Source and Timing May Influence Sepsis Monotherapy or Combination Therapy

NASHVILLE—Two researchers at the Society of Critical Care Medicine’s 2009 Critical Care Congress agreed that antibiotic monotherapy yields the best outcomes for empiric treatment of sepsis; but such was not the case in the matter of severe sepsis and septic shock.

Dennis G. Maki, MD, Ovid O. Meyer Professor of Medicine and Head of the Section of Infectious Diseases, University of Wisconsin Hospitals and Clinics, Madison, said the evidence is “underwhelming” that combination therapy is better in severe sepsis and septic shock, calling for large randomized controlled trials to definitively ascertain its value. “Our goal should be targeted antimicrobial therapy guided by our suspicion of the possible source of the infection and our knowledge of the likely pathogens at that source,” he said. “If you get it wrong in the beginning, you have a greatly increased mortality.”

“Septic shock and sepsis without shock are fundamentally different diseases,” said Anand Kumar, MD, Associate Professor of Medicine, University of Manitoba, Canada. He contended that there is some evidence pointing to better outcomes with combination therapy in sicker septic patients and those with septic shock. “Speed is life,” he said, “but a sledge hammer helps too.”

TWO IS NOT BETTER THAN ONE

Although major sepsis management guidelines make no specific recommendations about using monotherapy or combination therapy, the implication is that combination therapy is preferred, Dr. Maki observed. But while combination therapy intuitively seems like a good idea, the evidence suggests it is not, he said.

The price of combination therapy, which can be high, may not affect just the hospital’s bottom line, noted Dr. Maki. Sequelae from unnecessary antibiotic use can include superinfection, Clostridium difficile–associated disease, and liver and kidney toxicity.

In what Dr. Maki called an “elegant” meta-analysis, researchers looked at 64 trials that compared β-lactam monotherapy to treat sepsis versus β-lactam/aminoglycoside combination therapy. There were no differences between the treatments in all-cause mortality or in the development of resistance; however, combination therapy was associated with increased rates of treatment failure and adverse events, particularly nephrotoxicity.

In a meta-analysis in which Dr. Maki was involved, 17 trials were examined that compared monotherapy with combination therapy for patients with gram-negative bacteremia. The therapies used most often were β-lactams and aminoglycosides, alone or in combination.

“We found that with enteric bacteria, there was no evidence whatsoever that using two drugs was better than using a single effective drug,” except in the case of Pseudomonas aeruginosa bacteremia, for which combination therapy halved mortality, Dr. Maki said. He believes that pseudomonal sepsis may be the outlier that mandates the use of two drugs.

One report showed that combination therapy to treat intra-abdominal sepsis with metronidazole and ciprofloxacin was superior to that with third-generation cephalosporin, Dr. Maki acknowledged. However, in two studies, treatment with carbopenem proved to be just as good as conventional combination therapy.

The best model available for sepsis due to Staphylococcus aureus is staphylococcal endocarditis, he suggested. A large review from researchers in New Zealand found no benefit to combination therapy, except in patients with prosthetic valves. Combination therapy was associated with an increase in nephrotoxicity. Similarly, although somewhat surprisingly, two cohort studies indicated that the addition of rifampin to antibiotic therapy increased mortality rate and/or incidence of nephrotoxicity.

For hospital-acquired pneumonia, Dr. Maki cited the results of six randomized controlled trials that all showed similar outcomes with monotherapy or combination therapy. For pneumococcal bacteremia, cohort studies report conflicting results. In the case of Clostridium difficile, there are no clinical trials or even good cohort data, Dr. Maki said.

GOOD TIMING

Early treatment is crucial, but what if the ideal therapeutic window of 30 minutes to initiate antimicrobial therapy is missed? According to Dr. Anand Kumar, the use of combination therapy may help reverse the cascade of sepsis.

“Time is an indirect measure of the microbial load,” he suggested. From an infectious disease perspective, “speed of clearance of the microbial pathogen is the critical determinant of outcome in septic shock.”

Dr. Kumar put forth the concept of the “shock threshold,” which can be different for different people depending on such factors as age. “But for everybody, the same sequence eventually occurs: Once you go past the shock threshold, the clock is ticking. At some point, anyone who remains in septic shock will become irreversibly committed to death.”

A multicenter study published in 2006 led by Dr. Kumar documented that survival rates decline with each hour of delay in antimicrobial administration for septic shock. “We were appalled to find that only about 5% of patients received antimicrobial therapy within the first half hour of documentation of hypotension.”

In an as-yet unpublished meta-analysis, Dr. Kumar and colleagues found, as previous research has, that there appears to be no significant benefit of combination antibiotic therapy in sepsis overall.

However, a subanalysis of the 12 studies with information about sepsis severity showed that underlying mortality risk—and not such factors as the infectious pathogen or choice of antibiotics—was the only independent predictor of whether combination therapy would be beneficial. Specifically, among patients in the monotherapy group, if mortality risk was less than 15%, monotherapy resulted in the best outcome; if mortality risk was more than 25%, combination therapy showed a clear benefit. Similar results were found in the subgroup analysis of the eight studies that identified patients with and without septic shock.

“The question is not whether combination therapy helps or hurts you, but rather when does combination therapy help or hurt you,” Dr. Kumar summarized.

Additional information comes from an unpublished analysis of a septic shock database in which Drs. Maki and Kumar both are involved. Again, combination therapy was shown to be superior to monotherapy in this cohort of sicker septic shock patients, with a 9% difference in mortality rates.

—Elizabeth G. Douglas

Suggested Reading
Dellinger RP, Levy MM, Carlet JM, et al, for the International Surviving Sepsis Campaign Guidelines Committee. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327.
Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.
Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ. 2004;328(7441):668.
Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis. 2004;4(8):519-527.

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