Combination antibiotics in early septic shock---synergistic effect?

In hospital medicine there exists a dialectical tension between the idea of “antimicrobial stewardship,” which encourages restricted use of antibiotics, and that of “adequately broad spectrum therapy” in which combinations of antibiotics are advocated for a variety of reasons.


The best discussion I've found on the purported reasons for combinations of antibiotics (some of which are better clinically validated than others) is in Mandell's ID textbook, Part I Chapter 18. Reasons for combination therapy include coverage of the likely spectrum when the pathogen and/or its antimicrobial sensitivity is unknown. The most time honored and clinically accepted example of this is meningitis. Sepsis and pneumonia are emerging as increasingly important examples in this category, given recent data that mortality is reduced when the spectrum is covered at the initiation of therapy as opposed to adding drugs later in the course as microbiologic data become available. (Shoot first, ask questions later). Another reason for combination therapy is prevention of emergent resistance. The best validated example is treatment of tuberculosis. A third reason is antimicrobial synergy. The most universally accepted example of this is the treatment of enterococcal endocarditis.


So the title of an article in the September issue of Critical Care Medicine is a little deceiving: Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: A propensity-matched analysis. My first reaction was that this is something we already knew based on the reason cited above. But that's not what this study was about. It compared monotherapy with an agent to which the offending pathogen was proven to be susceptible to double coverage by agents having different mechanisms of action, to which the pathogen was susceptible. From the paper:

Using a Cox proportional hazards model, combination therapy was associated with decreased 28-day mortality (444 of 1223 [36.3%] vs. 355 of 1223 [29.0%]; hazard ratio, 0.77; 95% confidence interval, 0.67-0.88; p = .0002). The beneficial impact of combination therapy applied to both Gram-positive and Gram-negative infections but was restricted to patients treated with β-lactams in combination with aminoglycosides, fluoroquinolones, or macrolides/clindamycin. Combination therapy was also associated with significant reductions in intensive care unit (437 of 1223 [35.7%] vs. 352 of 1223 [28.8%]; odds ratio, 0.75; 95% confidence interval, 0.63-0.92; p = .0006) and hospital mortality (584 of 1223 [47.8%] vs. 457 of 1223 [37.4%]; odds ratio, 0.69; 95% confidence interval, 0.59-0.81; p less than .0001). The use of combination therapy was associated with increased ventilator (median and [interquartile range], 10 [0-25] vs. 17 [0-26];p = .008) and pressor/inotrope-free days (median and [interquartile range], 23 [0-28] vs. 25 [0-28]; p = .007) up to 30 days.

So now there are two reasons to use combination antibiotic therapy with the initiation of treatment of septic shock: adequacy of coverage and synergy.


A related editorial discussed general issues related to combination antibiotic therapy in a variety of settings. The editorial cites a lot of data and deserves a careful read.