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Strategies for Combating Resistance CID 2006:42 (Suppl 4) S173

S U P P L E M E N T A R T I C L E

Hospital-Based Strategies for Combating Resistance

Robert C. Owens, Jr.,1,2 and Louis Rice3

1Department of Medicine, University of Vermont College of Medicine, Burlington; 2Departments of Infectious Diseases and Clinical Pharmacy,

Maine Medical Center, Portland; and 3Medical Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio

Selective pressures generated by the indiscriminate use of b-lactam antibiotics have resulted in increased

bacterial resistance across all b-lactams classes. In particular, the use of third-generation cephalosporins has

been associated with the emergence of extended-spectrum b-lactamaseproducing and AmpC b-lactamase

producing Enterobacteriaceae and vancomycin-resistant enterococci. Conversely, b-lactams (e.g., cefepime,

piperacillin-tazobactam, and ampicillin-sulbactam) have not demonstrated such strong selective pressures.

Chief among institutional strategies to control outbreaks of multidrug-resistant bacteria are infection-control

measures and interventional programs designed to minimize the use of antimicrobial agents that are associatedwith strong relationships between use and resistance. Successful programs include antimicrobial stewardship

programs (prospective audit and feedback), formulary interventions (therapeutic substitutions), formulary

restrictions, and vigilant infection control. Fourth-generation cephalosporins, such as cefepime, have proven

to be useful substitutes for third-generation cephalosporins, as a part of an overall strategy to minimize the

selection and impact of antimicrobial-resistant organisms in hospital settings.

The management of nosocomial infections has become

an urgent health care priority. Hospital-acquired infec-

tions cause increases in mortality, morbidity, and length

of hospital stay and have an enormous impact on health

care costs. By one estimate, the average excess cost at-

tributable to each such infection is 1$15,000 [1]. Anincreasing number of nosocomial infections are due to

multidrug-resistant pathogens that may require the use

of more expensive agents or may be treatable only with

relatively toxic agents. The cost burden is further ag-

gravated by such pathogens, because hospital stays are

generally longer for patients with infections caused by

resistant organisms [2]. Controlling the development

and spread of multidrug-resistant bacteria in the hos-

pital setting requires a combination of approaches that

need to be applied in a disciplined and coordinated

manner. This review will discuss selected experiences,

as reported in the medical literature, of hospitals and

health care facilities that have confronted the problems

Reprints and correspondence: Dr. Louis Rice, Medical Service, Louis Stokes

Cleveland VA Medical Center, 10701 East Blvd., Cleveland, OH 44106 (louis

[email protected]).

Clinical Infectious Diseases 2006;42:S17381

2006 by the Infectious Diseases Society of America. All rights reserved.

1058-4838/2006/4208S4-0004$15.00

associated with nosocomial drug-resistant pathogens.

The relative merits of hospital-based strategies for con-

trolling outbreaks of resistant organisms and for treat-

ing the infections that they cause will also be discussed.

A particular emphasis will be placed on approaches to

the prevention and management of infections causedby extended-spectrum b-lactamase (ESBL)producing

and AmpC b-lactamaseproducing bacteria.

THE IMPORTANCE OF INFECTION-

CONTROL MEASURES

In general, antimicrobial resistance develops from a

confluence of factors: failures of institutional hygiene;

enhancement of resistance mechanisms in well-estab-

lished clones through gene-capture genetic units, such

as plasmids, integrons, or transposons; and facilitation

of the coselective process under different selectivepressures [3, 4]. At least one-third of all nosocomial

infections, whether caused by susceptible or resistant

pathogens, are thought to be preventable through in-

fection-control programs [5].

In cases in which isolation precautions for control-

ling the dissemination of multidrug-resistant bacteria

have been established, compliance may nevertheless be

poor, which undermines the usefulness of such mea-


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S174 CID 2006:42 (Suppl 4) Owens, Jr. and Rice

sures. A study in a Paris university hospital [6] found that, in

general, caregivers poorly adhered to infection-control practices

aimed at containing multidrug-resistant bacteria and that phy-

sicians wrote isolation orders for only 4 of 10 patients who

required such measures. Personnel were also notably deficient

in complying with hand-washing guidelines and with proper

glove and gown use.

High rates of patient transfer between units and betweenhospitals may intensify an outbreak of resistant bacteria [7].

However, initiating barrier precautions to contain the spread

of resistant organisms often is not practical for hospitals that

must contend with a highly mobile patient population. A study

of risk factors for colonization with ESBL-producing Escherichia

coli and Klebsiella species found that the duration of hospital-

ization was the only independent risk factor for colonization

with these organisms [8]. It was also noted that a large pro-

portion of colonized patients had been admitted from another

health care facility.

Interhospital transmission of resistant bacteria was demon-

strated in a study of 15 hospitals in Brooklyn, New York [9].

Isolates of Acinetobacter baumannii and Pseudomonas aerugi-

nosa were collected from the hospitals over the course of a 3-

month period in 1999. A high proportion of A. baumannii

isolates were multidrug resistant. Ribotyping revealed that a

single clone accounted for 160% of the A. baumannii isolates,

which were recovered from patients at all 15 hospitals. For P.

aeruginosa, 3 clones accounted for nearly half of the multidrug-

resistant isolates and were shared by most hospitals. In another

report of clonal dissemination of a resistant pathogen, a hospital

in Italy identified P. aeruginosa containing a metallo-b-lacta-

mase gene; the strains appeared to be clonally related [10].Transmission of resistance to broad-spectrum b-lactams does

not occur solely by migration of a single clone. In Japan, an

outbreak of metallo-b-lactamaseproducing P. aeruginosa re-

sistant to broad-spectrum b-lactams and carbapenems was

found to have proliferated multifocally, by plasmid-mediated

dissemination of the metallo-b-lactamase gene in pseudomonal

strains of different genetic backgrounds [11]. On the basis of

this and other evidence, the interhospital spread of resistant

strains emphasizes why control measures aimed at suppressing

the emergence of such strains are not merely the responsibility

of a single hospital or localized group of medical centers [12].

In addition to large hospitals with mobile populations,long-term care facilities are another high-risk environment

for bacteria with multidrug resistance. For residents in a

skilled-care unit, Trick et al. [13] determined the frequency

of and risk factors for colonization with several antimicrobial-

resistant bacterial species. Approximately 1 of 4 residents who

were culture positive for a resistant bacterial species also was

cocolonized by 11 resistant species. Risk factors for coloni-

zation varied by pathogen, with total dependence on health

care workers being a specific risk factor for colonization with

ESBL-producing Klebsiella pneumoniae. A review of 74 pub-

lished studies demonstrated significant commonality of risk

factors across multidrug-resistant organisms, such as Staph-

ylococcus aureus, vancomycin-resistant enterococci, Clostrid-

ium difficile, and ESBL-producing gram-negative bacilli [14].

Advanced age and interinstitutional transfer of patients, es-

pecially from a nursing home, were 2 of the major risk factorspredicting nosocomial colonization or infection with individ-

ual multidrug-resistant organisms.

Paterson et al. [15] successfully controlled an outbreak of

ESBL-producing E. coliorganisms in a liver transplantationunit

by means of gut decontamination with norfloxacin, contact

isolation, and feedback on hand hygiene. In that case, the ge-

notypic relatedness of all recovered isolates indicated horizontal

transfer of the ESBL-positive strains [15]. Patients were isolated

in individual rooms with sinks and nonmedicated soap. Nurses

and other health care providers were stopped after leaving each

room and were asked by the infection-control department to

participate in a teaching exercise. The glove-juice samplingprocedure indicated that nurses and physicians were culture

positive (32% and 23%, respectively) for such organisms as

methicillin-resistant S. aureus and vancomycin-resistant enter-

ococci but not for ESBL-producing E. coli. Staff members were

confidentially informed of their culture positivity and were ed-

ucated about the significance of hand washing. Contact pre-

cautions (gloves and gowns) were required for all ESBL-positive

patients and their environments, which lasted for their current

and all future admissions. Norfloxacin (400 mg every 12 h for

5 days) was used to reduce the density of ESBL organisms in

the stool samples of identified patients. The results of the de-

contamination effort were fleeting, because 40% of patients had

positive cultures 14 days after receiving the last dose of norflox-

acin, and 60% had positive cultures at 28 days. The strategy was

successful in curtailing the outbreak of ESBL-producing isolates;

however, the authors suggested caution in using so-called fluor-

oquinolone decontamination regimens, because of the potential

for high percentages of these organisms being quinolone resistant.

Although there are some cases in which standard infection-con-

trol measures are inadequate and additional measures must be

utilized [16], such programs are nevertheless integral for con-

taining nosocomial transmission of organisms.

ASSOCIATION OF USE OF THIRD-GENERATION

CEPHALOSPORINS WITH NOSOCOMIAL

OUTBREAKS OF RESISTANT PATHOGENS

In the 1970s, Levy et al. [17] developed a biological model that

demonstrated a clear relationship between antimicrobial use

and drug-resistance selection among E. coli in humans. With

regard to the development of ESBL-based resistance, total prior

antibiotic use, including exposure to noncephalosporin anti-


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biotics, has been identified as an important risk factor for in-

fection with ESBL-producing E. coli or K. pneumoniae [18]. A

more common observation is a strong correlation between an-

timicrobial resistance and the use of specific third-generation

cephalosporins, especially among K. pneumoniae isolates [19

23]. In a study of hospitalized patients in Taiwan, the risk of

infection with ESBL-producing K. pneumoniae was 113 times

greater among patients who had been exposed to ceftazidimewithin the prior 30 days than it was among patients who had

not been similarly exposed [24].

An investigation in a pediatric intensive care unit (ICU)

found that previous treatment with third-generation cephalo-

sporins and aminoglycosides, in addition to age !12 weeks, was

independently associated with colonization or infection with

multidrug-resistant K. pneumoniae. Patients who were exposed

to the antibiotics had 130 times the risk of colonization or

infection, compared with patients who were not similarly ex-

posed [25].

Overall, the association of antibiotic use with the develop-

ment of multidrug resistance underscores the fact that makingsuboptimal antimicrobial choices has global implications. The

use of a particular antimicrobial agent may not only select for

overgrowth of bacterial strains with innate resistance, but also

may select for the development of diverse genetic vectors that

encode and are capable of disseminating resistance mechanisms

[12]. Genetic elements of this kind may spread widely through

the worlds bacterial populations.

ANTIBIOTIC RESTRICTION MEASURES

The established connection between antibiotic use, particularly

of third-generation cephalosporins, and the selection of ESBL-and AmpC-producing organisms has encouraged modifications

in patterns of antimicrobial utilization. Selected changes have

proven to be effective for minimizing the prevalence of these

bacteria in health care facilities.

Patterson et al. [22] measured the prevalence of multidrug-

resistant K. pneumoniaeat 2 hospitals, before and after an acute

intervention, which included restrictions on antibiotic use and

physician education regarding the association between cefta-

zidime use and the presence of multidrug-resistant K. pneu-

moniae. Following the intervention, ceftazidime use decreased,

and piperacillin-tazobactam use increased at both institutions.

The changes were associated with a significant decrease in cef-tazidime resistance among K. pneumoniae isolates. Similar ob-

servations were made in a retrospective analysis of data from

10 hospitals [26]; antimicrobial usage and antimicrobial resis-

tance trends for prominent nosocomial pathogens were com-

pared, as were antimicrobial control programs and policies,

across all hospitals. A strong positive correlation was noted

between ceftazidime usage and the prevalence of ceftazidime-

resistant P. aeruginosa and of ceftazidime-resistant Enterobac-

teriaceae. Likewise, control programs and policies were asso-

ciated with lower prevalence rates of some resistant bacterial

strains and less antibiotic usage.

In another study, a high prevalence of ceftazidime-resistant

K. pneumoniae in the hospital ICU prompted an intervention

that included rigorously enforcing barrier precautions and cef-

tazidime restriction. Following the interventions, the suscep-

tibility rate of K. pneumoniae increased by4-fold in isolatesrecovered in the ICU. Although the combined hand hygiene

and antibiotic policy was only instituted in the ICU, a modest

increase in the susceptibility of K. pneumoniae isolates among

total hospital isolates occurred [23]. The benefits of antibiotic

restriction for minimizing multidrug-resistant outbreaks are,

however, not always apparent. This situation was described in

a report by Toltzis et al. [27], who restricted ceftazidime use

in a pediatric ICU; the result was a small, but not significant,

reduction in the overall prevalence of ceftazidime-resistant

gram-negative bacteria. However, if one looks at the organisms

associated with AmpC b-lactamase production, where one

would expect to see a difference, resistance decreased from

68.2% to 45.9% ( ).P! .05

Although restriction of third-generation cephalosporins is

nevertheless an effective method for controlling outbreaks of

ESBL-producing bacteria, such measures must be undertaken

cautiously. A formulary change that restricts cephalosporins, as

well as other antimicrobials, may sometimes promote the emer-

gence of pathogens with new and different resistance profiles.

This phenomenon was observed following a formulary change

that was instituted to limit an outbreak of vancomycin-resistant

enterococci. The change resulted in a decrease in usage, not

only of cephalosporins, but also of imipenem, clindamycin, andvancomycin. To compensate, an emphasis was placed on the

use of b-lactam/lactamase-inhibitor combinations [28]. Sig-

nificant reductions were observed in the monthly number of

patients colonized with methicillin-resistant S. aureusand cef-

tazidime-resistant K. pneumoniae. However, the proven clonal

spread of these strains via person-to-person transmission, a

decrease in patient density and in the average length of hospital

stay, and the marked decrease in the overall use of antimicrobial

agents could have confounded these data [29]. Nonetheless,

there was a significant increase in the number of patients for

whom cultures were positive for cefotaxime-resistant Acineto-

bacterspecies [28]. A study of a 500-bed urban teaching facilityin New York City successfully illustrated the relationship be-

tween antimicrobial use and resistance selection [30]. The ef-

fects of various countermeasures used to contain both the en-

dogenous selection and horizontal transmission of resistant

gram-negative bacilli were also documented. An initial series

of infections caused by A. baumannii (multidrug resistant but

ceftazidime susceptible) led to the increased use of ceftazidime.

From this reliance on ceftazidime, significant numbers of in-


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fections due to both ceftazidime-resistant A. baumannii (in

1988) and ceftazidime-resistant (ESBL-producing) K. pneu-

moniae(in 1993) arose, requiring the greater use of imipenem.

To gain perspective, between 1993 and 1995, 37% of all K.

pneumoniaestrains isolated produced ESBLs. The resultant in-

crease in imipenem use and continued selective pressureexerted

by ceftazidime and cefotetan culminated with the development

of A. baumannii strains that are resistant to imipenem andceftazidime; K. pneumoniaethat now are resistant to ceftazidime

(an ESBL), ceftotetan (an ACT-1 plasmid-mediatedAmpC-type

b-lactamase), and imipenem (via outer membrane porin loss);

and imipenem-resistant P. aeruginosa. Selective pressure exerted

by both ceftazidime and imipenem undoubtedly contributed

to the genesis of these resistant organisms, and, once estab-

lished, horizontal transmission amplified their dissemination.

Quale et al. [31] reported that an advanced outbreak of

ESBL-producing K. pneumoniae was occurring in 2002 in the

New York City area. They collected 281 ESBL-producing isolates

of K. pneumoniae from 15 hospitals in the Brooklyn area. Iso-electric points suggested a predominance of SHV-5 enzymes

mixed with other smaller numbers of other enzymes, including

the plasmid-mediated AmpC b-lactamase ACT-1. For the iso-

lates, susceptibilities (expressed as percentages) to several an-

timicrobial agents were reported, including ceftazidime (13%),

cefoxitin (34%), ciprofloxacin (42%), ceftriaxone (48%), pi-

peracillin-tazobactam (55%), amikacin (57%), cefepime (86%),

and imipenem (99%). The high rate of resistance to cepha-

mycin (66%) and the low rate of resistance to cefepime strongly

suggest the copresence of AmpC and ESBL enzymes. Antimi-

crobial utilization data indicated that the use of cephalosporins

(as a group) and aztreonam correlated strongly with the prev-

alence of ESBL-producing strains at each institution via mul-

tivariate analysis ( ).Pp .014

Neighboring hospitals in Brooklyn, New York, also experi-

enced significant outbreaks of ESBL-producing Enterobacter-

iaceae and Acinetobacter species. From their experience arose

a case-control study of their clinical outcomes [9]. Longer hos-

pital stays following the infection were noted for patients in-

fected with ESBL-producing K. pneumoniae, compared with

control subjects (median length of stay, 29 vs. 11 days [Pp

]; mean SD, vs. days [ ]). Patients.03 37 25 15 10 Pp .04

infected with ESBL-producing isolates had a higher, but notstatistically significant, mortality rate than did control subjects

(44% vs. 34%) [9].

Once an outbreak of ESBL-producing strains has been ef-

fectively managed at the hospital level, it is important to

recognize that these organisms have likely disseminated into

the surrounding community, including long-term care facil-

ities [30, 32, 33]. Strains can be reintroduced to the hospital

from these venues, which further emphasizes the importance

of effective and prospective infection-control programs for

ESBL control.

MORE TARGETED USE OF CARBAPENEMS

The carbapenems have been important antimicrobial agents for

treating nosocomial gram-negative infections, especially those

caused by ESBL-producing organisms. Surveillance data from

the Meropenem Yearly Susceptibility Test Information Collec-

tion on antimicrobial resistance in gram-negative isolates from

European ICUs found that the 2 most frequently used members

of this antibiotic classmeropenem and imipenemhave re-

mained highly active against important species of gram-nega-

tive bacteria recovered from European ICUs that actively use

meropenem [34]. The susceptibility of Enterobacteriaceae to

carbapenems was generally198%, whereas that ofP. aeruginosa

and A. baumannii was 68%82%.

Although carbapenems are still highly effective against ESBL-

producing bacteria, carbapenem-resistant strains are beginning

to emerge, probably because of the increased reliance by cli-nicians on this class of antimicrobials. The prevalence of mul-

tidrug-resistant A. baumannii, including strains with resistance

to carbapenems, has increased markedly, along with the prev-

alence of carbapenem-resistant strains ofP. aeruginosa. A single

carbapenem-resistant epidemic strain of A. baumanniiwas re-

cently reported to have infected patients at 5 hospitals in

Buenos Aires, Argentina [35]. A concurrent outbreak of mul-

tidrug-resistant P. aeruginosa and A. baumannii was reported

in 15 hospitals in Brooklyn, New York [9]. Ribotyping revealed

that a relatively small number of clones accounted for the ma-

jority of patient isolates of these 2 bacterial species. For A.

baumannii, 53% of isolates were resistant to meropenem and/or imipenem. In an Italian study of 8 P. aeruginosa isolates

recovered from 7 patients in different wards of a single hospital,

all isolates showed high levels of resistance to carbapenems; 7

of the 8 isolates appeared to be clonally related [10].

The latest issue to concern the carbapenems is the description

of geographically isolated outbreaks of enterobacteriaceae (par-

ticularlyK. pneumoniae) that possess carbapenem-hydrolyzing

enzymes belonging to the KPC family ofb-lactamases [36]. In

some KPC-producing isolates, additional porin channel alter-

ations were noted [37]. The isolation of these organisms has,

thus far, been limited to certain geographic regions, and these

organisms certainly pose a therapeutic challenge in centers thatdeal with infections caused by them. Because carbapenem re-

sistance due to KPC-producing organisms can be difficult to

detect with automated susceptibility testing methods, vigilance

should be maintained in terms of monitoring for treatment

failures when carbapenems are used [37].

In summary, the increased use of carbapenems to combat

the growing prevalence of multidrug-resistant bacteria, partic-

ularly ESBL-producing strains, shows early signs of eroding the


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effectiveness of the carbapenems. A more highly targeted and

restrained use of these drugs, aimed at preserving their anti-

microbial activity, is probably warranted.

HOSPITAL CASE STUDIES: REPLACEMENT OF

CEFTAZIDIME WITH CEFEPIME

Recognizing that exposure to third-generation cephalosporins

plays a role in the selection of multidrug-resistant organisms,

a number of studies have evaluated the effect of substitution

of the fourth-generation cephalosporin cefepime for third-gen-

eration cephalosporins on susceptibility patterns. Empey et al.

[38] reviewed antibiotic use and antimicrobial resistance before

and after a university hospital formulary change that was aimed

at reducing utilization of third-generation cephalosporins. After

the formulary change to cefepime, the use of ceftazidime and

cefotaxime underwent a combined decrease of 89%. Cefepime

use was associated with a significant decrease in infections due

to ceftazidime-resistant K. pneumoniae and P. aeruginosa.

Because cefepime MICs are less affected by the expressionof AmpC b-lactamases, replacing third-generation cephalospo-

rins with cefepime appears to be effective in reversing reduced

hospital-wide susceptibility to hyperproducers of this b-lacta-

mase. The gene encoding the AmpC b-lactamase is naturally

present in many species of Enterobacteriaceae and in some

nonfermentative gram-negative bacilli, including Serratia mar-

cescens, P. aeruginosa, indole-positive Proteae (e.g., Morganella

species), Citrobacterspecies, and Enterobacterspecies.

In one hospital, the use of a ceftazidime-glycopeptide com-

bination as initial empirical therapy for neutropenic fever re-

sulted in a 75% reduced rate of susceptibility to ceftazidime

among Enterobacteriaceae with AmpC b-lactamasemediatedresistance [39]. After a cefepime-amikacin combination was

used as an alternate empirical therapy, a significant improve-

ment was observed in the susceptibility of inducible Entero-

bacteriaceae to ceftazidime. Susceptibility to amikacin, cotri-

moxazole, and ciprofloxacin increased as well, and the reduced

susceptibility to ceftazidime exhibited by noninducible Enter-

obacteriaceae (e.g., Klebsiella species) was also reversed. After

formulary replacement of ceftazidime with cefepime as empir-

ical therapy for febrile neutropenia, Orrick et al. [40] also re-

ported improvements in susceptibility of AmpC b-lactamase

producing organisms, in this case, to ceftazidime and to ticar-

cillin-clavulanate. A similar pattern of significantly improvedantimicrobial susceptibility among inducible Enterobacteri-

aceae was reported after a switch to cefepime in a medical/

surgical ICU [41].

The improvements in antimicrobial susceptibility observed

following implementation of programs to restrict third-gen-

eration cephalosporins can produce clinically significant ben-

efits. In a study of outcomes among critically ill patients, a 27%

reduction in third-generation cephalosporin use was accom-

panied by a dramatic increase in cefepime use. The new treat-

ment program led to a significant decrease in the infection-

related hospital-wide mortality rate, from 36% to 19% [42].

The improved outcomes were associated with an increase in

the antimicrobial susceptibilities ofE. coliand Klebsiellaspecies.

Rotation is another strategy used to limit antimicrobial ex-

posure to minimize selection of resistant organisms. In a ro-

tation scheme, changes in the choice of antibiotic administeredfor a condition occur cyclically, according to a prearranged

schedule. Gruson et al. [43] studied the effect of a combination

of antibiotic restriction and rotation on the incidence of ven-

tilator-assisted pneumonia. Their scheme restricted the use of

ciprofloxacin and ceftazidime through a multistage program in

which a b-lactam and aminoglycoside were prescribed empir-

ically. The chosen b-lactam was cefepime, piperacillin-tazo-

bactam, imipenem, or ticarcillin-clavulanic acid. Each was the

preferred choice of empirical therapy for 1 month, at which

time the next b-lactam, in predetermined order, became the

preferred choice. The b-lactams were variously associated with

one of several aminoglycosides. Comparison of the 2 yearsbefore and after the program showed a significant decrease in

the number of cases of ventilator-assisted pneumonia. The total

number of potentially resistant gram-negative bacteria respon-

sible for ventilator-assisted pneumonia decreased, whereas the

antimicrobial susceptibilities of these bacteria increased.

Taken together, the results of these studies suggest that, by

substituting cefepime for third-generation cephalosporins, the

resistance profile of gram-negative bacteria producing common

ESBLs and AmpC b-lactamases can, in some cases, be reversed.

The CTX-M type ESBLs, which hydrolyze cefepime efficiently

and are of growing importance outside (but not, as yet, inside)

the United States, suggest that continued monitoring of cefe-

pime susceptibilities and enzyme characteristics will be im-

portant [44]. Substituting cefepime for third-generation ceph-

alosporins appears to offer an alternative to treatment with

carbapenems in selected cases of nosocomial infection due to

multidrug-resistant organisms.

COST ISSUES: ANALYZING HOSPITAL

CONVERSION FROM CEFTAZIDIME TO

CEFEPIME

A comprehensive review of hospital-based strategies for com-

bating drug-resistant nosocomial infections must address theissue of treatment and hospitalization costs and how they might

be minimized. A workshop entitled Measuring the Economic

Costs of Antimicrobial Resistance in Hospital Settings, spon-

sored by Emory University and the Centers for Disease Control

and Prevention, was conducted in November 2000 [45]. At the

workshop, the excess direct costs of treating a patient with a

nosocomial infection caused by a resistant pathogen were de-

lineated. Because infections due to resistant pathogens result


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in longer hospital stays, usually as a result of failure of initial

therapies, excess per-bed daily costs contribute substantially to

the costs of treating such infections. Other excess costs derive

from the need for patient isolation, additional costs associated

with the acquisition and administration of antimicrobials, and

the costs of other infections and complications that often are

associated with infection with resistant pathogens. Additional

procedures and laboratory costs, as well as physician staff time

and infection-control staff, are further costs associated with

nosocomial infections due to resistant organisms.

A pharmacoeconomic analysis conducted in a French uni-

versity hospital group found that, on a daily basis, the most

costly antibiotic treatments were prescribed for ICU patients,

patients with device-related nosocomial pneumonia, and pa-

tients with multidrug-resistant bacterial infections [46]. Un-

documented nosocomial infection accounted for20% of over-

all antibiotic costs. The authors of that study concluded that

antibiotic treatment for nosocomial infection represents a sig-

nificant part of hospital expenditure, which should be mod-erated by controlling the use of highly expensive prescriptions.

An analysis by Owens, Jr., et al. [47] concluded that sig-

nificant cost savings might be realized by a formulary switch

from the third-generation cephalosporin ceftazidime to ce-

fepime. The survey was based on antibiotic usage patterns

and treatment costs encountered at Hartford Hospital in Con-

necticut. Significant savings could be realized by following the

different dose recommendations of the Food and Drug Ad-

ministration for cefepime (twice-daily administration) and

ceftazidime (thrice-daily administration), which are also sup-

ported by pharmacokinetic-pharmacodynamic differences be-tween the 2 cephalosporins [48]. On the basis of these factors

and of the then-current usage patterns and drug acquisition

costs, the investigators estimated that replacing ceftazidime

on the hospital formulary could result in a potential annual

savings of1$50,000.

In addition to decreased direct drug costs, greater savings

might derive from an increase in clinical efficacy gained by

switching from ceftazidime to cefepime. When ceftazidime and

cefepime treatment were compared in a study of 100 patients

with hospital-acquired pneumonia, cefepime was indeed found

to be more cost effective [49]. The mean drug-specific cost ofcefepime treatment was $266.59, versus $359.93 for ceftazidime.

In addition to the cost of the 2 antibiotics, the figures also

reflected the significantly lower costs of concomitant medica-

tions in the cefepime group. The lower costs, in turn, reflected

the higher rates of clinical efficacy (78% vs. 60%; ) andPp .05

microbiological efficacy (77% vs. 55%; ) reported inPp .04

that study for cefepime and ceftazidime, respectively [49].

ANTIMICROBIAL STEWARDSHIP PROGRAMS

The use of the term antimicrobial stewardship program im-

plies a multidisciplinary, programmatic, prospective interven-

tional approach to optimizing the use of anti-infectives. An-

timicrobial stewardship programs should be multidisciplinary

and should involve an infectious diseases physician and an

infectious diseases clinical pharmacist, both of whom should

be compensated for their time. Additional team members

should optimally include a microbiologist, a data analyst, and

a representative of the infection-control department. The In-

fectious Diseases Society of Americas guidelines for antimi-

crobial stewardship programs, which have been endorsed by

multiple societies, will be published soon and will provide more

details about the rationale, benefits, and implementation and

coordination of such programs. A variety of prospective pro-

grammatic strategies have been proposed, but, in reality, they

can be simplified into 1 of 2 main categories: prior authori-

zation and concurrent review with feedback [50]. Of course,

the 2 categories are not mutually exclusive, and hybrid pro-grams using a blend of the central strategies have been created.

Why are programmatic multidisciplinary strategies important?

Carling et al. [51] demonstrated that, among similarly matched

hospitals, only hospitals that used the programmatic prospec-

tive interventional programs were able to significantly affect

parenteral antimicrobial use patterns and costs, in contrast to

hospitals that relied solely on passive strategies. These passive

or adjunctive interventions may, in our opinion, serve as tools

to augment the 2 main strategies and may include the use of

stop orders, antibiotic order forms, closed formularies, selective

susceptibility reporting, educational sessions, and restriction of

pharmaceutical promotional activities. The outcomes and im-plementation methods for antimicrobial stewardship programs

have been extensively reviewed elsewhere [52]. In brief, these

programs have demonstrated reductions in both inappropriate

and overall antimicrobial use, decreased expenditures, and im-

proved patient safety; some of them have even demonstrated

improved antibiotic susceptibilities [5357].

A recent example of this programmatic approach evaluated

the impact of an interventional program on antimicrobial use,

cost savings, and antimicrobial resistance. The multidisciplinary

team consisted of an infectious diseases physician, 2 pharma-

cists, a microbiologist, a laboratory technologist, an internal

medicine physician, and a computer systems analyst [58]. In-

terventions included an antibiotic order form, providing cli-

nicians with feedback based on the data collected, and verbally

communicating with prescribers about new orders for third-

generation cephalosporins and carbapenems centered around

antimicrobial selection, specifically the collateral resistance po-

tential associated with third-generation cephalosporin and car-

bapenem use [58]. Over the course of the study, an increased


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rate of cefepime use, relative to use of third-generation ceph-

alosporins, was associated with decreasing rates of resistance to

third-generation cephalosporins among Proteus mirabilis and

Enterobacter cloacaebut not among E. coliand K. pneumoniae.

The increased rate of aminopenicillin-sulbactam use relative

to the third-generation cephalosporins, in conjunction with a

sustained reduction in vancomycin use, was associated with a

reduction in methicillin-resistant S. aureus rates [58]. In ad-dition, P. aeruginosa rates of resistance to carbapenems de-

creased to zero. This decrease was strongly associated with the

reduction in carbapenem consumption over time.

A joint committee of the Society for Healthcare Epidemi-

ology of America and the Infectious Diseases Society of America

has developed a set of recommendations for the prevention and

reduction of antimicrobial resistance in hospitals [59], as fol-

lows:

1. Hospitals should have a system for monitoring anti-

microbial resistance of both community-acquired and

nosocomial isolates (by hospital location and patientsite) on a monthly basis or at a frequency appropriate

to the volume of isolates recovered,

2. Hospital locations or prescribing services should mon-

itor the use of antimicrobials on a monthly basis or at

a frequency appropriate to the prescription volume,

3. Hospitals should monitor the relationship between an-

timicrobial use and resistance and should assign re-

sponsibility through practice guidelines or other insti-

tutional policies, and

4. Hospitals should apply contact precautions to specific

patients known or suspected to be colonized or infected

with epidemiologically important microorganisms thatcan be transmitted by direct or indirect contact.

These recommendations can serve as talking points in the in-

itiation of programs supported by hospital administration and

managed by infectious diseases experts.

CONCLUSION

The problem of increasing antimicrobial resistance, which is

due, in part, to suboptimal antimicrobial use, coupled with the

fact that a growing number of pharmaceutical companies have

abandoned anti-infective research and development, has re-

sulted in a growing public health crisis. Because hospitals are

characterized by high-density antibiotic use, they are target-

rich venues for proactive interventions to improve antimicro-

bial use. Reasons for suboptimal infection control and anti-

microbial use in modern times are similar: insufficient resources

(both human and financial), apathy, and ignorance. With re-

gard to gram-negative organisms, the emergence of ESBL-pro-

ducing K. pneumoniae and E. coli and AmpC-producing En-

terobacteriaceae, such as Enterobacterspecies and S. marcescens,

has resulted in increased morbidity and mortality, as well as

increased health care costs. With little to no help on the way

from the antimicrobial pipeline for the most resistant gram-

negative bacterial infections, antimicrobial resistance needs to

be considered a priority by clinicians and administrators alike.

McGowan, Jr., et al. [60] stated recently that guidelines for the

prevention and control of antimicrobial resistance must targetspecific drug-organism combinations, because the risks and

predictors for them are dissimilar. Minimizing or eliminating

the use of certain antimicrobial agents has been shown to be

an effective strategy for dealing with third-generation cepha-

losporinresistant gram-negative bacilli. To pretend that we

know the absolute method for the treatment of the evolving

b-lactamase crisis within the world of gram-negative bacilli is

the antithesis of science. However, the literature is now replete

with the negative effects of certain agents (e.g., third-generation

cephalosporins) on the ecological profiles of hospital and in-

stitutional flora. This has led many institutions to remove these

agents from the formulary or to place restrictions on their use,as well as to introduce more heterogeneity into their antimi-

crobial prescribing habits. It has also become clear that not all

cephalosporins are equal with regard to their inherent resistance

selection potential and their usefulness in treating resistant or-

ganisms. The fourth-generation cephalosporins, such as cefe-

pime, appear to be capable of being used, in place of third-

generation cephalosporins, for the empirical and definitive

treatment of infections without adversely affecting resistance

profiles or the environment. We must continue to be proactive

and study strategies for the containment and treatment of in-

fections caused by antimicrobial-resistant organisms, as well as

to modify and expand our approaches when more information

becomes available.

Acknowledgments

Financial support. This work is supported by Elan and Bristol-Myers

Squibb. Editorial support was provided by Accel Medical Education.

Potential conflicts of interest. R.C.O., Jr. has received research grants

from Bristol-Myers Squibb, Elan, Bayer, Pfizer, and Wyeth. L.R. has served

as a consultant to Wyeth, Elan, Merck, Cubist, Theravancet, Pinnacle,

Cumbre, and Pfizer; has served on the speakers bureaus of Wyeth, Elan,

Merck, and Cubist; and has received grant support from Wyeth and Elan.

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highly effective against esbl

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