Combination Antibiotics

Mazen Kherallah, MD, FCCP

King Faisal Specialist Hospital & Research Center

Mortality RateAppropriate vs Inappropriate Therapy

0

5

10

15

20

25

30

35

Mor

tali

ty r

ate%

Inappropriate therapy Appropriate therapy

Antimicrob agent Chemother 1997 May;41(5):1127-33

In Vitro Results of Combination Therapy

• Additive (indifferent) effect: the activity of two drugs in combination is equal to the sum (or a partial sum) of their independent activity when studied separately

• Synergistic effect: the activity of two drugs in combination is greater to the sum of their independent activity when studied separately

• Antagonistic effect: the activity of two drugs in combination is less to the sum (or a partial sum) of their independent activity when studied separately

Synergistic Effect

0

1

2

3

4

5

6

7

8

2 4 6 8 10 12 14 16 18 20 22 24

Hours

Log

No.

Vai

able

Org

anis

ms

Drug A

A+B

Drug B

Antagonistic Effect

0

1

2

3

4

5

6

7

8

2 4 6 8 10 12 14 16 18 20 22 24

Hours

Log

No.

Vai

able

Org

anis

ms

Drug AA+BDrug B

Additive (Indifferent) Effect

0

1

2

3

4

5

6

7

8

2 4 6 8 10 12 14 16 18 20 22 24

Hours

Log

No.

Vai

able

Org

anis

ms

Drug AA+BDrug B

Indications for the Clinical Use of Antimicrobial Combinations

• Prevention of the emergence of resistant organisms

• Polymicrobial infection

• Initial therapy

• Decreased toxicity

• Synergism

Prevention of the Emergence of Resistant Organisms

• Decreased resistant mycobacterium tuberculosis with combination treatment of

• Reduction of -lactamase induction with combination -lactam agents and aminoglycosides

Polymicrobial Infection

• Intraabdominal infection: ciprofloxacin and metronidazole

• Pelvic infection

• Mixed aerobic and anaerobic organism

• Availability of broad spectrum antibiotics such as carbapenems and -lactam- -lactamase inhibitors restrict the use of combination antibiotics

Initial Therapy

• Neutropenic patients: Ceftazidime and vancomycin

• In patients where the nature of infection is not clear yet: high dose ceftriaxone along with vancomycin in suspected pneumococcal meningitis in areas of high rate of penicillin resistance

Decreased Toxicity

• Decrease the toxic drug required for treatment and thus reduce the dose related toxicity

• No data from clinical trials that establish without doubt that combination therapy with different agents permits a reduction of the drug dose sufficient to reduce dose-related toxicity

SynergismEnhanced Uptake of Aminoglycoside when

Combined with -lactam agents

• Treatment of enterococcal endocarditis: ampicillin and gentamicin

• Viridans streptococcal endocarditis: penicillin and gentamicin

• Staphylococcal bacteremia: vancomycin and gentamicin

• Treatment of pseudomonas infections: -lactam agent and aminoglycosides

SynergismInhibition of Sequential Steps

• Sulfonamide with trimithoprim

• Treatment and prevention of chronic urinary tract infection, typhoid fever and shigellosis caused by organisms resistant to ampicillin

Disadvantages of the Inappropriate Use of Antimicrobial Combination

• Antagonism

• Increased cost

• Adverse effects

• Superinfection

Antagonism

• Few well-documented clinical examples of antagonism

• Bactericidal agents converts to bacteriostatic

• More prominent in immunocompromised patients or in infections where localized host defenses may be inadequate such as meningitis and endocarditis

-lactam - -lactam Antagonism

• Induction of B-lactamase by one agent, renders the second agent ineffective

• Enterobacter, Serratia, or pseudomonas

• The exact clinical significance of this phenomenon is not clear

Mortality in Bacterial Meningitis

0102030405060708090

100

Penicillin alone Penicillin andchlortetracyline

Mortality rate

Lepper and Dowlling, Arch Intern Med. 1951

Direct Interaction of Drugs

• If chloramphenicaol is inadvertently mixed together with erythromycin in the same parenteral infusion solution, they may form insoluble precipitates and hence lose activity

• Mixing ticarcillin or carbenicillin with aminoglycosides results in the inactivation of the aminoglycosides

Specific Antimicrobial Combinations

Double -LactamsOverview of synergy with reference to double

-lactam combination

• Mostly additive effects

• Rarely synergistic effect

• Sometimes antagonistic effect

• Antagonism was seen mainly when treating enterobacter or pseudomonas infections

DICP 1991 Sep;25(9):972-7

Double -LactamsDouble -lactam regimen compared to an

aminoglycoside/ -lactam regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients

• In vitro synergism was demonstrated in 73%

• Antagonism was not seen

• Outcome and nephrotoxicity were similar

• Incidence of secondary infection was higher in double -lactam group

Support Care Cancer 1993 Jul;1(4):186-94

Double -Lactams -lactam antibiotic therapy in febrile granulocytopenic

patients. A randomized trial comparing cefoperazone plus piperacillin, ceftazidime plus piperacillin, and imipenem

alone• Double beta-lactams therapy was as effective

as imipenem alone

• Superinfections occurred more often in the double beta-lactam group

• Cost of imipenem alone was lower than combination beta-lactams

Ann Intern Medicine 1991 Dec;1;115(11):849-59

-Lactam & AminoglycosidesMonotherapy versus -lactam-aminoglycoside combination

treatment for gram-negative bacteremia: a prospective, observational study

• Combination therapy has no advantage over treatment with an appropriate beta-lactam drug in nonneutropenic patients with gram-negative bacteremia

Antimicrob agent Chemother 1997 May;41(5):1127-33

-Lactam & AminoglycosidesEvaluation of bactericidal activity of cefpirome-

aminoglycoside combination agaist pseudomonas aeruginosa strains with intermediate sensitivity to cefpirome and in

various phenotypes of beta-lactam resistance

• Combination of cefpirome and aminoglycosides is bactericidal and showed synergistic effect

Pathol Biol (Paris) 1997 May;45(5):420-3

Monotherapy VS Combination TherapyCeftazidime VS Tobramycin/Ticarcillin in NAP

88%83%

0%10%20%30%40%50%60%70%80%90%

100%

% o

r f s

ucce

ss

Ceftazidime Tobramycin/Ticarcillin

Rapp et al, Pharmacology 1984;4:211-215

Fink, AAC 1994;38;547

Monotherapy for Severe Pneumonia

• Multicenter, double-blind trial (n=405)– Randomized to:

• Ciprofloxacin 400 mg q8h or• Imipenem/cilastatin 1000 mg q8h

Monotherapy For Severe PneumoniaDevelopment of Resistance on Therapy

Pathogen Cipro Imipenem

All organisms 9% 11%

Pseudomonasaeruginosa

33% 53%

Fink, AAC 1994;38;547

Bacteremia due to P. aeruginosa

Antibiotic Rx Combined Mono

Mortality ratesPneumonia 7/20 (35%) 7/8 (88%)

Critically ill 18/37 (47%) 11/12 (92%)

All patients 38/143 (27%) 20/43 (47%)

Hilf, Am J Med 1989:87;540

HAP due to P. aeruginosa

• Mortality high (>50%)

• Monotherapy inadequate– High rate of failure or relapse

– Emergence of resistance

Aminoglycoside plus B-lactam

• Rationale:– Synergy in vitro

– Improved survival

– Prevent emergence resistance

HAP due to P. aeruginosa

• Empirical therapy

• Combine 2 active drugs:– B-lactam+aminoglycoside

– B-lactam+quinolone

-Lactam & QuinolonesActivity of gatifloxacin and ciprofloxacin in combination with

other antimicrobial agents

• Combination effect of quinolones and macrolides, aminoglycosides, beta-lactams, and vancomycin was only additive (indifferent) against staphyloccocus aureus, E. coli, pseudomonas aeruginosa, enterococcus feacalis and streptococcus pneumoniae

Int J Antimicrob Agents. 2001 Feb;17(2):103-7

-Lactam & QuinolonesComparison of bactericidal activity of trovafloxacin

and ciprofloxacin, alone and in combination with cefepime, against P. aeruginosa

• Activity of trovafloxacin against p. aeruginosa showed synergistic effects when combined with beta-lactam agent

Chemotherapy 2000 Nov-Dec;46(6):383-9

Quinupristin-dalfopristin combined with beta-lactams for the treatment of experimental endocarditis due to Staphylococcus aureus

constitutively resistant to macrolide-lincosamide-streptogramin B antibiotics

• Synergistic effect

• Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA

Antimicrobial agents Chemother 2000 Jul;(7):1789-95

In vitro synergistic effect of double and triple combinations of beta-lactams, vancomycin,

and netilmicin against MRSA strains

• Synergistic effect was found between imipenem and vancomycin and between cefazolin and vancomycin

Antimicrobial agents Chemother 2000 Nov;(11):3055-60

Conclusion

• Combination antibiotics has clear cut (as well as borderline) indications

• Inappropriate use of antimicrobial combinations may have deleterious effect