Reviewed by Jesse Sutton, PharmD; Veterans Affairs Salt Lake City Healthcare System
There is a large and growing body of evidence that shorter antibiotic durations are equally efficacious compared to traditional, “long” durations for a variety of infectious syndromes including multiple experimental trials in cellulitis. But does a recent randomized trial for cellulitis contradict the less is more evidence?
Cranendonk and colleagues performed a multicenter, double-blind, non-inferiority trial comparing six versus 12 days of antibiotics in patients hospitalized with severe cellulitis. The study was conducted at 11 hospitals in the Netherlands from 2014 to 2017. Patients were treated with intravenous flucloxacillin followed by step-down to oral flucloxacillin at the discretion of the treating provider. Patients were randomized to six- or 12-days total duration if the cellulitis had improved by day five. The primary outcome was cure at the 14-day follow-up visit without relapse at the 28-day follow-up visit. One hundred fifty-one of the 1,051 initially screened patients were included. Seventy-six patients were randomized to 12 days, and 73 patients were randomized to six days. Of note, this was less than the 158 patients necessary in each group for adequate power based on a 10% non-inferiority margin. The mean age was 60 years, and the lower extremity was the most common site of cellulitis in both groups (82-85%). Of note, the six-day group had a higher proportion of patients with previous cellulitis (33% vs. 43%), obesity (38% vs. 45%), antibiotics prior to admission (34% versus 44%), and larger area of erythema (755 cm2 [interquartile range 378, 1155] vs. 916 cm2 [461, 1208]). There were no differences in clinical cure (50% vs. 49%; adjusted relative risk 0.7, 95% confidence interval -15 – 16) or modified clinical cure (aRR 6.6, 95% CI -8 to 21). Relapse within 90 days after cure was reported in 6% (2/35) in the 12-day group compared to 24% (8/34) in the six-day group (aRR -17.8, 95% CI [-24.8, -0.8]). The authors concluded they were not able to confirm or refute the non-inferiority of six-days to 12-days due to the wide confidence intervals. They did highlight recurrences at 90 days were more common in patients randomized to six days. This conclusion should be cautiously interpreted considering the imbalance in characteristics between groups, small number of patients, outcome definition and assessment, and unclear biologic plausibility. Relapse at 90 days, defined as any new antibiotic prescription for cellulitis by a non-study provider, was a patient-reported outcome based on telephone follow-up, not an in-person assessment based on objective criteria. The 90-day relapse outcome included less than 50 patients per group from the initial, imbalanced population. Lastly, it is curious that different treatment durations, which resulted in similar clinical cure and recurrence rates at 28 days, would result in a higher likelihood of recurrent cellulitis two to three months in the future. While it is possible the difference is due to treatment duration, it is also possible the higher proportion of patients with a history of cellulitis and risk factors for cellulitis were more likely to be treated in the future. While this study may not resoundingly support the “shorter is better” mantra due to the limited sample size, it does not seem to contradict the growing body of evidence when emphasizing the lack of difference in primary outcome and limitations in 90-day recurrence endpoint.
Cranendonk DR, Opmeer BC, van Agtmael MA, et al. Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre, randomized, double-blind, placebo-controlled, non-inferiority trial. Clin Microbiol Infect 2019; doi: 10.1016/j.cmi.2019.09.019. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31618678