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614 PART 5: Infectious Disorders

Second, there may be progression of the primary infection requiring TABLE 68-5 Differential Diagnosis of Fever >72 Hours Despite Broad-
modification of the initial empirical regimen. This occurs in about 15% Spectrum Antibacterial Therapy
of neutropenic fevers and may be manifested by isolation of a pathogen-
resistant to the empiric β-lactam (the majority are coagulase-negative Fever is due to a nonbacterial process
staphylococci), progression of a clinical focus, persistent bacteremia Viral infection (HSV, CMV)
despite antibacterial therapy, or severe sepsis/septic shock 113 Fungal infection (invasive candidiasis, invasive aspergillosis, invasive non-Aspergillus
Third, patients may develop a recrudescent neutropenic fever after mold infection)
266
an initial defervescence (~15% occurrence). 112,113,267-269 Thirty percent of
these are clinically documented infections, 40% are microbiologically Noninfectious fever (blood products, drugs, etc)
documented, and 30% are unexplained. 269 Bacterial infection is resistant to the antibiotic regimen
Fourth, treatment-related toxicities may lead to discontinuation of the Second or subsequent infection has developed
initial empirical therapy. This is uncommon among the β-lactam-based
regimens (0.3%-3.2%). Discontinuance due to nephrotoxicity among Bacterial infection is not responding because of inadequate antibiotic serum/tissue levels
262
aminoglycoside-containing regimens occurs in 5.5% of cases. 208 Infection is associated with an undrained focus (eg, abscess or prosthetic material [IV catheters])
Fifth, patients may die during treatment of their neutropenic fever. CMV, cytomegalovirus; HSV, herpes simplex virus.
This is relatively rare, ranging from 3.3% for piperacillin/tazobactam
regimens to 6.1% for other β-lactam regimens. 262
Modification of the initial empirical regimen, regardless of the reason, infectious cause. The reevaluation should occur between days 3 and
is a common reason cited for failure of the initial regimen in clinical 5 and include a thorough examination to identify a focus. Cultures of
trials. One of the most common modifications has been the addition of blood (one set from each lumen of the central venous catheter and
a glycopeptide antibiotic. This occurs in 20% to 33% of cases. In one one set from a peripheral vein), urine, and other potentially infected
262
trial, glycopeptides constituted 88% of the modifications to the initial sites should be submitted. Repeat chest radiography or diagnostic
regimen. Some of these modifications have been deemed unnecessary, imaging studies such as ultrasonography or high-resolution com-
177
particularly if for persistent fever alone without clear evidence of gram- puterized tomographic (HRCT) studies may be performed when
positive infection. 21,113 Widespread vancomycin use has been linked to abnormalities suggest a specific organ as a potential site for infec-
colonization and infection by vancomycin-resistant Enterococcus spp. 270 tion. When reevaluation fails to identify the etiology of the persistent
There are a number of factors that influence treatment failure. In fever, the clinician may elect either to continue the initial empirical
one study from Athens, treatment failure occurred more often among regimen if the patient shows no clinical deterioration or to modify
21
patients with hematological malignancies that those with solid tumors the empirical regimen appropriate to the findings of the reevaluation
(30% vs 12%). Severe sepsis, a documented focus of infection, and a bac- (Table 68-6).
terium resistant to the β-lactam agent in the initial regimen have been Neutropenic patients with fever beyond 3 to 5 days of broad-spectrum
associated with treatment failures. In contrast, patients with unex- antibacterial therapy are at risk of having an infection that is outside the
264
plained neutropenic fevers are more likely to have treatment success. spectrum of activity of the initial empirical regimen. The frequency with
Time to Response and Duration of Antibacterial therapy: The expected which central venous access device–related coagulase-negative staphylo-
time to response to the initial empirical regimen varies with the coccal bloodstream infections are observed under these circumstances
underlying condition and the risk for medical complications. The have compelled some to employ a glycopeptide as the first modification
median time to defervescence for high-risk patients is 5 113,115,177,271 to to the initial empirical antibacterial regimen. 177
7 days. In contrast, the median times to response for low-risk An invasive fungal infection as the cause for the ongoing fever was
204
patients are shorter (2-3 days) 218,219 and are influenced by the timing first demonstrated by Pizzo and colleagues in 1982. 21,65,266,272,273 Such
21
of myeloid reconstitution. 28 patients are candidates for empirical antifungal therapy with ampho-
275
The IDSA recommendations for duration of the antibacterial regimen tericin B deoxycholate, 273,274 a lipid formulation of amphotericin B,
276
encompass the period until neutrophil recovery (absolute neutrophil an echinocandin, or an extended spectrum azole. 277,278 However, the
count >0.5 × 10 /L for at least 2 consecutive days), resolution of all
9
signs and symptoms of infection, and normothermia for ≥48 hours. 21,129
Treatment duration is determined by resolution of signs at site of infec- TABLE 68-6 Considerations for Regimen Modification: Day 5
tion or by the pathogen isolated, and is generally at least until myeloid
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reconstitution. For high-risk patients with prolonged severe neutrope- Progressive necrotizing mucositis/gingivitis Anaerobic coverage (metronidazole)
nia who have defervesced and for whom no focus of infection appears to Progressive ulcerating mucositis/gingivitis Antiviral therapy (acyclovir)
be ongoing, some recommend that the initial empirical regimen may be Dysphagia Antifungal (± antiviral) therapy if
discontinued after 4 to 5 days without fever and after fluoroquinolone- pseudomembranous pharyngitis
based antibacterial chemoprophylaxis has been reinstituted while the
patient remains under careful observation. Cellulitis or inflammatory changes at venous Antistaphylococcal therapy (vancomycin)
Neutropenic fever typically develops on day 12 to 15 of the chemo- access sites
therapy cycle. Defervescence following empirical therapy is expected at Interstitial pulmonary infiltrates TMP-SMX ± erythromycin
31
a median of day 2 to 3 or day 5 for low- and high-risk patients, respec- Consider bronchoalveolar lavage
tively. If the patients receive antibacterial therapy for 4 to 5 days beyond
defervescence, duration of antibacterial therapy is 6 versus 10 days for Focal pulmonary infiltrates Observe if ANC is recovering
low- versus high-risk patients. Consider lung biopsy
Empiric amphotericin B
Considerations for the Approach to Persistent or Recrudescent Fever in
the Neutropenic Cancer Patient: Fever persisting beyond 72 hours Abdominal foci Typhlitis
on broad-spectrum antibiotic therapy should be reevaluated care- Diverticulitis
fully. 65,224 Table 68-5 lists several possible explanations for this. A
nonbacterial etiology for the fever should be considered. Factors Anaerobic disease coverage
such as localized tenderness, change in sensorium, hyperventilation, Perirectal focus
hypotension, progressive renal insufficiency, and acidosis suggest an ANC, absolute neutrophil count; TMP-SMX, trimethoprim-sulfamethoxazole.

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