Journal of Antimicrobial Chemotherapy (1990) 25, 423-433

A randomized clinical study of cefoperazone and sulbactam versus gentamicin and clindamycin in the treatment of intra-abdominal infections

'St. Vincent Medical Center, Toledo; bHershey Medical Center, Hershey; 'University of Tennessee, Memphis; 4The V.A. Medical Center, Portland, USA This report summarizes the experience of investigators in four medical centres who compared the combination of cefoperazone/sulbactam against gentamirin/clindamycin in the treatment of intra-abdominal infections. One hundred and fifty-two patients were enrolled in the study and all were evaluable for safety and tolerance, 110 were evaluable for efficacy. Of the 76 patients (49 male, 27 female) treated with cefoperazone/sulbactam 66 (86-8%) were cured, five (6-6%) improved and five (6-6%) failed to respond to treatment. Of 34 patients treated with gentamicin/ dindamycin, 21 (61-8%) were cured, four (11-8%) improved and nine (264%) failed. Cure rates for patients receiving cefoperazone/sulbactam were significantly higher than those of patients receiving gentamicin/clindamycin (P < 0006). Failures in both groups were attributable in part to pseudomonal and enterococcal infection and abscess formation. The addition of sulbactam to cefoperazone rendered cefoperazone-rcsistant organisms susceptible to cefoperazone in 11 of the 76 cases (144%) and thus permitted treatment with this agent. The present study confirms the safety and clinical efficacy of cefoperazone/sulbactam and suggests that this combination is a viable alternative to an aminoglycoside plus clindamycin for intra-abdominal infections.

Introduction Intra-abdominal infections caused by endogenous gastrointestinal microflora are usually polymicrobial and involve aerobic and anaerobic bacteria. The successful treatment of these infections requires surgical intervention together with antimicrobial therapy aimed at both the aerobic and anaerobic intestinal flora (Tally et ai, 1981; Nichols, 1983). An aminoglycoside plus clindamycin fulfills this latter requirement and has been considered the antimicrobial treatment of choice in some countries for intraabdominal infections. However, potentially severe adverse reactions such as nephrotoxicity, ototoxicity and pseudomembranous colitis can occur as complications of such therapy (Schentag, Ona & Plant, 1982; Solomkin et al., 1983; Flint et al., 1985). In addition, the high cost of multiple daily parcnteral infusions and repeated measurements of aminoglycoside concentrations are disadvantages of this mode of treatment (Rapp, Bannon & Biveus, 1982). Sulbactam (CP45.899, penicillanic acid sulfone) is a chemically stable, irreversible inhibitor of many /Mactamases. This compound has little inherent antimicrobial 423 0305-7453/90/030423 +11 $02.00/0

© 1990 The British Society for Antimicrobial Chemotherapy

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Lois E. Janregni*, Peter C Appdbaum*, Timothy C. Fabian', George Hageage*, Larry Strausbangtrv and Louis F. Martin''

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activity in vitro, however when combined with a /Mactam antimicrobial such as cefoperazone, it expands the spectrum of activity (Jones et al., 1985a, b). The extended spectrum of antimicrobial activity and compatible pharmacokinetic properties suggest that the combination of cefoperazone plus sulbactam could be a suitable, potentially less toxic, alternative to the use of an aminoglycoside plus clindamycin in patients with intra-abdominal infections (Jones et al., 1985a, b; Reitberg et al., 1988; Schwartz et al., 1988). The aim of the present study was to test this hypothesis in a clinical setting by comparatively evaluating the safety and efficacy of a fixed parenteral combination of cefoperazone plus sulbactam versus the combination of gentamicin and clindamycin.

Study design This study, conducted at four investigational centres (St. Vincent Medical Center, Toledo, Hershey Medical Center, Hershey, University of Tennessee, Memphis, and the V.A. Medical Center, Portland), was designed as a randomized, comparative antimicrobial trial and received approval from the Institutional Review Board of each institution. Patients 18 years of age or older, with known or suspected serious intraabdominal infection requiring both surgical and antimicrobial treatment were entered into the study. Prior to enrolment, written informed consent was obtained from all participants. At each centre, patients were assigned to one of two treatment groups based on independent, computer generated, randomization codes programmed to enroll two patients in the cefoperazone/sulbactam group for each patient assigned to the gentamicin/clindamycin group. Patients were excluded if one or more of the following criteria were present: pregnancy or lactation, terminal illness, severe immunosuppression, successful or suppressive antimicrobial therapy within four days prior to enrollment or history of hypersensitivity to aminoglycosides, cephalosporins, clindamycin or penicillin. Criteria for evaluation of efficacy and safety Patients were considered clinically assessable for efficacy if (1) the presence of a clinically proven infection was established, i.e., the occurrence of intestinal perforation with bacterial soiling of the peritoneal cavity or the presence of pus in an abscess, an inflamed organ or exudation from a wound, (2) the completion of a minimum of five days of antimicrobial treatment and (3) the continuation of clinical follow-up for at least four weeks following the cessation of antimicrobial therapy. Patients were excluded from the efficacy evaluation if a suspected infection was not confirmed at surgery, i.e., viscus perforation without infection or lack of recovery of a pathogen from cultures taken at surgery, for protocol violations entailing the inadvertent administration of other antimicrobials and for failure to return for follow-up examinations. Clinical success was defined as resolution of infection four weeks after completion of antimicrobial therapy without the need for any intervening additional antimicrobials, drainage or re-operation. Patients whose primary infective process was controlled but who had persisting clinical disability or who developed superinfections were considered to be improved. Clinical failure was defined as the need to institute additional

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Patients and methods

Cefoperazone and nlbactam in abdominal sepsis

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Antimicrobial therapy Patients who were randomized to the cefoperazone/sulbactam group received a fixed combination of 2 g of cefoperazone (Pfizer Inc., New York) and 1 g of. sulbactam every 12 h. Those patients in the gentamicin/clindamycin group were given gentamicin (Schering Laboratories, Kenilworth) at a dosage of 4-5-6 mg/kg/d given in divided doses every 8h. Clindamycin phosphate (Upjohn Laboratories, Kalamazoo) was administered in doses of 2400 mg/d at 6-8 h intervals. All drugs were infused in 100 ml of saline diluent by the intravenous route over 30 min. Serum creatinine and peak and trough concentrations of gentamicin (by enzyme immunoassay (Kabakoff, Leung & Singh, 1978) were monitored at least twice weekly. These measurements served to make dosing adjustments for gentamicin (Noone et al., 1974). Peak gentamicin serum concentrations of 6 to 8 mg/L 30 min after the end of infusion, were maintained. Microbiologic procedures

All patients had at least two paired sets of aerobic and anaerobic blood cultures drawn by separate venipunctures prior to initiation of antimicrobial therapy. Aerobic and anaerobic cultures were obtained by aspiration of pus from the site of infection. If clinical conditions allowed, bacteriological samples were obtained prior to the initiation of antimicrobial therapy. If initial blood cultures yielded a pathogen, repeat blood cultures were obtained every two days until they yielded no further growth. Follow-up cultures of specimens from the primary infected site were obtained at intervals of four days if abnormal drainage was present Standard microbiological methods were used to identify bacterial isolates (Lennette et al., 1985). Standard antibiotic disc susceptibility tests (Bauer et al., 1966) of cefoperazone, gentamicin and clindamycin were carried out on all aerobes isolated. A disc susceptibility test of cefoperazone plus sulbactam was also obtained, using the standards for cefoperazone as break points. The disc elution method was used to detennine susceptibility of the anaerobic isolates (Sutter, Citron & Edelstein, 1985). In addition, minimum inhibitory concentrations (MICs) of all aerobic

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antimicrobials to control the intra-abdominal infection or to drain an abscess surgically or wound infection, or death related to infection. Patients were assessed daily during hospitalization and up to four weeks after completion of therapy for fever, organ system failure, infectious complications, and any adverse effects possibly related to the antimicrobials used. Each patient had a standard battery of laboratory studies performed prior to initiation of antimicrobial therapy, every three to five days during the course of therapy, on the last day of therapy, and one week post-therapy. Any unexplained abnormal laboratory values were repeated until they returned to normal or until an explanation for their continued abnormality was found. Laboratory tests included a complete blood count, chemistry profile, direct Coombs test, prothrombin time, partial thromboplastin time, and urinalysis. Criteria for microbiological evaluation included the isolation of at least one pathogen from the established site of infection prior to or just after the initiation of antimicrobial therapy. Bacteriological efficacy was denned as (1) eradication—elimination of the source of infection with no further material to culture or lack of growth on cultures of residual drainage, (2) partial eradication—elimination of one or more but not all pathogens, (3) persistence—inability to eliminate initial pathogens.

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isolates were determined by the microtitre technique (Lennette et al., 1985). The following break points were used for classification of the isolates as sensitive, clindamycin ^ 0 - 5 mg/1, gentamicin

A randomized clinical study of cefoperazone and sulbactam versus gentamicin and clindamycin in the treatment of intra-abdominal infections.

This report summarizes the experience of investigators in four medical centres who compared the combination of cefoperazone/sulbactam against gentamic...
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