THERAPEUTICS FOR THE CLINICIAN Comparison of Azithromycin and Cefadroxil for the Treatment of Uncomplicated Skin and Skin Structure Infections Maureen B. Jennings, DPM; James M. McCarty, MD; Neil M. Scheffler, DPM; Anthony D. Puopolo, MD; Constance D. Rothermel, PhD In this multicenter, investigator-blind trial, we tively. Clinical success rates assessed between compared the efficacy and safety of azithro- days 28 and 32 were 100% (82/82) for azithro- mycin and cefadroxil for the treatment of mycin compared with 90% (75/83) for cefadroxil uncomplicated skin and skin structure infec- ( Pϭ.007). Corresponding rates of eradication tions (SSSIs). A total of 296 patients were ran- for S aureus were 100% (59/59) versus 89% domized to receive either azithromycin (500 mg (56/63), respectively; and for S pyogenes, 100% on day 1, followed by 250 mg once a day on (4/4) versus 83% (5/6), respectively. The inci- days 2 to 5) or cefadroxil (500 mg twice a day dence of treatment-related adverse events was for 10 days). Outpatients, ranging in age from similar in the 2 treatment groups. However, 5 of 18 to 75 years, with acute uncomplicated SSSIs the 139 patients (4%) in the cefadroxil group were enrolled in the study. Clinical and bacteri- discontinued therapy because of treatment- ologic response was assessed between days 10 related adverse events compared with none of and 13 (primary end point) and between the 152 patients in the azithromycin group days 28 and 32. In a modified intent-to-treat (Pϭ.02). Five-day therapy with azithromycin was analysis, clinical success rates assessed as effective as 10-day therapy with cefadroxil for between days 10 and 13 were 97% (111/114) for treating uncomplicated SSSIs. azithromycin and 96% (101/105) for cefadroxil Cutis. 2003;72:240-244. ( Pϭ.717). For azithromycin and cefadroxil, cor- responding rates of bacteriologic eradication for Staphylococcus aureus were 94% (64/68) and ncomplicated skin and skin structure infec- 86% (60/70), respectively, and for Streptococcus tions (SSSIs) are among the most common pyogenes, 80% (4/5) and 100% (6/6), respec- U problems encountered in medical practice1 and include impetigo, erysipelas, cellulitis, folliculi- tis, and simple abscesses. SSSIs commonly are caused Accepted for publication March 14, 2003. by Staphylococcus aureus and Streptococcus pyogenes.2 Dr. Jennings is from the New York College of Podiatric Medicine, Mild to moderate uncomplicated SSSIs usually New York. Dr. McCarty is from the Valley Children’s Medical respond to appropriate oral antimicrobial therapy, Group, Madera, California. Dr. Scheffler is from the American Center for Foot Health Research, Baltimore, Maryland. Dr. Puopolo and first-generation cephalosporins and antistaphy- 2 is from the Milford Emergency Associates, Milford, Massachusetts. lococcal penicillins are often the drugs of choice. Dr. Rothermel is from Pfizer Inc, New York, New York. Azithromycin, an azalide antibiotic, has a pro- This study was supported by a research grant from Pfizer Inc. longed half-life of 68 hours,3 which allows for once- Dr. Rothermel is an employee of and owns stock in Pfizer Inc. daily dosing and shorter regimens for treating a The other authors report no conflict of interest. Reprints: Maureen B. Jennings, DPM, New York College of wide range of infections. In previous studies of Podiatric Medicine, 1800 Park Ave, New York, NY 10035 SSSIs, azithromycin has demonstrated clinical and (e-mail: [email protected]). bacteriologic efficacy comparable to that of 240 CUTIS® Therapeutics for the Clinician dicloxacillin in adults4 and to that of dicloxacillin,5 (hematology, serum chemistry, and urinalysis). The flucloxacillin,5 or cefaclor6 in children. baseline clinical assessment was substantiated by In this study, we compared the efficacy and Gram stain and culture of material obtained from safety of a 5-day regimen of once-daily azithromycin the infection site. Pathogens were identified, and with a 10-day regimen of twice-daily cefadroxil for susceptibility to both study drugs was determined the treatment of patients with uncomplicated by disk diffusion, according to the National SSSIs. Results for a subset of patients (40) in this Committee for Clinical Laboratory Standards.8 trial have been reported previously.7 Additional assessments were performed between days 5 and 7, 10 and 13, and 28 and 32 and included Methods evaluation of clinical signs and symptoms, concomi- Patients—Patients were eligible for the study if they tant illness or concurrent medication, clinical and were outpatients between the ages of 18 and 75 years bacteriologic response (including the collection of and had signs or symptoms of an acute SSSI that war- material for culture, if available), and safety assess- ranted treatment with oral antibiotics. ments (including laboratory tests). Women of childbearing age were required to Response to Therapy—Assessment of clinical have a negative pregnancy test before entry in the and bacteriologic efficacy included both modified study and were to use adequate contraception both intent-to-treat (MITT) and per protocol analyses. during and for 3 months after the end of the study. Generally, the MITT population is more represen- Types of infections appropriate for inclusion in this tative of the patients encountered in clinical prac- study included primary pyodermas (cellulitis, follic- tice. The clinical MITT population included all ulitis, furuncles, carbuncles, paronychia, ecthyma, patients who had received at least one dose of study and erysipelas) and secondary bacterial infections drug, had the appropriate baseline diagnosis, and complicating preexisting skin lesions, such as had one follow-up evaluation. Bacteriologically, traumatic lesions (abrasions, wounds), eczematous evaluable MITT patients included clinical MITT dermatitis, exfoliative erythrodermas, dermato- patients who had a pathogen isolated at baseline. phytosis, vesicular or bullous eruptions (varicella, The per protocol population included clinical pemphigus), and intertrigo. Patients were excluded MITT patients who had received at least 50% of if they had a history of hypersensitivity to the total dose of study drug, had received no addi- macrolides or ␤-lactams, chronic skin ulcers or tional antibiotics during the study, had a suscepti- infected burns, use of systemic or topical antibiotics ble baseline pathogen, and had an evaluation within 72 hours of study enrollment, concurrent between days 10 and 13. The primary efficacy end topical or systemic steroid therapy, use of an inves- point was the clinical response obtained between tigational drug within the previous 30 days, or other days 10 and 13. Clinical response was defined as clinically significant medical conditions (hemato- cure (complete resolution of pretreatment signs and logic, immunologic, renal, hepatic, or cardiovascu- symptoms), improvement (partial resolution of signs lar disease; psychiatric disorders; or alcohol or drug and symptoms, without the need for additional dependency). Also excluded were patients not suit- antibiotic therapy), or failure (no change or wors- able for outpatient therapy, including elderly debil- ening of signs and symptoms, or requirement for itated patients, or those with hospital-acquired additional antibiotic therapy). infections, known or suspected bacteremia, or sig- The secondary efficacy end point was the bacte- nificant underlying health problems that could riologic response obtained between days 10 and 13 compromise response to therapy. and was defined as eradication (elimination of base- Study Design—This was a randomized, investigator- line pathogen, or absence of material for culture in blind, comparative trial conducted at 10 centers in patients with a clinical response of cure or improve- the United States. Patients were assigned randomly ment), persistence (presence of baseline pathogen to receive either azithromycin (500 mg on day 1, between days 10 and 13), recurrence (presence of followed by 250 mg once a day on days 2 to 5) or baseline pathogen between days 28 and 30 in cefadroxil (500 mg twice a day for 10 days). The patients whose response between days 10 and 13 was study was approved by the Institutional Review eradication), and superinfection (presence of a new Board at each study center, and informed consent pathogen, accompanied by persistence or worsening was obtained from each patient. of signs and symptoms of infection). Data Collection—Data were collected at 4 time Safety—All patients who received at least one points. The baseline visit (day 1) included a medi- dose of study drug were included in the safety anal- cal history, physical examination, signs and symp- ysis. Safety data included adverse events summa- toms assessment, and clinical laboratory tests rized by the investigator’s assessment of severity VOLUME 72, SEPTEMBER 2003 241 Therapeutics for the Clinician Table 1. Demographic and Baseline Characteristics Characteristic Azithromycin (nϭ152) Cefadroxil (nϭ139) Mean ageϮSD, y 33.9Ϯ13.9 32.3Ϯ14.0 Sex, n Female 68 59 Male 84 80 Mean weight, kg Female 75.2 75.0 Male 85.1 84.6 Race, n White 93 86 Black 26 23 Asian 2 2 Other 31 28 Diagnosis, n* Primary pyoderma 133 114 Secondary bacterial infection 19 25 Other 8 3 *Some patients had more than one primary diagnosis. (mild, moderate, or severe) and laboratory analyses between days 10 and 13. Failure to meet both inclu- (hematology, clinical chemistry, and urinalysis). sion or exclusion criteria was the most common Statistics—The log-rank test was