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Empirical oral and IV antibiotics had similar effects for febrile neutropenia during chemotherapy in low-risk patients with cancer


ACP J Club. 2000 Mar-Apr;132:52. doi:10.7326/ACPJC-2000-132-2-052

Related Content in this Issue
• Companion Abstract and Commentary: Empirical oral and IV antibiotics had similar effects for febrile neutropenia during chemotherapy in low-risk patients with cancer

Source Citation

Freifeld A, Marchigiani D, Walsh T, et al. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. N Engl J Med. 1999;341:305-11. [PubMed ID: 10423464]



For low-risk hospitalized cancer patients with febrile neutropenia during cancer chemotherapy, are oral empirical broad-spectrum antibiotics (ciprofloxacin and amoxicillin-clavulanate) as safe and effective as monotherapy with intravenous (IV) ceftazidine?


Randomized (unclear allocation concealment*), blinded (patients and clinicians),* controlled trial with follow-up to resolution of neutropenia.


2 hospitals in the United States.


163 patients (mean age 42 y, range 5 to 74 y, 78% women) had 284 episodes of febrile neutropenia during cancer chemotherapy. Patients had fever with neutropenia that was expected to resolve within 10 days; were hemodynamically stable; and had no gastrointestinal, neurologic, or pulmonary complications. They had no neurologic or mental status changes; no intravascular, catheter, or catheter-tunnel infection; and no new pulmonary infitrate. Patients were able to swallow medications, had not received antibiotics other than trimethoprim–sulfamethoxazole within 72 hours, had adequate hepatic and renal function, had no allergies to study medications, and had no serious comorbid conditions. 82% of episodes were followed up.


Analysis included 84 patients who were allocated to oral ciprofloxacin, 30 mg/kg of body weight (maximum 750 mg/8 h), and amoxicillin–clavulanate, 40 mg/kg (maximum dose 500 mg/8 h), and 79 patients who were allocated to IV ceftazidime, 90 mg/kg (maximum dose 2 g/8 h). All medication was given in 3 divided doses/d until neutropenia resolved. Changes in medication were based on predefined criteria.

Main outcome measures

Successful therapy defined as survival with no change in drug regimen plus resolution of neutropenia with no evidence of active infection. Adverse events were also analyzed.

Main results

After adjustment for treatment assignment, the groups did not differ for rate of episodes of successful therapy (71% in the oral group vs 67% in the IV group, P = 0.5). More episodes were considered treatment failures in the IV group because of need for change in treatment (32% for IV vs 13% for oral, P < 0.001), and more episodes failed in the oral group because of patients’ inability to tolerate the treatment (16% for oral vs 1% for IV, P < 0.001). No deaths occurred.


Oral ciprofloxacin plus amoxicillin–clavulanate and intravenous ceftazidime were equally safe and effective for hospitalized patients with febrile neutropenia after cancer chemotherapy.

*See Glossary.

Source of funding: Not stated.

For correspondence: Dr. A. Freifeld, University of Nebraska Medical Center, Infectious Diseases Section, 985400 Nebraska Medical Center, Omaha, NE 68198-5400, USA. FAX 301-402-0172.


Febrile neutropenia is a common dose-limiting complication of cancer chemotherapy for which the standard treatment has been prompt hospitalization and institution of empirical broad-spectrum IV antibiotics. It has recently become apparent that patients with febrile neutropenia differ for risk for medical complications and death. Talcott and colleagues (1, 2) validated the identification of lower-risk outpatients with febrile neutropenia and tumors who had responded to cancer chemotherapy and had no associated medical comorbid conditions. Medical complications occurred in < 2% of patients, and no deaths occurred. The potential of identifying a lower-risk group of patients with febrile neutropenia has prompted investigators to study such alternative modes of treatment as ambulatory IV and oral therapy. Published studies have been limited by their design and small sample sizes.

The studies by Freifeld and Kern and their colleagues provide evidence that broad-spectrum oral antibiotics are safe and effective when given in a hospital setting to appropriately identified low-risk patients, such as those with solid tumors and short-lived neutropenia without associated medical comorbid conditions.

Freifeld and colleagues report the first large study comparing inpatient oral with IV therapy to use a double-blind design, thus eliminating the inherent bias toward an early change in treatment in the oral therapy group. However, 52 of 284 randomized episodes (18%) of febrile neutropenia were not followed (evenly distributed in the oral and IV groups) and were excluded from analysis for various reasons. A separate analysis that included this group was not done, and this introduces uncertainty as to whether the differences present in this group of episodes could affect the overall outcome of the study. Treatment was considered to have failed because 16% of patients in the oral antibiotic group and 1% in the IV group were unable to tolerate the regimen. The unusually high doses of ciprofloxacin (30 mg/kg up to 750 mg every 8 h) probably contributed to this intolerance.

Kern and colleagues also compared inpatient oral with IV treatment in low-risk patients with febrile neutropenia, but their study differs from the study by Freifeld and colleagues in that it was open-label, used ceftriaxone plus amikacin as the IV arm, used a more standard dose of ciprofloxacin (750 mg twice/d) in the oral arm, allowed patients to be enrolled only once, and included an intention-to-treat analysis. 19 patients (11%) in each group had absolute neutrophil counts > 500/mm3 at enrollment. In 25 of these patients, neutrophil counts remained > 500/mm3, which lowered the overall success rates in both the IV and oral groups when these patients were excluded.

Oral antibiotic treatment for febrile neutropenia offers many potential benefits related to avoiding or shortening hospitalization: improved quality of life, reduced costs, and decreased acquisition of nosocomial organisms. The studies by Freifeld and Kern and their colleagues suggest that oral antibiotics will be useful in the outpatient treatment of patients with febrile neutropenia. However, the efficacy, safety, and feasibility of outpatient oral antibiotic treatment of patients with febrile neutropenia are separate questions, which should be addressed in large, well-designed, randomized trials. Successful outpatient treatment of febrile neutropenia will involve the careful selection of low-risk patients on the basis of medical, personal, and social factors, which could not be addressed by the above studies (3).

Elizabeth Phillips, MD
University of Toronto
Toronto, Ontario, Canada


1. Talcott JA, Finberg R, Mayer RJ, Goldman L. The medical course of cancer patients with fever and neutropenia. Clinical identification of a low-risk subgroup at presentation. Arch Intern Med. 1988;148:2561-8. [PubMed ID: 3196123]

2. Talcott JA, Siegel RD, Finberg R, Goldman L. Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. J Clin Oncol. 1992;10:316-22. [PubMed ID: 1732432]

3. Uzun O, Anaissie EJ. Outpatient therapy for febrile neutropenia: who, when, and how? J Antimicrob Chemother. 1999;43:317-20. [PubMed ID: 10223585]