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Combination Antibiotics

Combination Antibiotics. Mazen Kherallah, MD, FCCP King Faisal Specialist Hospital & Research Center. Mortality Rate Appropriate vs Inappropriate Therapy. Antimicrob agent Chemother 1997 May;41(5):1127-33. In Vitro Results of Combination Therapy.

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Combination Antibiotics

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  1. Combination Antibiotics Mazen Kherallah, MD, FCCP King Faisal Specialist Hospital & Research Center

  2. Mortality RateAppropriate vs Inappropriate Therapy Antimicrob agent Chemother 1997 May;41(5):1127-33

  3. 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

  4. Synergistic Effect

  5. Antagonistic Effect

  6. Additive (Indifferent) Effect

  7. Indications for the Clinical Use of Antimicrobial Combinations • Prevention of the emergence of resistant organisms • Polymicrobial infection • Initial therapy • Decreased toxicity • Synergism

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. Disadvantages of the Inappropriate Use of Antimicrobial Combination • Antagonism • Increased cost • Adverse effects • Superinfection

  15. 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

  16. -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

  17. Mortality in Bacterial Meningitis Lepper and Dowlling, Arch Intern Med. 1951

  18. 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

  19. Specific Antimicrobial Combinations

  20. 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

  21. 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

  22. 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

  23. -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

  24. -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

  25. Monotherapy VS Combination TherapyCeftazidime VS Tobramycin/Ticarcillin in NAP Rapp et al, Pharmacology 1984;4:211-215

  26. 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

  27. Monotherapy For Severe PneumoniaDevelopment of Resistance on Therapy Fink, AAC 1994;38;547

  28. Bacteremia due to P. aeruginosa Hilf, Am J Med 1989:87;540

  29. HAP due to P. aeruginosa • Mortality high (>50%) • Monotherapy inadequate • High rate of failure or relapse • Emergence of resistance

  30. Aminoglycoside plus B-lactam • Rationale: • Synergy in vitro • Improved survival • Prevent emergence resistance

  31. HAP due to P. aeruginosa • Empirical therapy • Combine 2 active drugs: • B-lactam+aminoglycoside • B-lactam+quinolone

  32. -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

  33. -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

  34. 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

  35. 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

  36. Conclusion • Combination antibiotics has clear cut (as well as borderline) indications • Inappropriate use of antimicrobial combinations may have deleterious effect

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