setting of severe or life-threatening pulmonary infections, antifungal therapy should
also be included (see Table 75-1). Modifications of therapy may also be based on
isolation of a resistant pathogen. For example, resistant gram-positive infections such
as MRSA may be treated with vancomycin, linezolid, or daptomycin, whereas
require therapy with polymyxin, colistin, or tigecycline.
Antibacterials in Patients with Neutropenia and Fever
Initial Empiric Therapy (Site Unknown)
Low Risk (Anticipated Neutropenia ≤7 Days, Clinically Stable, No Medical Comorbidities)
Candidate for oral therapy Adults: ciprofloxacin
a + amoxicillin–clavulanate (alternate clindamycin if
penicillin allergic), moxifloxacin
Requires IV therapy (see High Risk below)
High Risk (Anticipated Neutropenia >7 Days, Clinically Unstable, or Medical Comorbidities)
Piperacillin–tazobactam, antipseudomonal carbapenem,
Clinically unstable: consider addition of aminoglycoside, fluoroquinolone, or
Modifications of Initial Therapy
Low-risk patients: if IV therapy initially, consider switch to oral therapy
without clinical or microbiologic
Clinically stable: continue antibiotics
Unstable: Hospitalize (if outpatient), IV therapy (if initially treated with oral),
broaden antibacterial coverage to include anaerobes, resistant gram-negative
rods, and resistant gram-positive organisms. Consider antifungal therapy for
Candida species, or antimold therapy if previously receiving azole prophylaxis
Consider empiric antifungal therapy on days 4–7, especially if neutropenia is
expected to continue >7 days or the patient has other risk factors for fungal
Multidrug-resistant pathogen MRSA: add vancomycin, linezolid or daptomycin
VRE: add linezolid or daptomycin
carbapenemase-producing Enterobacteriaceae: polymyxin-β-colistin or
Head, Eyes, Ears, Nose, Throat
clindamycin or metronidazole or switch to antipseudomonal carbapenem
(imipenem–cilastatin or meropenem)
Consider adding antifungal or antiviral therapy for HSV
Oral vesicular lesions Add antiviral therapy for HSV
Oral thrush Add antifungal therapy (fluconazole)
Consider extended-spectrum azoles (posaconazole, voriconazole) or an
echinocandin if refractory to fluconazole
Esophagus (See antifungal therapy for oral thrush)
Consider acyclovir for HSV if laboratory or clinicalsuspicion of disease.
Assess CMV risk and (if high) consider ganciclovir or foscarnet
If suspicion of mold infection: add lipid-based formulation of amphotericin B.
Reassess antistaphylococcal activity of empiric regimen; consider vancomycin
Vancomycin for periorbital cellulitis
(i.e., piperacillin–tazobactam), consider adding metronidazole, or switch to
imipenem–cilastatin or meropenem. Assure pseudomonal coverage for
For perirectal pain: consider enterococcal coverage for infection (not
Diarrhea Add metronidazole if Clostridium difficile documented or suspected. Oral
vancomycin should be used for severe and/or complicated C. difficile
Contact isolation of rotavirus or norovirus documented
Pneumonia Add fluoroquinolone or macrolide for atypical pathogens (Mycoplasma,
Add vancomycin or linezolid. (Note: daptomycin is NOT indicated for
pneumonia due to inactivation by lung surfactant)
For patients with additional (pathogen-specific) risk factors or clinical/lab
Consider the addition of a mold-active antifungal
(seasonal) Consider oseltamivir against influenza
PCP: institute TMP–SMX or (for sulfa-allergic patients)
CMV: add ganciclovir if high risk
Consider growth factors (G-CSF, GM-CSF)
Vesicular lesions HSV, VZV treatment: acyclovir, famciclovir, or valacyclovir
Cellulitis, wound infection Consider adding vancomycin (or alternative MRSA) therapy
infection, tunnel tract infection
Remove catheter whenever possible. Add empiric vancomycin (or alternative
MRSA therapy). Adjust based on culture and susceptibility results
Central nervous system Antipseudomonal β-lactam (cefepime, ceftazidime, or meropenem) +
vancomycin. Add ampicillin if meropenem not used
Encephalitis High-dose acyclovir
Urinary tract Change based on pathogen identification and susceptibility
Bloodstream infections Gram negative: add aminoglycoside and switch to antipseudomonal
Gram positive: add vancomycin, linezolid or daptomycin
aExclude option if patient received fluoroquinolone prophylaxis.
bAll modifications should be based on clinical and microbiologic data.
activity, but has not been investigated in this patient population.
ddaptomycin excluded for pneumonia.
The duration of therapy is based on the infecting organism and site of infection
(often up to 14 days), and should continue at least until the ANC is 500/μL or greater
For patients with documented infections unresponsive to modification of therapy,
new or worsening sites of infection should be suspected. Clinical, laboratory, and
radiographic investigations should be undertaken or repeated. For hemodynamically
unstable patients, antimicrobial therapy should be broadened and the patient should
be considered for empiric antifungal therapy.
QUESTION 1: S.B. is a 55-year-old woman with chronic myelogenous leukemia. She was admitted to the
cultures remained negative. How should she be treated?
Persistent fevers may be from noninfectious sources or from untreated infection.
With the exception of consideration for antifungal therapy in some patients, those
with persistent fever who are clinically stable do not routinely require a change in
empiric therapy unless guided by clinical changes or culture results.
outpatients with persistent fever should be hospitalized and receive IV therapy.
Empiric addition of vancomycin in patients with persistent fever does not decrease
the time to fever resolution in this population
160 and should therefore be discouraged.
In contrast, persistently febrile patients who are hemodynamically unstable without a
clear source of infection should have their initial therapy modified to broaden
coverage against resistant gram-positive and gram-negative organisms, as well as
4 Patients with initial monotherapy with ceftazidime or cefepime can be
switched to vancomycin with an antipseudomonal carbapenem (such as imipenem–
cilastatin or meropenem) in combination with either an aminoglycoside, aztreonam,
4 Antifungal therapy targeting Candida species should also be
considered (see Case 75-4, Question 3).
CASE 75-4, QUESTION 2: S.B., on day 4, continues to feel “lousy” and has started to complain of
Because S.B. has new abdominal pains suggestive of enterocolitis, her antibiotic
regimen should be modified. Although cefepime provides excellent coverage against
imipenem–cilastatin or another broad-spectrum regimen with both aerobic and
anaerobic activity should be considered.
CASE 75-4, QUESTION 3: S.B.’s antibiotic regimen was changed to imipenem–cilastatin. Despite the
Early diagnosis and prompt treatment of systemic fungal diseases are critical to
patient survival. However, significant challenges exist in making an accurate and
timely diagnosis of invasive fungal infections. Therefore, patients who are
neutropenic with protracted (4–7 days) fever despite the administration of broad-
spectrum antibiotics should be considered for empiric antifungal therapy, especially
patients whose neutropenia is anticipated to exceed 7 days.
risk of mold infections (i.e., those with prolonged neutropenia, allogeneic HSCT
recipients, and/or those receiving high-dose corticosteroids) should be initiated on
antifungals after 4 days of persistent fever unless they are currently receiving
antimold prophylaxis. Considerations for earlier empiric antifungal therapy (i.e.,
days 2–4) should be made in patients with persistent fever and hemodynamic
Newer diagnostic tests (e.g., β-D-glucan tests or galactomannan assays), along
with additional diagnostic support, may allow for early preemptive therapy (i.e.,
institution of therapy based on biomarker evidence of disease prior to the
162 Such approaches may also be used to support
decisions to withhold empiric antifungal therapy. As an example, persistently febrile
patients on appropriate antibacterials who are clinically stable without clinical or
radiographic signs of fungal infection have had negative serologic assays for
invasive fungal infection and have had no recovery of fungi from any body site may
have empiric antifungal agents withheld.
Considerations about the choice of empiric antifungals should include prior or
current antifungal prophylaxis, risk of mold infections, risks of antifungal-related
toxicities, drug interactions, route of administration, clinical stability, and costs.
is difficult to compare data among clinical trials evaluating empiric antifungal
therapy in neutropenic cancer patients because of differences in trial design. Such
differences may include inclusion of low-risk patients, lack of blinding, changes in
concomitant antibacterials obscuring antifungal therapy end points, prior antifungal
prophylaxis, use of composite end points of safety and efficacy, and different
25 Although select studies have also demonstrated that empiric
antifungal therapy can decrease fungal-related deaths, overall mortality has not been
23 This is the case particularly for patients with invasive disease and
In patients requiring therapy, antifungal coverage should be directed at Candida
species. Highest-risk patients with persistent or recurrent fever after 4 to 7 days of
appropriate antibacterial therapy and anticipated to have prolonged (i.e., >10 days)
neutropenia should be considered for antimold therapy.
CASE 75-4, QUESTION 4: Should amphotericin B or acyclovir therapy be considered in S.B.?
Historically, amphotericin B deoxycholate (AmBD) was most commonly used in
this setting because of its reliable activity in vitro against most Candida and
Aspergillus species. Comparative trials have also evaluated the role of lipid-based
formulations of amphotericin B in the treatment of suspected or documented
infections in this population. Liposomal amphotericin B (LAmB),
165 and amphotericin B colloidal dispersion
reductions in nephrotoxicity compared with AmBD. In addition, LAmB is least likely
to be associated with infusion-related side effects.
164 Although there are limited data
to suggest that the continuous infusion of AmBD may also reduce nephrotoxicity,
efficacy regarding this method of administration in patients with documented
infections has not been established. Therefore, continuous infusion of AmBD cannot
be routinely recommended at this time. Considering the availability of other agents,
empiric amphotericin B products are generally reserved for patients at highest risk of
mold infections unable to receive alternative antifungals. When initiated as empiric
therapy, amphotericin B administration is often preceded by attempts to minimize
nephrotoxicity (e.g., saline loading) and premedications to minimize infusion-related
reactions. Close monitoring of tolerability, renal function, and electrolytes is
required during administration.
In stable patients at low risk of mold infections or drug-resistant Candida species
(e.g., C. krusei and some strains of C. glabrata), fluconazole may be preferable to
169,170 Patients with suspected mold infections (e.g., aspergillosis),
hemodynamic instability, or in whom an azole was used as prophylaxis should not
receive fluconazole. Although itraconazole possesses enhanced activity in vitro
against Aspergillus species and has reduced toxicity relative to amphotericin B,
issues regarding tolerability with the oral solution, erratic bioavailability with the
capsule formulation, potential for cross-resistance with other azoles, lack of a
parenteral treatment option, and considerations of alternative treatment options
generally limit its usefulness. Posaconazole possesses a broad spectrum of activity in
vitro against a variety of yeasts and molds. It is currently available in both an oral
and intravenous formulation. Voriconazole (an azole antifungal agent with increased
activity against Aspergillus and non-albicans Candida relative to fluconazole) has
been tested in this population. When compared with LAmB, voriconazole failed to
meet the pre-established criteria for noninferiority.
166 However, some believe that
voriconazole should be considered as an alternative to amphotericin B preparations
for empiric therapy in patients requiring initial empiric antifungal therapy who are at
increased risk of mold infections (owing to receipt of prior azole prophylaxis) or for
those patients suspected of having invasive candidiasis.
potential (relative to fluconazole) for drug interactions (including
immunosuppressives and chemotherapy) and adverse events (e.g., phototoxicity,
hepatotoxicity), voriconazole therapy should be monitored closely. IV use of
voriconazole is contraindicated in patients with severe renal dysfunction. In addition,
serum drug concentration monitoring for posaconazole and voriconazole may be
considered in patients with suspected malabsorption.
9 Most recently, isavuconazole
(a broad-spectrum, triazole antifungal) has been approved for both oral and IV
administration for the treatment of invasive aspergillosis and mucormycosis.
Potential advantages (relative to voriconazole) include improved oral
bioavailability, predictable pharmacokinetics, and a reduction in the potential for
drug interactions. For treatment of invasive aspergillosis, isavuconazole’s efficacy
was noninferior to that of voriconazole.
The echinocandins (e.g., caspofungin, micafungin, anidulafungin) possess in vitro
activity against Candida species (including non-albicans Candida) and Aspergillus
species. Caspofungin is at least as effective and better tolerated than LAmB as
empiric therapy in this patient population.
173 Because of their safety profile and in
vitro activity, echinocandins are often considered for patients requiring initial
empiric antifungal therapy and who are at increased risk of mold infections (owing to
receipt of prior azole prophylaxis). Caspofungin is currently FDA approved for such
use. Published experience with other echinocandins (e.g., micafungin, anidulafungin)
as empiric therapy in the febrile neutropenic patient is lacking at present.
In summary, empiric antifungal therapy is indicated for persistent (4–7 days) or
recurrent fever on appropriate antibacterials if the duration of neutropenia exceeds 7
4 Low-risk patients who are clinically stable do not routinely need antifungal
4 Persistently febrile patients who are clinically stable without computed
tomography signs of infection and have no serologic or culture results suggestive of
infection may have antifungal therapy withheld.
4 Patients receiving fluconazole
prophylaxis requiring addition of empiric antifungals should be considered for
antifungals with activity against azole-resistant Candida species and mold
In the setting in which an antimold agent was used for prophylaxis,
switching antifungal classes or conversion to IV therapy should be performed.
Empiric use of antiviral agents in the febrile neutropenic patient is not indicated
without evidence of such disease.
In contrast, clinical evidence of HSV or VZV
involving the skin or mucous membranes should be treated with antivirals (e.g.,
4 When oral therapy is used, valacyclovir is generally
favored over acyclovir because of improved oral bioavailability and need for less
frequent dosing. With the exception of patients undergoing bone marrow
174 CMV is an uncommon source of infection in the febrile neutropenic
patient. However, ganciclovir, valganciclovir, foscarnet, or less commonly cidofovir
treatment should be initiated in patients with documented CMV infections
(antigenemia, polymerase chain reaction for CMV DNA, or detection of CMV
mRNA). Because both ganciclovir and valganciclovir can cause or worsen existing
neutropenia, caution and close monitoring is warranted when these agents are
prescribed in this setting. Treatment with neuraminidase inhibitors (such as
oseltamivir or zanamivir) may be initiated empirically for influenza in the setting of
exposure or outbreaks if the patient is presenting with an influenza-like illness.
Likewise, if RSV is identified, appropriate antiviral therapy should be initiated.
CASE 75-4, QUESTION 5: S.B. became afebrile 2 days after micafungin was initiated, yet she remained
As previously discussed, the duration of neutropenia is the most important factor
affecting outcome in neutropenic cancer patients. Because of this, there has been
considerable interest in enhancing the immune system in these patients.
One of the earliest approaches used to boost the patient’s defense against infections
was the transfusion of WBCs. In the 1970s, granulocyte transfusions were used
adjunctively in patients with persistent neutropenia and documented infections who,
despite appropriate antibiotics, failed to respond after 24 to 48 hours. This approach
had limited value because of the difficulties in obtaining adequate cells for
transfusion, as well as the problems with alloimmunization and risk of infection
transmission. In addition, the questionable efficacy of WBC transfusions has
decreased the use of this strategy.
175 Therefore, granulocyte transfusions are not
routinely indicated in this population. However, patients with progressive bacterial
or fungal infections unresponsive to appropriate antimicrobial therapy may be
Because these agents have not demonstrated a consistent and significant effect on
other infection-related parameters (e.g., duration of fever, use of antibiotics, costs of
treatment), the use of CSFs as adjunctive therapy to antibiotics for febrile
neutropenic patients is controversial.
31,83–85 Patients already receiving CSFs for
primary or secondary prevention may be continued during treatment of febrile
84 Those patients administered pegfilgrastim for primary or secondary
prevention should not require subsequent doses of CSFs due to persistence of high
CSF concentrations for prolong periods.
Patients with high risks for infection-related complications not receiving CSFs for
prophylaxis may be considered for therapy.
85 Such risks include expected prolonged
(>7 days) and profound (<100 cells/μL) neutropenia in clinically unstable patients
unresponsive to initial empiric therapy, age older than 65 years, uncontrolled
malignancy, pneumonia, sepsis and multiorgan dysfunction (characteristic of sepsis
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