Editorial Commentary: Increasing Evidence That Certain Antibiotics Should Be Avoided for Shiga Toxin-Producing Escherichia coli Infections: More Data Needed.

Shiga toxin–producing Escherichia coli (STEC) causes gastrointestinal manifestations ranging from mild nonbloody diarrhea to severe hemorrhagic colitis. Some strains can cause life-threatening postdiarrheal hemolytic uremic syndrome (HUS). Despite the medical community’s nearly 35-year experience with these pathogens, the optimal clinical management to decrease the likelihood of HUS remains unsettled. Most concur that current best practices for managing STEC O157 infections include early diagnosis, supportive care (especially ensuring adequate hydration), monitoring for early evidence of HUS, and avoidance of antibiotic treatment unless required for another infection [1–3]. However, the question of possible risks and benefits of antibiotic treatment of STEC, especially O157, diarrhea has been debated for decades. Early observations of patients with STEC O157 infection noted that those who had received antibiotics seemed more likely to develop HUS [4]. However, proof of a causative association has been elusive. The question has not been well suited for randomized clinical trials because patients are often empirically treated with antibiotics before STEC is diagnosed, and by the time a diagnosis is made the events that lead to HUS are likely already under way. Observational studies have all struggled with ways to account for (or have simply ignored) the fact that sicker patients are probably both more likely to get treated with antibiotics and more likely to develop HUS, regardless of any causal effect. The proposed mechanism for harm is increased production of toxin stimulated by the antibiotic, release of toxin from stimulated or dying bacteria, or both. These theories have been supported by in vitro [5–10] and animal model [6, 11] studies showing that exposure of certain STEC strains to certain antibiotic classes (eg, fluoroquinolones, trimethoprim-sulfamethoxazole [TMP-SMX], βlactams, and others) at certain doses can increase production and release of Shiga toxins or worsen severity of infections. However, some in vitro studies have shown that certain antibiotics (eg, macrolides, rifaximin, tigecycline, fosfomycin, and others) at certain doses can reduce or not alter Shiga toxin production by certain STEC strains [5, 7, 10, 12], and studies of mice and pigs have suggested that certain antibiotics (eg, azithromycin and fosfomycin) may improve or, at least, not worsen outcomes [6, 11, 13]. Better information about the effects of treatment with various antibiotic regimens could inform treatment decisions, not only for diarrheal illness, but also for those now rare patients with invasive STEC infections, such as O80:H2 reported from France [14]. In this issue of Clinical Infectious Diseases, Freedman et al describe a rigorous meta-analysis that attempted to quantify the risk that any form of antibiotic treatment of diarrhea caused by all varieties of STEC confers for the development of HUS. They thoroughly searched for applicable data and objectively graded the risk of bias (RoB) of all 17 studies in their analysis. In addition, the authors appropriately classified studies into those that did (12 studies) and did not (5 studies) apply widely accepted laboratorybased HUS case definitions. However, in our opinion, the dearth of good data made it an impossible task. The published literature is simply not broad enough to provide a definitive answer about the entire universe of STEC infection and antibiotic combinations, especially when considering important factors including antibiotic class, dose, duration, and timing of treatment. The large majority (14 of 17) of studies in their primary analysis and all of the studies in their subanalysis of best studies (ie, the 5 low-RoB studies that used a strict HUS case definition) were exclusively of STEC O157 infections. Moreover, the amount of data on individual antibiotic classes was limited. For example, only 2 of the 5 best studies included patients treated with macrolides and only 9 patients in those studies were reported as Received 10 February 2016; accepted 11 February 2016; published online 24 February 2016. Correspondence: R. K. Mody, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, MS C-09, Atlanta, GA 30329 (rmody@cdc.gov). Clinical Infectious Diseases 2016;62(10):1259–61 Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/cid/ciw101