In the

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

linezolid or daptomycin may be used for the treatment of VRE. For multidrugresistant gram-negative pathogens, carbapenems are often used to treat ESBLproducing organisms, whereas carbapenemase-producing Enterobacteriaceae may

require therapy with polymyxin, colistin, or tigecycline.

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Table 75-1

Antibacterials in Patients with Neutropenia and Fever

a

Condition Therapy

b

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

Children: cefixime

Requires IV therapy (see High Risk below)

High Risk (Anticipated Neutropenia >7 Days, Clinically Unstable, or Medical Comorbidities)

Piperacillin–tazobactam, antipseudomonal carbapenem,

c ceftazidime, or

cefepime

Clinically unstable: consider addition of aminoglycoside, fluoroquinolone, or

vancomycin to regimen above

Modifications of Initial Therapy

Unexplained Fever

Defervescence with negative

cultures

Continue antibiotics

Low-risk patients: if IV therapy initially, consider switch to oral therapy

Persistent fever (2–4 days)

without clinical or microbiologic

evidence of infection

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

infections

If initial regimen did not include vancomycin: re-evaluate risk factors for grampositive infection, consider adding vancomycin

Documented Infection(s)

Multidrug-resistant pathogen MRSA: add vancomycin, linezolid or daptomycin

d

VRE: add linezolid or daptomycin

ESBLs:switch to a carbapenem

carbapenemase-producing Enterobacteriaceae: polymyxin-β-colistin or

tigecycline

Head, Eyes, Ears, Nose, Throat

Necrotizing ulceration If initial regimen did not include anaerobic therapy (carbapenem or βlactam/β-lactamase inhibitor; i.e., piperacillin–tazobactam), consider adding

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

Sinus tenderness, periorbital

cellulitis, nasal ulceration

If suspicion of mold infection: add lipid-based formulation of amphotericin B.

Reassess antistaphylococcal activity of empiric regimen; consider vancomycin

Vancomycin for periorbital cellulitis

Gastrointestinal Tract

Acute abdominal pain/perianal If initial regimen did not include carbapenem or β-lactam/β-lactamase inhibitor

(i.e., piperacillin–tazobactam), consider adding metronidazole, or switch to

imipenem–cilastatin or meropenem. Assure pseudomonal coverage for

perirectal infection

For perirectal pain: consider enterococcal coverage for infection (not

colonization)

Consider antifungal

Diarrhea Add metronidazole if Clostridium difficile documented or suspected. Oral

vancomycin should be used for severe and/or complicated C. difficile

infections.

Contact isolation of rotavirus or norovirus documented

Respiratory Tract

Pneumonia Add fluoroquinolone or macrolide for atypical pathogens (Mycoplasma,

Legionella).

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

evidence of infection:

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

Vascular access device

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

carbapenem

Gram positive: add vancomycin, linezolid or daptomycin

aExclude option if patient received fluoroquinolone prophylaxis.

bAll modifications should be based on clinical and microbiologic data.

cAntipseudomonal carbapenem is imipenem–cilastatin or meropenem. Doripenem provides comparable in vitro

activity, but has not been investigated in this patient population.

ddaptomycin excluded for pneumonia.

CMV, cytomegalovirus; ESBL, extended-spectrum β-lactamase; G-CSF, granulocyte colony-stimulating factor;

GM-CSF, granulocyte-macrophage colony-stimulating factor; HSV, herpes simplex virus; IV, intravenous; KPCs,

Klebsiella producing carbapenemases; MRSA, methicillin-resistant Staphylococcus aureus; PCP, Pneumocystis

jiroveci; TMP–SMX, trimethoprim–sulfamethoxazole; VRE, vancomycin-resistant enterococcus; VZV, varicellazoster virus.

Source: National Comprehensive Cancer Network. Myeloid growth factors (version 1.2015). www.nccn.org.

Accessed September 4, 2015; Freifeld A et al. Clinical practice guideline for the use of antimicrobial agents in

neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis.

2011;52:e56.

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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

and rising.

4

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.

4

No Etiology Identified

CASE 75-4

QUESTION 1: S.B. is a 55-year-old woman with chronic myelogenous leukemia. She was admitted to the

hospital with a 4-day history of fevers and night sweats. On admission, her temperature was 102.3°F, and her

WBC count was 100,000 cells/μL, with an ANC of 500 cells/μL. Blood and urine cultures were obtained, and

cefepime was empirically started. For the next 3 days, S.B. remained persistently febrile and neutropenic. All

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.

3

,

4 However,

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.

4

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

anaerobes.

3

,

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,

or ciprofloxacin.

3

,

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

abdominal pains. What is the significance of this complaint? Should her antibiotic regimen be modified again?

Because S.B. has new abdominal pains suggestive of enterocolitis, her antibiotic

regimen should be modified. Although cefepime provides excellent coverage against

the common gram-negative pathogens, it has limited activity against select grampositive pathogens (e.g., MRSA or VRE) and anaerobes. A change from cefepime to

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

change, she continues to have a low-grade fever and does not feel better. What is S.B.’s risk for having a

systemic fungal infection? What is the significance of fungal infections in neutropenic cancer patients?

ANTIFUNGAL THERAPY

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.

4

,

161 Patients at highest

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

instability.

4

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

development of symptoms).

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.

4

,

104

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.

23

It

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

endpoint criteria.

25 Although select studies have also demonstrated that empiric

antifungal therapy can decrease fungal-related deaths, overall mortality has not been

affected.

23 This is the case particularly for patients with invasive disease and

persistent neutropenia.

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.

4

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),

163–166 amphotericin

B lipid complex,

165 and amphotericin B colloidal dispersion

167 have demonstrated

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,

168

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.

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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

amphotericin B.

4

,

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.

161 Because of the increased

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.

4

,

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.

171

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.

172

,

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

days.

4 Low-risk patients who are clinically stable do not routinely need antifungal

therapy.

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

infections.

4

In the setting in which an antimold agent was used for prophylaxis,

switching antifungal classes or conversion to IV therapy should be performed.

4

ANTIVIRAL THERAPY

Empiric use of antiviral agents in the febrile neutropenic patient is not indicated

without evidence of such disease.

4

In contrast, clinical evidence of HSV or VZV

involving the skin or mucous membranes should be treated with antivirals (e.g.,

acyclovir, valacyclovir).

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

transplantation,

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.

4

Likewise, if RSV is identified, appropriate antiviral therapy should be initiated.

4

ANTIMICROBIAL ADJUVANTS

CASE 75-4, QUESTION 5: S.B. became afebrile 2 days after micafungin was initiated, yet she remained

neutropenic with an ANC of 480 cells/μL. An induction chemotherapy regimen consisting of idarubicin plus

cytarabine was initiated for her chronic myelogenous leukemia. Because the chemotherapy will further reduce

her ANC 7 to 10 days after treatment, is there any way to facilitate marrow recovery and reduce the duration

of neutropenia in S.B.?

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.

Granulocyte Transfusions

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

considered as candidates.

3

Hematopoietic Growth Factors

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.

4

,

31,83–85 Patients already receiving CSFs for

primary or secondary prevention may be continued during treatment of febrile

neutropenia.

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.

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Patients with high risks for infection-related complications not receiving CSFs for

prophylaxis may be considered for therapy.

3

,

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

syndrome), and invasive fungal infection.

84

,

85