Professional Documents
Culture Documents
Mazen Kherallah, MD, FCCP King Faisal Specialist Hospital & Research Center
Mortality Rate
Appropriate vs Inappropriate Therapy
35 30
Mortality rate%
Synergistic Effect
8
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
7 6 5 4 3 2 1 0 2 4 6 8 10 12 14 16 18 20 22 24
Hours
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
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
Mortality rate
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
Combination therapy has no advantage over treatment with an appropriate beta-lactam drug in nonneutropenic patients with gramnegative bacteremia
83%
% or f success
Ceftazidime
Tobramycin/Ticarcillin
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
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
Conclusion
Combination antibiotics has clear cut (as well as borderline) indications Inappropriate use of antimicrobial combinations may have deleterious effect