The New England

Journal of Medicine

©Copyright, 1999, by the Massachusetts Medical Society

A DOUBLE-BLIND COMPARISON OF EMPIRICAL ORAL AND INTRAVENOUS

ANTIBIOTIC THERAPY FOR LOW-RISK FEBRILE PATIENTSWITH NEUTROPENIA DURING CANCER CHEMOTHERAPY

ALISON FREIFELD, M.D., DONNA MARCHIGIANI, R.N., THOMAS WALSH, M.D., STEPHEN CHANOCK, M.D., LINDA LEWIS, M.D., JOHN HIEMENZ, M.D., SHARON HIEMENZ, R.N., JEANNE E. HICKS, M.D., VEE GILL, PH.D., SETH M. STEINBERG, PH.D.,

AND PHILIP A. PIZZO, M.D.

ABSTRACT

BackgroundAmong patients with fever and neu-tropenia during cancer chemotherapy who have alow risk of complications, oral administration of em-pirical broad-spectrum antibiotics may be an accept-able alternative to intravenous treatment.

MethodsWe conducted a randomized, double-blind, placebo-controlled study of patients (age, 5 to74 years) who had fever and neutropenia during che-motherapy for cancer. Neutropenia was expected tobe present for no more than 10 days in these pa-tients, and they had to have no other underlying con-ditions. Patients were assigned to receive either oralciprofloxacin plus amoxicillin–clavulanate or intrave-nous ceftazidime. They were hospitalized until feverand neutropenia resolved.

ResultsA total of 116 episodes were included ineach group (84 patients in the oral-therapy groupand 79 patients in the intravenous-therapy group).The mean neutrophil counts at admission were 81per cubic millimeter and 84 per cubic millimeter, re-spectively; the mean duration of neutropenia was 3.4and 3.8 days, respectively. Treatment was successfulwithout the need for modifications in 71 percent ofepisodes in the oral-therapy group and 67 percent ofepisodes in the intravenous-therapy group (differencebetween groups, 3 percent; 95 percent confidenceinterval, ¡8 percent to 15 percent; P=0.48). Treatmentwas considered to have failed because of the needfor modifications in the regimen in 13 percent and 32percent of episodes, respectively (P<0.001) and be-cause of the patient’s inability to tolerate the regi-men in 16 percent and 1 percent of episodes, respec-tively (P<0.001). There were no deaths. The incidenceof intolerance of the oral antibiotics was 16 percent,as compared with 8 percent for placebo (P=0.07).ConclusionsIn hospitalized low-risk patients whohave fever and neutropenia during cancer chemo-therapy, empirical therapy with oral ciprofloxacinand amoxicillin–clavulanate is safe and effective.(N Engl J Med 1999;341:305-11.)

©1999, Massachusetts Medical Society.

D

URING the treatment of cancer, the ap-pearance of fever with neutropenia is thefirst manifestation of a potentially life-threatening bacterial infection.1 Prompt

hospitalization of patients with cancer who have fe-ver and neutropenia and initiation of empirical intra-venous therapy with broad-spectrum antibiotics arethe standard of care. In over half of patients so treat-ed, however, no infectious source is found.2

Studies suggest that patients with cancer who havefever and neutropenia can be stratified into low-riskand high-risk groups, primarily according to the ex-pected duration of neutropenia and the presence orabsence of other underlying conditions (e.g., hypoten-sion, pulmonary compromise, and abdominal pain).3-6Low-risk patients with fever who have had neutro-penia for no more than 7 to 10 days and who do nothave any other underlying conditions have fewermedical complications and a lower risk of death thanhigh-risk patients.6-9 Therefore, inpatient treatmentwith intravenous antibiotics may be unnecessary forlow-risk patients, and a simplified empirical regimen ofbroad-spectrum oral antibiotics may be adequate.7-9

We conducted a randomized, double-blind, place-bo-controlled comparison of standard intravenousmonotherapy with ceftazidime and an oral regimenof ciprofloxacin plus amoxicillin–clavulanate as ini-tial treatment in febrile patients with neutropeniawho were at low risk for complications. The combi-nation of ciprofloxacin and amoxicillin–clavulanateprovides coverage similar to that of ceftazidime, in-From the National Cancer Institute (A.F., D.M., T.W., S.C., L.L.,S.M.S.) and the Warren Grant Magnusen Clinical Center (J.E.H., V.G.),National Institutes of Health, Bethesda, Md.; the H. Lee Moffitt CancerCenter, University of South Florida, Tampa (J.H., S.H.); and Children’sHospital and Harvard Medical School, Boston (P.A.P.). Address reprint re-quests to Dr. Freifeld at the University of Nebraska Medical Center, Infec-tious Diseases Section, 985400 Nebraska Medical Center, Omaha, NE68198-5400.

Volume 341

Number 5·305