INFECTIOUS DISEASE/ORIGINAL RESEARCH

INFECTIOUS DISEASE/ORIGINAL RESEARCH Randomized Controlled Trial of Trimethoprim-Sulfamethoxazole for Uncomplicated Skin Abscesses in Patients at Risk for Community-Associated Methicillin-Resistant Staphylococcus aureus Infection Gillian R. Schmitz, MD, David Bruner, MD, Rebecca Pitotti, RN, BSN, Cameron Olderog, MD, Timothy Livengood, MD, Justin Williams, MD, Kermit Huebner, MD, Jeffrey Lightfoot, MD, Brandon Ritz, MD, Christopher Bates, MD, Matthew Schmitz, MD, Mihriye Mete, PhD, Gregory Deye, MD From the Department of Emergency Medicine, Washington Hospital Center, Washington, DC (G. R. Schmitz); the Department of Emergency Medicine, Naval Medical Center, Portsmouth, VA (Bruner, Lightfoot); the Department of Emergency Medicine (Pitotti, Bates) and Department of Orthopaedic Surgery (M. Schmitz), Wilford Hall Medical Center, Lackland Air Force Base, TX; the Department of Emergency Medicine, Brooke Army Medical Center, Ft. Sam Houston, TX (Olderog, Livengood, Williams); the Department of Emergency Medicine, Darnall Army Medical Center, Ft. Hood, TX (Huebner, Ritz); Departments of Epidemiology and Statistics, Medstar Research Institute, Hyattsville, MD (Mete); and the Department of Clinical Pharmacology, Walter Reed Army Institute of Research, Silver Spring, MD (Deye). The opinions expressed in this document are solely those of the authors and do not represent an endorsement by or the views of the United States Air Force, the Department of Defense, or the United States Government. Study objective: Community-associated methicillin-resistant Staphylococcus aureus is now the leading cause of uncomplicated skin abscesses in the United States, and the role of antibiotics is controversial. We evaluate whether trimethoprim-sulfamethoxazole reduces the rate of treatment failures during the 7 days after incision and drainage and whether it reduces new lesion formation within 30 days. Methods: In this multicenter, double-blind, randomized, placebo-controlled trial, we randomized adults to oral trimethoprimsulfamethoxazole or placebo after uncomplicated abscess incision and drainage. Using emergency department rechecks at 2 and 7 days and telephone follow-up, we assessed treatment failure within 7 days, and using clinical follow-up, telephone follow-up, and medical record review, we recorded the development of new lesions within 30 days. Results: We randomized 212 patients, and 190 (90%) were available for 7-day follow-up. We observed a statistically similar incidence of treatment failure in patients receiving trimethoprim-sulfamethoxazole (15/88; 17%) versus placebo (27/102; 26%), difference 9%, 95% confidence interval 2% to 21%; P.12. On 30-day follow-up (successful in 69% of patients), we observed fewer new lesions in the antibiotic (4/46; 9%) versus placebo (14/50; 28%) groups, difference 19%, 95% confidence interval 4% to 34%, P.02. Conclusion: After the incision and drainage of uncomplicated abscesses in adults, treatment with trimethoprimsulfamethoxazole does not reduce treatment failure but may decrease the formation of subsequent lesions. [Ann Emerg Med. 2010;56:283-287.] Please see page 284 for the Editor s Capsule Summary of this article. Provide feedback on this article at the journal s Web site, www.annemergmed.com. 0196-0644/$-see front matter Copyright 2010 by the American College of Emergency Physicians. doi:10.1016/j.annemergmed.2010.03.002 INTRODUCTION Background and Importance Skin and soft tissue infections caused by community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) pose a clinical challenge because of their increasing incidence, as well as uncertain optimal medical management. CA-MRSA infections have been reported to account for more than 50% of skin and soft tissue infections observed at major medical centers in the United States. 1 CA-MRSA is resistant to cephalexin that had previously been a mainstay of treatment for skin infections. Although prescribing antibiotics with activity against CA- MRSA for skin and soft tissue infections has become increasingly common, 2,3 it remains unclear whether they benefit uncomplicated CA-MRSA abscesses after drainage. High cure rates (91%) have been observed without antibiotics. 4 To our knowledge, there are no previous controlled trials in adults to Volume 56, NO. 3 : September 2010 Annals of Emergency Medicine 283

Trimethoprim-Sulfamethoxazole for Skin Abscesses Schmitz et al Editor s Capsule Summary What is already known on this topic With the increasing prevalence of methicillinresistant Staphylococcus aureus, there is concern that incision and drainage may be insufficient treatment for skin abscesses. What question this study addressed After drainage of uncomplicated skin abscesses, does treatment with oral trimethoprim-sulfamethoxazole reduce treatment failure at 7 days? What this study adds to our knowledge This 212-adult, double-blind, randomized, controlled trial found similar rates of treatment failure in patients receiving antibiotics and placebo. How this might change clinical practice Antibiotics are unnecessary after abscess incision and drainage. evaluate antibiotics with activity against CA-MRSA in an emergency department (ED) setting, but trimethoprimsulfamethoxazole did not reduce treatment failure in a recent study of ED children. 5 Goals of This Investigation In ED adults with soft tissue abscesses, we evaluated whether trimethoprim-sulfamethoxazole reduced the rate of treatment failure by 15% relative to placebo during the 7 days after incision and drainage. Secondarily, we assessed the rate of new lesion formation within 30 days. MATERIALS AND METHODS Study Design We conducted a multicenter, double-blind, randomized, placebo-controlled trial (registered under identifiers NCT00822692 and NCT 00973765 at http://www. clinicaltrials.gov). The study was approved by the institutional review board at each site, with written informed consent. Setting This study was conducted at 4 military EDs that treat both civilians and military patients: Wilford Hall Medical Center (50,000 visits/year), Brooke Army Medical Center (50,000 visits/year), Darnall Medical Center (43,000 visits/year), and Portsmouth Medical Center (75,000 visits/year). Selection of Participants We enrolled a convenience sample of adults (aged 16 years or older) with uncomplicated skin abscesses requiring incision and drainage between November 20, 2007, and June 1, 2009 Figure. Study enrollment distribution. TMP-SMX, Trimethoprim-sulfamethoxazole. (Figure). We excluded patients who were immunocompromised (eg, diabetes, HIV, cancer), were pregnant or breast feeding, were allergic to sulfa drugs, had associated fever or signs of systemic illness, had received antibiotics in the previous week, or had been hospitalized in the previous month. We excluded abscesses on the face and known or suspected tracts or fistulas to deeper structures, or abscesses requiring operating room drainage. Data Collection and Processing Treating physicians enrolled patients 7 days a week, 24 hours a day, and completed a standard data collection form detailing age, sex, race, and location of abscess. Location of abscess was categorized into head and neck, trunk, axilla, extremity, or groin/buttock. The largest diameter of the abscesses and areas of cellulitis were measured with a standardized ruler in each enrollment packet. Interventions Abscesses were drained and packed with gauze according to standard practice, with incision length, irrigation, and use of ultrasonography at each physician s discretion. Cavity wound cultures were obtained and sent for aerobic and anaerobic culture and antimicrobial susceptibility testing. A block randomization scheme was prepared by the pharmacy, with allocation to each group achieved by opening sequentially numbered, sealed envelopes. Patients assigned to the antibiotic treatment group received trimethoprimsulfamethoxazole (160 mg/800 mg), and those assigned to the control group received identical-appearing placebo capsules, both with instructions to take 2 pills orally twice daily for 7 days. Thus, patients and physicians were blinded to treatment arm. Subjects were asked to return to the ED in 2 days and 7 days for wound rechecks, with repacking and additional visits as clinically appropriate. A study investigator blinded to treatment 284 Annals of Emergency Medicine Volume 56, NO. 3 : September 2010

Schmitz et al arm telephoned patients as needed to remind them to return for wound rechecks, inquire about potential medication-related adverse effects, and assess for presence of fever, worsening cellulitis, or new lesions if the patients did not return for follow-up. Methods of Measurement Our primary outcome was treatment failure within 7 days, defined as no improvement after 2 days, development of a new separate lesion within 7 days, or worsening infection within 7 days, leading to an intervention (ie, further antibiotic administration, additional incision and drainage, surgical debridement, or hospital admission). A worsening infection required evidence of an increased diameter of abscess or cellulitis, or the presence of fever or systemic response. Recheck physicians blinded to study arm recorded these outcomes and the supporting clinical findings on a standardized recheck form. Culture results and sensitivities were available if a patient failed treatment to guide therapy. Our secondary outcome was the development of new lesions, abscess or pustule, within 30 days of enrollment. Hence, patients with a primary outcome treatment failure based on a new lesion within 7 days were also classified according to this secondary outcome. One of the 4 study sites (Portsmouth Medical Center) did not collect data on this secondary outcome, and thus its subjects were excluded from this analysis. The secondary outcome was assessed through telephone calls from a study investigator (blinded to treatment arm), any return visits to the ED within 30 days, and review of all further treatment recorded in the medical records. Primary Data Analysis We selected a 15% difference in treatment failure as clinically important, as did a previous similar study. 4 Assuming a 2-sided comparison,.05, and.20, we calculated that 88 patients were needed in each treatment arm. Anticipating that some patients would be lost to follow-up, we intentionally enrolled more subjects than calculated. We analyzed our outcomes with 2 or the Fisher s exact test, using Intercooled Stata 9.2 (StataCorp, College Station, TX). Trimethoprim-Sulfamethoxazole for Skin Abscesses Table 1. Baseline characteristics of the participants. Characteristics Placebo (%) Trimethoprim- Sulfamethoxazole (%) Male 72/116 (62) 68/96 (71) White 62/108 (57) 47/91 (52) Abscess(es) 5 cm 12/116 (10) 6/96 (6) Culture results MRSA 47/100 (47) 50/84 (60) MSSA 22/100 (22) 13/84 (15) Coag neg staph 10/100 (10) 8/84 (10) S viridans 5/100 (5) 1/84 (1) No growth 8/100 (8) 2/84 (2) Other 8/100 (8) 10/84 (12) Abscess location Trunk 21/116 (18) 14/96 (15) Extremity 55/116 (47) 47/96 (49) Groin/buttock 20/116 (17) 20/96 (21) Axilla 14/116 (12) 5/96 (5) Head and neck 6/116 (5) 10/96 (10) Age, y (n 212) n 116 n 96 Median (IQR) 27 (21 38) 28 (21 38) Range 18 65 17 79 Cellulitis, cm (n 212) n 116 n 96 Median (IQR) 5 (0.5 7) 4.5 (2 8) Range 0 24 0 22 Abscess size, cm (n 212) n 116 n 96 Median (IQR) 2.8 (1.5 3.5) 2.5 (2 3) Range 0.5 7.5 0.5 7 MSSA, Methicillin-sensitive Staphylococcus aureus; IQR, interquartile range. RESULTS Characteristics of Study Subjects We assessed 220 patients for enrollment in the study, with trial flow shown in the Figure. We did not collect information on potential subjects who were not enrolled. Baseline characteristics were similar between the 96 subjects randomized to trimethoprimsulfamethoxazole and the 116 randomized to placebo (Table 1). No patients with abscesses associated with foreign bodies, infected sutures, or bites were enrolled. MRSA was cultured from 53% of subjects overall, with similar rates at the 4 study sites. All isolates were sensitive to trimethoprimsulfamethoxazole. For 7-day follow-up, 190 of 212 (90%) subjects were evaluable. We observed statistically similar rates of 7-day treatment failure between those receiving trimethoprimsulfamethoxazole and placebo (Table 2), and our observed 9% effect size was less than the 15% we predefined as clinically important. For the 3 sites collecting 30-day follow-up data, 43 subjects could not be contacted and were lost to follow-up, leaving 96 of 139 (69%) evaluable. We observed fewer abscesses within 30 days in the trimethoprim-sulfamethoxazole group (Table 3). Post hoc sensitivity analyses assuming extreme opposite outcomes for patients lost to follow-up would change the statistical significance of both primary and secondary outcomes. Ten patients receiving trimethoprim-sulfamethoxazole reported adverse effects: nausea (4), drowsy/dizzy (3), headache and night sweats (1), vaginal yeast infection (1), and a mild allergic reaction (1). One patient receiving placebo reported an adverse effect, ie, feeling drowsy. LIMITATIONS The principal limitation of this study was the loss to followup. Unequal outcome differences in those not returning or unable to be contacted could have altered our outcomes, particularly the 30-day evaluation. Our study is also limited in that it included a convenience sample, although we have no reason to believe that enrolled subjects systematically differed from those not enrolled. We studied only healthy adults, and thus our findings cannot apply to children or the immunocompromised. Finally, we did not standardize the Volume 56, NO. 3 : September 2010 Annals of Emergency Medicine 285

Trimethoprim-Sulfamethoxazole for Skin Abscesses Schmitz et al Table 2. Treatment failure at 7 days. Treatment Failure at 7 Days Placebo (n 102) Trimethoprim-Sulfamethoxazole (n 88) Difference, % (95% CI) P Value Total 27 (26%) 15 (17%) 9 ( 2 to 21).12 Nature of treatment failures n 27 n 15 Worsening infection* 15 9 New lesion 8 4 Not clinically improved 4 2 Intervention for treatment failures n 27 n 15 Admitted for IV antibiotics 5 2 IV antibiotics in ED only 3 1 Re-I&D only 3 2 Sent home with antibiotic 9 5 Both re-i&d and sent home with antibiotic 7 5 CI, Confidence interval; IV, intravenous; I&D, incision and drainage. *A worsening infection required evidence of an increased diameter of abscess or cellulitis, or the presence of fever or systemic response. Table 3. Development of new lesions within 30 days. New Lesions Within 30 Days Placebo (n 50) Trimethoprim-Sulfamethoxazole (n 46) Difference, % (95% CI) P Value Total 14 (28%) 4 (9%) 19 (4 34).02 Timing of new lesions, days n 14 n 4 7 5 2 7 9 2 Location of new lesion n 14 n 4 Same limb or body part 11 2 Elsewhere 3 2 incision and drainage technique, but rather left clinicians to use their standard practice. DISCUSSION Although a number of previous studies have evaluated abscess and wound healing, 4-11 to our knowledge we report the first randomized, double-blinded, placebo-controlled trial of trimethoprim-sulfamethoxazole in adults. MRSA has been cultured from 51% 1 to 80% 5 of patients with skin and soft tissue infections, and our rate (53%) was similar. Like those previously reported, 5 our isolates were uniformly sensitive to trimethoprim-sulfamethoxazole. Previous research of antibiotics for CA-MRSA abscesses has been mixed, with results both against 4,6,7 and for 8,9 such therapy. Most do not assess subsequent rates of new lesion development. 5,10,11 Before ours, 2 prospective randomized controlled trials have compared antibiotics versus placebo after abscess incision and drainage. Rajendran et al 4 found no improvement with cephalexin at 7 days, with 84% of patients cured with antibiotics and 91% without. Duong et al 5 also observed similar improvement between trimethoprim-sulfamethoxazole and placebo in ED children, with treatment failure in 4% of patients with antibiotics and 5% without. They also found significantly more new lesions in the placebo group at 10 days (26% versus 13%) but no such difference at 3 months. Our results confirm these 2 previous negative results, and together our trials support the contention that, despite the high frequency of CA-MRSA, antibiotics are not required after incision and drainage of uncomplicated abscesses. We did observe a nonsignificant trend toward efficacy; however, our study was not powered to identify treatment effects of less than 15%. Our findings support those of Duong et al 5 in that trimethoprimsulfamethoxazole may decrease the development of subsequent new lesions. However, this latter analysis is not as robust as our primary outcome because of the large number of subjects lost to follow-up and should be interpreted with caution. In conclusion, the addition of trimethoprim-sulfamethoxazole (160/800) to incision and drainage did not decrease rates of failure by 15% or more by 7 days compared with placebo. However, it may decrease new lesion development within 30 days. The authors thank the Emergency Medicine Foundation and the Surgeon General s Office for funding this study. The authors also thank James Barker, MD, and Vik Bebarta, MD, for their support and mentorship and Mihriye Mete, PhD, and Anneke Bush, PhD, for their assistance with data and statistical analysis. Supervising editor: Steven M. Green, MD Author contributions: GRS and DB conceived the study, designed the trial, and performed the majority of data collection. GRS obtained research funding and drafted the 286 Annals of Emergency Medicine Volume 56, NO. 3 : September 2010

Schmitz et al Trimethoprim-Sulfamethoxazole for Skin Abscesses article. GRS, DB, JW, and KH were the primary investigators at each of the 4 study sites and oversaw the conduct of the trial. RP enrolled many of the patients and updated and maintained the databases. RP, CO, TL, JL, BR, and CB made follow-up telephone calls. CO, TL, JL, BR, and CB helped collect data and maintain the study at each site. MS assisted with editing, background research, and writing the article. MM performed the statistical analysis. GD provided feedback for the grant and assisted with editing and writing the article. All authors contributed to revision of the article. GRS takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. This research was funded by EMF EMBRS grant 2007-2008 and the Surgeon General s Office. Publication dates: Received for publication January 20, 2010. Revision received February 11, 2010. Accepted for publication March 1, 2010. Available online March 26, 2010. Presented as an abstract at the Society of Air Force Clinical Surgeons, April 2009, Denver, CO; the Leadership and Advocacy Conference, April 2009, Washington, DC; and the Scientific Assembly, ACEP Research Forum, October 2009, Boston, MA. Address for correspondence: Gillian R. Schmitz, MD, 714 Carpenter Rd, Alexandria, VA 22314; 202-877-7632, fax 202-877-2468; E-mail GillianMD@gmail.com. REFERENCES 1. Frazee BW, Lynn J, Charlebois ED, et al. High prevalence of methicillin-resistant Staphylococcus aureus in emergency department skin and soft tissue infections. Ann Emerg Med. 2005;4:311-320. 2. Hersh AL, Chambers HF, Maselli JH, et al. National trends in ambulatory visits and antibiotic prescribing for skin and soft tissue infections. Arch Intern Med. 2008;168:1585-1591. 3. LoVecchio F, Perera N, Cassanova L, et al. Board-certified emergency physicians treatment of skin and soft tissue infections in the community-acquired methicillin-resistant Staphylococcus aureus era. Am J Emerg Med. 2009;27:68-70. 4. Rajendran PM, Young D, Maurer T, et al. Randomized, double blind, placebo-controlled trial of cephalexin for treatment of uncomplicated skin abscesses in a population at risk for methicillin resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2007;5:4044-4048. 5. Duong M, Markwell S, Peter J, et al. Randomized, controlled trial of antibiotics in the management of community-acquired skin abscesses in the pediatric patient. Ann Emerg Med. 2009. 6. Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J. 2004;2:123-127. 7. Paydar KZ, Hansen SL, Charlebois ED, et al. Inappropriate antibiotic use in soft tissue infections. Arch Surg. 2006;141: 850-856. 8. Ruhe JJ, Smith N, Bradsher RW, et al. Community-onset methicillin-resistant Staphylococcus aureus skin and soft tissue infections: impact of antimicrobial therapy on outcome. Clin Infect Dis. 2007;44:777-784. 9. Szumowski JD, Cohen DE, Kanaya F, et al. Treatment and outcomes of infections by methicillin-resistant Staphylococcus aureus at an ambulatory clinic. Antimicrob Agents Chemother. 2007;51:423-428. 10. Macfie J, Harvey J. The treatment of acute superficial abscesses: a prospective clinical trial. Br J Surg. 1977;64:264-266. 11. Barnes EV, Dooley DP, Hepburn MJ, et al. Outcomes of community-acquired, methicillin-resistant Staphylococcus aureus, soft tissue infections treated with antibiotics other than vancomycin. Mil Med. 2006;171:504-507. Did you know? You can save your online searches and get the results by e-mail. Visit www.annemergmed.com today to see what else is new online! Volume 56, NO. 3 : September 2010 Annals of Emergency Medicine 287