A Multicenter Study Comparing Intravenous Meropenem with Clindamycin Plus. Gentamicin for the Treatment of Acute Gynecologic and Obstetric Pelvic.
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A Multicenter Study Comparing Intravenous Meropenem with Clindamycin Plus Gentamicin for the Treatment of Acute Gynecologic and Obstetric Pelvic Infections in Hospitalized Women David L. Hemsell, Mark G. Martens, Sebastian Faro, Stanley Gall, and James A. McGregor
From the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas; the Gynecology Division, Department of Obstetrics and Gynecology, Emory University School of Medicine, Atlanta, Georgia; the Division of Infectious Diseases, Department of Obstetrics and Gynecology, University of Kansas School of Medicine, Kansas City, Kansas; the Department of Obstetrics and Gynecology, University of Louisville, College of Medicine, Louisville, Kentucky; and the Department of Obstetrics and Gynecology, University of Colorado, Denver, Colorado
Meropenem is a /3-lactam antibiotic of the carbapenem class that has been shown to be more stable to inactivation by human renal dehydropeptidase I than has imipenem, the other commercially available carbapenem [1, 2]. Thus, meropenem can be administered without the enzyme inhibitor cilastatin, which is given with imipenem to maintain therapeutic drug concentrations [1, 2]. In an animal model, meropenem was shown to cause fewer seizures than imipenem alone or imipenem with cilastatin [3]. Meropenem has demonstrated excellent in vitro activity against a broad spectrum of gram-negative and gram-positive aerobic and anaerobic bacteria, including strains of /3-lactamaseproducing Neisseria gonorrhoeae [4-6]. Meropenem has been reported to have in vitro activity superior 'to that of cefoxitin, cefotaxime, ceftazidime, ciprofloxacin, and piperacillin against
Informed consent was obtained from the patients, or their parents or guardians, and guidelines for human experimentation of the U.S. Department of Health and Human Services and/or those of the authors' institutions were followed in the conduct of the clinical research. Financial support: This work was supported in part by a grant from ZENECA Pharmaceuticals Group, Wilmington, Delaware. Reprints or correspondence: Dr. David L. Hemsell, Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9032. Clinical Infectious Diseases 1997;24(Suppl 2):S222-30 0 1997 by The University of Chicago. All rights reserved. 1058-4838/97/2402 — 0053$02.00
aerobes and to be comparable to metronidazole and clindamycin against clinically important anaerobes [7]. Although the combination of clindamycin plus gentamicin has been widely used in the empirical management of acute gynecologic and obstetric pelvic infections, there is great interest in monotherapeutic regimens that do not include aminoglycosides but provide similar microbial coverage. Data on tissue distribution indicate that in addition to its in vitro activity, meropenem achieves adequate concentrations in a wide range of sites within the body and rapidly penetrates the interstitial fluid of tissues not protected by a tight epithelial barrier [8]. We evaluated meropenem concentrations in gynecologic tissue from 64 patients who received 500 mg of meropenem administered as a 30-minute iv infusion before elective gynecologic surgery was performed [8a]. The highest concentrations were detected in samples obtained —1 hour (range, 30 minutes-90 minutes) after the start of the meropenem infusion, when mean concentrations of the drug ranged from —2 to 7 mg/L (i.e., 7.0 mg/L in the cervix; 3.6 mg/L in the myometrium; 2.3 mg/L in the endometrium, ovary, and uterus; and 1.9 mg/ L in the fallopian tubes). Although these tissue concentrations were lower than those achieved in plasma, they were well above the MIC 90 values necessary for inhibiting the growth of pathogens commonly involved in gynecologic infections [6]. This study was designed to compare the efficacy and safety of meropenem monotherapy with the efficacy and safety of clindamycin plus gentamicin in the treatment of hospitalized
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We conducted a multicenter trial to compare the efficacy and safety of meropenem with the efficacy and safety of clindamycin plus gentamicin in the treatment of 515 hospitalized patients with acute gynecologic and obstetric pelvic infections. At the end of treatment, the rates of satisfactory clinical and bacteriologic response were high (88%) in both treatment groups: the rates of response were 90% for the meropenem group and 86% for the clindamycin/gentamicin group. No serious adverse events occurred. The most frequently reported drug-related adverse clinical events in the meropenem group were nausea and injection-site reactions (> 1% of patients), and the most common drug-related laboratory abnormality was thrombocythemia. Similar. patterns of adverse events occurred in the clindamycin/gentamicin group; however, the incidence of diarrhea and eosinophilia was higher in this group. In summary, this trial demonstrated that meropenem is an effective and safe alternative to the combination of clindamycin plus gentamicin for the treatment of women with acute gynecologic and obstetric pelvic infections.
CID 1997;24 (Suppl 2)
Meropenem vs. Clindamycin/Gentamicin for Pelvic Infections
women with acute gynecologic and obstetric pelvic infections. Materials and Methods
results were interpreted on the basis of those guidelines [9]. Whenever possible, both MICs were determined, and agar disk diffusion methods were performed, but MIC testing was the preferred method. At least one pathogen had to be susceptible to both trial treatments if results were known before randomization or to randomized treatment if the results became known after treatment was started. SENSITITRE MIC trays (Radiometer America Inc., Westlake, OH) and Kirby-Bauer diffusion disks (Difco, Detroit) containing 10 pg of meropenem were used to determine susceptibilities to this drug. Commercially available MIC panels and disks were used to determine susceptibilities to clindamycin and gentamicin. The breakpoint for full susceptibility to meropenem was defined as an MIC of ag/mL or an inhibition zone of mm; for susceptibility to clindamycin, an MIC of 0.5-1 /..tg/mL for aerobes and 4 pg/mL for anaerobes; and for susceptibility to gentamicin, an inhibition zone of mm. These breakpoints were specified by the protocol for the recruitment of patients into the study. 43-Lactamase production was assessed with nitrocefin disks (BBL, Cockeysville, MD). Efficacy evaluation. The primary efficacy end points were the clinical and bacteriologic responses of evaluable patients at the end of treatment and, when possible, at follow-up (2-4 weeks after treatment ended). A satisfactory clinical response was defined as the disappearance or significant abatement of signs and symptoms of infection by the end of treatment; observations recorded for patients with these infections included uterine, adnexal, abdominal, or cervical tenderness, an elevated WBC count, and an elevated temperature (>38°C). Patients whose clinical signs and symptoms of infection remained unchanged or worsened during treatment and who required additional antimicrobial or surgical therapy were considered to have had unsatisfactory clinical responses. This category included patients with symptomatic superinfection that necessitated additional surgery or a change in antibiotic therapy. Clinical relapse was assessed at follow-up and was defined as a return of the primary clinical signs and symptoms of infection after an initial satisfactory response. Patients who relapsed were also considered to have had unsatisfactory clinical responses. The assessment of the bacteriologic response to treatment was based on the culture results for specimens obtained within 7 days after the last dose was administered. A satisfactory bacterial response was defined as the eradication of the pretreatment pathogens (success or presumed success if no specimen was available for culture after treatment) or as a clinically satisfactory outcome, with eradication of some pathogens for infections caused by two or more pathogens (partial success); these outcomes are in accordance with the guidelines of the Infectious Diseases Society of America. Unsatisfactory bacteriologic responses were defined as those in which the pretreatment pathogen(s) was not eradicated by the end of treatment (failure); those in which clinical signs of
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Study design, study procedures, and medication. We conducted this prospective, multicenter, open-label, randomized, comparative, parallel-group trial at eight study sites. Hospitalized women who were 18 years of age or older and had acute gynecologic and obstetric bacterial pelvic infections requiring parenteral antibiotic therapy were evaluated. Eligible patients had neutrophil counts of 1,000/mm 3 and were free of cystic fibrosis or nonpelvic infections requiring antibiotic therapy. Patients were assigned to treatment in a 1:1 ratio by means of a separate predetermined randomization schedule for each center. The following patients were excluded: those who were pregnant or nursing; those with histories of immediate hypersensitivity to penicillins, cephalosporins, aminoglycosides, clindamycin, or imipenem/cilastatin; or those with rapidly progressing underlying disease; those with marked hepatic disorders (i.e., those with serum transaminase levels two times above the normal values) or renal disorders (i.e., those with serum creatinine levels of mg/dL); those with CNS disorders; and those with active colitis. No concomitant antibiotics were allowed during the study. Patients who were previously treated unsuccessfully with other antibiotics, as evidenced by poor clinical response or persistently positive cultures, could be entered into the study after previous antibiotics were stopped and new specimens for culture were obtained. A patient's condition at study entry was subjectively classified as good, fair, poor, or critical, depending on the investigator's clinical judgment. Infection was confirmed by a positive culture of an appropriate specimen obtained within 3 days before the start of treatment from one of the following sites: the endometrium, supravaginal space, vaginal margin, or cervix; a wound; or blood. Doses of the study drugs were as follows: meropenem (500 mg) given over 20-30 minutes and clindamycin (900 mg) plus gentamicin (1.5 mg/kg, following a loading dose of 2.0 mg/kg). All drugs were given intravenously every 8 hours; serum concentrations of gentamicin were monitored to ensure that drug levels were both therapeutically adequate and nontoxic. A treatment period of at least 48 hours was required for clinical evaluability (the suggested treatment duration was 410 days, with a maximum duration of 28 days). Patients who missed any two doses during the first 48 hours or any two consecutive doses at any time during the treatment period were not eligible for evaluation of clinical efficacy. Pathogens were isolated, identified, and tested for in vitro susceptibility to each antibiotic. Susceptibility testing was conducted in accordance with the procedures approved by the National Committee on Clinical Laboratory Standards, and the
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tion and analysis of satisfactory response rates. The modified intent-to-treat analysis included only those patients who met the entry criteria. The incidences of adverse events judged to be treatment related by the investigator were summarized in the safety assessment. Between-group t tests were performed on mean changes between pretreatment and end-of-treatment laboratory values to assess the statistical significance of the changes. A sample size of 150 evaluable patients in each treatment group was expected. When a 90% satisfactory response rate for clindamycin plus gentamicin was assumed, the power to detect a satisfactory response rate of 80% for meropenem was estimated to be 55%; for a satisfactory response rate of 70% for meropenem, the power was estimated to be 97%. Statistical significance was determined at a P value of .05 in all analyses.
Results Demographic data. Demographic and clinical characteristics (table 1) were similar between groups of evaluable patients (n = 395), as well as for all intent-to-treat patients and evaluable patients (n = 515). The most frequent diagnoses among all patients were endometritis, pelvic inflammatory disease, and pelvic cellulitis. The majority of evaluable patients (124 [59%] of 211 in the meropenem group and 99 [54%] of 184 in the clindamycin/gentathicin group) had undergone cesarean section before entry into the study. Similar proportions of all (intent-to-treat) patients had undergone cesarean section (153 [59%] of 259 in the meropenem group and 144 [56%] of 256 in the clindamycin/gentamicin group). At follow-up, 274 patients (145 in the meropenem group and 129 in the clindamycin/ gentamicin group) were available for determination of clinical response; 197 (105 in the meropenem group and 92 in the clindamycin/gentamicin group) were available for determination of bacteriologic response. Efficacy. Of the 515 patients enrolled from eight centers, 395 patients (77%; 211 in the meropenem group and 184 in the clindamycin/gentamicin group) were evaluable for clinical and bacteriologic responses. The most common reason for unevaluability was failure to isolate a pretreatment pathogen (no pathogen was isolated for 24 patients in the meropenem group and for 35 patients in the clindamycin/gentamicin group). Other common reasons for unevaluability included resistance of the pretreatment pathogen to the study drugs (five patients in the meropenem group and six in the clindamycin/gentamicin group; P = .053), administration of another antibiotic(s) during the study period (two patients in the meropenem group and eight in the clindamycin/gentamicin group), inadequate treatment (i.e., treatment for
