepelman 1988 8/45 13/41 8.1 % 0.56 [ 0.26, 1.21 ]

Holloway 1985 2/15 3/18 1.6 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 4/48 10/47 6.0 % 0.39 [ 0.13, 1.16 ]

Koehler 1990 13/63 6/64 3.5 % 2.20 [ 0.89, 5.43 ]

Limson 1988 2/20 3/20 1.8 % 0.67 [ 0.12, 3.57 ]

Moreno 1997 1/30 0/28 0.3 % 2.81 [ 0.12, 66.17 ]

Mouton 1990 39/105 43/106 25.4 % 0.92 [ 0.65, 1.29 ]

Mouton 1995 14/111 20/118 11.5 % 0.74 [ 0.40, 1.40 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 2/17 3/18 1.7 % 0.71 [ 0.13, 3.72 ]

Sieger 1997 30/106 43/105 25.6 % 0.69 [ 0.47, 1.01 ]

Trujillo 1992 0/16 2/14 1.6 % 0.18 [ 0.01, 3.39 ]

Verzasconi 1995 6/45 8/42 4.9 % 0.70 [ 0.26, 1.85 ]

Subtotal (95% CI) 713 702 100.0 % 0.75 [ 0.62, 0.92 ]




5 C different BL

Duff 1982 12/31 16/43 81.7 % 1.04 [ 0.58, 1.87 ]

Landau 1990 4/20 3/20 18.3 % 1.33 [ 0.34, 5.21 ]

Subtotal (95% CI) 51 63 100.0 % 1.09 [ 0.63, 1.88 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 A same BL

Cometta 1994 35/148 25/144 14.9 % 1.36 [ 0.86, 2.16 ]

Coppens 1983 2/22 7/44 2.7 % 0.57 [ 0.13, 2.52 ]

D’Antonio 1992 43/144 35/142 20.7 % 1.21 [ 0.83, 1.77 ]

Dupont 2000 55/99 55/105 31.4 % 1.06 [ 0.82, 1.37 ]

Kljucar 1990 12/44 9/45 5.2 % 1.36 [ 0.64, 2.91 ]

Korzeniowski 1982 3/33 7/41 3.7 % 0.53 [ 0.15, 1.90 ]

Ribera 1996 11/45 14/45 8.2 % 0.79 [ 0.40, 1.54 ]

Sandberg 1997 8/26 11/35 5.5 % 0.98 [ 0.46, 2.09 ]

Takamoto 1994 12/77 13/80 7.5 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 638 681 100.0 % 1.09 [ 0.91, 1.29 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 B same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Biglino 1991 1/12 1/10 2.4 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 9.3 % 0.66 [ 0.17, 2.63 ]

Cardozo 2001 9/56 9/48 21.3 % 0.86 [ 0.37, 1.98 ]

Klastersky 1973 11/22 4/23 8.6 % 2.88 [ 1.07, 7.69 ]

Mergoni 1987 4/20 4/22 8.4 % 1.10 [ 0.32, 3.83 ]

Piccart 1984 7/42 11/43 23.9 % 0.65 [ 0.28, 1.52 ]

Sage 1987 10/26 2/22 4.8 % 4.23 [ 1.03, 17.29 ]

Sculier 1982 3/10 4/10 8.8 % 0.75 [ 0.22, 2.52 ]

Sexton 1998 1/26 1/25 2.2 % 0.96 [ 0.06, 14.55 ]

Sukoh 1994 6/30 5/33 10.4 % 1.32 [ 0.45, 3.88 ]

Subtotal (95% CI) 281 270 100.0 % 1.18 [ 0.83, 1.69 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









3 A different BL

Alvarez-Lerma 2001a 10/57 20/59 5.9 % 0.52 [ 0.27, 1.01 ]

Arich 1987 3/25 5/22 1.6 % 0.53 [ 0.14, 1.96 ]

Brown 1984 7/18 9/16 2.9 % 0.69 [ 0.34, 1.42 ]

Felisart 1985 9/37 18/36 5.5 % 0.49 [ 0.25, 0.94 ]

Finer 1992 24/220 22/195 7.0 % 0.97 [ 0.56, 1.67 ]

Gerecht 1989 4/24 13/22 4.1 % 0.28 [ 0.11, 0.74 ]

Gomez 1990a 6/39 5/39 1.5 % 1.20 [ 0.40, 3.61 ]

Havig 1973 1/24 2/26 0.6 % 0.54 [ 0.05, 5.60 ]

Jaspers 1998 12/39 15/40 4.4 % 0.82 [ 0.44, 1.52 ]

Mandell 1987 7/52 9/58 2.6 % 0.87 [ 0.35, 2.16 ]

Martin 1991 10/52 8/42 2.7 % 1.01 [ 0.44, 2.33 ]

McCormick 1997 13/65 8/63 2.4 % 1.58 [ 0.70, 3.54 ]

Muller 1987 16/73 5/33 2.1 % 1.45 [ 0.58, 3.62 ]

Rasmussen 1986 1/29 1/30 0.3 % 1.03 [ 0.07, 15.77 ]

Rubinstein 1995 40/267 59/238 18.7 % 0.60 [ 0.42, 0.87 ]

Sanfilippo 1989 0/13 1/13 0.4 % 0.33 [ 0.01, 7.50 ]

Smith 1984 35/96 58/99 17.1 % 0.62 [ 0.46, 0.85 ]

Speich 1998 4/41 7/43 2.0 % 0.60 [ 0.19, 1.90 ]

Stille 1992 22/186 26/151 8.6 % 0.69 [ 0.41, 1.16 ]

Thompson 1990 15/49 14/47 4.3 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 0.2 % 2.53 [ 0.12, 51.50 ]

Vergnon 1985 7/16 4/14 1.3 % 1.53 [ 0.56, 4.15 ]

Warren 1983 13/56 12/64 3.4 % 1.24 [ 0.62, 2.49 ]

Wing 1998 6/117 0/62 0.2 % 6.94 [ 0.40, 121.21 ]

Yellin 1993 1/56 1/34 0.4 % 0.61 [ 0.04, 9.39 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Subtotal (95% CI) 1731 1486 100.0 % 0.76 [ 0.66, 0.88 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







4 B different BL

Aguilar 1992 0/19 3/17 2.2 % 0.13 [ 0.01, 2.32 ]

Bergeron 1988 2/37 5/30 3.3 % 0.32 [ 0.07, 1.56 ]

Cone 1985 3/21 4/19 2.5 % 0.68 [ 0.17, 2.65 ]

Hoepelman 1988 8/45 13/41 8.1 % 0.56 [ 0.26, 1.21 ]

Holloway 1985 2/15 3/18 1.6 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 4/48 10/47 6.0 % 0.39 [ 0.13, 1.16 ]

Koehler 1990 13/63 6/64 3.5 % 2.20 [ 0.89, 5.43 ]

Limson 1988 2/20 3/20 1.8 % 0.67 [ 0.12, 3.57 ]

Moreno 1997 1/30 0/28 0.3 % 2.81 [ 0.12, 66.17 ]

Mouton 1990 39/105 43/106 25.4 % 0.92 [ 0.65, 1.29 ]

Mouton 1995 14/111 20/118 11.5 % 0.74 [ 0.40, 1.40 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 2/17 3/18 1.7 % 0.71 [ 0.13, 3.72 ]

Sieger 1997 30/106 43/105 25.6 % 0.69 [ 0.47, 1.01 ]

Trujillo 1992 0/16 2/14 1.6 % 0.18 [ 0.01, 3.39 ]

Verzasconi 1995 6/45 8/42 4.9 % 0.70 [ 0.26, 1.85 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Subtotal (95% CI) 713 702 100.0 % 0.75 [ 0.62, 0.92 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







5 C different BL

Duff 1982 12/31 16/43 81.7 % 1.04 [ 0.58, 1.87 ]

Landau 1990 4/20 3/20 18.3 % 1.33 [ 0.34, 5.21 ]

Subtotal (95% CI) 51 63 100.0 % 1.09 [ 0.63, 1.88 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0





Clinical failure by blinding.



Outcome: 6 Clinical failure by blinding



1 Non-blinded - same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Biglino 1991 1/12 1/10 0.7 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 2.6 % 0.66 [ 0.17, 2.63 ]

Cardozo 2001 9/56 9/48 6.0 % 0.86 [ 0.37, 1.98 ]

Cometta 1994 35/148 25/144 15.6 % 1.36 [ 0.86, 2.16 ]

Coppens 1983 2/22 7/44 2.9 % 0.57 [ 0.13, 2.52 ]

D’Antonio 1992 43/144 35/142 21.7 % 1.21 [ 0.83, 1.77 ]

Klastersky 1973 11/22 4/23 2.4 % 2.88 [ 1.07, 7.69 ]

Kljucar 1990 12/44 9/45 5.5 % 1.36 [ 0.64, 2.91 ]

Korzeniowski 1982 3/33 7/41 3.9 % 0.53 [ 0.15, 1.90 ]

Mergoni 1987 4/20 4/22 2.4 % 1.10 [ 0.32, 3.83 ]

Piccart 1984 7/42 11/43 6.7 % 0.65 [ 0.28, 1.52 ]

Ribera 1996 11/45 14/45 8.6 % 0.79 [ 0.40, 1.54 ]

Sage 1987 10/26 2/22 1.3 % 4.23 [ 1.03, 17.29 ]

Sandberg 1997 8/26 11/35 5.8 % 0.98 [ 0.46, 2.09 ]

Sculier 1982 3/10 4/10 2.5 % 0.75 [ 0.22, 2.52 ]

Sexton 1998 1/26 1/25 0.6 % 0.96 [ 0.06, 14.55 ]

Sukoh 1994 6/30 5/33 2.9 % 1.32 [ 0.45, 3.88 ]

Takamoto 1994 12/77 13/80 7.9 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 820 846 100.0 % 1.12 [ 0.93, 1.35 ]




2 Any blinding - same BL

Dupont 2000 55/99 55/105 100.0 % 1.06 [ 0.82, 1.37 ]

Subtotal (95% CI) 99 105 100.0 % 1.06 [ 0.82, 1.37 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )








3 Non-blinded - different BL

Aguilar 1992 0/19 3/17 1.0 % 0.13 [ 0.01, 2.32 ]

Alvarez-Lerma 2001a 10/57 20/59 5.2 % 0.52 [ 0.27, 1.01 ]

Arich 1987 3/25 5/22 1.4 % 0.53 [ 0.14, 1.96 ]

Bergeron 1988 2/37 5/30 1.5 % 0.32 [ 0.07, 1.56 ]

Cone 1985 3/21 4/19 1.1 % 0.68 [ 0.17, 2.65 ]

Duff 1982 12/31 16/43 3.5 % 1.04 [ 0.58, 1.87 ]

Felisart 1985 9/37 18/36 4.8 % 0.49 [ 0.25, 0.94 ]

Finer 1992 24/220 22/195 6.2 % 0.97 [ 0.56, 1.67 ]

Gerecht 1989 4/24 13/22 3.6 % 0.28 [ 0.11, 0.74 ]

Gomez 1990a 6/39 5/39 1.3 % 1.20 [ 0.40, 3.61 ]

Havig 1973 1/24 2/26 0.5 % 0.54 [ 0.05, 5.60 ]

Hoepelman 1988 8/45 13/41 3.6 % 0.56 [ 0.26, 1.21 ]

Holloway 1985 2/15 3/18 0.7 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 4/48 10/47 2.7 % 0.39 [ 0.13, 1.16 ]

Jaspers 1998 12/39 15/40 3.9 % 0.82 [ 0.44, 1.52 ]

Koehler 1990 13/63 6/64 1.6 % 2.20 [ 0.89, 5.43 ]

Landau 1990 4/20 3/20 0.8 % 1.33 [ 0.34, 5.21 ]

Limson 1988 2/20 3/20 0.8 % 0.67 [ 0.12, 3.57 ]

Mandell 1987 7/52 9/58 2.2 % 0.87 [ 0.35, 2.16 ]

Martin 1991 10/52 8/42 2.3 % 1.01 [ 0.44, 2.33 ]

McCormick 1997 13/65 8/63 2.1 % 1.58 [ 0.70, 3.54 ]

Moreno 1997 1/30 0/28 0.1 % 2.81 [ 0.12, 66.17 ]

Mouton 1990 39/105 43/106 11.3 % 0.92 [ 0.65, 1.29 ]

Mouton 1995 14/111 20/118 5.1 % 0.74 [ 0.40, 1.40 ]

Muller 1987 16/73 5/33 1.8 % 1.45 [ 0.58, 3.62 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 2/17 3/18 0.8 % 0.71 [ 0.13, 3.72 ]

Rasmussen 1986 1/29 1/30 0.3 % 1.03 [ 0.07, 15.77 ]

Sieger 1997 30/106 43/105 11.4 % 0.69 [ 0.47, 1.01 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Speich 1998 4/41 7/43 1.8 % 0.60 [ 0.19, 1.90 ]

Stille 1992 22/186 26/151 7.6 % 0.69 [ 0.41, 1.16 ]

Thompson 1990 15/49 14/47 3.8 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 0.2 % 2.53 [ 0.12, 51.50 ]

Trujillo 1992 0/16 2/14 0.7 % 0.18 [ 0.01, 3.39 ]

Vergnon 1985 7/16 4/14 1.1 % 1.53 [ 0.56, 4.15 ]

Warren 1983 13/56 12/64 3.0 % 1.24 [ 0.62, 2.49 ]

Wing 1998 6/117 0/62 0.2 % 6.94 [ 0.40, 121.21 ]

Subtotal (95% CI) 2000 1809 100.0 % 0.82 [ 0.72, 0.94 ]




4 Any blinding - different BL

Brown 1984 7/18 9/16 6.8 % 0.69 [ 0.34, 1.42 ]

Rubinstein 1995 40/267 59/238 44.5 % 0.60 [ 0.42, 0.87 ]

Sanfilippo 1989 0/13 1/13 1.1 % 0.33 [ 0.01, 7.50 ]

Smith 1984 35/96 58/99 40.8 % 0.62 [ 0.46, 0.85 ]

Verzasconi 1995 6/45 8/42 5.9 % 0.70 [ 0.26, 1.85 ]

Yellin 1993 1/56 1/34 0.9 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 495 442 100.0 % 0.62 [ 0.50, 0.77 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









1 Non-blinded - same BL

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Biglino 1991 1/12 1/10 0.7 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 2.6 % 0.66 [ 0.17, 2.63 ]

Cardozo 2001 9/56 9/48 6.0 % 0.86 [ 0.37, 1.98 ]

Cometta 1994 35/148 25/144 15.6 % 1.36 [ 0.86, 2.16 ]

Coppens 1983 2/22 7/44 2.9 % 0.57 [ 0.13, 2.52 ]

D’Antonio 1992 43/144 35/142 21.7 % 1.21 [ 0.83, 1.77 ]

Klastersky 1973 11/22 4/23 2.4 % 2.88 [ 1.07, 7.69 ]

Kljucar 1990 12/44 9/45 5.5 % 1.36 [ 0.64, 2.91 ]

Korzeniowski 1982 3/33 7/41 3.9 % 0.53 [ 0.15, 1.90 ]

Mergoni 1987 4/20 4/22 2.4 % 1.10 [ 0.32, 3.83 ]

Piccart 1984 7/42 11/43 6.7 % 0.65 [ 0.28, 1.52 ]

Ribera 1996 11/45 14/45 8.6 % 0.79 [ 0.40, 1.54 ]

Sage 1987 10/26 2/22 1.3 % 4.23 [ 1.03, 17.29 ]

Sandberg 1997 8/26 11/35 5.8 % 0.98 [ 0.46, 2.09 ]

Sculier 1982 3/10 4/10 2.5 % 0.75 [ 0.22, 2.52 ]

Sexton 1998 1/26 1/25 0.6 % 0.96 [ 0.06, 14.55 ]

Sukoh 1994 6/30 5/33 2.9 % 1.32 [ 0.45, 3.88 ]

Takamoto 1994 12/77 13/80 7.9 % 0.96 [ 0.47, 1.97 ]

Subtotal (95% CI) 820 846 100.0 % 1.12 [ 0.93, 1.35 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 Any blinding - same BL

Dupont 2000 55/99 55/105 100.0 % 1.06 [ 0.82, 1.37 ]

Subtotal (95% CI) 99 105 100.0 % 1.06 [ 0.82, 1.37 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







3 Non-blinded - different BL

Aguilar 1992 0/19 3/17 1.0 % 0.13 [ 0.01, 2.32 ]

Alvarez-Lerma 2001a 10/57 20/59 5.2 % 0.52 [ 0.27, 1.01 ]

Arich 1987 3/25 5/22 1.4 % 0.53 [ 0.14, 1.96 ]

Bergeron 1988 2/37 5/30 1.5 % 0.32 [ 0.07, 1.56 ]

Cone 1985 3/21 4/19 1.1 % 0.68 [ 0.17, 2.65 ]

Duff 1982 12/31 16/43 3.5 % 1.04 [ 0.58, 1.87 ]

Felisart 1985 9/37 18/36 4.8 % 0.49 [ 0.25, 0.94 ]

Finer 1992 24/220 22/195 6.2 % 0.97 [ 0.56, 1.67 ]

Gerecht 1989 4/24 13/22 3.6 % 0.28 [ 0.11, 0.74 ]

Gomez 1990a 6/39 5/39 1.3 % 1.20 [ 0.40, 3.61 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Havig 1973 1/24 2/26 0.5 % 0.54 [ 0.05, 5.60 ]

Hoepelman 1988 8/45 13/41 3.6 % 0.56 [ 0.26, 1.21 ]

Holloway 1985 2/15 3/18 0.7 % 0.80 [ 0.15, 4.18 ]

Iakovlev 1998 4/48 10/47 2.7 % 0.39 [ 0.13, 1.16 ]

Jaspers 1998 12/39 15/40 3.9 % 0.82 [ 0.44, 1.52 ]

Koehler 1990 13/63 6/64 1.6 % 2.20 [ 0.89, 5.43 ]

Landau 1990 4/20 3/20 0.8 % 1.33 [ 0.34, 5.21 ]

Limson 1988 2/20 3/20 0.8 % 0.67 [ 0.12, 3.57 ]

Mandell 1987 7/52 9/58 2.2 % 0.87 [ 0.35, 2.16 ]

Martin 1991 10/52 8/42 2.3 % 1.01 [ 0.44, 2.33 ]

McCormick 1997 13/65 8/63 2.1 % 1.58 [ 0.70, 3.54 ]

Moreno 1997 1/30 0/28 0.1 % 2.81 [ 0.12, 66.17 ]

Mouton 1990 39/105 43/106 11.3 % 0.92 [ 0.65, 1.29 ]

Mouton 1995 14/111 20/118 5.1 % 0.74 [ 0.40, 1.40 ]

Muller 1987 16/73 5/33 1.8 % 1.45 [ 0.58, 3.62 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Rapp 1984 2/17 3/18 0.8 % 0.71 [ 0.13, 3.72 ]

Rasmussen 1986 1/29 1/30 0.3 % 1.03 [ 0.07, 15.77 ]

Sieger 1997 30/106 43/105 11.4 % 0.69 [ 0.47, 1.01 ]

Speich 1998 4/41 7/43 1.8 % 0.60 [ 0.19, 1.90 ]

Stille 1992 22/186 26/151 7.6 % 0.69 [ 0.41, 1.16 ]

Thompson 1990 15/49 14/47 3.8 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 0.2 % 2.53 [ 0.12, 51.50 ]

Trujillo 1992 0/16 2/14 0.7 % 0.18 [ 0.01, 3.39 ]

Vergnon 1985 7/16 4/14 1.1 % 1.53 [ 0.56, 4.15 ]

Warren 1983 13/56 12/64 3.0 % 1.24 [ 0.62, 2.49 ]

Wing 1998 6/117 0/62 0.2 % 6.94 [ 0.40, 121.21 ]

Subtotal (95% CI) 2000 1809 100.0 % 0.82 [ 0.72, 0.94 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









4 Any blinding - different BL

Brown 1984 7/18 9/16 6.8 % 0.69 [ 0.34, 1.42 ]

Rubinstein 1995 40/267 59/238 44.5 % 0.60 [ 0.42, 0.87 ]

Sanfilippo 1989 0/13 1/13 1.1 % 0.33 [ 0.01, 7.50 ]

Smith 1984 35/96 58/99 40.8 % 0.62 [ 0.46, 0.85 ]

Verzasconi 1995 6/45 8/42 5.9 % 0.70 [ 0.26, 1.85 ]

Yellin 1993 1/56 1/34 0.9 % 0.61 [ 0.04, 9.39 ]

Subtotal (95% CI) 495 442 100.0 % 0.62 [ 0.50, 0.77 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0





Clinical failure by ITT versus per-protocol analysis.



Outcome: 7 Clinical failure by ITT versus per-protocol analysis



1 ITT - same BL (type 1)

Ribera 1996 11/45 14/45 77.8 % 0.79 [ 0.40, 1.54 ]

Sculier 1982 3/10 4/10 22.2 % 0.75 [ 0.22, 2.52 ]

Subtotal (95% CI) 55 55 100.0 % 0.78 [ 0.43, 1.40 ]




2 ITT assuming failure for drop-outs - same BL (type 2)

Cometta 1994 45/148 36/144 30.0 % 1.22 [ 0.84, 1.77 ]

Klastersky 1973 14/22 6/23 4.8 % 2.44 [ 1.14, 5.20 ]

Kljucar 1990 18/44 14/45 11.4 % 1.31 [ 0.75, 2.31 ]

Korzeniowski 1982 5/33 9/41 6.6 % 0.69 [ 0.26, 1.86 ]

Piccart 1984 20/42 18/43 14.6 % 1.14 [ 0.71, 1.83 ]

Sage 1987 18/26 7/22 6.2 % 2.18 [ 1.12, 4.22 ]

Sandberg 1997 19/26 12/35 8.4 % 2.13 [ 1.27, 3.57 ]

Sexton 1998 1/26 1/25 0.8 % 0.96 [ 0.06, 14.55 ]

Takamoto 1994 18/77 21/80 17.0 % 0.89 [ 0.52, 1.54 ]

Subtotal (95% CI) 444 458 100.0 % 1.32 [ 1.09, 1.60 ]




3 Per protocol - same BL (type 3 studies)

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Coppens 1983 2/22 7/44 4.5 % 0.57 [ 0.13, 2.52 ]

D’Antonio 1992 43/144 35/142 33.9 % 1.21 [ 0.83, 1.77 ]

Dupont 2000 67/99 66/105 61.6 % 1.08 [ 0.88, 1.32 ]

Subtotal (95% CI) 277 303 100.0 % 1.10 [ 0.91, 1.33 ]



0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )






4 Type 4 studies - same BL

Biglino 1991 1/12 1/10 4.6 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 18.0 % 0.66 [ 0.17, 2.63 ]

Cardozo 2001 9/56 9/48 41.1 % 0.86 [ 0.37, 1.98 ]

Mergoni 1987 4/20 4/22 16.1 % 1.10 [ 0.32, 3.83 ]

Sukoh 1994 6/30 5/33 20.2 % 1.32 [ 0.45, 3.88 ]

Subtotal (95% CI) 143 135 100.0 % 0.95 [ 0.56, 1.61 ]




5 ITT - different BL (type 1)

Duff 1982 12/31 16/43 6.9 % 1.04 [ 0.58, 1.87 ]

Felisart 1985 9/37 18/36 9.4 % 0.49 [ 0.25, 0.94 ]

Gomez 1990a 6/39 5/39 2.6 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 8/45 13/41 7.0 % 0.56 [ 0.26, 1.21 ]

Iakovlev 1998 4/48 10/47 5.2 % 0.39 [ 0.13, 1.16 ]

Jaspers 1998 12/39 15/40 7.7 % 0.82 [ 0.44, 1.52 ]

Mouton 1990 39/105 43/106 22.1 % 0.92 [ 0.65, 1.29 ]

Rapp 1984 2/17 3/18 1.5 % 0.71 [ 0.13, 3.72 ]

Sieger 1997 30/106 43/105 22.3 % 0.69 [ 0.47, 1.01 ]

Stille 1992 22/186 26/151 14.8 % 0.69 [ 0.41, 1.16 ]

Wing 1998 6/117 0/62 0.3 % 6.94 [ 0.40, 121.21 ]

Subtotal (95% CI) 770 688 100.0 % 0.76 [ 0.64, 0.92 ]




6 ITT assuming failure for drop-outs - different BL (type 2)

Alvarez-Lerma 2001a 22/57 32/59 9.1 % 0.71 [ 0.48, 1.06 ]

Bergeron 1988 4/37 13/30 4.2 % 0.25 [ 0.09, 0.69 ]

Cone 1985 10/21 14/19 4.3 % 0.65 [ 0.38, 1.09 ]

Finer 1992 53/220 49/195 15.1 % 0.96 [ 0.68, 1.34 ]

Holloway 1985 8/15 7/18 1.9 % 1.37 [ 0.65, 2.90 ]

Koehler 1990 23/63 13/64 3.8 % 1.80 [ 1.00, 3.22 ]

Martin 1991 20/52 20/42 6.4 % 0.81 [ 0.51, 1.29 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Moreno 1997 7/30 6/28 1.8 % 1.09 [ 0.42, 2.85 ]

Mouton 1995 21/111 46/118 13.0 % 0.49 [ 0.31, 0.76 ]

Rubinstein 1995 79/267 95/238 29.2 % 0.74 [ 0.58, 0.94 ]

Speich 1998 7/41 9/43 2.6 % 0.82 [ 0.33, 1.99 ]

Verzasconi 1995 9/45 11/42 3.3 % 0.76 [ 0.35, 1.66 ]

Warren 1983 16/56 12/64 3.3 % 1.52 [ 0.79, 2.94 ]

Yellin 1993 18/56 6/34 2.2 % 1.82 [ 0.80, 4.13 ]

Subtotal (95% CI) 1071 994 100.0 % 0.83 [ 0.73, 0.94 ]




7 Per protocol - different BL (type 3 studies)

Arich 1987 3/25 5/22 4.1 % 0.53 [ 0.14, 1.96 ]

Brown 1984 7/18 9/16 7.3 % 0.69 [ 0.34, 1.42 ]

Gerecht 1989 4/24 13/22 10.4 % 0.28 [ 0.11, 0.74 ]

Havig 1973 1/24 2/26 1.5 % 0.54 [ 0.05, 5.60 ]

Limson 1988 2/20 3/20 2.3 % 0.67 [ 0.12, 3.57 ]

Mandell 1987 7/52 9/58 6.6 % 0.87 [ 0.35, 2.16 ]

McCormick 1997 13/65 8/63 6.3 % 1.58 [ 0.70, 3.54 ]

Muller 1987 16/73 5/33 5.3 % 1.45 [ 0.58, 3.62 ]

Rasmussen 1986 1/29 1/30 0.8 % 1.03 [ 0.07, 15.77 ]

Smith 1984 35/96 58/99 44.0 % 0.62 [ 0.46, 0.85 ]

Thompson 1990 15/49 14/47 11.0 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 0.5 % 2.53 [ 0.12, 51.50 ]

Subtotal (95% CI) 555 476 100.0 % 0.76 [ 0.62, 0.95 ]




8 Type 4 studies - different BL

Aguilar 1992 0/19 3/17 24.4 % 0.13 [ 0.01, 2.32 ]

Landau 1990 4/20 3/20 19.9 % 1.33 [ 0.34, 5.21 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Sanfilippo 1989 0/13 1/13 9.9 % 0.33 [ 0.01, 7.50 ]

Trujillo 1992 0/16 2/14 17.6 % 0.18 [ 0.01, 3.39 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0


(Continued . . . )





Vergnon 1985 7/16 4/14 28.2 % 1.53 [ 0.56, 4.15 ]

Subtotal (95% CI) 99 93 100.0 % 0.79 [ 0.40, 1.56 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







1 ITT - same BL (type 1)

Ribera 1996 11/45 14/45 77.8 % 0.79 [ 0.40, 1.54 ]

Sculier 1982 3/10 4/10 22.2 % 0.75 [ 0.22, 2.52 ]

Subtotal (95% CI) 55 55 100.0 % 0.78 [ 0.43, 1.40 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









2 ITT assuming failure for drop-outs - same BL (type 2)

Cometta 1994 45/148 36/144 30.0 % 1.22 [ 0.84, 1.77 ]

Klastersky 1973 14/22 6/23 4.8 % 2.44 [ 1.14, 5.20 ]

Kljucar 1990 18/44 14/45 11.4 % 1.31 [ 0.75, 2.31 ]

Korzeniowski 1982 5/33 9/41 6.6 % 0.69 [ 0.26, 1.86 ]

Piccart 1984 20/42 18/43 14.6 % 1.14 [ 0.71, 1.83 ]

Sage 1987 18/26 7/22 6.2 % 2.18 [ 1.12, 4.22 ]

Sandberg 1997 19/26 12/35 8.4 % 2.13 [ 1.27, 3.57 ]

Sexton 1998 1/26 1/25 0.8 % 0.96 [ 0.06, 14.55 ]

Takamoto 1994 18/77 21/80 17.0 % 0.89 [ 0.52, 1.54 ]

Subtotal (95% CI) 444 458 100.0 % 1.32 [ 1.09, 1.60 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









3 Per protocol - same BL (type 3 studies)

Abrams 1979 0/12 0/12 0.0 % 0.0 [ 0.0, 0.0 ]

Coppens 1983 2/22 7/44 4.5 % 0.57 [ 0.13, 2.52 ]

D’Antonio 1992 43/144 35/142 33.9 % 1.21 [ 0.83, 1.77 ]

Dupont 2000 67/99 66/105 61.6 % 1.08 [ 0.88, 1.32 ]

Subtotal (95% CI) 277 303 100.0 % 1.10 [ 0.91, 1.33 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0







4 Type 4 studies - same BL

Biglino 1991 1/12 1/10 4.6 % 0.83 [ 0.06, 11.70 ]

Carbon 1987 3/25 4/22 18.0 % 0.66 [ 0.17, 2.63 ]

Cardozo 2001 9/56 9/48 41.1 % 0.86 [ 0.37, 1.98 ]

Mergoni 1987 4/20 4/22 16.1 % 1.10 [ 0.32, 3.83 ]

Sukoh 1994 6/30 5/33 20.2 % 1.32 [ 0.45, 3.88 ]

Subtotal (95% CI) 143 135 100.0 % 0.95 [ 0.56, 1.61 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









5 ITT - different BL (type 1)

Duff 1982 12/31 16/43 6.9 % 1.04 [ 0.58, 1.87 ]

Felisart 1985 9/37 18/36 9.4 % 0.49 [ 0.25, 0.94 ]

Gomez 1990a 6/39 5/39 2.6 % 1.20 [ 0.40, 3.61 ]

Hoepelman 1988 8/45 13/41 7.0 % 0.56 [ 0.26, 1.21 ]

Iakovlev 1998 4/48 10/47 5.2 % 0.39 [ 0.13, 1.16 ]

Jaspers 1998 12/39 15/40 7.7 % 0.82 [ 0.44, 1.52 ]

Mouton 1990 39/105 43/106 22.1 % 0.92 [ 0.65, 1.29 ]

Rapp 1984 2/17 3/18 1.5 % 0.71 [ 0.13, 3.72 ]

Sieger 1997 30/106 43/105 22.3 % 0.69 [ 0.47, 1.01 ]

Stille 1992 22/186 26/151 14.8 % 0.69 [ 0.41, 1.16 ]

Wing 1998 6/117 0/62 0.3 % 6.94 [ 0.40, 121.21 ]

Subtotal (95% CI) 770 688 100.0 % 0.76 [ 0.64, 0.92 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









6 ITT assuming failure for drop-outs - different BL (type 2)

Alvarez-Lerma 2001a 22/57 32/59 9.1 % 0.71 [ 0.48, 1.06 ]

Bergeron 1988 4/37 13/30 4.2 % 0.25 [ 0.09, 0.69 ]

Cone 1985 10/21 14/19 4.3 % 0.65 [ 0.38, 1.09 ]

Finer 1992 53/220 49/195 15.1 % 0.96 [ 0.68, 1.34 ]

Holloway 1985 8/15 7/18 1.9 % 1.37 [ 0.65, 2.90 ]

Koehler 1990 23/63 13/64 3.8 % 1.80 [ 1.00, 3.22 ]

Martin 1991 20/52 20/42 6.4 % 0.81 [ 0.51, 1.29 ]

Moreno 1997 7/30 6/28 1.8 % 1.09 [ 0.42, 2.85 ]

Mouton 1995 21/111 46/118 13.0 % 0.49 [ 0.31, 0.76 ]

Rubinstein 1995 79/267 95/238 29.2 % 0.74 [ 0.58, 0.94 ]

Speich 1998 7/41 9/43 2.6 % 0.82 [ 0.33, 1.99 ]

Verzasconi 1995 9/45 11/42 3.3 % 0.76 [ 0.35, 1.66 ]

Warren 1983 16/56 12/64 3.3 % 1.52 [ 0.79, 2.94 ]

Yellin 1993 18/56 6/34 2.2 % 1.82 [ 0.80, 4.13 ]

Subtotal (95% CI) 1071 994 100.0 % 0.83 [ 0.73, 0.94 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









7 Per protocol - different BL (type 3 studies)

Arich 1987 3/25 5/22 4.1 % 0.53 [ 0.14, 1.96 ]

Brown 1984 7/18 9/16 7.3 % 0.69 [ 0.34, 1.42 ]

Gerecht 1989 4/24 13/22 10.4 % 0.28 [ 0.11, 0.74 ]

Havig 1973 1/24 2/26 1.5 % 0.54 [ 0.05, 5.60 ]

Limson 1988 2/20 3/20 2.3 % 0.67 [ 0.12, 3.57 ]

Mandell 1987 7/52 9/58 6.6 % 0.87 [ 0.35, 2.16 ]

McCormick 1997 13/65 8/63 6.3 % 1.58 [ 0.70, 3.54 ]

Muller 1987 16/73 5/33 5.3 % 1.45 [ 0.58, 3.62 ]

Rasmussen 1986 1/29 1/30 0.8 % 1.03 [ 0.07, 15.77 ]

Smith 1984 35/96 58/99 44.0 % 0.62 [ 0.46, 0.85 ]

Thompson 1990 15/49 14/47 11.0 % 1.03 [ 0.56, 1.89 ]

Thompson 1993 2/80 0/40 0.5 % 2.53 [ 0.12, 51.50 ]

Subtotal (95% CI) 555 476 100.0 % 0.76 [ 0.62, 0.95 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0









8 Type 4 studies - different BL

Aguilar 1992 0/19 3/17 24.4 % 0.13 [ 0.01, 2.32 ]

Landau 1990 4/20 3/20 19.9 % 1.33 [ 0.34, 5.21 ]

Naime Libien 1992 0/15 0/15 0.0 % 0.0 [ 0.0, 0.0 ]

Sanfilippo 1989 0/13 1/13 9.9 % 0.33 [ 0.01, 7.50 ]

Trujillo 1992 0/16 2/14 17.6 % 0.18 [ 0.01, 3.39 ]

Vergnon 1985 7/16 4/14 28.2 % 1.53 [ 0.56, 4.15 ]

Subtotal (95% CI) 99 93 100.0 % 0.79 [ 0.40, 1.56 ]




0.1 0.2 0.5 1.0 2.0 5.0 10.0


A P P E N D I C E S

Appendix 1. Search strategy

Type of patients Interventions RCT filter

pneumonia* OR (aminoglycoside* OR random* OR

infection* OR infect* OR netilmicin* OR control* OR

sepsis OR septic?emia* OR gentamicin* OR single OR double OR blind* OR

bacter* OR bacter?emia* amikacin* OR placebo OR

tobramycin* OR clinical OR

streptomycin* OR comparative OR



(Continued)

isepamicin* OR prospectiv*

sisomicin*)

W H A T ’ S N E W

Last assessed as up-to-date: 10 November 2005.

2 September 2008 Amended Converted to new review format.

H I S T O R Y

Protocol first published: Issue 4, 2001

Review first published: Issue 1, 2006

C O N T R I B U T I O N S O F A U T H O R S

Mical Paul (MP): Performed the search and scanned abstracts; retrieved full-text articles and applied inclusion and exclusion criteria;

performed quality assessment, data extraction,and analysis. MP communicated with authors; wrote protocol and review.

Ishay Silbiger (IS): Applied inclusion and exclusion criteria, and performed quality assessment, data extraction and analysis.

Simona Grozinsky (SG): Extracted the data

Karla Soares-Weiser (KSW): Assisted with inclusion and exclusion of studies; performed quality assessment, data extraction and analysis;

assisted with the writing and reviewed all versions of protocol and review.

Leonard Leibovici (LL): Assisted with inclusion and exclusion of studies; performed quality assessment, data extraction and analysis;

assisted with communication with authors; assisted with the writing and reviewed all versions of protocol and review.

D E C L A R A T I O N S O F I N T E R E S T

We certify that we have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject

matter of this review (eg employment, consultancy, stock ownership, honoraria, expert testimony).



S O U R C E S O F S U P P O R T

Internal sources

• Rabin Medical Center - Beilison Campus, Israel.

External sources

• EU 5th Framework - TREAT project (grant number: 1999-11459), Not specified.

• Department for International Development, UK.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Aminoglycosides [∗therapeutic use]; Anti-Bacterial Agents [∗therapeutic use]; Bacterial Infections [∗drug therapy]; beta-Lactams

[∗therapeutic use]; Cause of Death; Drug Therapy, Combination; Gram-Negative Bacterial Infections [drug therapy]; Gram-Positive

Bacterial Infections [drug therapy]; Randomized Controlled Trials as Topic

MeSH check words

Humans



beta lactam antibiotic monotherapy versus beta lactam ... · this record should be cited as: paul...

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