Oral Therapy for Febrile, Neutropenic Patients
Abstracts & Commentary
Sources: Freifeld A, 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;341:305-311; Kern WV, et al. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. N Engl J Med 1999;341:312-318.
Freifeld and colleagues conducted a randomized, double-blind, placebo-controlled trial comparing oral ciprofloxacin (750 mg q8h) and amoxicillin/clavulanate (500 mg q8h) with intravenous ceftazidime (2 g q8h) for the empiric treatment of febrile neutropenic cancer patients. All patients were hospitalized during the period of fever and neutropenia. Neutropenia was expected to last for no more than 10 days, and patients were free of serious other medical conditions, abdominal symptoms, signs of catheter-related infection, and new pulmonary infiltrates. Criteria for changes in the initial regimen were prospectively defined. Empirical therapy was considered successful if the patients survived the episode of fever and neutropenia without modification of the regimen or evidence of active infection at resolution.
There were a total of 116 episodes in each treatment group. Infection was documented in approximately one-third of episodes; most were soft tissue or mucosal infections. There were five bacteremias in the oral therapy group and 12 in the intravenous therapy group. Treatment efficacy was similar in both groups (71% in the oral therapy group, 67% in the intravenous therapy group). Failure in the intravenous therapy group was more likely to have been due to the need to add anti-infective agents (32%) than in the oral therapy group (13%). Failure in the oral therapy group was more likely to be due to intolerance of the regimen (16%). Fever resolved by day 5 in 90% of all episodes. There were no deaths.
In a similar, but unblinded study, Kern and colleagues randomized patients to receive either oral ciprofloxacin (750 mg q12h) plus amoxicillin/clavulanate (625 mg q8h) or ceftriaxone (2 g daily) plus amikacin (20 mg/kg daily). The anticipated duration of neutropenia was 10 days or less, and patients with serious complicating illness or evidence of catheter infection were excluded. Patients were hospitalized for the duration of the fever. Successful empiric therapy required resolution of therapy for three consecutive days, resolution of signs of infection if present on entry, eradication of the original pathogen, and lack of recurrence for one week after the end of therapy. The success rate of evaluable patients assigned to oral therapy was 86% (138/161); the success rate of patients receiving intravenous therapy was 84% (127/151). Twelve percent of the patients were bacteremic. There were six deaths due to infection, two in the oral therapy group and four in the intravenous therapy group. Rates of secondary infection and adverse events were similar in the two treatment groups. Patients in the oral therapy group had a high rate of gastrointestinal symptoms (26%), while only patients receiving IV therapy experienced nephrotoxicity (4%) or catheter-related complications (11%).
Comment by Robert muder, md
The current standard of treatment for cancer patients with fever and neutropenia consists of administration of broad-spectrum intravenous antibiotic therapy.1 However, previous studies have indicated that certain febrile, neutropenic cancer patients are at relatively low risk for serious complications.2 These include ambulatory patients who are free of serious comorbid illness or uncontrolled malignancy. Preliminary trials have indicated that these patients might be successfully managed with oral therapy. These two recent randomized trials confirm that empiric oral therapy is as safe and effective as standard, broad spectrum intravenous therapy. Although the two studies used somewhat different study designs and drug regimens, the patient populations studied and the results were quite similar.
Several important cautions are in order, however. The patients in both trials were carefully selected for limited, anticipated duration of neutropenia, and for the absence of complicating medical conditions. Further, patients were hospitalized until resolution of fever in one trial, and resolution of fever and neutropenia in the other. Patients could be carefully monitored for signs of clinical deterioration or drug toxicity, and appropriate changes in regimen or institution of supportive care could be undertaken. Because oral therapy is less expensive than intravenous therapy, and because oral therapy can be given as an outpatient, one can easily envision pressure by insurers or HMOs to treat low-risk episodes of febrile neutropenia on a purely outpatient basis. This would be premature, and potentially unsafe. In the study of Freifeld et al, for example, 4% of patients suffered a serious adverse event such as hypotension or cecitis. All survived; however, any delay in recognition or treatment might well have been disastrous.
It may be that certain febrile neutropenic patients can, with appropriate careful monitoring, be managed with oral therapy on an outpatient basis. Identification of appropriate patients and regimens will require additional well-designed trials. Until these are completed, I agree with the authors of the accompanying editorial3 that management of episodes of febrile neutropenia should occur in the inpatient setting.
References
1. Hughes WT, et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 1997;25:551-573.
2. Talcott JA, et al. The medical course of cancer patients with fever and neutropenia. Arch Intern Med 1988; 148:2561-2568.
3. Finberg RW, Talcott JA. Fever and neutropenia—How to use a new treatment strategy. N Engl J Med 1999; 341:362-363.