Combination Antibiotics

Mazen Kherallah, MD, FCCP King Faisal Specialist Hospital & Research Center

Mortality Rate
Appropriate vs Inappropriate Therapy
35 30

Mortality rate%

25 20 15 10 5 0 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
8

Log No. Vaiable Organisms

7 6 5 4 3 2 1 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours Drug A A+B Drug B

Antagonistic Effect
8
Log No. Vaiable Organisms

7 6 5 4 3 2 1 0 2 4 6 8 10 12 14 16 18 20 22 24
Hours

Drug A A+B Drug B

Additive (Indifferent) Effect

8
Log No. Vaiable Organisms

7 6 5 4 3 2 1 0 2 4 6 8 10 12 14 16 18 20 22 24
Hours

Drug A A+B Drug 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 doserelated toxicity

Synergism
Enhanced 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

Synergism
Inhibition 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

100 90 80 70 60 50 40 30 20 10 0 Penicillin alone Penicillin and chlortetracyline

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 -Lactams
Overview 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 -lactam regimen compared to an aminoglycoside/ -lactam regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients

Double -Lactams

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

Monotherapy versus -lactam-aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study

-Lactam & Aminoglycosides

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

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

-Lactam & Aminoglycosides

Evaluation of bactericidal activity of cefpiromeaminoglycoside 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 Therapy

Ceftazidime VS Tobramycin/Ticarcillin in NAP
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 88%

83%

% or f success

Ceftazidime

Tobramycin/Ticarcillin

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

Monotherapy for Severe Pneumonia

Multicenter, double-blind trial (n=405)
Randomized to:
Ciprofloxacin 400 mg q8h or Imipenem/cilastatin 1000 mg q8h

Fink, AAC 1994;38;547

Monotherapy For Severe Pneumonia

Development of Resistance on Therapy
Pathogen All organisms Pseudomonas aeruginosa Cipro 9% 33% Imipenem 11% 53%

Fink, AAC 1994;38;547

Bacteremia due to P. aeruginosa

Antibiotic Rx
Pneumonia Critically ill All patients

Combined Mono Mortality rates

7/20 (35%) 18/37 (47%) 38/143 (27%) 7/8 (88%) 11/12 (92%) 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 & Quinolones

Activity 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 & Quinolones

Comparison 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 betalactams for the treatment of experimental endocarditis due to Staphylococcus aureus constitutively resistant to macrolide-lincosamidestreptogramin 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