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Background. Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost.
Methods. In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less.
Results. Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency.
Conclusions. In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy. (N Engl J Med 1999;341:312-8.)
From the Sektion Infektiologie und Klinische Immunologie, Medizinische Universitatsklinik und Poliklinik, Ulm, Germany (W.V.K.); the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (A.C.); the Allgemeen Ziekenhuis Middelheim, Antwerp, Belgium (R.B.); the Institut Jules Bordet, Brussels, Belgium (J.L., M.P.); and the Royal Brompton Hospital, London (H.G.). Address reprint requests to Dr. Kern at the Medizinische Universitatsklinik und Poliklinik, Sektion Infektiologie und Klinische Immunologie, D-89070 Ulm, Germany, or at winfried.kern@medizin.uni-ulm.de.
Participants in the trial are listed in the Appendix.
The participants and centers, listed according to the number of eligible patients enrolled in the trial, were as follows: Patras University Hospital, Patras, Greece (63) -- H. Bassaris and A. Skoutelis; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (40) -- G. Zanetti; Institut Jules Bordet, Brussels, Belgium (35) -- F. Crokaert; Hospital Universitario, Salamanca, Spain (27) -- D. Caballero; St. Savas Hospital, Athens, Greece (23) -- A. Efremidis; National Institute of Oncology and St. Elisabeth Hospital, Bratislava, Slovak Republic (22) -- V. Krcmery, Jr.; Evangelismos Hospital, Athens, Greece (18) -- C. Alexopoulos; Chaim Sheba Medical Center, Tel Hashomer, Israel (17) -- E. Rubinstein; Ibni Sina Hospital, Ankara, Turkey (16) -- H. Akan; Hopital Universitaire Erasme, Brussels, Belgium (11) -- J.-P. Thys; Medizinische Universitatsklinik, Ulm, Germany (10) -- W.V. Kern; Universitatsspital, Zurich, Switzerland (10) -- A. Schaffner and F. Follath; Hadassah University Hospital, Jerusalem, Israel (8) -- M. Shapiro; Zentralkrankenhaus St. Jurgenstra(beta)e, Bremen, Germany (8) -- B. Sievers; Rabin Medical Center, Petah Tikva, Israel (8) -- M. Weinberger; Allgemeen Ziekenhuis Middelheim, Antwerp, Belgium (7) -- R. de Bock; National Cancer Institute, Genoa, Italy (6) -- C. Viscoli and R. Rosso; Hacettepe University Hospital, Ankara, Turkey (5) -- M. Akova; Hopitaux Civils de Charleroi, Charleroi, Belgium (5) -- J.-C. Legrand; Centre Hospitalier Universitaire, Luxembourg, Luxembourg (4) -- R. Hemmer; Kinderspital, Zurich, Switzerland (4) -- D. Nadal; Hospital General y Universitario Vall d'Hebron, Barcelona, Spain (2) -- A. Estibalez; Hopital Avicenne, Bobigny, France (2) -- R. Lortholary and C. Larroche; Masaryk University Hospital, Brno, Czech Republic (1) -- H. Kubesova; Hospital Universitario La Fe, Valencia, Spain (1) -- M. Sanz; Study Coordinators -- W.V. Kern and A. Cometta; Data Review Committee -- R. de Bock (coordinator), A. Cometta, F. Crokaert, D. Engelhard, H. Gaya, W.V. Kern, J. Langenaeken (data manager), A. Padmos, and M. Paesmans (statistician); Advisory Board -- T. Calandra, J. Klastersky, C. Viscoli, and S.H. Zinner; Microbiology Reference Laboratory -- M. Galazzo and J. Bille; Chair -- M.P. Glauser.
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