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MAJOR ARTICLE Ertapenem Once Daily Versus PiperacillinTazobactam 4 Times per Day for Treatment of Complicated Skin and Skin-Structure Infections in Adults: Results of a Prospective, Randomized, Double-Blind Multicenter Study Donald R. Graham,1 Christopher Lucasti,2 Osvaldo Malafaia,5 Ronald L. Nichols,3 Paul Holtom,4 Nora Quintero Perez,6 Andrea McAdams,7 Gail L. Woods,7 T. Paulette Ceesay,7 Richard Gesser,7 and the Ertapenem Complicated Skin and Skin Structure Infections Study Groupa 1 Springfield Clinic, Springfield, Illinois; 2South Jersey Infectious Disease, Somers Point, New Jersey; 3Tulane University School of Medicine, New Orleans, Louisiana; 4Los Angeles County and University of Southern California Medical Center, Los Angeles; 5Hospital Evangelico, Curitiba, Brazil; 6 Hospital Civil de Guadalajara, Mexico; and 7Merck Research Laboratories, West Point, Pennsylvania We conducted a prospective, randomized, double-blind trial comparing ertapenem (1 g once daily) with piperacillin-tazobactam (3.375 g every 6 h) as parenteral treatment for 540 adults with complicated skin and skin-structure infections. The most common diagnoses were skin or soft-tissue abscesses and lower-extremity infections associated with diabetes. The mean duration ( standard deviation) of therapy was 9.1 3.1 days for ertapenem and 9.8 3.3 days for piperacillin-tazobactam. At the assessment of primary efficacy end point, 10–21 days after treatment, 82.4% of those who received ertapenem and 84.4% of those who received piperacillin-tazobactam were cured. The difference in response rates, adjusting for the patients’ assigned strata, was ⫺2.0% (95% confidence interval, ⫺10.2% to 6.2%), indicating that the response rates in the 2 treatment groups were equivalent. Cure rates for the 2 treatment groups were similar when compared by stratum, diagnosis, and severity of infection. The frequency and severity of drug-related adverse events were similar in the treatment groups. Complicated skin and skin-structure infections (CSSSIs), such as perineal cellulitis or abscesses, extensive cellulitis, posttraumatic or postsurgical skin or soft-tissue in- Received 20 September 2001; revised 8 January 2002; electronically published 9 May 2002. Financial support: Merck. a Members of the study group are listed at the end of the text. Reprints or correspondence: Dr. Donald R. Graham, Springfield Clinic, 1025 S. 7th St., Springfield, IL 62703 ([email protected]); or Richard Gesser, Merck & Co., Inc., 10 Sentry Pkwy., BL3-4, Blue Bell, PA 19442 (richard_gesser @merck.com). Clinical Infectious Diseases 2002; 34:1460–8 2002 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2002/3411-0006$03.00 1460 • CID 2002:34 (1 June) • Graham et al. fection, and lower-extremity infections in patients with diabetes mellitus, are deeper, more indolent, and more severe than are routine soft-tissue infections. They are often caused by a mixture of gram-positive and gramnegative aerobic and anaerobic bacteria, although Staphylococcus aureus and streptococci are the predominant pathogens. In community-acquired infections, nonfermentative gram-negative bacilli, which are generally associated with nosocomial infections, are infrequently involved [1, 2]. Empiric treatment of CSSSI requires parenteral coverage of a broad spectrum of potential pathogens and often includes an extended-spectrum cephalosporin plus an agent active against anaerobes, such as me- tronidazole or clindamycin, or a b-lactam/b-lactamase inhibitor combination. These regimens are effective treatment for CSSSI, but they are complicated by the requirement for administration of multiple parenteral doses each day or administration of 11 agent. Potential limitations of such regimens may include a greater risk for infusion-related complications, greater difficulty arranging outpatient antibacterial therapy, greater risk for medication errors, additional costs associated with administering several daily infusions, and, for multipledrug regimens, a greater likelihood of drug toxicity [3–5]. Ertapenem (formerly MK-0826; Merck) is a newly approved, once-daily parenteral b-lactam antimicrobial that can be used as monotherapy for the treatment of various communityacquired and mixed aerobic and anaerobic infections, including CSSSI, complicated intra-abdominal infections, communityacquired pneumonia, complicated urinary tract infections, and acute pelvic infections. This structurally unique carbapenem is highly active in vitro against the bacteria typically associated with community-acquired infections, including methicillinsusceptible S. aureus (MSSA) and many streptococci, anaerobes, and Enterobacteriaceae; it has minimal activity against enterococci and nonfermentative gram-negative bacilli, such as Pseudomonas species [6, 7]. Like other b-lactam antimicrobials, ertapenem is not effective against methicillin-resistant S. aureus (MRSA). We undertook this study to compare the safety, tolerability, and efficacy of ertapenem with those of piperacillintazobactam for treatment of patients with CSSSI. PATIENTS, MATERIALS, AND METHODS Patients. Men and women ⭓18 years of age with CSSSI that required parenteral antimicrobial therapy were eligible for the study. Patients had to have signs and symptoms of acute infection (i.e., purulent drainage or collection or ⭓3 of the following findings: fever, WBC counts of 110,000 cells/mL [with 15% immature forms], local erythema extending 11 cm from the wound edge, lymphangitis, or localized swelling, tenderness or pain, fluctuance, warmth, or induration) in the absence of chronic infection or indwelling foreign material. Surgical drainage or debridement of infected wounds or abscesses, if necessary, had to have been completed ⭐48 h after the initiation of therapy. Exclusion criteria for the study were as follows: pregnancy or lactation (in women), history of serious allergy to or intolerance of any b-lactam (patients with a history of a mild rash caused by a b-lactam could be enrolled), rapidly progressive or terminal illness, receipt of long-term immunosuppressive therapy, AIDS, infected burn wounds, necrotizing fasciitis, osteomyelitis, septic arthritis, gangrene or need for amputation, deep-vein thrombosis, need for concomitant systemic antimicrobials in addition to study drugs, concurrent infection that could potentially interfere with evaluation of the patient’s response to the study therapy, requirement for peritoneal dialysis or hemodialysis, infection with a pathogen known to be resistant to either of the study medications, receipt of 124 h of systemic antimicrobial therapy known to be effective against presumed or documented pathogens during the 72 h before study entry, and predefined abnormal laboratory test results (i.e., hematocrit !25% or hemoglobin !8 mg/dL; platelet count !75,000/mL, coagulation test results 11.5 times the upper limit of normal [ULN], levels of transaminases 16 times the ULN, and bilirubin or alkaline phosphatase levels 13 times the ULN). Patients previously treated with antimicrobial therapy for 124 h could be enrolled if there was clinical evidence of treatment failure after ⭓3 days of therapy and if a pathogen susceptible to both study drugs was recovered. Patients with polymicrobial infections with resistant pathogens could remain in the study at the investigator’s discretion, if ⭓1 infecting organism was susceptible to both study drugs. Study design and antimicrobial therapy. The study was a double-blind (with sponsor blinding) multicenter equivalence trial conducted in the United States and internationally from April 1998 through November 1999. The design of the study followed the recommendations of the Infectious Diseases Society of America (IDSA) [8]. The institutional review board at each participating site approved the protocol, and written consent was obtained from all patients. Patients were randomly assigned to receive treatment for 7–14 days with either ertapenem (1 g iv once daily) or piperacillin-tazobactam (3.375 g iv every 6 h). To ensure blinding, patients in the ertapenem group also received subsequent placebo infusions of normal saline every 6 h. All infusions were administered within a 30 min period. Therapy was begun in the hospital or infusion suite; clinically stable patients, after 2 days of therapy, could continue intravenous therapy at home or in the hospital. Follow-up oral antimicrobial therapy was not permitted. Patients were assigned at entry to 1 of 2 strata. Stratum I included patients with underlying decubitus ulcers, diabetes mellitus, or other neuropathic conditions that we anticipated could compromise the response to antibacterial therapy. Stratum II consisted of patients with all other types of CSSSI (listed in table 1). Microbiologic assessments. Specimens of purulent material from deep within the infection were obtained from all patients for performance of aerobic and anaerobic culture at baseline and, if clinically indicated, at follow-up. Blood samples for culture were collected when clinically indicated. Wound specimens from all international sites were shipped to the R. M. Alden Research Laboratory, Santa Monica-University of California at Los Angeles Medical Center (Santa Monica) for anaerobic culture and susceptibility testing. Susceptibility to Ertapenem vs. Pip-Taz for Skin Infections • CID 2002:34 (1 June) • 1461 Table 1. Baseline characteristics of randomized and clinically evaluable patients with complicated skin or skin-structure infection who were treated with ertapenem or piperacillin-tazobactam (Pip-Taz). Randomized patients, by treatment group Characteristic or diagnosis Female sex Ertapenem (n p 274) Pip-Taz (n p 266) Clinically evaluable patients, by treatment group Ertapenem (n p 185) Pip-Taz (n p 174) 93 (33.9) 96 (36.1) 62 (33.5) 58 (33.3) 48.7 16.5 48.0 17.4 47.8 15.9 46.1 16.8 LE infection associated with diabetes 53 (19.3) 45 (16.9) 35 (18.9) 31 (17.8) Othera 10 (3.7) 7 (2.7) 7 (3.8) 5 (2.9) 63 (23.0) 52 (19.5) 42 (22.7) 36 (20.7) Cellulitis with drainage 40 (14.6) 35 (13.2) 29 (15.7) 24 (13.8) Cutaneous abscess 26 (9.5) 35 (13.2) 20 (10.8) 24 (13.8) Deep soft-tissue abscess 49 (17.9) 53 (19.9) 30 (16.2) 36 (20.7) Perineal cellulitis/abscess 24 (8.8) 14 (5.3) 20 (10.8) 11 (6.3) Age, mean years SD Diagnosis, by stratum Stratum I Total Stratum II Posttraumatic wound 47 (17.2) 45 (16.9) 30 (16.2) 26 (14.9) Surgical-site infection 16 (5.8) 20 (7.5) 9 (4.9) 10 (5.7) Otherb Total Severe infection NOTE. 9 (3.3) 12 (4.5) 5 (2.7) 7 (4.0) 211 (77.0) 214 (80.5) 143 (77.3) 138 (79.3) 49 (17.9) 46 (17.3) 40 (21.6) 31 (17.8) LE, lower extremity. a Includes acute pressure ulcer and neuropathy with LE infection. b Includes complicated cellulitis with systemic signs, infected pyoderma, deep soft-tissue infection or ulcer, suppurative hydradenitis, tenosynovitis, necrotizing soft-tissue infection, and uncomplicated skin infection (the latter 2 in the randomized population only). ertapenem and piperacillin-tazobactam was determined by disk diffusion or microtiter or agar dilution in accordance with the guidelines of the National Committee for Clinical Laboratory Standards [9–11]. Clinical and microbiologic assessments. At baseline, the severity of each sign and symptom was scored by the investigator. Infections were considered to be severe overall if a rating of “severe” was assigned for all 3 wound parameters (i.e., tenderness, erythema, and swelling) and the patient had a temperature 138.4C or a WBC count of 115,000 cells/mL. Infections in bacteremic patients were considered to be severe if ⭓1 baseline wound parameter was rated “severe.” Adjuvant surgery performed ⭐48 h after the initiation of therapy was considered to be integral to the initial management of the infection; patients requiring nonroutine surgery thereafter were considered to have treatment failure. Clinical response assessments based on wound signs and symptoms were made by the investigator on days 3–5 of study therapy; at completion of study therapy; and at the test-of-cure (TOC) assessment, which occurred 10–21 days after the completion of study therapy. The primary efficacy end point was the proportion of patients with an investigator assessment of “cure” at the TOC assessment. For this primary analysis, pa1462 • CID 2002:34 (1 June) • Graham et al. tients had to have received ⭓48 h of therapy to be considered to have treatment failure, and patients had to have had an appropriately timed TOC assessment and to have received ⭓5 days of therapy to be considered to have an evaluable cure. A microbiologic response was assessed for each pathogen identified at baseline. For patients for whom follow-up cultures were not performed, the microbiologic responses for baseline pathogens were assumed on the basis of the clinical response. The overall microbiologic response was considered to be favorable if all pathogens identified at baseline were eradicated or presumed eradicated. Emergent pathogens were considered to be “superinfections,” if they were first isolated during therapy, and “new infections,” if first isolated after the completion of therapy. Safety assessment. Patients who received ⭓1 dose of the study drug were evaluated to determine the drug’s safety and were monitored for adverse events daily during the period of study therapy and for 14 days thereafter. The investigator categorized the intensity of each clinical and laboratory adverse event (as “mild,” “moderate,” or “severe”) and the likelihood that the event had a causal relation to the study drug (as “definitely not,” “probably not,” “possibly,” “probably,” or “definitely”). The local tolerability of each study drug, as indicated by reactions at the infusion site, was evaluated by the investigator daily. At the discretion of the investigator, these or other local reactions could also be reported as adverse events. Statistical analyses. This study was designed to show whether the response rates in the 2 treatment groups were equivalent, in accordance with IDSA and US Food and Drug Administration guidelines [8]. Equivalence was demonstrated if the 95% (2-sided) confidence interval for the difference in response rates between treatment groups (i.e., [response rate in the ertapenem group] ⫺ [ response rate in the piperacillintazobactam group]) contained “0” and if the lower limit was as follows: not less than ⫺10%, if the control response rate was ⭓90%; ⫺15%, if the control response rate was !90% and ⭓80%; and ⫺20%, if the control response rate was !80% and ⭓70%. Confidence intervals were calculated with use of the normal approximation to the binomial distribution, accounting for stratification by means of the Cochran approach [12, 13]. A test of treatment by stratum interaction (the Breslow-Day test of homogeneity of odds ratios [14]) was performed to decide whether results could be pooled between the randomization strata. The efficacy variables were analyzed using an evaluablepatients-only approach and a modified intent-to-treat (MITT) approach [8]. The MITT population included all patients who received ⭓1 dose of a study drug and who had a CSSSI. Patient evaluability was determined under blinded conditions, before analyses were done, on the basis of previously specified criteria. Clinically evaluable patients were also considered to be microbiologically evaluable if a pathogen was isolated from the wound present at baseline. Assuming an 80% response rate in both treatment groups and a significance level of 0.025, a sample size of 120 evaluable patients per group was required to provide at least an 80% probability that the lower limit of the 95% confidence interval for the difference in the response rates between the 2 groups would not be less than ⫺15%. RESULTS Patients and therapy. Five hundred forty patients were randomized to receive either ertapenem (n p 274 ) or piperacillintazobactam (n p 266). Of these, 185 in the ertapenem group and 174 in the piperacillin-tazobactam group were clinically evaluable. Patients were most commonly considered to be nonevaluable if their outcome assessment was either missing or did not occur during the protocol-defined follow-up period (which was the case for 17.2% of the patients randomized) or if they received an inadequate or inappropriate course of study therapy (which was the case for 15.9% of the patients randomized). The baseline demographic characteristics and the disease characteristics of the randomized and the clinically evaluable populations were generally similar between the 2 treatment groups (table 1). Baseline wound care procedures were similar in each treatment group. In the clinically evaluable population wound management procedures were performed before or within 48 h of enrollment in 153 patients (82.7%) in the ertapenem group and 147 patients (84.5%) in the piperacillintazobactam group. One hundred seven patients (57.8%) in the ertapenem group and 98 patients (56.3%) in the piperacillintazobactam group underwent incision and drainage of the wound. Eleven patients in each group required a surgical procedure other than routine minor debridement or wound care 148 h after study therapy was begun, including lower-extremity amputations for 6 patients in each treatment group; these patients were considered to have clinical failure. The mean (SD) duration of study therapy in the clinically evaluable population was 9.1 3.1 days (range, 3–16 days) for patients in the ertapenem group and 9.8 3.3 days (range, 3–18 days) for patients in the piperacillin-tazobactam group. The median duration of therapy was 9.0 days in both treatment groups. Baseline microbiologic test results. A pathogen was isolated at baseline from 155 clinically evaluable patients (83.8%) in the ertapenem group and 151 clinically evaluable patients (86.8%) in the piperacillin-tazobactam group. Approximately 40% of the evaluable patients in each treatment group had a polymicrobial infection; overall, 18% were infected with ⭓1 anaerobic pathogen. The distribution of organisms was generally similar in the treatment groups. S. aureus (including 3 MRSA per group) was the most frequently isolated pathogen, present at baseline in 37.8% and 40.8% of the clinically evaluable patients in the ertapenem and piperacillin-tazobactam treatment groups, respectively. For 49 patients in each treatment group, S. aureus was the only infecting pathogen; in the remainder, it was one component of a polymicrobial infection. Most isolates tested were susceptible to both study drugs, except enterococci (5 [31.3%] of 16 isolates susceptible to ertapenem, and 14 [87.5%] of 16 susceptible to piperacillin-tazobactam) and Pseudomonas aeruginosa (10 [71.4%] of 14 isolates susceptible to ertapenem, and 14 [100%] of 14 susceptible to piperacillin-tazobactam). Efficacy. In the clinically evaluable population, 82.4% of patients (95% CI, 77.0%–87.8%) in the ertapenem group and 84.4% of patients (95% CI, 79.0%–89.7%) in the piperacillintazobactam group were classified as “cured” at the time of the TOC assessment. The difference in response rates between the groups, adjusting for assigned stratum, was ⫺2.0% (95% CI, ⫺10.2% to 6.2%), which indicated that the response rates for the 2 groups were equivalent. In the supportive MITT analysis, which included 527 patients (97.6% of all randomized patients), cure rates were 69.8% for the ertapenem group and 73.5% for Ertapenem vs. Pip-Taz for Skin Infections • CID 2002:34 (1 June) • 1463 the piperacillin-tazobactam group. Lower success rates in this analysis reflect the more conservative approach of the MITT assessment, in which patients with inadequate information or indeterminate outcomes were considered to have treatment failure. The difference in rates for the MITT analysis was ⫺3.6% (95% CI, ⫺11.6% to 4.4%), which further demonstrated that the response rates in the 2 treatment groups were similar. The clinical outcomes at TOC are shown in table 2 by primary diagnosis and severity of infection. Cure rates in both treatment groups were generally similar for most diagnoses. Among patients with cutaneous or deep abscesses, who accounted for 30.6% (110 of 359 patients) of the clinically evaluable population, cure rates were similar in the 2 groups: 90.0% (45 of 50 patients) in the ertapenem group and 95.0% (57 of 60 patients) in the piperacillin-tazobactam group. Among patients with severe infections, the cure rate was 80.0% (32 of 40 patients) in the ertapenem group and 71.0% (22 of 31 patients) in the piperacillin-tazobactam group. At the end of treatment assessment, the cure rate was 86.6% (160 of 185 patients) among patients who received ertapenem and 87.7% (152 of 173 patients) among patients who received piperacillintazobactam. The difference, adjusted for stratum, was ⫺1.2% (95% CI, ⫺8.6% to 6.3%), further supporting the results of the primary efficacy analysis. For patients in stratum I, the treatment success rate at the end of study therapy was 78.6% (33 of 42 patients) in the ertapenem group and 77.8% (28 of 36 patients) in the piperacillin-tazobactam group; for patients in stratum II, the rates were 88.8% (127 of 143 patients) and 90.5% (124 of 137 patients), respectively. Bacterial eradication rates among evaluable patients at the end of treatment and at the time of TOC, respectively, were as follows: 83.2% (129 of 155 patients) and 82.6% (128 of 155 patients) in the ertapenem group, and 86.0% (129 of 150 patients) and 83.4% (126 of 151 patients) in the piperacillintazobactam group. Both a favorable clinical response and a favorable microbiologic response at the time of TOC were observed in 127 (81.9%) of 155 patients in the ertapenem group and 124 (82.1%) of 151 patients in the piperacillin-tazobactam group. The difference, adjusting for stratum, was ⫺0.2% (95% CI, ⫺9.3% to 9.0%), which again supported the findings of the primary analysis. For this population, the cure rate and the bacterial eradication rate at the time of TOC were similar for all major pathogens (table 3). No pathogen detected at baseline subsequently developed resistance to either study drug, and non-baseline, emergent pathogens were isolated infrequently. The types and frequencies of emergent bacteria were similar in both treatment groups, and, not surprisingly, the types of bacteria were those com- Table 2. Proportion of clinically evaluable patients with favorable clinical (cure) response assessments at the test of cure (TOC) visit, in a study of patients with complicated skin or skin-structure infection who were treated with ertapenem or piperacillin-tazobactam (Pip-Taz). Pip-Taz group (n p 174) Ertapenem group (n p 185) Proportion of patientsa Percentage of patients (95% CI) Proportion of patientsa Percentage of patients (95% CI) 23/35 65.7 (49.8–81.7) 22/31 71.0 (54.7–87.2) 5/7 71.4b 5/5 100.0 28/42 66.7 (52.2–81.1) 27/36 75.0 (60.7–89.3) Cellulitis with purulent drainage 27/29 93.1 (83.7–100.0) 21/24 87.5 (74.0–100.0) Cutaneous abscess 16/20 80.0 (62.0–98.0) 23/24 95.8 (87.7–100.0) Deep soft-tissue abscess 29/30 96.7 (90.1–100.0) 34/36 94.4 (86.9–100.0) Perineal cellulitis/abscess 18/20 90.0 (76.5–100.0) 9/11 81.8 (57.9–100.0) Posttraumatic wound infection 25/30 83.3 (69.8–96.9) 22/26 84.6 (70.5–98.8) 7/9 77.8b 8/10 80.0 (53.9–100.0) 2/5 b 40.0 3/7 42.9 124/143 86.7 (81.1–92.3) 120/138 87.0 (81.3–92.6) 120/145 82.8 (76.6–88.9) 125/143 87.4 (82.0–92.9) 32/40 80.0 (67.4–92.6) 22/31 71.0 (54.7–87.2) Stratum, characteristic or diagnosis Stratum I LE infection associated with diabetes Other Total b Stratum II Surgical site infection Other Total b Severity of infection Moderate Severe NOTE. a b LE, lower extremity. No. of clinically evaluable patients with favorable assessment/number with assessment at the TOC visit. Confidence intervals were calculated only for groups with ⭓10 patients. 1464 • CID 2002:34 (1 June) • Graham et al. Table 3. Proportion of favorable clinical (cure) or microbiologic (eradication) response assessments at the test-of-cure visit, by pathogen isolated at baseline, in a study of patients with complicated skin or skinstructure infection who were treated with ertapenem or piperacillin-tazobactam (Pip-Taz). No. (%) of patients with favorable clinical response, by treatment group Isolate(s) No. (%) of patients with favorable microbiologic response, by treatment group Ertapenem Pip-Taz Ertapenem Pip-Taz 114/149 (76.5) 116/148 (78.4) 118/147 (79.6) 121/148 (81.8) MSSA and MRSA 54/71 (76.1) 56/71 (78.9) 55/71 (77.5) 58/71 (81.7) MSSA onlyb 54/67 (80.6) 55/68 (80.9) 54/67 (80.6) 56/68 (82.3) 4/5 (80.0) 8/11 (72.7) 4/5 (80.0) 8/11 (72.7) Streptococcus pyogenes 13/16 (81.3) 15/16 (93.8) 14/16 (87.5) 15/16 (93.8) Streptococcus agalactiae 7/13 (53.8) 5/10 (50.0) 7/13 (53.8) 7/10 (70.0) Other b-hemolytic streptococci 9/9 (100) 8/11 (72.7) 9/9 (100.0) 8/11 (72.7) 18/20 (90.0) Gram-positive aerobic cocci Any a Coagulase-negative staphylococci Other streptococci 22/23 (95.7) 18/20 (90.0) 22/23 (95.7) Enterococci 5/10 (50.0) 6/9 (66.7) 7/10 (70.0) 7/9 (77.8) Gram-positive aerobic bacilli 1/1 (100.0) 1/1 (100.0) 1/1 (100.0) 1/1 (100.0) Any 55/70 (78.6) 50/66 (75.8) 58/70 (82.9) 54/66 (81.8) Escherichia coli 16/17 (94.1) 12/15 (80.0) 17/17 (100) 12/15 (80.0) Other Enterobacteriaceaec 26/36 (72.2) 29/35 (82.9) 27/36 (75.0) 31/36 (86.1) Gram-negative aerobic bacilli Pseudomonas aeruginosa 7/10 (70.0) 3/5 (60.0) 7/10 (70.0) 4/5 (80.0) Other gram-negative aerobic bacilli 6/7 (85.7) 6/11 (54.5) 7/7 (100) 7/10 (70.0) 8/10 (80.0) 6/6 (100) 8/10 (80.0) 6/6 (100) Any 30/35 (85.7) 24/27 (88.9) 30/35 (85.7) 25/27 (92.6) Peptostreptococcus species 27/31 (87.1) 20/22 (90.9) 27/31 (87.1) 21/22 (95.5) 3/4 (75.0) 4/5 (80.0) 3/4 (75.0) 4/5 (80.0) Any 47/48 (97.9) 43/50 (86.0) 48/48 (100) 44/50 (88.0) Bacteroides fragilis group 11/11 (100) 12/13 (92.3) 11/11 (100) 12/13 (92.3) 9/9 (100) 4/5 (80.0) 9/9 (100) 4/5 (80.0) 12/12 (100) 16/17 (94.1) 12/12 (100) 17/17 (100) 15/16 (93.8) 11/15 (73.3) 16/16 (100) 11/15 (73.3) Gram-positive anaerobic bacilli Gram-positive anaerobic cocci Other anaerobic gram-positive cocci Gram-negative anaerobic bacteria Porphyromonas species Prevotella species Other gram-negative anaerobic bacteriad NOTE. a MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant S. aureus. Among patients with monomicrobial infections due to MSSA and/or MRSA, cure and eradication rates, respectively, were 81.6% (40/49) and 81.6% (40/49) in the ertapenem group and 84.0% (42/50) and 86.0% (43/50) in the Pip-Taz group. Among patients with polymicrobial infections, cure and eradication rates, respectively, were 66.7% (14/21) and 68.2% (15/22) in the ertapenem group and 66.7% (14/21) and 71.4% (15/21) in the Pip-Taz group. b Among patients with monomicrobial MSSA infections, cure and eradication rates, respectively, were 83.3% (40/48) and 83.3% (40/48) in the ertapenem group and 84.0% (42/50) and 86.0% (43/50) in the Pip-Taz group. Among patients with polymicrobial infections, cure and eradication rates, respectively, were 73.7% (14/19) and 73.7% (14/19) in the ertapenem group and 72.2% (13/18) and 72.2% (13/18) in the Pip-Taz group. c In the ertapenem group, the following organisms were identified: Citrobacter braakii (n p 1 ), Citrobacter freundii (n p 1), Enterobacter aerogenes (n p 3 ), Enterobacter cloacae (n p 6 ), Klebsiella oxytoca (n p 1 ), Klebsiella pneumoniae (n p 7 ), Morganella morganii (n p 3 ), Proteus vulgaris (n p 4 ), Proteus mirabilis (n p 6 ), Providencia rettgeri (n p 1 ), Serratia marcescens (n p 2), and Serratia rubidaea (n p 1 ). In the Pip-Taz group, the following organisms were identified: Citrobacter koseri (n p 1), C. freundii (n p 1), E. cloacae (n p 11), Enterobacter gergoviae (n p 1 ), K. pneumoniae (n p 5 ), M. morganii (n p 3 ), P. vulgaris (n p 4), P. mirabilis (n p 8), and Providencia stuartii (n p 1). d In the ertapenem group, the following organisms were identified: unspecified gram-negative anaerobic rods (n p 2 ), Bacteroides capillosus (n p 2 ), Bacteroides ureolyticus (n p 3 ), Bilophila wadsworthia (n p 1 ), Dialister pneumonosintes (n p 1), unspecified Fusobacterium species (n p 1 ), Fusobacterium gonidiaformans (n p 3 ), Fusobacterium naviforme (n p 1 ), and Fusobacterium necrophorum (n p 2 ). In the Pip-Taz group, the following organisms were identifed: unspecified gram-negative anaerobic rods (n p 2), B. ureolyticus (n p 1 ), B. wadsworthia (n p 3 ), D. pneumonosintes (n p 4 ), unspecified Fusobacterium species (n p 1), Fusobacterium necrophorum (n p 1), Fusobacterium nucleatum (n p 1), and Veillonella species (n p 2). monly associated with skin infections or acquired in the hospital setting. Safety profile. Two hundred seventy-one patients in the ertapenem group and 258 patients in the piperacillin-tazobactam group were included in the safety analyses. Drug-related clinical adverse events were reported during therapy for 67 patients (24.7%) in the ertapenem group and 60 patients (23.3%) in the piperacillin-tazobactam group; investigators reported that laboratory adverse events occurred in 36 patients (14.2%) in the ertapenem group and 36 patients (14.6%) in the piperacillin-tazobactam group. The most common drugrelated adverse events are listed in table 4. There were no seizures reported in patients while they were receiving study therapy. Therapy was discontinued due to a drug-related adverse clinical event for 3 patients in the ertapenem group and 6 in the piperacillin-tazobactam group. Two patients receiving piperacillin-tazobactam and 0 patients in the ertapenem group stopped therapy due to a drug-related adverse laboratory event. One patient in the piperacillin-tazobactam group died during study therapy, and 1 patient in each group had an adverse event during study therapy that resulted in death after therapy was completed. No deaths were attributed to use of a study drug. Local tolerability. A local reaction of moderate to severe intensity was recorded for 19 (7.0%) of 270 patients in the ertapenem group and 23 (8.9%) of 258 patients in the piperacillin-tazobactam group. The most common symptoms were pain and erythema. Study therapy was discontinued due to an infused vein complication for 1 patient in the piperacillintazobactam group and for 0 patients in the ertapenem group. DISCUSSION In this study of CSSSIs, the cure rates among patients who received ertapenem and among patients who received piperacillin-tazobactam were equivalent overall (82.4% vs. 84.4%) and similar to or somewhat higher than those reported in other, similarly designed clinical trials [15–19]. As shown by others, cure rates for foot infections associated with diabetes, which are often complicated by compromised vascularity, were lower for both treatment groups in this study. Clinical response rates for diabetes-associated lower-extremity infections in this study were ∼78% in both treatment groups at the completion of study therapy and decreased slightly to 65.7% (ertapenem group) and 71.0% (piperacillin-tazobactam group), at the TOC assessment (10–21 days after the end of treatment). This finding reflected the need for subsequent surgical intervention for patients with complicating underlying conditions, such as vascular insufficiency. The organisms identified in this study and the response rates associated with each pathogen are also similar to those seen in other studies [15, 17], with one exception. In our 1466 • CID 2002:34 (1 June) • Graham et al. Table 4. Most common drug-related clinical and laboratory adverse events reported among patients with complicated skin or skin-structure infection who were treated with ertapenem or piperacillin-tazobactam (Pip-Taz). No. (%) of patients, by treatment group Adverse effect Ertapenem Pip-Taz Clinical Local infusion-related reactions a 17 (6.3) 14 (5.4) Diarrhea 15 (5.5) 23 (8.9) Nausea 10 (3.7) 7 (2.7) 5 (1.8) 3 (1.2) Increased ALT levelc 9 (4.3) 8 (3.7) d b Rash Laboratory value Increased AST level 12 (5.1) 10 (4.2) Increased alkaline phosphatase 2 (0.8) 5 (2.1) Increased platelet count 8 (3.2) 4 (1.7) NOTE. ALT, alanine transaminase; AST, aspartate transaminase. a The most common local reactions were pain (ertapenem group, 4.0% of patients; Pip-Taz group, 3.9%), phlebitis (ertapenem group, 3.0%; Pip-Taz group, 2.7%), and erythema (ertapenem group, 3.0%; Pip-Taz group, 1.6%). b Two patients with diarrhea in each treatment group had pseudomembranous colitis. c Values were 58–134 U/L for the ertapenem group and 40–271 U/L for the Pip-Taz group. For patients with data from follow-up, ALT level elevations were transient, and later values were within normal limits. d Values were 54–228 U/L for the ertapenem group and 40–131 U/L for the Pip-Taz group. For patients with data from follow-up, AST level elevations were transient, and later values were within normal limits, except for 1 patient in the Pip-Taz group, whose AST level increased to 3.3 times the upper limit of normal. study, anaerobes were recovered from 17%–20% of clinically evaluable patients; in studies that have focused primarily on the microbiology of skin and soft-tissue infections, 33%–52% of specimens have yielded anaerobes [1, 2]. One possible reason for this difference is that, in our study, specimens from sites in various nations were mailed to a reference laboratory in California for culture, and fastidious anaerobes may not have survived. Additionally, anaerobic culture and identification methods used at the local laboratories likely varied from site to site. As is the case for most studies of skin infections, S. aureus was the pathogen most commonly isolated in this study. As anticipated, because both study drugs lacked activity against MRSA in vitro, cure rates for all patients infected with S. aureus (both MSSA and MRSA) were lower (ertapenem group, 76.1%; piperacillin-tazobactam group, 78.9%) than for patients infected with MSSA only (80.6% and 80.9%, respectively). To more accurately assess the efficacy of study drugs against MSSA in patients with complicated infections, cure rates were determined separately for monomicrobial and polymicrobial infections. Not surprisingly, treatment success rates were higher for patients with monomicrobial MSSA infections (ertapenem group, 83.3%; piperacillin-tazobactam group, 84.0%) than for patients infected with MSSA as part of a polymicrobial infection (73.7% and 72.2%, respectively). Bacterial eradication rates for all S. aureus (i.e., MSSA and MRSA) infections in this study (table 3) were similar to rates reported elsewhere (60% to ∼85%) [15–18]. Ertapenem has excellent in vitro activity against MSSA and many streptococci, gram-negative enteric bacilli, and anaerobes, all of which are frequently involved in communityacquired and mixed infections of the skin and soft tissues. In contrast to imipenem and meropenem, which are often used to treat nosocomial infections, ertapenem has minimal in vitro activity against P. aeruginosa and Acinetobacter species. Although none of these carbapenems is considered to be firstline therapy against enterococci, imipenem has the most activity against them and ertapenem, the least. For empiric treatment of community-acquired infections of the skin and skin structures, however, therapy directed specifically against these organisms generally is not required. P. aeruginosa and enterococci are identified in ∼2%–8% of such infections [2], and, because most infections are polymicrobial, the pathogenicity of these organisms is uncertain. In this study, we recovered 19 enterococcal isolates (3.1% of the total isolates) and 15 P. aeruginosa isolates (2.5% of the total), and most were components of a polymicrobial infection. This low rate of isolation of these bacteria is consistent with rates reported by other investigators. Clinical and microbiologic success rates for patients infected with each of these organisms were generally similar in both treatment groups (table 3), regardless of the susceptibility of these bacteria. However, the small numbers preclude our drawing meaningful conclusions about the role of P. aeruginosa or enterococci as pathogens or the efficacy of ertapenem or piperacillin-tazobactam for treatment of infections with these organisms. The most common drug-related adverse events for both drugs were infused-vein complications, diarrhea, nausea, and mild to moderate transient elevations of liver transaminase levels. Serious adverse events were equally uncommon in both treatment groups. Although patients in both groups received 4 daily infusions of study agents and, therefore, theoretically were at equal risk for infusion-related complications, 3 infusions in the ertapenem group were placebo. In practice, patients treated with ertapenem would receive a single daily infusion and thus would be expected to have fewer venous complications. In summary, in this study, ertapenem at a dosage of 1 g once daily was as effective as piperacillin-tazobactam at a dosage of 3.375 g 4 times daily for the treatment of CSSSIs. Ertapenem was generally well tolerated, and its safety and tolerability profile was similar to that of piperacillin-tazobactam. MEMBERS OF THE COMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS STUDY GROUP J. Eric Bauwens (Phoenix, AZ), Francie Ekengren (Wichita, KS), Robert Eng (East Orange, NJ), Robert Brooks Gainer II, (Morgantown, WV), Claudia Garreaud (Santiago, Chile), Ronald Geckler (Baltimore, MD), Michael Gelfand (Memphis, TN), John Gezon (Salt Lake City, UT), Donald R. Graham (Springfield, IL), Charles Hanna (Spartanburg, FL), Abel Jasovich (Buenos Aires, Argentina), Stanley Klein (Torrance, CA), Terrance Kurtz, (Des Moines, IA), Juan Lema (Lima, Peru), David Livingston (Newark, NJ), Gustavo Lopardo (Buenos Aires, Argentina), Christopher Lucasti (Somers Point, NJ), Ana Lucia (Sao Paulo, Brazil), Jon T. Mader (Galveston, TX), Osvaldo Malafaia (Curitiba Brazil), Eugene Mangiante (Memphis, TN), Hector Marcano (Caracas, Venezuela), Barry Miskin (Palm Beach, FL), Ronald Nahass (Somerville, NJ), Ronald L. Nichols (New Orleans, LA), Pablo Okhuysen (Houston, TX), Lawrence Parish (Philadelphia, PA), Michael Patzakis (Los Angeles, CA), Nora Quintero Perez (Guadalajara, Mexico), John Poole (Guatemala City, Guatemala), Russell Postier (Oklahoma City, OH), Jeffrey Salomone (Atlanta, GA), Robert Schwartz (Fort Myers, FL), Harold Standiford (Baltimore, MD), James Tan (Akron, OH), Alan Tice (Tacoma, WA), Samuel Eric Wilson (Orange, CA), and Dietmar Wittmann (Milwaukee, WI). References 1. Summanen PH, Talan DA, Strong C, et al. Bacteriology of skin and soft-tissue infections: comparison of infections in intravenous drug users and individuals with no history of intravenous drug use. Clin Infect Dis 1995; 20(Suppl 2):S279–82. 2. Gerding DN. Foot infections in diabetic patients: the role of anaerobes. Clin Infect Dis 1995; 20(Suppl 2):S283–8. 3. Foran RM, Brett JL, Wulf PH. Evaluating the cost impact of intravenous antibiotic dosing frequencies. DICP Ann Pharmacother 1991; 25: 546–52. 4. Nettleman MD, Bock MJ. The epidemiology of missed medication doses in hospitalized patients. Clin Perform Qual Health Care 1996; 4:148–53. 5. Snedden S, Rudoy R, Arrieta A, et al. Meropenem vs. cefotaxime-based therapy for the initial treatment of infants and children hospitalised with non-CNS infections. Clin Drug Invest 1999; 17:9–20. 6. Goldstein EJC, Citron DM, Merriam CV, Warren Y, Tyrrell KL. Comparative in vitro activities of ertapenem (MK-0826) against 1,001 anaerobes isolated from human intra-abdominal infections. Antimicrob Agents Chemother 2000; 44:2389–94. 7. Fuchs PC, Barry AL, Brown SD. In vitro activities of ertapenem (MK0826) against clinical bacterial isolates from 11 North American medical centers. Antimicrob Agents Chemother 2001; 45:1915–8. 8. Beam TR Jr, Gilbert DN, Kunin CM. General guidelines for the clinical evaluation of anti-infective drug products. Clin Infect Dis 1992; 15(Suppl 1):S5–32. 9. National Committee for Clinical Laboratory Standards (NCCLS). Performance standards for antimicrobial disk susceptibility tests: approved standard. NCCLS document M2-A6. Wayne, PA: NCCLS, 1997. 10. National Committee for Clinical Laboratory Standards (NCCLS). Methods for dilution antimicrobial susceptibility tests for bacteria that Ertapenem vs. Pip-Taz for Skin Infections • CID 2002:34 (1 June) • 1467 11. 12. 13. 14. 15. grow aerobically: approved standard. NCCLS document M7-A5. Wayne, PA: NCCLS, 2000. National Committee for Clinical Laboratory Standards (NCCLS). Methods for antimicrobial susceptibility testing of anaerobic bacteria, approved standard. 4th ed. NCCLS document M11-A4. Wayne, PA: NCCLS, 1997. Cochran WG. Some methods for strengthening the common chi-square tests. Biometrics 1954;10:417–51. Cochran WG. Sampling techniques. New York: John Wiley, 1977. Breslow NE, Day NE. The analysis of case-control studies. International Agency for Research on Cancer (IARC) Scientific Publications 32. Lyon, France: IARC, 1980. Tan JS, Wishnow RM, Talan DA, et al. Treatment of hospitalized patients with complicated skin and skin structure infections: double-blind 1468 • CID 2002:34 (1 June) • Graham et al. 16. 17. 18. 19. randomized, multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. Antimicrob Agents Chemother 1993; 37:1580–6. File TM, Tan JS. Efficacy and safety of piperacillin-tazobactam in skin and soft tissue infections. Eur J Surg 1994; 573(Suppl):51–5. Siami G, Christou N, Eiseman I, et al. Clinafloxacin versus piperacillintazobactam in treatment of patients with severe skin and soft tissue infections. Antimicrob Agents Chemother 2001; 45:525–31. Nichols RL. Optimal treatment of complicated skin and skin structure infections. J Antimicrob Chemother 1999; 44:19–23. Nichols RL, Graham DR, Barriere SL, et al. Treatment of hospitalized patients with complicated gram-positive skin and skin structure infections: two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin, or vancomycin. J Antimicrob Chemother 1999; 44:263–73.