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CHAPTER 68: Approach to Infection in Patients Receiving Cytotoxic Chemotherapy for Malignancy 615

two randomized trials upon which the practice of empirical antifungal wherein false-positive serum galactomannan tests may be expected.
therapy has been based failed to demonstrate a treatment effect with Further to this, false-positive serum tests have been reported in asso-
respect to defervescence compared to an untreated control group 273,274 ciation with administration of certain antibiotics such as piperacillin/
Most persistent fevers in the setting of severe neutropenia do not tazobactam or amoxicillin derived from cross-reacting species of mold
represent invasive fungal infections. Among severely neutropenic cancer such as Penicillium spp. 298,304-306 While this has implications for clinicians
patients, the reported proven/probable invasive fungal infection event using this test to investigate the possibility of invasive aspergillosis while
rate has been 2% to 15%. 279-281 Invasive fungal infection as the cause of coadministering drugs like piperacillin/tazobactam for the treatment of
the persistent neutropenic fever in clinical trials of empirical antifungal infection, improved manufacturing processes have largely eliminated
therapy was observed in only 3.6%. These observations notwithstand- the rate of false positivity. 307
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ing, empirical antifungal therapy has been prescribed to 22% to 69% of
patients receiving intensive cytotoxic anticancer therapy after 5 to 7 days Duration of Antibacterial Therapy: In general, the IDSA and ASCO rec-
of broad-spectrum antibacterial therapy. Such patients should undergo ommendations for duration of the antibacterial regimen encompass
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a second workup for persistent fever to investigate the possibility of the period until neutrophil recovery (absolute neutrophil count >0.5 ×
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invasive fungal infection, which includes blood cultures from vascular 10 /L for at least 2 consecutive days), all signs and symptoms of
access sites, HRCT images of the chest, 133,134 and serum galactoman- infections have resolved and the temperature has remained normal
21,129
nan (GM) studies. In 60% of persistently febrile neutropenic patients for 48 hours or more. For high-risk patients with prolonged
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with normal or nondiagnostic chest roentgenograms, the chest HRCT severe neutropenia who have defervesced and for whom no focus
demonstrates a pulmonary infiltrate. Such procedures can permit of infection appears to be ongoing, the antibiotic regimen may be
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earlier diagnosis and management of invasive mold infections involving discontinued after 2 weeks, provided the patient remains under care-
the lungs by approximately 1 week. The bronchoalveolar lavage GM ful observation. Some investigators have advocated substituting a
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test has been useful in establishing the diagnosis of invasive pulmonary fluoroquinolone-based antibacterial chemoprophylaxis regimen for
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aspergillosis in persistently febrile neutropenic cancer patients. 284,285 the systemic antibacterial regimen under these circumstances. The
Surveillance cultures for detecting potential fungal pathogens have response assessment definitions used in clinical trials of antibacterial
had some limited usefulness. Filamentous fungi in a nasopharyngeal therapy have often included a stipulation that the patient must remain
surveillance culture of a persistently febrile, neutropenic patient on afebrile for 4 to 5 days in addition to resolution of other signs and
broad-spectrum antibiotics, with new focal pulmonary infiltrates raises symptoms of infection in order for a response to be valid. While the
suspicion of Aspergillus pneumonia ; however, this does not substitute time until response to empirical antibacterial therapy varies with
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115,309
for HRCT of the chest followed by bronchoalveolar lavage for culture, the underlying causes of neutropenia, the median time to response
106,110-112,115,164,177
microscopy, and GM detection. The recovery of Candida albicans from (defervescence) for high-risk patients is 5 to 7 days
21
218,219
oropharyngeal, rectal, or urine surveillance cultures has a low positive and 2 to 4 days for low-risk patients. If the antibacterial regimen
predictive value of 10% to 15% for systematic candidiasis. The recovery is to be administered for an additional 4 to 5 days by the above crite-
of other non-albicans Candida species, particularly from multiple sites, ria, then high-risk patients and low-risk patients would be expected
has a positive predictive value of >70% for systemic infection. 287,288 In to have received a 9- to 12-day and 6- to 9-day course of antibacterial
contrast, the failure to recover Candida species in surveillance cultures therapy, respectively.
has been associated with a negative predictive value of >90% for inva-
sive disease from C albicans or C tropicalis. This experience suggests SPECIFIC INFECTION SYNDROMES IN PATIENTS
287
that clinicians cannot use surveillance cultures to predict the presence of UNDERGOING CYTOTOXIC CHEMOTHERAPY
a candidal infection (except perhaps for C tropicalis). The clinician may
be reassured, however, by negative surveillance cultures, that antifungal Infections occur at a limited number of sites in febrile neutropenic
224
therapy may not be indicated. Several prediction rules for invasive can- patients and usually involve microorganisms colonizing those sites.
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didiasis (IC) in the ICU setting have been studied. Ostrosky-Zeichner The systems commonly involved are the GI tract (oropharynx, gingiva
and colleagues observed an IC rate of 10% to 18% with the following and teeth, esophagus, gut, and perirectal tissues), respiratory system
criteria: mechanical ventilation, use of any systemic antibiotic, presence (sinuses, middle ear, nasopharynx, tracheobronchial tree, and lung
of an indwelling central venous catheter within 3 days of admission, and parenchyma), and skin (biopsy sites, vascular access sites such as indwell-
≥2 of the following: total parenteral nutrition, dialysis, major surgery, ing central venous catheter exit sites, tunnel sites, or insertion sites).
Surrogate molecular markers of yeasts and molds are showing prom- ■
pancreatitis, corticosteroid, or other immunosuppressive drug use. 289,290 OROPHARYNGEAL MUCOSAL AND ESOPHAGEAL INFECTIONS
ise in the diagnosis of invasive fungal infection. Galactomannan is a The natural history of oral mucositis is influenced by the cytotoxic
component of the cell wall of Aspergillus spp, certain dematiaceous fungi therapy–induced neutropenia, which plays a permissive role in the
97
such as Alternaria spp, and some Penicillium spp, 291-293 and has been clinical expression of acute-on-chronic periodontal infections. This
310
used to aid in the diagnosis of invasive aspergillosis. 283,294 An enzyme- process usually reaches its maximum intensity at the time of neutrophilic
linked immunosorbant serum assay that uses a rat monoclonal antibody nadir, approximately days 10 to 14. 90,92,94,95 At this time, polymicrobial
EB-A2 that targets the (1→5)-β-D-galactofuranoside side chains of infection becomes superimposed on the chemotherapy-induced mucosi-
the Aspergillus spp galactomannan has been developed for the diag- tis. This, in turn, extends the morbidity into the third and fourth weeks
295
nosis of invasive aspergillosis. The antibody may cross react with following the commencement of chemotherapy. Although oropharyngeal
296
galactomannan-like materials from other molds such as Penicillium spp, bacterial flora (viridans group streptococci, anaerobic gram-negative
Paecilomyces spp, and Alternaria spp or from foods that may become bacilli, and anaerobic gram-positive cocci) probably contribute to disease
297
exposed to molds originating from the soil during growth or harvesting in most cases of simple mucositis, fungi (eg, C albicans) play important
such as rice, pasta, cereals, vegetables, and even milk consumed by pathogenic roles in up to 60% of the oral infections among patients with
298
299
premature infants. Translocation of dietary antigens into the blood of acute leukemia. In addition, reactivated latent HSV infections of the
300
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healthy adults is well documented. The antibody also reacts with the oral cavity have been reported in 50% to 90% of seropositive patients
301
lipoteichoic acid of Bifidobacterium spp, organisms that heavily colonize undergoing remission-induction therapy or HSCT with a median onset
the gut of neonates and infants. Translocation of Bifidobacterium spp between 7 and 11 days. 312,313 Acute exacerbations of preexisting, asymp-
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has occurred in the setting of reduced integrity of the intestinal mucosal tomatic, chronic periodontitis occurred in 59% of one series of adult
barrier. The clinical setting of severe mucositis or intestinal graft- patients undergoing remission-induction therapy for acute leukemia.
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versus-host diseases with intestinal mucosal damage may be circumstances These infections typically occurred when the ANC was <0.13 × 10 /L.
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