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Beta-Lactam Antibiotic Therapy in Febrile Granulocytopenic Patients: A Randomized Trial Comparing Cefoperazone plus Piperacillin, Ceftazidime plus Piperacillin, and Imipenem Alone

Drew J. Winston, MD; Winston G. Ho, MD; David A. Bruckner, ScD; and Richard E. Champlin, MD
[+] Article, Author, and Disclosure Information

Grant Support: By Grant CA-23175 from the National Cancer Institute and a research grant from Pfizer Pharmaceuticals.

Requests for Reprints: Drew J. Winston, MD, Room 42-121 CHS, Department of Medicine, UCLA Medical Center, Los Angeles, CA 90024.

Current Author Addresses: Dr. Winston: Room 42-121 CHS, Department of Medicine, UCLA Medical Center, Los Angeles, CA 90024.

Dr. Ho: St. Joseph Hospital Regional Cancer Center, 1100 West Stewart Drive, Orange, CA 92668.

Dr. Bruckner: Room A2-250, Clinical Microbiology Laboratories, UCLA Medical Center, Los Angeles, CA 90024.

Dr. Champlin: Section of Bone Marrow Transplantation, Department of Hematology, M.D. Anderson Hospital, 1515 Holcombe Boulevard, Houston, TX 77030.

© 1991 American College of PhysiciansAmerican College of Physicians

Ann Intern Med. 1991;115(11):849-859. doi:10.7326/0003-4819-115-11-849
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Objective: To compare the efficacy, toxicity, and cost-effectiveness of double beta-lactam therapy with monotherapy.

Design: A randomized, controlled trial.

Patients: Febrile, granulocytopenic patients (429).

Interventions: Patients were randomly assigned to receive iv cefoperazone (3 g every 12 hours) plus piperacillin (75 mg/kg body weight every 6 hours), ceftazidime (2 g every 8 hours) plus piperacillin (75 mg/kg every 6 hours), or imipenem alone (1.0 g or 0.5 g every 6 hours). Patients also received prophylactic vitamin K.

Measurements: Clinical improvement, eradication of the infecting organism, and toxicity in 403 evaluable patients with one or more infections.

Main Results: Cefoperazone and ceftazidime, when given in combination with piperacillin, were equally effective (response rates of 75% (104 of 138 patients) and 74% (101 of 137 patients), respectively). Monotherapy with imipenem had a response rate of 82% (111 of 136 patients) and was as effective as double beta-lactam therapy. Overall antibiotic-related toxicity was minimal, although seizures were associated with high doses of imipenem. Seizures occurred in 3 of 29 patients (10.3%) who were receiving 4 g/d of imipenem, in 3 of 136 patients (2.2%) who were receiving cefoperazone plus piperacillin, in 0 of the 132 patients who were receiving ceftazidime plus piperacillin, and in 1 of 106 patients (0.9%) who were receiving 2 g/d of imipenem (P < 0.005). The 2-g daily dose of imipenem was as effective as the 4-g daily dose. Diarrhea was more frequent in patients receiving cefoperazone, whereas nausea occurred more often with imipenem. No antibiotic-related hemorrhage or nephrotoxicity was observed. Superinfections caused by betalactam-resistant, gram-negative bacilli were uncommon but occurred more frequently with double beta-lactam therapy than with imipenem monotherapy (11 of 268 patients compared with 1 of 135 patients; P = 0.06). Xanthomonas maltophilia superinfections occurred only in patients receiving imipenem (3 of 135 patients compared with 0 of 268 patients; P = 0.03). Imipenem monotherapy was the least expensive therapy.

Conclusions: Cefoperazone and ceftazidime were equally effective when used in combination antibiotic therapy with piperacillin. Twice-daily cefoperazone is less expensive than ceftazidime given three times daily. Monotherapy with imipenem, at a daily dose of 2 g, is as efficacious as double beta-lactam therapy and costs less than combination therapy.





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