Ampicillin/Sulbactam Vs. Cefoxitin for the Treatment of Pelvic Inflammatory Disease

Objective: The safety and efficacy of ampicillin plus sulbactam were compared with those of cefoxitin in the treatment of women with pelvic inflammatory disease (PID). Methods: This single-site, randomized, prospective, third-party-blinded, comparative, parallel-treatment study enrolled 93 women with a diagnosis of PID. Patients were treated with either ampicillin/sulbactam (2 g/1 g, administered intravenously [IV], every 6 h) or cefoxitin (2 g, administered IV, every 6 h) for a minimum of 12 doses. Patients with cultures positive for Chlamydia trachomatis also received concurrent oral or IV doxycycline (100 mg twice daily). Patients with cultures negative for C. trachomatis received prophylactic oral doxycycline (100 mg twice daily) for 10–14 days after treatment with either ampicillin/sulbactam or cefoxitin was completed. Results: Ninety-three patients were entered in the study: 47 in the ampicillin/sulbactam arm and 46 in the cefoxitin arm. All 93 patients were evaluable for safety; 61 (66%) were evaluable for efficacy. Demographic characteristics were similar for the groups. Of the 27 evaluable ampicillin/sulbactam-treated patients, 67% experienced clinical cure, 30% improved, and 4% failed treatment. Respective values for the 34 cefoxitin-treated patients were 68%, 24%, and 9% (P = 0.67). Pathogens were eradicated in 70% of the women given ampicillin/sulbactam vs. 56% of those who received cefoxitin (P = 0.64). Conclusions: Overall, ampicillin/sulbactam demonstrated clinical and bacteriologic efficacy at least equivalent to that of cefoxitin in the treatment of women with acute PID. The use of ampicillin/sulbactam for this indication may avoid the complex dosing regimens associated with other treatments.

vius, other Prevotella species, and peptostreptococci. 7 The polymicrobial nature of PID requires empiric therapy with a broad-spectrum antimicrobial agent or combination. 8,9 Complicating effective therapy, however, has been the development of significant antibiotic resistance 8-1 through production of penicillinase by N. gonorrhoeae and of 13lactamase by various other causative pathogens of PID.  Although combination therapy with gentamicin and clindamycin has been considered the "gold standard, ''8,11 in recent clinical trials 9,,1z the combination of the [3-1actam ampicillin and the [3-1actamase inhibitor sulbactam has demonstrated excellent activity against pathogens associated with pelvic infections in women. 1,4 The present study was undertaken to directly compare the efficacy and safety of ampicillin/ sulbactam and cefoxitin, a semisynthetic cephamytin, in women with PID.

SUBJECTS AND METHODS
Eligible for enrollment were females 14 years of age or older who provided informed written consent (including parental or legal guardian consent for patients <18 years of age) and who had a diagnosis of PID based on medical history, clinical laboratory findings, physical examination, and clinical signs and symptoms of infection, including abdominal, adnexal, or cervical motion tenderness. Leukocyte count ->10,000 mm", temperature -> 100. 4 F, left shift (bands -> 10%), or endocervical discharge positive for gram-negative intraccllular diplococci were also required. Ultrasonography was employed, as necessary, to rule out the presence of abdominal abscess.
Before study initiation, the study protocol and statement of informed consent were reviewed and approved by the institutional review committee.
Criteria for exclusion were known hypersensitivity to cephalosporins or penicillins; need for concomitant antibiotic therapy; terminal illness with death likely within 48 h; severe underlying disease that might interfere with evaluation of the therapeutic response; successful antimicrobial therapy within 4 days prior to study entry; ongoing treatment with another investigational drug; impaired immunological function or neutropenia (neutrophil count <1,500 mm3); serum creatinine >1.5 mg/dl; pregnancy; or known liver disease (liver function test ->twice normal value).
Patients provided medical and surgical histories and underwent physical examination. Within 48 h prior to initiation of therapy, endocervical specimens were taken for aerobic culture of N. gonorrhoeae, C. trachomatis, Mycoplasma hominis, and Ureaplasma urealyticum. Uncontaminated specimens from normally sterile sites taken during culdocentesis, laparoscopy, or laparotomy were also cultured for aerobes and anaerobes. Follow-up endocervical cultures were not required, except to document treatment failure. Because PID may have a clinical presentation similar to, or may occur concurrently with, pyelonephritis, at least 2 blood cultures with specimens from separate sites were performed to aid in the differential diagnosis; follow-up cultures were obtained if bacterial growth was noted. All probable bacterial pathogens were tested for susceptibility to ampicillin, ampicillin/sulbactam, and cefoxitin.
Within 24 h of admission, patients were tested for C. trachomatis by the immunofluorescent antibody test. A positive result was defined as C. trachomatis on either this test or culture. Pretreatment blood samples were collected for complete blood count with differential, volume, and platelet count. Prothrombin time and partial thromboplastin time were performed in patients with signs of bleeding disorders. Blood chemistry profiles included alanine and aspartate aminotransferases, serum creatinine, and blood urea nitrogen.
Urinalysis was also performed. Pretrcatment and follow-up radiographic and sonographic procedures were carried out at the investigator's discretion.
Patients were randomly assigned to receive either ampicillin/sulbactam (2 g/1 g) or cefoxitin (2 g) both administered intravenously (IV) every 6 h. Doxycycline, 100 mg twice daily, either oral or IV, was administered concurrently to patients with cultures positive for C. trachomatis. Because of the significant possibility of false negatives, patients with cultures negative for C. trachomatis were empirically treated with 10-14 days of oral doxycycline, 100 mg twice daily, after the study ended. A minimum of 12 doses of ampicillin/sulbactam and cefoxitin were given.
Based on the clinical judgment of the investigator, other antibiotics or non-pharmacological inter-ventions were administered to treatment failures.
Patients were withdrawn from the study for the following reasons: obvious therapeutic failure of the study drug; primary pathogen isolated from an initial culture, or any subsequent culture taken during the treatment period, resistant to the study drug(s) and patient failure to respond to therapy within 48 h; a significant adverse event (including significant alteration in laboratory parameters); or request for withdrawal by the patient or the parent (guardian) of a minor patient.
An initial clinical evaluation was performed on the first day of therapy, at least every other day thereafter, and at the end of study drug treatment. Signs and symptoms of pelvic infection were evaluated. Temperature was recorded, and the presence or absence of abdominal abscess was noted.
One week after treatment with study drug ended, all patients underwent a follow-up assessment. An endocervical specimen was taken at this time from patients with initial C. trachomatis or N. gonorrhoeae infection to test for eradication. An additional follow-up was carried out 4-6 weeks after the end of treatment.
Whenever possible, sexual partners of patients testing positive for sexually transmitted disease (STD) species were treated. At time of discharge, patients were instructed by the treating physician to avoid vaginal sexual exposure before follow-up visits. The use of condoms was encouraged.
The clinical response to treatment was evaluated as cure: disappearance of presenting signs and symptoms by the end of therapy and at follow-up; improvement: partial alleviation of signs and symptoms by the end of therapy and at follow-up; failure: no significant effect on signs and symptoms; or indeterminate: results not evaluable or not fitting into one of the other categories.
Bacteriologic response to treatment was defined as eradication: disappearance of culturable material or elimination of the principal pathogen(s) at the end of therapy and at follow-up; partial eradication: some, but not all, multiple causative pathogens absent after completion of therapy; eradication/ superinfection: elimination of the principal pathogen(s) and emergence of a different organism during, or at the end of, therapy and at follow-up; persistence of the principal pathogen at the end of therapy and at follow-up; or indeterminate: results not evaluable or not definable per protocol. Demographic characteristics were compared by means of the Wilcoxon rank-sum and Fisher's exact tests. The Mantel-Haenszel X e test was used to compare clinical and bacteriologic outcomes with the 2 treatments. Duration of hospitalization for the 2 groups was compared with the Wilcoxon rank-sum test.

RESULTS
Of the 93 women who entered the trial, 27 of 47 treated with ampicillin/sulbactam and 34 of 46 given cefoxitin were evaluable for clinical and bacteriologic efficacy (Table 1). In both treatment groups, patients not evaluable were primarily those lost to follow-up. The demographic characteristics evaluated were statistically similar between groups (P > 0.34 for all variables). Seven patients in the ampicillin/sulbactam group and 4 in the cefoxitin group had documented abdominal abscesses.
Reasons for exclusion from efficacy analyses ( Table 2)  2), and age <14 years (1 vs. 0). Concomitant antibiotics were administered due either to failure of study medication or to nursing error. No significant difference in clinical efficacy was noted between the 2 treatments (P 0.67) (Fig. 1). Of the 27 evaluable patients who received ampicillin/sulbactam, 67% (N 18) were cured and 30% (N 8) were improved; treatment failed in 4% (N 1). Respective values for the 34 evaluable patients treated with cefoxitin were 68% (N 23),  Clinical responses to ampicillin/sulbactam and ce-24% (N 8), and 9% (N 3). In both treatment groups, most patients who were clinically improved required antibiotic therapy that continued poststudy. None required surgical intervention. Primary pathogens isolated in each treatment group are detailed in Table 3. Overall, ampicillin/ sulbactam eradicated a higher percentage of causative pathogens than cefoxitin, although the difference was not statistically significant (P 0.64) (Fig.  2). Pathogens were eradicated in 70% (N 19) of evaluable patients treated with ampicillin/sulbactam. Eradication followed by superinfection occurred in 7% (N 2), persistence in 4% (N 1), and 19% (N 5) had an indeterminate response. Patients with indeterminate responses were pri- I ) ) ) ) ) ) ) ) ) ! ) ! (N=27)Ampicillin/Sulbactam m marily those for whom no adequate post-therapy culture was obtained or to whom other IV antibiotics were being administered at study entry. Values for cefoxitin-treated patients were 56% (N 19), 9% (N 3), 3% (N 1), and 26% (N 9). Two patients (6%) in this group experienced partial eradication of causative pathogens. Organisms responsible for superinfection were 3/1. horninis and C. trachomatis in patients receiving ampicillin/sulbactam, and N. gonorrhoeae and 3/1. hominis in patients treated with cefoxitin. Indeterminate responses were primarily due to the absence of post-therapy culture results and the administration of IV antibiotics prior to study entry.
In only 2 of the 13 patients with documented C. All patients who received study medication were included in an intent-to-treat analysis.

DISCUSSION
The results of this controlled clinical trial indicate that ampicillin/sulbactam is as safe and effective for the treatment of PID as cefoxitin. These findings are consistent with those from a number of other studies comparing ampicillin/sulbactam with either A recent meta-analysis evaluated the effectiveness of a large number of single-drug and combination therapies in women with PID. z Ampicillin/ sulbactam, with the addition of doxycycline when appropriate, had clinical and bacteriologic efficacy comparable to that of clindamycin plus gentamicin, tobramycin, or amikacin; metronidazole plus doxycycline; either cefoxitin, cefotetan, or cefotaxime plus doxycycline; ciprofloxacin or ofloxacin; or the combination of amoxicillin, clavulanic acid, and doxycycline. Ampicillin/sulbactam was also less expensive than most of these regimens, including those involving cefoxitin, e This last conclusion is supported by results of a recent pharmacoeconomic analysis that directly compared the cost-effectiveness of these two agents. Conversion from cefoxitin to ampicillin/sulbactam at a university teaching hospital resulted in an initial annual savings of $30,000 to $50,000. 21 In summary, PID, a common infection among sexually active women, may entail a significant risk of long-term sequelae, including chronic abdominal pain, ectopic pregnancy, and infertility. 22 Effective treatment of this disease requires broad antimicrobial coverage that traditionally has been achieved with relatively expensive combination therapy involving administration of as many as three agents with different dosage schedules. 23,24 The combination of the 3-1actam ampicillin with the [3-1actamase inhibitor sulbactam has demonstrated excellent clinical and bacteriologic efficacy in patients with PID, and is less expensive than many other therapies, including cefoxitin.