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|Fever in Neutropenic patients
Fever and Neutropenia -- How to Use a New Treatment Strategy
The first effective treatment for patients with fever and neutropenia was the combination of an antipseudomonal penicillin, carbenicillin, and gentamicin in a strategy of early empirical therapy triggered by fever alone. (2) The studies of Pizzo and colleagues refined this approach. Small, randomized trials showed that terminating antibiotics before the resolution of neutropenia often led quickly to septic shock and that adding amphotericin B for persistent neutropenia and fever prevented fungal superinfection. (3,4) Even with these innovations, the death rates for patients with fever and neutropenia remained fearsome, and all treatment was given in the hospital.
In the 1980s, the options for antibiotic treatment improved. A large, randomized study (5) demonstrated that a single broad-spectrum drug, ceftazidime, could safely replace the standard combination of an antipseudomonal penicillin and an aminoglycoside. Despite this finding, because of their previous experience with rapidly fatal pseudomonas infections, wary clinicians were reluctant to use ceftazidime alone in patients who often were very ill from intensive chemotherapy.
However, risk-assessment studies began to refine clinicians' intuitions about
the medical instability of their patients. A retrospective study by Talcott
et al. (6) of 261 episodes of fever and neutropenia treated in the hospital
provided justification, in part, for the anxiety of clinicians. In one of
five episodes, serious, potentially life-threatening medical complications
developed, such as hypotension, respiratory failure, and altered mental status.
However, not all patients were at similarly high risk.
The ability to make distinctions about risk offered new possibilities for treatment. If fever and neutropenia do not always have the same clinical significance, then the strategy for treating them may vary according to circumstance.
This issue of the Journal includes reports on two large, prospective, randomized studies of low-risk patients (defined variously by the investigators) that expand our options for the management of fever and neutropenia in patients with cancer. (8,9) The results of these studies show that oral antibiotics may be safely substituted for intravenous antibiotics in low-risk patients with fever and neutropenia.
As reported by Kern et al., (8) the International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer conducted an open-label, randomized trial at 25 hospitals, comparing intravenous ceftriaxone plus amikacin with oral amoxicillin-clavulanate plus ciprofloxacin in patients with cancer and granulocytopenia (defined as <1000 granulocytes per cubic millimeter) that was expected to last 10 days or less. Patients were eligible if their condition was judged to be clinically stable and if they had no clinical evidence of any specific infection. Patients with allogeneic bone marrow transplants, recent treatment with antibiotics, renal failure, respiratory insufficiency, or a high probability of death within 48 hours were excluded. Most of the patients had fever that developed at home after they received treatment for solid tumors, although approximately 30 percent had hematologic cancers. All patients were hospitalized until their fevers resolved; the median duration of granulocytopenia was six to seven days. Success was defined as the resolution of fever and infection and any manifestation of infection, and the success rates were similar in the two treatment groups. In this study of 353 patients, there were six deaths from primary infection.
The trial conducted by Freifeld et al. (9) compared oral amoxicillin-clavulanate plus ciprofloxacin with intravenous ceftazidime alone in 232 episodes of neutropenia (defined as <500 neutrophils per cubic millimeter) that were projected by the patients' physicians to last no more than 10 days and that occurred in patients without important coexisting illness. The use of a double-blind design (with a dummy intravenous or oral treatment, as appropriate) eliminated any bias toward modifying therapy earlier in the oral-therapy group. In this study, as in the study by Kern et al., most of the patients had solid tumors, but the average duration of neutropenia was shorter (3.4 days in the oral-therapy group and 3.8 days in the intravenous-therapy group). The patients were hospitalized for the duration of fever and neutropenia, and there were no deaths. There were no significant differences between the treatment groups in the frequency of the need to change the antibiotic regimen or in drug-related toxic effects.
Now that these studies have provided us with more convenient, versatile antibiotic strategies for treating low-risk patients with fever and neutropenia, when should we use them? Do these studies of oral therapy justify our using outpatient treatment? The authors of both of these rigorous, careful studies, which were designed to assess the relative efficacy of antibiotic regimens given to inpatients, caution that they do not. We agree. Although clinical experience with the treatment of patients with fever and neutropenia on an outpatient basis has grown in the past decade, (10,11) this approach has yet to be validated in large, randomized studies designed to assess this critical question: Is outpatient treatment of fever and neutropenia, away from the watchful eyes and readily available emergency equipment of the hospital, as safe as inpatient treatment, or at least safe enough?
In the largest study conducted to date, Malik and colleagues (12) examined 169 episodes of fever and neutropenia and found that inpatients and outpatients treated with ofloxacin alone were equally likely to have their fever and neutropenia resolve without requiring a change in their antibiotic regimen. Although this finding indicates that identical regimens have equal efficacy in inpatients and outpatients, it says little about the safety of outpatient treatment. Three patients in the outpatient group died; at least one of these deaths was apparently preventable. In comparison, two patients in the inpatient group died. The power of this study to find a 100 percent increase in mortality in the outpatient group (from 2 percent to 4 percent) was only 8 percent, which is evidence of the difficulty of designing trials with serious but uncommon end points that are of a practical size. Was the additional death in the outpatient group a fluke that could be averted by better surveillance of outpatients in the future? Or was it a signal that outpatient care is inherently less safe and could be shown to be so if measured by more sensitive indicators? What clinical outcomes will we accept as evidence of the safety of an innovation designed primarily to reduce costs? The answer is not yet clear.
The two studies in this issue of the Journal provide data about convenient new ways of treating fever and neutropenia in patients with cancer. But the challenge remains how to use these new approaches most appropriately. Given the ever-increasing pressure to reduce costs, there is every reason for some to cheer the decreasing lengths of hospital stays and to bank on the savings possible through greater outpatient treatment.
But in making treatment decisions, we should remain clear about what we know and what we do not. That oral antibiotics will have an increasing role in the empirical treatment of fever and neutropenia is something we know. That we can, with confidence, identify and safely treat some of the patients with this condition on an outpatient basis is something we do not know.
Robert W. Finberg, M.D., James A. Talcott, M.D. - Harvard Medical School , Boston, MA 02115
The New England Journal of Medicine -- July 29, 1999 -- Vol. 341, No. 5
A Double-Blind Comparison of Empirical Oral and Intravenous Antibiotic Therapy for Low-Risk Febrile Patients With Neutropenia during Cancer Chemotherapy
Alison Freifeld, Donna Marchigiani, Thomas Walsh, Stephen Chanock, Linda Lewis, John Hiemenz, Sharon Hiemenz, Jeanne E. Hicks, Vee Gill, Seth M. Steinberg, Philip A. Pizzo
The New England Journal of Medicine -- July 29, 1999 -- Vol. 341, No. 5
Oral versus Intravenous Empirical Antimicrobial Therapy for Fever in Patients with Granulocytopenia Who Are Receiving Cancer Chemotherapy
Winfried V. Kern, Alain Cometta, Robrecht de Bock, John Langenaeken, Marianne Paesmans, Harold Gaya, Giorgio Zanetti, Thierry Calandra, Michel P. Glauser, Francoise Crokaert, Jean Klastersky, Athanasios Skoutelis, Harry Bassaris, Stephen H. Zinner, Claudio Viscoli, Dan Engelhard, Andrew Padmos, for the International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer