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 .
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)
. 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% .
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 .
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.
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 .
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) 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
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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