Ambulatory Antimicrobial Therapy for Hematologic Malignancies

Introduction

Historically, fever in neutropenic patients has been considered a medical emergency that requires hospitalization and the parenteral administration of broad-spectrum antibiotics until resolution of symptoms.[1,2] Identification of patients who are at low risk for serious sequelae (eg, sepsis, death) allows caregivers to consider ambulatory treatment, including both outpatient oral antibiotic treatment and at-home administration of intravenous antibiotics. Consequently, even though definitive evidence supporting this approach is still lacking, increasing numbers of low-risk patients with fever and neutropenia are being placed in these settings.

Potential advantages of ambulatory treatment are self-evident: lower costs, less exposure to nosocomial pathogens, and improved quality of life. Such treatment, however, requires the accurate identification of low-risk patients, an appropriate infrastructure for implementing these options, and easy access to emergency treatment should the patient’s condition deteriorate.

The purpose of this article is to review the components of evaluation and treatment that make ambulatory antimicrobial therapy feasible and successful in patients with fever and neutropenia, to review the effective use of ambulatory care in such patients, and to compare the advantages of ambulatory antimicrobial therapy with its potential risks and drawbacks.

Identifying Appropriate Patients for Outpatient Care

Over the last decade, research has made it possible to reliably identify a subset of patients in whom serious complications of infection are unlikely to occur. These low-risk patients might be appropriate for outpatient therapy. Features that delineate high-risk vs low-risk patients are not universally accepted, but several characteristics have been suggested as indicators of relative risk. These include status at the time of presentation (inpatient vs outpatient), acute medical comorbidity, control of cancer, type of underlying neoplasm, type of treatment, predicted duration of neutropenia, and presentation of infections (eg, pneumonia).

In 1988, a decision rule for stratifying patients was published, wherein the first substantial progress was made in clarifying which features were most likely to stratify for low-risk patients.[3] Relevant features for this stratification were derived from a retrospective analysis of 261 medical records obtained from 184 cancer patients with febrile neutropenia, among whom four risk groups were identified based on outcome (infection-related morbidity and mortality). Validity of this risk-assessment model was subsequently demonstrated in a prospective study of 444 patients.[4]

Groups of Patients Identified at Risk

The first of the four defined risk groups included bone marrow transplant recipients with hematologic malignancies and other patients who developed fever and neutropenia during their hospitalization. Patients in this group had the highest risk for complications, including high morbidity and mortality. The second high-risk group included outpatients with comorbid conditions, such as hypotension, altered mental status, respiratory failure, bleeding, dehydration, abdominal pain, and spinal cord compression; morbidity and mortality were high in this group as well.

The third group included outpatients with uncontrolled cancer, but without comorbidity; as in the previous two groups, serious complications and mortality were seen. This group, as well, was associated with serious complications and mortality. The fourth group was composed of clinically stable outpatients without comorbidity, most of whom had solid tumors and were receiving conventional chemotherapy. These patients—approximately 40% of those with fever and neutropenia and 60% to 70% of outpatients—reported a low rate of serious complications and no mortality.

Among the conclusions drawn from these studies were 1) a low-risk subpopulation indeed could be identified, and 2) patients in this study were at a low enough risk to study their management with a less intensive regimen than the standard inpatient, parenteral treatment. A pilot study by the same group tested this latter idea,[5] as have other investigators,[6-11] with the growing consensus that risk assessment is possible and that outpatient treatment, either completely or in the form of early discharge, is feasible.

Definition of Low-Risk Patients

Low-risk patients can be loosely defined as being clinically stable, having controlled malignancies, and presenting with no significant acute comorbidity. The term, “significant,” is, of course, a clinical judgment, but here indicates any condition suggesting clinical instability or requiring hospitalization—with or without neutropenia.[1] Another significant predictor of risk in these patients is the degree and duration of neutropenia. For instance, a study from the National Cancer Institute (NCI) revealed that 95% of patients with neutropenia lasting seven days or less responded to the initial antibiotic therapy, whereas only 32% of patients with greater than 15 days of neutropenia responded to treatment.[12] Furthermore, the overall risk of medical complications was lower for patients whose neutropenia resolved in less than seven days.

Degree of neutropenia also contributes to risk, with increasing severity correlating with increased frequency of infectious complications.[13] Because patients with solid tumors are more likely to have short-duration neutropenia, these patients may, in general, have a lower risk of complications than patients with hematologic malignancies. Some patients with leukemia in remission who are intensively treated patients may also have low-risk presentations.[1,2,14] Although the duration and degree of neutropenia may be difficult to anticipate, both may be influenced by the intensity of the patient’s previous chemotherapy and the patient’s estimated bone marrow reserve.

Although this type of underlying neoplasm is associated with risk, in part because of the intensity of chemotherapy, not all patients with hematologic malignancies belong in this high-risk category. Talcott’s original risk assessment scheme included patients with acute leukemia in remission among low-risk patients.[3] Several studies have upheld the validity of this assessment, such as those conducted by the Ambulatory and Supportive Care Oncology Research Program (ASCORP) at the M. D. Anderson Cancer Center in Houston, Texas, which included patients with controlled leukemia, as well as those with solid tumors.[4,5,14] One such study showed that while patients with solid tumors had a significantly better response rate (91%), patients with hematologic malignancies still responded well to therapy, at a rate of 60% (P = .002). Low-risk presentations, while occurring more frequently in patients with solid tumors, do occur among patients with aggressively treated hematologic malignancies.[2]

When fatal infections occur during episodes of fever and neutropenia, they usually occur in the terminal phase of disease and are due to untreatable cancer, not inadequate supportive care.[15] Therefore, many patients with controlled hematologic malignancies may qualify as low risk and may potentially become candidates for ambulatory therapy. Some experts consider such patients to be at intermediate or moderate risk.