Gram Negative Sepsis: Does Double Coverage Show Mortality Benefit

1. Gram Negative Sepsis: Does Double Coverage Show Mortality Benefit?

2. Why Double Coverage? Synergy Broaden Coverage Prevent Resistance 1. Synergy: is there an additive effect with anti-microbial therapy that works to reduce mortality? 2. Broaden coverage: with combination therapy, is there not an increased likelihood that the infecting pathogen will be sensitive to at least one component of the multi-drug regimen? 3. Prevent resistance: is it not known that using more than one drug targeting the same organism that inhibits growth or kills via unique mechanism will prevent the development of bacterial resistance to a single class of drugs? This is certainly true for TB and HIV. Is it true for all anti-infective therapy? Many gram negative rods have acquired and/or intrinsic resistance and they are virulent The pathogenic capability of Gram-negative bacteria is often associated with certain components of Gram-negative cell walls, in particular, the lipopolysaccharide (also known as LPS or endotoxin) layer LPS triggers a robust immune response characterized by cytokine production 1. Synergy: is there an additive effect with anti-microbial therapy that works to reduce mortality? 2. Broaden coverage: with combination therapy, is there not an increased likelihood that the infecting pathogen will be sensitive to at least one component of the multi-drug regimen? 3. Prevent resistance: is it not known that using more than one drug targeting the same organism that inhibits growth or kills via unique mechanism will prevent the development of bacterial resistance to a single class of drugs? This is certainly true for TB and HIV. Is it true for all anti-infective therapy? Many gram negative rods have acquired and/or intrinsic resistance and they are virulent The pathogenic capability of Gram-negative bacteria is often associated with certain components of Gram-negative cell walls, in particular, the lipopolysaccharide (also known as LPS or endotoxin) layer LPS triggers a robust immune response characterized by cytokine production

3. Synergy Definition: increased rate of killing when anti-microbials are combined Criteria: MIC’s of the 2 agents decrease by four-fold when combined (stringent but accepted) Methods to determine synergy are time-kill curves and checkerboard analysis. Neither report results in terms of MIC (?)

4. Time-Kill Study Time-kill Study Known number of organisms placed into liquid culture with known conc. of antibiotic(s) At specific times, broth plated and colonies counted Reduction in size of colony plotted against time is better at predicting antibiotic activity in vivo than MIC…

6. Checkerboard Analysis

8. Antibiotic Therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients… Synergy was evaluated by checkerboard assay and time-kill curve with 123 organisms 71/123 specimens met criteria for synergy w/ time-kill analysis, 17 with checkerboard Concordance btwn 2 methods when criteria for synergy met by one: 49% No discussion about which drugs used for synergy testing

9. However… No correlation between results of in vitro synergism with patient outcome Conclusion: synergy, even when present, does not improve mortality and is therefore not a valid reason for double gram-negative coverage in bacteremia

10. Places where synergy appropriate Strep viridans endocarditis Using aminoglycoside (gent/strepto) with a beta-lactam (PCN or CTX) decreases treatment time from 4 to 2 weeks Enterococcus endocarditis Ampicillin is not bactericidal in setting of endocarditis unless combined with gentamicin

11. Broaden Spectrum

12. What does the literature say Meta-analyses (2) B-lactam monotherapy versus B-lactam-aminoglycoside combo therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. Paul, et al. BMJ. March 2004. Does combination antimicrobial therapy reduce mortality in gram-negative bacteremia? A meta-analysis. Safdar et al. The Lancet. 2004.

13. Paul et al. BMJ 2004 Objective: compare B-lactam alone vs. B-lactam and aminoglycoside Setting: “severe infection”?non-neutropenic pts meeting criteria for “sepsis” Primary outcome measured: all cause fatality by intention to treat (by 30d) 64 studies, 7586 patients

14. Results no difference in all cause fatality (RR .90, 95% CI, 0.77-1.06) this includes gram positive sepsis Subgroup analysis: no survival advantage in gram negative sepsis (1835 pts) including P. aeruginosa (426 patients) No difference in the rate of resistance development Nephrotoxcity more common in combination therapy RR (0.36 ? 0.47)

15. Issues/concerns Of 64 trials, year of publish 1973 through 2001 This means actual patient data from several years before publish date as a general rule OLD!!! Since 1981 these new antibiotics have been introduced: ceftazidime, aztreonam, ciprofloxacin and imipenem Only 12 studies compared the same beta-lactam, while 31 compared different ones when combined with aminoglycoside!!!

16. Antibiotics used Beta-lactams: Oxacillin, penicillin, ampicillin (+/- sulbactam), carbenicillin, ticaricillin, moxalactam, mezlocillin,piperacillin (+/- tazobactam), azlocillin, nafcillin, cloxacillin Ceftazidime, cefoperazone, cefotaxime, cefazolin, ceftizoxime, cefoxitin, cefradine, cefuroxime, ceftriaxone, cefamandole, cefepime Aminoglycosides: Gentamicin, tobramycin, amikacin, netilimicin, streptomycin carbapenems: Imipenem, meropenem

17. Mezlocillin Moxalactam Azlocillin Cefoperazone Cefradine Cefamandole ?????? ?

18. Safdar et al. 2004 Objective: compare single antibiotic versus combination antibiotic therapy Setting: documented bacteremia Primary outcome measured: mortality 17 studies, 3077 patients 5 prospective cohort 2 prospective RCT 10 retrospective cohort Most studies used beta-lactam and aminoglycoside mono or combo therapy

19. Antibiotics Used “ the detail provided in each study regarding the specific antimicrobial used varied greatly.” Antipseudomonal penicillins Aminoglycosides Ciprofloxacin Several different antimicrobial classes were used singly and in combo in the study by Kreger: Chloramphenicol, tetracycline, kanamycin, gentamicin, penicillins, cephalosporins

20. Results No mortality benefit with combination therapy OR 0.96 CI 95% 0.70—1.32 Subgroup analyses: did not change result year of publication study design severity of illness Subgroup analysis of P. aeruginosa showed mortality benefit with combo therapy OR 0.50 CI 95% 0.30-0.79

21. P. Aeruginosa-mortality benefit with combo therapy? 5/17 studies looked at specifically P. aeruginosa bacteremia 4/5 retrospective cohort, 1/5 prospective cohort 3/5 patient populations with neutropenia, malignancy 1/5 studied only HIV/AIDS patients with PCP 1/5 surgery, renal dx, and 48% had PNA Note that the underlying populations used in each study varied greatly Note that the underlying populations used in each study varied greatly

22. P. Aeruginosa subgroup All included studies showed a trend towards mortality benefit with combo therapy, but not all data achieved statistical significance Summary odds ratio: 0.50 (0.32-0.79, p=.007) suggesting a 50% relative reduction in mortality with the use of combo therapy

23. Hilf et al.  prospective cohort 200 patients from different hospitals around Pittsburgh Mean age 59, range one week to 96 years 23% community acquired 77% nosocomial bacteremia 58% immunosupressed (cytotoxic drugs, corticosteroid tx, radiation tx, hematologic malignancy or neutropenic (ANC 3000) Outcome was death or survival at 10 days after documented pseudomonas bacteremia Data obtained from different hospitals is good, but they are all located in the same geographical location, which is important given patterns of resistance of organisms in differnent communities 77% nosocomially acquired pathogens, we know these tend to be more “resistant” Data obtained from different hospitals is good, but they are all located in the same geographical location, which is important given patterns of resistance of organisms in differnent communities 77% nosocomially acquired pathogens, we know these tend to be more “resistant”

24. How antibiotics were used in this study Whether combo therapy used was NOT RANDOM, 143/200 patients (70%) received two drugs 90% received an aminoglycoside (gent, amikacin, tobramycin 75% received a beta-lactam: piperacillin,ticaricillin, mezlocillin, cefoperazone,carbenicillin, imipenem, cefotaxime, ceftazidime Most common combo therapy was tobramycin plus ticaricillin. 7% rec’d no anti-pseudomonal abx, all died within 10 days of onset of bacteremia

25. Other considerations… The patient population receiving combo therapy was “comparable” to those receiving monotherapy But higher frequency of neutropenics in combo therapy group Bias towards monotherapy since neutropenics had poorer prognosis before sepsis

26. Results 143 pts w/ combo therapy had a 27% mortality rate 43 patients w/ monotherapy had a rate of 47% (p= 0.023) The probability of survival during 30-day period following + blood cx was better for those w/ combo therapy (p=0.041)

27. What can we conclude antibiotic use in gram negative sepsis: early appropriate anti-infective therapy Double gram-negative coverage does not confer mortality benefit

28. Except… in the setting of P. aeruginosa bacteremia in the immunocompromised 2/3 days of aminoglycoside plus anti-pseudomonal beta-lactam may improve survival

29. Future Need more studies with the following qualities: More recent data, at least since the late 1980’s Multi-center studies to control for geographic differences in resistance patterns Use antibiotics commonly present in pharmacies of US hospitals Prospective randomized trials

30. References Hilf, et al. (1989) Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. The American Journal of Medicine, 87, 540-546. Fehri, Lina et al. (2007) Activities of antimicrobial peptides and synergy with enrofloxacin against mycoplasma pulmonis. Antimicrobial Agents and Chemotherapy, 2 (51), 468-474. Paul et al. (2004) B lactam monotherapy versus B lactam-aminoglycoside combination therapy for sepsis in immunocompeten patients: systematic review and meta-analysis of randomised trials. British Medical Journal, 1-14. Safdar et al. (2004). Does combination antimicrobial therapy reduce mortality in gram-negative bacteremia? A met-analysis. The Lancet, 4, 519-527 Leibovici et al. (1997). Monotherapy versus B-lactam-Aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study. Antimicrobial agents and chemotherapy, (41) 5, 1127-1133. Chamot, E. et al. (2003). Effectiveness of combination antimicrobial therapy for Pseudomonas aeruginosa bacteremia. Antimicrobial agents and chemotherapy, (47) 9, 2756-2764 Chatzinikolau, I et al. Recent experience with Pseudomonas aeruginosa bacteremia in patients with cancer. Archives of Internal Medicine, (160), 501-509. Kanj, Souha and Sexton, D. “Treatment of Pseudomonas aeruginosa infections.” UpToDate March 26 2010: 1-3.