Combination Antibiotics
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Combination Antibiotics
Mazen Kherallah, MD, FCCP
King Faisal Specialist Hospital & Research Center
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Mortality RateAppropriate vs Inappropriate Therapy
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Antimicrob agent Chemother 1997 May;41(5):1127-33
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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
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Synergistic Effect
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Antagonistic Effect
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Additive (Indifferent) Effect
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Drug AA+BDrug B
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Indications for the Clinical Use of Antimicrobial Combinations
• Prevention of the emergence of resistant organisms
• Polymicrobial infection
• Initial therapy
• Decreased toxicity
• Synergism
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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
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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
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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
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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
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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
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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
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Disadvantages of the Inappropriate Use of Antimicrobial Combination
• Antagonism
• Increased cost
• Adverse effects
• Superinfection
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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
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-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
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Mortality in Bacterial Meningitis
0102030405060708090
100
Penicillin alone Penicillin andchlortetracyline
Mortality rate
Lepper and Dowlling, Arch Intern Med. 1951
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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
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Specific Antimicrobial Combinations
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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
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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
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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
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-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
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-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
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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
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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
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Monotherapy For Severe PneumoniaDevelopment of Resistance on Therapy
Pathogen Cipro Imipenem
All organisms 9% 11%
Pseudomonasaeruginosa
33% 53%
Fink, AAC 1994;38;547
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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
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HAP due to P. aeruginosa
• Mortality high (>50%)
• Monotherapy inadequate– High rate of failure or relapse
– Emergence of resistance
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Aminoglycoside plus B-lactam
• Rationale:– Synergy in vitro
– Improved survival
– Prevent emergence resistance
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HAP due to P. aeruginosa
• Empirical therapy
• Combine 2 active drugs:– B-lactam+aminoglycoside
– B-lactam+quinolone
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-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
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-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
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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
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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
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Conclusion
• Combination antibiotics has clear cut (as well as borderline) indications
• Inappropriate use of antimicrobial combinations may have deleterious effect