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Empiric Antifungal Therapy for the Neutropenic Patient

Empiric Antifungal Therapy for the Neutropenic Patient

ABSTRACT: One of the major challenges facing oncologists today is invasive fungal infection. Difficult to diagnose and deadly when missed, invasive fungal infection—primarily by Candida and Aspergillus organisms—is the major infectious cause of death associated with chemotherapy-induced myelosuppression. In this review, the problem will be described and evidence-based approaches to management, including assessment for risk factors and empiric antifungal therapy, will be discussed. Finally, the future of diagnostic and therapeutic strategies for protecting the immunocompromised patient will be considered. [ONCOLOGY 15(3):351-369, 2001]


Since the inception of antineoplastic therapies, management of
chemotherapy-induced neutropenia has posed a challenge to oncologists. At one time,
neutropenic infection led to death in 25% of all cases. The introduction of safe
and effective broad-spectrum antibiotics and the validation of empiric
antibacterial therapy for neutropenic fever have sharply reduced infectious
morbidity and mortality. However, the major challenge facing oncologists today
is invasive fungal infection. Difficult to diagnose and deadly when missed,
invasive fungal infection is the major infectious cause of death associated with
chemotherapy-induced myelosuppression.

Invasive Fungal Infections
and Chemotherapy-Induced Neutropenia

The occurrence of invasive fungal infection can be viewed as a
consequence of medical progress. Prior to the advent of antineoplastic therapy,
invasive fungal infection was rarely recognized in patients with neoplastic
diseases.[1] The first reports of invasive fungal infection in cancer therapy
noted that only after the introduction of antineoplastic therapy were these
infections found in autopsied leukemia patients. In those initial reports,
leukopenia, mucosal injury, and concomitant bacterial infection were associated
with invasive fungal infection, and it was speculated that these were
contributing factors.

With the expanding use of antineoplastic therapy, invasive
fungal infection was seen more frequently in leukemic therapy as well as in the
therapy of lymphomas and solid tumors. As new strategies evolved to effectively
control serious bacterial infections during neutropenia, substantially more
patients survived to develop invasive fungal infection. Numerous reports
documented the rising frequency of invasive fungal infection during the 1960s
and 1970s.[2-4] The risk of invasive fungal infection was found to be associated
with the type of underlying disease—higher rates were reported in patients
undergoing treatment for acute leukemia, intermediate rates in patients
receiving therapy for lymphoma, and the lowest rates in patients treated for
solid tumors.[4-6]

Representative frequencies of invasive fungal infection for
various disease treatment categories are shown in Table 1. Data from studies
conducted in the 1960s and 1970s may not accurately reflect the current risk of
developing these infections because antineoplastic treatment regimens and
supportive care measures have changed dramatically. Nevertheless, the data
provide some perspective on the relative risks for invasive fungal infection in
the absence of measures to reduce these risks (in wide use today). The data give
a qualitative sense of the risk to a patient with a given disease or treatment
category, and, although rates are frequently quoted by disease, it is the
antineoplastic treatment strategy used in a given disease category that seems to
have the greatest impact on risk of invasive fungal infection.

During the 1980s, with the introduction of new antineoplastic
regimens and many of the supportive care measures in use today, the rates of
nosocomial fungal infections continued to rise in multiple patient populations,
including oncology patients.[7-9] In fact, the rate of nosocomial fungal
infections doubled in all hospitalized patients.[7]

Candida assumed the rank of the fourth most common bloodstream
pathogen, forging ahead of a number of historically important bacterial
pathogens. Some reports noted that many leukemia and bone marrow transplant
patients were found to have invasive fungal infection at autopsy, with an
alarming proportion not being documented antemortem.[10-12] Concerns grew that
invasive fungal infections were frequently underdiagnosed and that rates were
substantially higher than initially thought.

Major Fungal Pathogens

Fungi are ubiquitous in nature. Although there are more than
200,000 fungal species, fewer than 150 are known to be human pathogens. Fungi
are generally grouped by morphology as either yeasts or filamentous moulds.


Yeasts are the most frequent fungal colonizers and causes of
invasive fungal infections in humans. Relatively few yeast species cause
disease. The genus Candida is the most common, accounting for 60% to 70% of
invasive fungal infections in cancer patients. There are approximately 200
species in the genus Candida. These organisms are present on many plants, and
several species are also part of the normal flora within human and animal
gastrointestinal tracts. Most normal healthy individuals carry one or more
species, but they are only a minor constituent of the gut flora (which
is predominantly bacterial).

Historically, C albicans was the most important pathogenic

species. In recent years, however, non-albicans species represent an
increasing proportion of Candida blood isolates in oncology as well as general
hospital patient populations.[13-15] In cancer patients, approximately half of
candidal fungemias today are non-albicans species, including C tropicalis, C
glabrata, C parapsilosis, C krusei,
and several others (Table 2).

There is a propensity for certain Candida species to cause
infection in specific disease groups. C glabrata and C parapsilosis are
reported in a relatively greater proportion of patients with solid tumors and
lymphoma, whereas C tropicalis is encountered more frequently in patients
treated for leukemia and C krusei is more common in bone marrow transplant

There is also an association between certain medical practices
and specific Candida species. For example, antileukemic regimens that give rise
to greater mucosal barrier damage have been associated with C tropicalis. The
use of polyene antifungal agents is associated with C lusitania. The use of
triazole antifungal agents has been associated with C krusei and C glabrata
pathogens. The use of intravenous devices has been associated with outbreaks of
C parapsilosis, C krusei,
and C tropicalis.

Several reports have noted that the use of azole antifungal
agents has been associated with a marked shift in Candida species.[16-20] The
emergence of non-albicans species poses a challenge to clinicians, because they
may be less susceptible to antifungal agents.[14,21]


The other major group of fungal pathogens is moulds. Aspergillus
is the most common mould found in cancer patients, representing approximately
two-thirds of mould pathogens and 15% to 25% of all invasive fungal infections.
(and other moulds) are not ordinarily found in or on the human body.
Rather, they are most commonly acquired by inhalation of airborne organisms. The
most prevalent species are A fumigatus and A flavus, with A niger, A
and others being much less common.

Other Fungal Pathogens

In the last 2 decades, other formerly rare fungal organisms have
emerged as opportunistic pathogens. Among these are Fusarium spp, Acremonium

spp, Penicillium spp, dematiaceous moulds such as Pseudalleschera boydii,
spp, Alternaria spp, Paecilomyces spp, Trichosporon spp, members of
the Mucorales order, Trichophyton spp, Microsporum, and others. Descriptions of
these new human pathogens can be found in the journals Transplant Infectious
and Clinical Infectious Diseases.[21,22]

It is important to note that except for the genus Candida,
infection of humans by most fungal species occurs "accidentally," with
the human host not representing a significant reservoir of organisms. This means
that in most instances fungal infections are not contracted by person-to-person
contact, but rather acquired through exposure to a source in nature or the
hospital environment.

Recovery of such nonresident organisms in a patient suspected of
having an infection should, therefore, be of much greater concern than recovery
of organisms that are ordinarily part of the body flora (eg, Candida) and have
no clinical meaning per se. The clinical significance of fungal isolates from
mucosal or external body surfaces as potential causes of invasive infection must
be considered in the context of other factors, such as the degree of host
compromise, the integrity of host barriers, and so forth, in order to interpret
whether their presence supports a diagnosis of invasive fungal infection.


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