Looking back to see the post-antibiotic era

Now online in Lancet ID an impressive and important retrospective study describing the faith of 437 patients with BSI caused by carbapenamase-producing Enterobacteriaceae (CPE). When scanning the conclusions of your weekly diarrhea of new papers (as I do) this one might have escaped your attention: (in short) “Appropriate therapy is good. Combination therapy too. Patients with BSIs due to CPE should receive active therapy.” Yet, there is much more interesting stuff in this paper.

With 26 hospitals in 10 countries they collected – in 10 years – 437 patients with CPE BSI (1.4 episode/hsopital/month). The primary enpoint was day-30 mortality (after BSI) and appropriate antibiotic therapy was defined as administration of at least 1 active drug against the blood isolate within 5 days after BSI. Which implies that inappropriate is truly inappropriate. The study is actually on Klebsiella pneumoniae (>85% of all isolates) with KPC (>75% of carbapenamases).

30-day mortality was 38% and 61% in patients that received appropriate and inappropriate therapy, respectively. That is an absolute difference of 23% and a relative difference of 60%. Now the question is what part of that increase can be attributed to antibiotic resistance. In the multivariable analysis appropriate therapy had a hazard rate of 0.45 (95% CI 0.33-0.62), which confirms that Klebsiella BSI should be treated with antibiotics! Yet, resistance does not explain all of the difference, as source of infection, severity of infection (Pitt score and severe sepsis), comorbidity, and time (mortality was higher between 2004-2011 than in 2012-13) were also independently associated with 30-day mortality. The most interesting association was “being treated in a high-mortality-risk center”, with a hazard rate of 2.37 (95% CI 1.74-3.22), propbably as strong as inappropriate therapy.

What is a high-mortality-risk center, other than the words mean? It is defined as “centres with low and high mortality using TreeNet considering all other variables; therefore, sites classified as high-risk centres were those with high mortality after consideration of patients’ features”. I can imagine that there is an interest in knowing where these centers are; and that the investigators are not interested in disclosing that information. The last author, Jesus Rodriguez-Bano, told me that, unfortunately, relevant additional information for patient outcome, such as source control and supportive therapies had not been collected. Yet, high-mortality-risk center looks like another threat for patients, apart from antibiotic resistance.

Other interesting results are the (lack of) association with outcome if appropriate therapy is defined with a cutoff of 2 instead of 5 days, and the listing of appropriate monotherapy (colistin 35%, beta-lactams 30%, tigecycline 18%, and aminoglycosides 13%).


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