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10.1146/annurev.med.55.091902.103826

Annu. Rev. Med. 2004. 55:51926

doi: 10.1146/annurev.med.55.091902.103826
c 2004 by Annual Reviews. All rights reserved
Copyright
First published online as a Review in Advance on Oct. 15, 2003

MANAGEMENT OF INFECTIONS IN THE

NEUTROPENIC PATIENT

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Kenneth V.I. Rolston

Department of Infectious Diseases, Infection Control and Employee Health,
The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030;
email: krolston@mdanderson.org

Key Words risk assessment, bacterial/fungal infections, empiric therapy, infection

prevention
Abstract Neutropenic patients continue to be at increased risk for developing serious infections despite substantial advances in supportive care. Epidemiologic shifts
occur periodically and need to be detected early because they influence prophylactic,
empiric, and specific therapy strategies. Although effective in preventing bacterial and
some fungal infections, prophylaxis must be used with caution because it is associated
with the emergence of resistance. The choices for empiric therapy include combination
regimens and monotherapy. Specific choices depend on local factors (epidemiology,
susceptibility/resistance patterns, availability). Various treatment settings (hospitalbased, early discharge, outpatient) are also available, and the choice depends on the
patients risk category. Early diagnosis and treatment of many fungal and viral infections remains suboptimal. Infection control and prevention are important strategies,
especially with the emergence of multidrug-resistant organisms.

INTRODUCTION
It has been four decades since Bodey et al. first described the relationship between
neutropenia and infection (1). Although the risk of infection increases when the
absolute neutrophil count (ANC) falls below 1000/mm3, the currently accepted
definition of neutropenia is an ANC of 500/mm3 (2). The severity and duration of
neutropenia are both important and influence not only the frequency and severity
of infection but also the response to therapy and overall outcome. It has been
estimated that all patients who have severe neutropenia (<100/mm3) for 3 weeks
or more will develop a serious infection (3).
In addition to quantitative neutropenia, many patients with hematologic disorders (e.g., acute leukemias) have defects in neutrophil function as well, and
are at increased risk of infection despite adequate or even increased numbers of
neutrophils.
0066-4219/04/0218-0519$14.00

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Chemotherapy-induced neutropenia is often superimposed on other immunological deficits (impaired humoral or cell-mediated immunity) that might be present
because of the underlying malignancy. In such patients, infections associated with
those immunologic deficits must be considered in addition to infections generally
associated with neutropenia.
The spectrum of infection in neutropenic patients undergoes periodic changes,
and geographic/institutional differences are also common. Knowledge of local
epidemiology and of susceptibility/resistance patterns is vital to the appropriate
management of neutropenic patients. Standard management includes the prompt
administration of broad-spectrum, empiric antibiotic therapy after hospitalization (2).
Recent understanding of the syndrome of febrile neutropenia has made it
possible to recognize low-risk subsets among neutropenic patients, and to consider
options such as oral, outpatient therapy (4).

SPECIAL CONSIDERATIONS
Patients with neutropenia often fail to develop symptoms and signs of infection
because of a blunted inflammatory response. Only 8% of patients with severe
neutropenia who develop pneumonia produce purulent sputum compared to 84%
who are not neutropenic (5). Chest radiographs show that neutropenic patients
with pneumonia often do not develop pulmonary infiltrates; those with urinary
tract infections may not have localized symptoms such as dysuria; and some may
have meningitis without overt meningeal symptoms or signs.
Fever may be the initial and often the only sign of infection. Occasionally, an infection may develop in the absence of fever, as with organisms such as Clostridium
septicum, or if the patient is receiving corticosteroids. Approximately 50%60%
of febrile episodes in neutropenic patients never have clinical or microbiological
evidence of infection, hence the designation unexplained fever. Most of these
patients respond to antibiotic therapy, which suggests that these fevers are probably
caused by low-grade, undetected infections.
Patients with neutropenia can develop infections at unusual sites, with uncommon manifestations, and by opportunistic pathogens that seldom cause infection in
immunocompetent hosts. Typhilitis, an inflammatory process most commonly involving the caecum, occurs almost exclusively in patients with acute leukemia (6).
Perirectal infections with extensive tissue necrosis extending into the rectum also
occur predominantly in patients with acute leukemia (7). Endocarditis is a rare
infection in neutropenic patients, presumably because most of these patients are
also thrombocytopenic and fail to make the fibrin/platelet mesh that is critical
for the formation of bacterial vegetations. Infections can disseminate rapidly in
many patients with severe neutropenia, underscoring the importance of early,
broad-spectrum antibiotic therapy. However, a low-risk subset also exists, particularly among patients with solid tumors and short-lived neutropenia. Clinical and

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statistically derived risk-prediction rules have been developed in order to identify such patients (810). Finally, it is important to consider noninfectious causes
of fever such as transfusion reactions, chemotherapy or other drug-related fever,
allergic reactions, and occasionally tumor fever.

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SPECTRUM OF INFECTION
Infections that occur during the early phases of a neutropenic episode are predominantly bacterial. Fungal infections are generally seen in patients with severe and
prolonged neutropenia and in those receiving multiple courses of broad-spectrum
antibiotics. Most large cancer treatment centers have reported a predominance of
Gram-positive pathogens as a cause of bacteremia in neutropenic patients (11).
However, institutional differences do exist; many centers often encounter Gramnegative bacilli instead. Additionally, most tissue-based infections (pneumonia,
typhilis/enterocolitis, perirectal infections) and polymicrobial infections are frequently Gram-negative (12). Yeasts such as Candida spp. and Trichosporon spp.
and molds such as Aspergillus spp., the Zygomycetes, and Fusarium spp. are the
usual causes of fungal infections. Viral infections are uncommon, but herpesviruses
(HSV, VZV, CMV, HHV6) and community respiratory viruses are the most frequent pathogens. Table 1 lists the common pathogens encountered in neutropenic
patients.

EMPIRIC THERAPY
The administration of empiric, broad-spectrum antibiotic therapy is considered
the standard of care for febrile episodes in neutropenic patients (2). Several therapeutic choices are available (Table 2). Individual institutions must tailor the use
of specific agents based on local epidemiology and local susceptibility/resistance
patterns. Some experts favor combination regimens that are potentially bactericidal over single-agent regimens (monotherapy), especially in high-risk patients
with documented Gram-negative infections. However, most head-to-head clinical
trials have not demonstrated the superiority of combination therapy over monotherapy (2). Combination regimens may reduce the overall emergence of resistance,
but may be associated with increased toxicity and cost.
Combinations that do not include a glycopeptide (e.g., vancomycin) consist of
an aminoglycoside (e.g., amikacin, tobramycin, gentamicin) along with a cephalosporin (e.g., cefepime, ceftazidime), carbapenem (e.g., imipenem, meropenem),
quinolone (e.g., ciprofloxacin), or an antipseudomonal penicillin/beta-lactamase
inhibitor (e.g., piperacillin/tazobactam). When more potent Gram-positive coverage is indicated, combining vancomycin with ceftazidime, imipenem, meropenem,
or a quinolone might be indicated. Other specific Gram-positive agents (e.g., linezolid, quinupristin/dalfopristin) are not yet indicated for use in empiric regimens.

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TABLE 1 Common causes of documented

infections in neutropenic patients
Bacteria
Gram-positive
Staphylococcus spp.
Viridans streptococci
Enterococcus spp.
Corynebacterium spp.
Bacillus spp.
Gram-negative
Escherichia coli
Pseudomonas aeruginosa
Klebsiella spp.
Enterobacter spp.
Proteus spp.
Stenotrophomonas maltophilia
Fungi
Candida albicans and other Candida spp.
Trichosporon beigelli
Aspergillus fumigatus and other Aspergillus spp.
Zygomycetes
Fusarium spp.
Viruses
Herpesviruses
Respiratory syncytial virus
Influenza virus
Parainfluenza virus
Adenovirus

Based on current susceptibility patterns, cefepime, meropenem, and imipenem are

the most appropriate agents for monotherapy (13, 14).
The response rates of most empiric regimens range from 55% to 85% (2). It
is customary to treat for 7296 h before making alterations, in order to allow the
initial regimen to produce a response. These alterations depend on the clinical setting (e.g., suspected catheter-related infection, abdominal or pelvic focus, central
nervous system infection) and microbiologic data. The most common modifications are the addition of a glycopeptide, if not used initially, or the addition of
an antifungal agent. Strengthening Gram-negative or anaerobic coverage when
indicated is also commonplace. The choice of antifungal agents depends on the
use of antifungal prophylaxis and the nature of the fungal infections (yeast versus mold). In general, amphotericin B or one of its lipid preparations is used
in this setting. Newer agents such as voriconazole and caspofungin are also being evaluated for empiric antifungal therapy in persistently febrile neutropenic
patients (15).

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TABLE 2 Traditional choices for empiric therapy in febrile neutropenic patients

Combination Regimens (without glycopeptide)
Aminoglycoside

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Combination Regimens (with a glycopeptide)a

Vancomycin

+antipseudomonal penicillin
beta/lactamase inhibitor
+extended spectrum cephalosporin
+carbapenem or quinolone
+antipseudomonal penicillin
beta/lactamase inhibitor
+extended spectrum cephalosporin
+carbapenem
+quinolone or monobactam

Single-Agent Regimens (monotherapy)

Carbapenemb
Extended spectrum cephalosporin
Antipseudomonal penicillin + beta/lactamase inhibitorc
a

Linezolid and quinoprinstin/dalfopristin not recommended for empiric therapy.

Imipenem and meropenem (but not ertapenem).

May need additional clinical data.

SPECIFIC THERAPY
When a specific pathogen is isolated, therapy can be adjusted to the organism
isolated, based on local susceptibility patterns. Table 3 lists the agents used most
often, including some newer options. The isolation of a specific pathogen, especially if it is a Gram-positive organism, does not necessarily permit the use of
narrow-spectrum agents in patients with severe neutropenia (particularly those
with significant mucositis), since these patients may have occult Gram-negative
or polymicrobial infections. Our antifungal armamentarium is expanding; several
newer triazoles (voriconazole, posaconazole, ravuconazole) and echinocandins
(caspofungin, anidulafungin, micafungin) have either recently become available
or are nearing approval by the US Food and Drug Administration. Our ability to
treat most viral infections is still quite limited; new antiviral agents are needed.

LENGTH OF THERAPY
The length of therapy depends on the type of infection (bacteremia, urinary tract
infection, pneumonia, etc.), the organism isolated (S. aureus, coagulase-negative
staphylococci, P. aeruginosa, Candida spp., etc.), and the persistence of or recovery from neutropenia. Most experts continue therapy until (a) all signs and symptoms of infection have resolved, (b) the patient has been afebrile for 34 days,
(c) cultures, if initially positive, have been rendered negative, and (d) radiographic
evidence of infection, if initially present, shows signs of resolution. Some experts

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TABLE 3 Therapeutic agents for the treatment of documented

infections in febrile neutropenic patients
Antibacterial Agents
Narrow-spectrum (Gram-positive)
Nafcillin, oxacillin
Vancomycin (teicoplanin, where available)
Linezolid
Quinupristin/dalfopristin
Narrow-spectrum (Gram-negative)
Aminoglycosides
Monobactams (aztreonam)
Quinolones (ciprofloxacin)
Narrow-spectrum (anaerobic)
Metronidazole
Clindamycin
Broad-spectrum
Meropenem, imipenem
Cefepime, ceftazidime
Piperacillin/tazobactam
Moxifloxacin, gatifloxacin (additional clinical data needed)
Trimethoprim/sulfamethoxazole
Antifungal Agents
Amphotericin B (including lipid preparations)
Fluconazole, itraconazole, voriconazole
Caspofungin
Antiviral Agents
Acyclovir
Valacyclovir
cGanciclovir
Foscarnet
Cidofovir
Ribavirin

recommend continuing therapy until resolution of neutropenia (ANC 500/mm3

for 2 consecutive days) (2).

RISK ASSESSMENT AND RISK-BASED THERAPY

It has long been recognized that not all febrile neutropenic patients have the same
risk of developing serious infection-related or other complications. However, it
has only recently become possible to identify low-risk patients accurately and in
a timely manner, using clinical criteria and/or statistically derived prediction rules
(810, 16, 17). Low-risk patients can be discharged early after initial stabilization
in the hospital or can be treated for the febrile episode without any hospitalization
(8, 18, 19). Most outpatient regimens are quinolone-based (e.g., ciprofloxacin +

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amoxicillin/clavulanate or clindamycin) and can be administered orally, although

parenteral outpatient therapy is also feasible in low-risk patients who are unable to
tolerate oral therapy. An experienced team and the appropriate infrastructure are
essential for a risk-based program to be successful.

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INFECTION PREVENTION
Antibacterial prophylaxis (generally with a quinolone such as ciprofloxacin) has
been found to reduce the frequency of documented Gram-negative infections,
but it may have no impact, or occasionally may lead to an increase in Grampositive infections (20). Increased survival as a result of antibacterial prophylaxis
has not been demonstrated. The emergence of resistant organisms is a significant
drawback of chemoprophylaxis (21). Consequently, it is recommended only for
patients anticipated to have severe and prolonged neutropenia (ANC 100/mm3
for >1014 days). Antifungal prophylaxis (e.g., fluconazole/itraconazole) has been
shown to reduce the frequency of infections caused by Candida spp. (22, 23). Mold
infections are much more difficult to prevent, and effective strategies are yet to be
developed. Some of the newer antifungal agents with activity against filamentous
fungi (e.g., voriconazole, posaconazole) are being evaluated for the prevention of
fungal infections.

SUMMARY
The management of febrile neutropenic patients has evolved considerably. Although hospital-based, empiric therapy remains the standard for high-risk patients,
newer strategies such as early discharge or oral, out-patient therapy are becoming the norm for low-risk patients. The most important factors for the selection
of antimicrobial agents for empiric use are local microbiology and susceptibility/
resistance patterns. Better strategies for infection prevention are needed, particularly for fungal and viral infections. These issues will continue to challenge
clinicians caring for febrile neutropenic patients for the foreseeable future.
The Annual Review of Medicine is online at http://med.annualreviews.org

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Annual Review of Medicine

Volume 55, 2004

CONTENTS
Effect of Completed Human Genome Sequence on Development of Novel
Therapeutics for Human Disease, Christopher P. Austin
Toward Alzheimer Therapies Based on Genetic Knowledge, John Hardy

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Inherited Diseases Involving G Proteins and G Protein--Coupled

Receptors, Allen M. Spiegel, Lee S. Weinstein
The Scientific Basis for the Current Treatment of Parkinson's Disease, C.
Warren Olanow
Progress in Antisense Technology, Stanley T. Crooke
Serum Proteomics in the Early Diagnosis of Cancer, Kevin P. Rosenblatt,
Peter Bryant-Greenwood, J. Keith Killian, Arpita Mehta, David Geho,
Virginia Espina, Emanuel F. Petricoin, Lance A. Liotta
Molecular Neurobiology of Drug Addiction, Jennifer Chao, Eric J.
Nestler
Beta Cell Replacement for Type 1 Diabetes, Peter G. Stock, Jeffrey A.
Bluestone
Cochlear Implantation for the Treatment of Deafness, Benjamin J.
Copeland, Harold C. Pillsbury
Drug-Eluting Stents, T. Cooper Woods, Andrew R. Marks
New Approaches to Hemodialysis, Andreas Pierratos
Emerging Infectious Threats to the Blood Supply, Roger Y. Dodd, David
A. Leiby
Lead Poisoning, Herbert Needleman
The Impact of Minimally Invasive Surgical Techniques, Sir Ara Darzi,
Yaron Munz
Implementing a Research Agenda for Complementary and Alternative
Medicine, Jonathan D. Berman, Stephen E. Straus
Basic Advances and New Avenues in Therapy of Spinal Cord Injury,
Bruce H. Dobkin, Leif A. Havton
Clinical Management of Tuberculosis in the Context of HIV, Bouke C. de
Jong, Dennis M. Israelski, Elizabeth L. Corbett, Peter M. Small
HIV-Associated Lipodystrophy: Pathogenesis, Prognosis, Treatment, and
Controversies, Polyxeni Koutkia, Steven Grinspoon
Human Papillomavirus Vaccines and Prevention of Cervical Cancer,
Kathrin U. Jansen, Alan R. Shaw
Opportunities for Control of Meningococcal Disease in the United States,
Pratima L. Raghunathan, Scott A. Bernhardt, Nancy E. Rosenstein
Recent Advances in the Development of HIV-1 Vaccines Using
Replication-Incompetent Adenovirus Vectors, John W. Shiver, Emilio A.
Emini
Left Ventricular Diastolic Dysfunction and Diastolic Heart Failure,
William H. Gaasch, Michael R. Zile
Mechanisms of Pulmonary Fibrosis, Victor J. Thannickal, Galen B.
Toews, Eric S. White, Joseph P. Lynch III, Fernando J. Martinez
Systemic Mastocytosis, Cem Akin, Dean D. Metcalfe

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239
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319

333

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373
395
419

The erbB Family: Targets for Therapeutic Development Against Cancer

and Therapeutic Strategies Using Monoclonal Antibodies and Tyrosine
Kinase Inhibitors, Eric K. Rowinsky
Nonmyeoablative Immunotherapy for Solid Tumors, Richard W. Childs,
John Barrett
Rituximab: Expanding Role in Therapy for Lymphomas and Autoimmune
Diseases, William Rastetter, Arturo Molina, Christine A. White

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Botulinum Toxin and Other New Approaches to Migraine Therapy, Avi

Ashkenazi, Stephen D. Silberstein
Management of Infections in the Neutropenic Patient, Kenneth V.I.
Rolston

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