Ciprofloxacin plus Piperacillin Compared with Tobramycin plus Piperacillin as Empirical Therapy in Febrile Neutropenic Patients

A Randomized, Double-Blind Trial

16 July 2002 | Volume 137 Issue 2 | Pages 77-87

Background: Therapy with an aminoglycoside and a ß-lactam remains common empirical therapy for febrile neutropenic patients. Concerns of aminoglycoside-induced ototoxicity and nephrotoxicity have led to studies of alternate regimens.

Objective: To determine whether ciprofloxacin–piperacillin is equivalent to tobramycin–piperacillin as empirical therapy for neutropenic fever.

Design: Randomized, double-blind multicenter trial.

Setting: Seven U.S. university-affiliated hospitals and one private research center.

Patients: Febrile (temperature 38 °C), neutropenic (neutrophil level < 1 x 10⁹ cells/L) hospitalized patients who had leukemia, lymphoma, or solid tumors, or were undergoing bone marrow transplantation.

Interventions: Patients received piperacillin, 50 mg/kg of body weight intravenously every 4 hours, and ciprofloxacin, 400 mg intravenously every 8 hours, or tobramycin, 2 mg/kg intravenously every 8 hours.

Measurements: Success was defined as resolution of infection and previously positive cultures without the need to give additional antimicrobial agents.

Results: 543 febrile episodes were evaluated, of which 471 were clinically evaluable (234 in the ciprofloxacin–piperacillin group and 237 in the tobramycin–piperacillin group). Success rates in the ciprofloxacin–piperacillin group (63 of 234 febrile episodes) and tobramycin–piperacillin group (52 of 237 episodes) were similar (27% vs. 22%, respectively; difference, 5.0 percentage points [95% CI, –2.3 to 12.8 percentage points]), as was survival (96.2% of patients receiving ciprofloxacin–piperacillin versus 94.1% of patients receiving tobramycin–piperacillin; difference, 2.1 percentage points [CI, –2.2 to 6.4 percentage points]). Additions to the initial antimicrobial regimen were the most common reason for treatment failure in both groups (accounting for 67% of failures in the ciprofloxacin–piperacillin group and 72% in the tobramycin–piperacillin group; difference, 5.0 percentage points [CI, –13.8 to 3.7 percentage points]). Fevers resolved faster in patients receiving ciprofloxacin–piperacillin than in patients receiving tobramycin–piperacillin (mean, 5 vs. 6 days) (P = 0.005). No significant differences in adverse events or toxicity were noted (P = 0.083).

Conclusion: Ciprofloxacin–piperacillin is as safe and effective as tobramycin–piperacillin for empirical therapy of neutropenic fever.

Editors' Notes Context Hospitalized patients with neutropenia have high risks for opportunistic gram-negative infections. An aminoglycoside in combination with an antipseudomonas ß-lactam, a traditional empirical therapy for febrile neutropenic patients, is limited by potential nephrotoxicity. Contribution This large randomized trial showed that ciprofloxacin plus piperacillin and tobramycin plus piperacillin were equally effective empirical therapies for hospitalized patients with fever and neutropenia. Side effects, including nephrotoxicity, were common with both regimens and did not differ significantly. Implications Combination therapy with the ß-lactam piperacillin plus a quinolone (ciprofloxacin) or an aminoglycoside (tobramycin) is a viable option for neutropenic febrile patients. –The Editors

 

Author and Article Information

From Wake Forest University School of Medicine, Winston-Salem, North Carolina; University of Maryland Cancer Center, Baltimore, Maryland; Ireland Cancer Center, Rainbow Babies and Children's Hospital, University Hospitals of Cleveland, and Case Western Reserve University, Cleveland, Ohio; Bayer Corp., West Haven, Connecticut; and University of Virginia Health System, Charlottesville, Virginia.

Disclosure: Bayer Corp., Pharmaceutical Division, is the manufacturer of Cipro (ciprofloxacin), a drug in one of the treatment regimens investigated in this study.

Acknowledgments: The following investigators from the named institutions contributed patients to the study: Victor Fainstein, Infectious Disease Association of Houston; Daniel Kett, University of Miami School of Medicine; Princy Kumar and Eduardo Vejas, Georgetown University Medical Center; and Alan Saven, Scripps Clinical Research Foundation.

Grant Support: By Bayer Corp., Pharmaceutical Division.

Requests for Single Reprints: Gerald R. Donowitz, MD, University of Virginia Health System, Division of Infectious Diseases, PO Box 801343, Charlottesville, VA 22908-1343.

Potential Financial Conflicts of Interest:Employment: D.C. Haverstock, S.F. Kowalsky. Consultancies: J.C. Wade. Honoraria: J.C. Wade, M.D. Reed. Grants Received or Pending: J.C. Wade, J.E. Peacock, D.A. Herrington, H.M. Lazarus, M.D. Reed, D.D. Hurd, D.A. Cushing, C.P. Harman, G.R. Donowitz.

Current Author Addresses: Drs. Peacock, Herrington, and Hurd and Ms. Sinclair: Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1042.

Dr. Wade: Fred Hutchinson Cancer Center, P.O. Box 19024, Seattle, WA 98109.

Drs. Lazarus and Reed: University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106.

Dr. Donowitz and Ms. Harman: University of Virginia Health System, P.O. Box 801343, Charlottesville, VA 22908.

Dr. Kowalsky and Mr. Haverstock: Bayer Corporation, 400 Morgan Lane, West Haven, CT 06516-4175.

Ms. Cushing: 18 Channel View Road, Cape Elizabeth, ME 04107.

Author Contributions: Conception and design: J.E. Peacock, J.C. Wade, S.F. Kowalsky, G.R. Donowitz.

Analysis and interpretation of the data: J.E. Peacock, D.A. Herrington, J.C. Wade, H.M. Lazarus, M.D. Reed, D.C. Haverstock, S.F. Kowalsky, G.R. Donowitz.

Drafting of the article: S.F. Kowalsky, C.P. Harman, G.R. Donowitz.

Critical revision of the article for important intellectual content: J.E. Peacock, D.A. Herrington, J.C. Wade, H.M. Lazarus, M.D. Reed, S.F. Kowalsky, G.R. Donowitz.

Final approval of the article: J.E. Peacock, J.C. Wade, S.F. Kowalsky, G.R. Donowitz.

Provision of study materials or patients: J.E. Peacock, D.A. Herrington, J.C. Wade, H.M. Lazarus, M.D. Reed, J.W. Sinclair, D.D. Hurd, C.P. Harman, G.R. Donowitz.

Statistical expertise: D.C. Haverstock.

Obtaining of funding: J.E. Peacock, J.C. Wade, H.M. Lazarus, G.R. Donowitz.

Administrative, technical, or logistic support: M.D. Reed, J.W. Sinclair, D.A. Cushing, C.P. Harman.

Collection and assembly of data: J.C. Wade, M.D. Reed, J.W. Sinclair, S.F. Kowalsky, D.A. Cushing, C.P. Harman, G.R. Donowitz.