The American Journal of Surgery 194 (2007) 367–374 Clinical surgery–American Ertapenem or ticarcillin/clavulanate for the treatment of intra-abdominal infections or acute pelvic infections in pediatric patients Albert E. Yellin, M.D.a,*, Jeffrey Johnson, M.D.b, Iliana Higareda, M.D.c, Blaise L. Congeni, M.D.d, Antonio C. Arrieta, M.D.e, Doreen Fernsler, B.S.f, Joseph West, Ph.D.f, Richard Gesser, M.D.f aDepartment of Surgery, Keck School of Medicine of the University of Southern California, 1200 N State St, Rm 9610, Los Angeles, CA 90033, USA bDepartment of Pediatrics, Keck School of Medicine of the University of Southern California, 1240 N Mission Rd, L902, Los Angeles, CA 90089-9300, USA cHospital Civil de Guadalajara, Hospital 278, 4420 El Retiro St, Guadalajara, Jalisco Mexico dAkron Children’s Hospital, Division of Infectious Diseases, Locust Professional Bldg, 300 Locust St, Ste 4, Akron, OH 44308-1062, USA eChildren’s Hospital of Orange County, Pediatric Infectious Diseases, 455 South Main Street, Orange, CA 92868, USA fMerck Research Laboratories, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA Manuscript received June 20, 2006; revised manuscript January 20, 2007 Abstract Background: Ertapenem, a group I carbapenem antibiotic, has been shown to be safe and effective in treating adults with complicated intra-abdominal (cIAI) or acute pelvic infection (API). This study evaluated ertapenem for treating these infections in children. Methods: In an open-label study, children aged 2 to 17 years with cIAI or API were randomized 3:1 to receive ertapenem or ticarcillin/clavulanate. Children 13 to 17 years of age received 1 g parenterally daily, and those 2 to 12 years of age received 15 mg/kg twice daily. Patients Ͻ60 kg received ticarcillin/ clavulanate 50 mg/kg 4 to 6 times daily and 3.1g4to6times daily for those Ն60 kg. Patients were assessed for safety and tolerability throughout the study and for efficacy after the completion of therapy. Results: One hundred five patients, 72 (69%) with cIAI, received Ն1 dose of study drug and were included in the safety analysis. Eighty-one patients were treated with ertapenem. Infusion site pain was the most common drug-related adverse event in both groups. In the modified intent-to-treat analysis, the age-adjusted posttreatment clinical response rates were 87% (43/50 patients) and 100% (25/25 patients) in the cIAI and API patients, respectively, for ertapenem and 73% (11/15 evaluable patients) and 100% (8/8 evaluable patients), respectively, for ticarcillin/clavulanate. Overall age-adjusted response rates were 91% (68/75 evaluable patients) for ertapenem and 83% (19/23 evaluable patients) for the comparator. Conclusions: This study suggests that ertapenem is generally safe and efficacious for treating cIAI or API in pediatric patients. © 2007 Published by Excerpta Medica Inc. Keywords: Ertapenem; Pediatric; Intra-abdominal; Acute pelvic infection Complicated intra-abdominal infections (cIAIs), caused pri- adequately powered trials have shown the safety and effi- marily by ruptured or gangrenous appendicitis with or with- cacy of ertapenem for treatment of cIAI and API in adults out peritonitis, are important causes of morbidity in children [4–6]. Because the pathophysiologic processes and patho- [1,2]. Acute pelvic infections (APIs), similar to cIAIs, are gens involved in cIAI and API are similar in adults and often mixed infections caused by enteric pathogens. These children, children should respond similarly to treatment include postpartum or obstetrical surgery infectious compli- with ertapenem when infections are caused by susceptible cations in adolescent females [3]. Previous well-controlled, bacteria. Ertapenem, a group 1 carbapenem, is active in vitro against most pathogens likely to be encountered in the treatment of cIAI (ie, infections requiring both operative * Corresponding author. Tel.: ϩ1-323-226-7737; fax: ϩ1-323-226- drainage and antimicrobial therapy) including Escherichia 5815. coli and other Enterobacteriaceae, Clostridium clostridio- E-mail address: [email protected] forme, Eubacterium lentum, Peptostreptococcus species, 0002-9610/07/$ – see front matter © 2007 Published by Excerpta Medica Inc. doi:10.1016/j.amjsurg.2007.01.023 368 A.E. Yellin et al. / The American Journal of Surgery 194 (2007) 367–374 and Bacteroides spp including Bacteroides fragilis. In acute or cramping or tenderness or sonographic/radiographic ev- pelvic infections, such as postpartum endomyometritis, sep- idence suggesting a pelvic abscess; and (3) either fever (oral tic abortion, and postsurgical gynecologic infections, ertap- temperature Ͼ38°C), WBC Ͼ10,500/mm3, or a WBC dif- enem is effective against pathogens such as Streptococcus ferential with Ͼ10% band forms. agalactiae, E coli, B fragilis, Porphyromonas asaccharo- Enrollment was limited to immunologically competent lytica, Peptostreptococcus species, and Prevotella bivia. patients. Because specific ertapenem dosing guidelines for Unlike the group 2 carbapenems, imipenem and mero- pediatric patients with renal insufficiency are not available, penem, ertapenem has substantially less activity against children with significant renal impairment (serum creatinine nonfermentative gram-negative bacteria and thus is not in- Ͼ1.25 times the upper limits of normal) were excluded from dicated in the treatment of infections caused by Pseudomo- the study. nas aeruginosa or Acinetobacter species. Like other cur- rently approved beta-lactam agents, ertapenem is not active Interventions against methicillin/oxacillin-resistant staphylococci [7–9]. For children 3 months to 12 years of age, ertapenem was The aims of this study were to evaluate the safety, tol- administered twice daily as a 15-mg/kg parenteral dose to a erability, and efficacy of ertapenem versus a comparator maximum total daily dose of 1 g. Children 13 years of age ticarcillin/clavulanate control group in pediatric patients (3 or older received1gofertapenem as a single daily dose. months–17 years of age) with cIAI or API caused by sus- Treatment was always initiated with a 30-minute intrave- ceptible pathogens. nous (IV) infusion, but intramuscular dosing could be used if the patient met protocol-defined criteria (hemodynami- Methods cally stable and no coagulopathy). Dosing was based on preliminary results from a single-dose pharmacokinetic Study design study in pediatric patients and was chosen to approximate This was a prospective, multicenter, randomized, open- the exposure and pharmacokinetic /pharmacodynamic effi- label, comparative-controlled study conducted from March cacy determinants of 1 g daily dosing in adults [10]. 2002 to January 2004 at 15 sites in the United States, The comparator antibiotic regimen, IV ticarcillin/clavu- Mexico, and Brazil (12 sites in the United States). The lanate (50 mg/kg, based on the ticarcillin component), was protocol was approved by each center’s institutional review administered 4 or 6 times a day (for patients Ͻ60 kg) or committee. Written informed consent was obtained for each 3.1 g (3 g of ticarcillin and 100 mg of clavulanic acid) 4 or patient from his/her parent or guardian according to the 6 times a day (for patients Ն60 kg). Each infusion was guidelines of each institution. administered over a 30-minute period. These doses are ap- Children between 3 months and 17 years of age were proved for pediatric use in children 3 months of age and eligible to participate if they were diagnosed with cIAI with older for the indications of intra-abdominal infection and rupture and extension into the peritoneal cavity or API (in pelvic infections, including endometritis. the absence of pelvic inflammatory disease) that was likely Study therapy could be completed in the hospital, an to be treatable with 3 to 14 days of parenteral therapy and outpatient clinic, or with home infusion after at least 2 days was not complicated by preexisting conditions that could of in-hospital or clinic-based infusion therapy. Treatment confounded the evaluation of the study drugs. Patients with was to be continued for a minimum of 5 days for cIAI and intra-abdominal infection were either enrolled postopera- 3 days for API. The maximum suggested duration of ther- tively after visual confirmation of established intra-abdom- apy was 14 days. All therapy was to be administered par- inal infection including appendicitis complicated by perfo- enterally; the protocol did not allow for a switch to oral ration and/or abscess or were enrolled preoperatively based follow-up treatment. In addition to the antibiotic therapy, on the need for surgical intervention and the presence of medical and surgical treatment of the infectious process was each of the following criteria: (1) evidence of systemic performed according to guidelines established by the par- inflammatory response (at least 1 of the following: fever ticipating institution and was consistent with the investiga- [oral temperature Ͼ38.5°C], white blood cell [WBC] count tor’s usual clinical practice. Culture and sensitivity assays of Ͼ15,000/mm3, drop in blood pressure, increased pulse and appropriate bacterial specimens was requested at baseline, respiratory rate, hypoxemia, or altered mental status), (2) at any time that there was clinical or laboratory evidence of localized physical findings including pain/tenderness and persistence or progression of the infectious process (includ- rigidity consistent with intra-abdominal infection, and (3) ing persistent fever, elevated white blood cell count, or supportive