Lit of the Week – 4/19/16
Talan DA, Mower WR, Krishnadasan A, Abrahamian FM, Lovecchio F, Karras DJ,Steele MT, Rothman RE, Hoagland R, Moran GJ. Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess. N Engl J Med. 2016 Mar 3;374(9):823-32. doi: 10.1056/NEJMoa1507476. PubMed PMID: 26962903.
Clinical question / background:
- Compared to placebo, does administration trimethoprim-sulfamethoxazole improve cure rates of non-complicated cutaneous abscesses drained in the ED?
- Randomized, double-blind, placebo-controlled trial at 5 North American emergency departments
- 1265 patients randomized
- 636 TMP-SMX group
- 629 placebo group
- Inclusion: Patients (> 12 y/o) with uncomplicated cutaneous abscess diagnosed on physical or ultrasonographic exam that had been present <1 week and had a diameter of at least 2 cm with purulent discharge on drainage
- Exclusion: Suspected osteomyelitis or septic arthritis, diabetic foot decubitus, or ischemic ulcer, mammalian bite, IVDU, long-term care residence, incarceration, immunodeficiency (i.e. ANC <500/mm3), iommunosuppressive drugs, active chemotherapy, known AIDS, creatinine clearance <50mL/min, taking warfarin, phenytoin, or methotrexate, pregnant or lactating
- Analysis groups:
- Modified Intention-to-Treat: Participants who took at least one dose of the active drug or placebo and had an in-person or telephone assessment through the test-of-cure visit, as well as those who withdrew from the trial, were lost to follow-up before final classification, or had missing or unassigned outcomes
- Per-Protocol: Participants who either took ≥75% of the total doses of study drug or placebo during first 5 days and had an in-person test-of-cure or were determined to have had clinical failure before the test-of-cure visit and received ≥75% of the doses provided during the first 48 hours of the treatment period
Primary outcome: Clinical Cure of Abscess (Test-of-cure Visit = 7 – 14d after treatment period, Extended Follow–up Visit = 42 – 56d after treatment period)
- Secondary outcomes: Composite cure (i.e. resolution of all symptoms and signs of infection, or improvement such that no additional antibiotic therapy or surgical drainage procedure was necessary), surgical drainage procedures, changes in erythema size, invasive infections (sepsis, bacteremia, endocarditis, osteomyelitis, septic arthritis, necrotizing fasciitis, or pneumonia), skin infections at the same site and at a different site, hospitalizations, similar infection in household contacts, days missed from normal activities, days missed from work or school, days analgesics were used
- 320mg of TMP and 1600mg of SMX BID for 7 days
- 4 pills containing microcrystalline cellulose BID for 7 days
- Significant increase in cure rates in patients who received TMP-SMX compared to patients who received placebo in both analysis groups
- Clinical Cure of Abscess in Modified Intention-to-Treat Population:
- TMP-SMX: 507/630 patients (80.5%) vs Placebo: 454/617 patients (73.6%)
- Absolute Difference: 6.9% (2.1 – 11.7%), NNT = 14
- Clinical Cure of Abscess in Per-Protocol Population:
- TMP-SMX: 487/524 patients (92.9%) vs placebo: 457/533 patients (85.7%)
- Absolute Difference: 7.2% (3.2 – 11.2%), NNT = 14
- No difference between groups in secondary outcomes
- Patients with uncomplicated cutaneous abscesses had improved cure rates with a 7 day course of TMP-SMX compared to patients who received only a placebo
- Multicenter, double-blinded, randomized clinical trial
- Before initiation of trial, trial personnel underwent standardized training on the general technique and trial-specific procedures for I&D
- 4% of the MRSA isolates tested were susceptible to trimethoprim-sulfamethoxazole
- There was a moderate degree of nonadherence with only 64.7% of the study population determined to be 100% adherent and another 17.2% were 76 – 99% adherent. But this is probably what happens in everyday practice. This could bias the results against trimethoprim-sulfamethoxazole.
- This study provided a power of 90% to detect a between-group difference of 7.5%, which was not met by this study in any of its trial populations. The key to understanding this issue is to recall the difference between a superiority study and a non-inferiority study. This was a superiority study and hence a statistical difference can be found even if the observed delta is less than the delta used to power the study. Because the 95% CI did not cross zero, statistical significance was found. One has to determine, however, what is clinically significant as the threshold for clinical significance was not defined. Because the effect size was not huge, Dr. Talan and co-authors suggest that collaborative decision making with the patient should be used.