Meredith Barlow, M.D. Eric Tuers, M.D. 11/16/2016 Journal Club: Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess Meredith Barlow, M.D. Eric Tuers, M.D. 11/16/2016

Question: 56 year old male with history of DM type 1, HTN, and HLD presents to clinic with large indurated, fluctuant mass on left lower jaw measuring approximately 2.5cm in diameter. 42 year old typically healthy female presents with a 2cm diameter fluctuant indurated mass on the right anterior chest wall below the breast Plan is to I&D the abscesses. Should a course of antibiotics be added to help improve the outcome?

Background The abscess: collections of pus within the dermis and deeper skin tissues Any process leading to a breach in the skin barrier can also predispose to the development of a skin abscesses Increased risk in those with close contact with others who have active infection with skin abscesses S. aureus (either methicillin-susceptible or methicillin- resistant S. aureus) occurs in up to 75 percent of abscesses Uptodate online reference: accessed 11/12/2016

Background Cutaneous abscesses are an important issue because they are common throughout the world, as well at in our clinics Between 1993 – 2005 ER visits for skin and soft tissue infections in the US increased from 1.2 million to 3.4 million, mostly due to increased abscesses Community acquired MRSA emerged as the most common pathogen causing purulent skin/soft tissue infections in many parts of the world Trimethoprim – sulfamethoxazole (TMP-SMX) has retained in vitro activity against MRSA, is one of the most commonly prescribed antibiotics for MRSA.

Background Usual primary treatment is to drain the abscess, and previous studies did not show a benefit of adjunctive antibiotics Many providers do not prescribe antibiotic coverage for uncomplicated abscesses as a drained abscess typically resolves without antibiotics, but may take several days or even weeks to resolve After an initial I and D, some patients will require an additional surgical drainage procedure to address accumulations of pus, or will have worsening infection despite I and D requiring abx. So, does the addition of antibiotics alter this?

Article Talan, D. et al. Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess. New England Journal of Medicine. 374;9 (March 3, 2016).

PICO P: Patient/Population/Problem I: Variable of Interest C: Comparison/Control O: Outcome T: Type of Question

Type of Question

PICO P: Patients age 12 and older with uncomplicated cutaneous abscesses that get drained. I: Cure rate for drained abscess with adjunct treatment of TMP- SMX C: TMP - SMX vs. Placebo O: Clinical cure vs. clinical failure T: Intervention/Therapy

Purpose and Study Design Purpose: To evaluate if 7 days administration of trimethoprim-sulfamethoxazole 320mg-1600mg (2 tabs of Bactrim DS) BID vs. placebo in patients with uncomplicated skin abscesses who underwent I&D and were treated on an outpatient basis. Study Design: Multicenter, double-blind, randomized trial of 5 US Emergency Departments

P: Population Outpatients older than age 12 years, who had an uncomplicated abscess that was being treated with drainage

Trial populations Trial populations Modified intention to treat These participants 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 classification, or had missing or unassigned outcomes Per protocol Participants who either took >/= 75% total doses of TPM-SMX or placebo during first 5 days and had an in person test of cure visit 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

Trial populations FDAGEEP population (FDA Guidance Early End-Point Population) Those who received at least one dose of study drug, or placebo, and completed the follow up evaluation at 48 – 72 hours after the start of trial treatment Safety population Those who underwent randomization, got the drug or placebo, and did not return 100% of the doses at the end of the treatment

I: Variable of Interest Response to abscess treatment with I and D with TMP – SMX at rechecks scheduled at days 3-4, 8-10, and 14-21 (vs response to just I and D). Criteria for clinical failure at day 3-4 included: Fever attributable to the abscess Increase in erythema > 25% from baseline Worsening wound swelling or tenderness Criteria for clinical failure at day 8-10 included: Fever, no decrease in maximal region of erythema from baseline, no decrease in swelling or tenderness Criteria for clinical failure at day 14-21 (test of cure evaluation) included: Fever or more than minimal erythema, swelling, or tenderness

C: Comparison/Control

O: Outcome If we assumed that all participants in the mITT-1 population who were lost to follow up (58 in the TMP-SMX group and 39 in the placebo group) had a clinical cure rather than clinical failure, the cure rates would be 89.7% and 79.9%, respectively (difference 9.8 points; 95% CI, 5.7 to 13.9; P<0.001). Abscess cure rate greater in the TMP-SMX group (80.5%) vs. placebo group (73.6%) in the mITT-1 group (difference 6.9 percentage points with 95% confidence interval (2.1-11.7; P=0.005).

Number Needed to Treat mITT-1 Clinical Cure Clinical Failure Total Bactrim 507 123 630 Placebo 454 163 617 NNT= 1/ARR ARR= CER-EVR CER: Control event rate: 454/617= 0.74 EVR: Experimental event rate: 507/630= 0.8 NTT= 1/(0.74-0.8) = 17 (NNT of mITT-1 group) NNT of per-protocol group: 14

Secondary Outcomes

Adverse Events Similar between TMP-SMX and placebo group, and most adverse events were considered mild. Most common adverse event involved GI system (42.7% vs. 36.1%). NO CASES of C. diff-associated diarrhea occurred.

Discussion In this trial involving 1265 patients with drained cutaneous abscess: Patients who received TMP-SMX (dose 320mg-1600mg BID x7days) had higher cure rate than those who received placebo. Improved secondary outcomes in TMP-SMX group: Fewer subsequent surgical drainage procedures, new skin infections, and infections among household members 6-8 weeks after end of treatment period.

Discussion Practice guidelines for abscess drainage is sufficient for most patients, and adjunctive antibiotics should be given for patients who: have systemic response syndrome, DM, very young or very old, infected site with diameter >5cm, and surrounding cellulitis. Participants in this trial generally had small size of skin abscess measuring 2-3cm. HOWEVER MOST PARTICIPANTS HAD TOTAL LESION SIZE, INCLUDING ASSOCIATED ERYTHEMA, OF GREATER THAN 5CM AND THUS MET OTHER GUIDELINE CRITERIA FOR ABX TREATMENT.

Limitations Physicians may have been biased against enrolling patients “perceived as higher risk,” such as those with DM. Therefore, low inclusion of diabetic patients. Higher dose of TMP-SMX (used 2 tabs DS Bactrim BID). Some degree of nonadherence, which would bias against TMP-SMX group, but higher dose of TMP-SMX may have mitigated against inadequate treatment. Abscesses may not have been fully drained in the beginning. Doesn’t give specifics of age range, only over age 12 years.

Critical Appraisal Is the question studied by these investigators similar enough to our question? Is the population studied similar to the population we are interested in? What are the flaws in the way the data was collected or analyzed? How could this affect the validity of the results? Blinding? Reliability of data collected? We can pose these questions to the audience and/or answer them ourselves. The question studied by the investigators is pretty much what we would want to know, do people with drained abscesses benefit from the addition of TMP-SMX. Many people essentially do what they did in this study, and add abx if there appears to be slow resolution with I and D. The study population did not include kids 12 and under, and we certainly see kids with abscesses, so they are not included. There did not appear to be significant flaws in the was the data was collected or analyzed, participants did not know what was in the pills they were taking, and the clinicians were blinded.

Critical Appraisal Are the results understandable and compelling? Are the results applicable to our patient? Can we use this treatment in our practice? Will our practice change based on this evidence? We can pose these questions to the audience and/or answer them ourselves. The results plausible, it makes sense that adding antibiotics will help intervene in those cases where there is perhaps early cellulitis, or pockets or satellite pockets of pus that did not get well drained. Also, many of the patients would have likely met criteria for abx treatment anyway given size of erythema and induration >5cm. Although it is good to know that abx can improve cure rates, we still likely would avoid abx use if possible so that we avoid the perils of overuse of abx, and the rare events related to TMP-SMX such as Stevens Johnson syndrome. I don’t think we will change our practice significantly, but if managing a case where you want to optimize the likelihood of a cure, then you might consider adding TMP – SMX.

Questions?