Introduction
A decade ago, it was inconceivable that febrile neutropenic cancer patients could be treated anywhere other than the inpatient hospital setting. This tradition of hospital-based, parenteral antibiotic therapy evolved from a series of studies describing the natural history of fever in cancer patients. Thirty years ago Bodey and colleagues demonstrated that the risk of infectious complications in cancer patients undergoing chemotherapy was directly related to the depth and duration of ensuing granulocytopenia. A particularly dramatic increase in serious infections was noted to occur at a granulocyte count of < 500 cells/mm³, rendering that count a benchmark of risk in the cancer patient population [1].
Later studies determined that neutropenic patients with potentially life-threatening bacteremias could not be readily distinguished, on the basis of presenting characteristics, from those with less significant infections (ie, urinary tract or minor viral infections) [2]. Fever alone appeared to be the most reliable indicator of a serious bacterial infection in the neutropenic patient. A substantial proportion of febrile episodes were associated with invasive bacterial infections. Withholding antibiotic therapy in febrile neutropenic patients, even for 1 or 2 days until culture results were available, was found to be a costly delay: Mortality from untreated gram-negative sepsis was approximately 80% [3].
The consequence of these early findings was that any patient presenting with fever during neutropenia was considered to be at high risk for a life-threatening infection and deserving of hospital admission for prompt delivery of empiric broad-spectrum intravenous (IV) antibiotics, procurement of appropriate microbiologic cultures, and close clinical monitoring throughout the neutropenic period, until the granulocyte count returned to 500 cells/mm³ or higher. This approach has become a standard of care, associated with survival rates > 95% for neutropenic episodes [4].
What, then, now permits us to contemplate the option of outpatient antibiotic therapy for febrile neutropenic patients? Although the economic and political forces that are driving changes in health-care delivery and reimbursement provide clear incentives to seek less expensive alternatives to inpatient care for many illnesses, it is important also to consider current care standards in a historical context. The stringent recommendations for management of febrile neutropenia were derived from observations made nearly three decades ago, primarily in patients undergoing intensive therapy for acute leukemia. These recommendations were applied broadly to all patients with fever and neutropenia, however, regardless of underlying cancer, type of chemotherapy, clinical status, or other medical conditions.
Until recently, it has been assumed that all cancer patients with neutropenia share equal risk for serious infectious complications when they become febrile. In recent years, however, there has been an evolution in the types of chemotherapeutic strategies and supportive-care approaches available for cancer patients. Moreover, there have been significant changes in the spectrum and character of infections that affect the neutropenic cancer patient. All of these changes have led to an increasing awareness that not all patients with fever and neutropenia are equal.
Changing Features of Fever and Neutropenia
Emergence of Gram-Positive Pathogens
During the 1960s and '70s, gram-negative bacteremia was a common cause of fever and infectious mortality in neutropenic cancer patients. However, the incidence of severe gram-negative infections decreased dramatically between the late 1970s and the early '80s, with gram-positive organisms becoming the most commonly isolated pathogens from preantibiotic blood cultures in most centers [5].
In a series of large studies performed by the European Organization for Research and Treatment of Cancer (EORTC) over the last decade, the proportion of bloodstream isolates from neutropenic patients that were gram-negative organisms declined progressively, from 71% in the mid-1970s to 31% in the late '80s [6-8]. In particular, Pseudomonas aeruginosa, which once accounted for the majority of gram-negative isolates and was associated with high mortality, is now a relatively rare entity. At the National Cancer Institute (NCI), for example, fewer than 10 cases of primary P aeruginosa bacteremia have been recognized during the past decade, among more than 800 episodes of fever and neutropenia.
Recent data from a number of clinical trials indicate that at least 60% of bacteremic episodes among febrile neutropenic patients are due to gram-positive organisms [8-11]. This trend may be related to the widespread use of in-dwelling central venous catheters and to fluoroquinolone prophylaxis, as the available fluoroquinolones lack reliable activity against many gram-positive species and may select for them as pathogens. Coagulase-negative staphylococci, Staphylococcus aureus, streptococci, enterococci, and even corynebacteria are among the more common organisms responsible for infection and are generally associated with a lower incidence of morbidity and mortality than gram-negative pathogens. There is ample evidence that, unlike the experience with gram-negative bacteremias, specific therapy against gram-positive pathogens (eg, vancomycin(Drug information on vancomycin)) need not be a component of the initial empiric antibiotic regimen, but rather, can be safely delayed until the return of blood culture results and identification of the organism, often a matter of 24 to 48 hours after presentation [9,12-14].
Decline in Incidence of Infections
In addition to changes in the types of infections seen, the overall incidence of documented infections has decreased, with a greater proportion of neutropenic patients having no identifiable cause of their fever (ie, fever of unknown origin). Over two-thirds of febrile neutropenic patients studied at the NCI in the past decade had fever of unknown origin, whereas in the 1970s and early '80s, between 50% to 70% of patients were noted to have documented infections [2,11].
Similar trends, although less striking, have been noted in the EORTC series of studies over a 15-year span. The importance of this observation lies in the fact that patients with fever of unknown origin generally have a less complicated course following the initiation of empiric antibiotic therapy, compared with those with a documented infection on presentation. Patients with fever of unknown origin can more frequently be sustained through neutropenia by the initial empiric regimen without changes, whereas antibiotic alterations are commonly required to contain a documented infection. In addition, mortality from febrile neutropenia is lower when no infection has been documented [6-8,15].
In summary, it appears that there is a population of cancer patients who are at relatively low risk for serious complications during febrile neutropenia. Such patients often have either no documented source of infection or have a mild, relatively easily controlled infectious process. Retrospective analyses have indicated that these patients tend to do very well, with few complications, following hospitalization and the institution of broad-spectrum, empiric IV antibiotic therapy. The ability to accurately identify low-risk patients prospectively could allow for a less intensive management approach in these patients.
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