730 • CID 2002:34 (15 March) • Hughes et al.
I D S A G U I D E L I N E S
2002 Guidelines for the Use of Antimicrobial
Agents in Neutropenic Patients with Cancer
Walter T. Hughes,1Donald Armstrong,2Gerald P. Bodey,3Eric J. Bow,7Arthur E. Brown,2Thierry Calandra,9
Ronald Feld,8Philip A. Pizzo,4,5Kenneth V. I. Rolston,3Jerry L. Shenep,1and Lowell S. Young6
1St. Jude Children’s Research Hospital, Memphis, Tennessee;
M. D. Anderson Cancer Center, Houston;
2Memorial Sloan-Kettering Cancer Center, New York, New York;
4Harvard Medical School, Boston, Massachusetts;
6Kuzell Institute for Arthritis, San Francisco, California;
9Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
3University of Texas
5Stanford University School of Medicine, Palo Alto,
8Princess Margaret Hospital, Toronto, Canada;
7University of Manitoba, Winnipeg, and
This article, prepared by the Infectious DiseasesSociety
of America (IDSA) Fever and Neutropenia Guidelines
Panel, updates guidelines established a decade ago by
the Infectious Disease Society of America for the use
of antimicrobial agents to treat neutropenic patients
with unexplained fever .
Fever is defined as a single oral temperatureof?38.3?C
(101?F) or a temperature of ?38.0?C (100.4?F) for ?1
h. Neutropenia is defined as a neutrophil count of !500
cells/mm3, or a count of !1000 cells/mm3with a pre-
dicted decrease to !500 cells/mm3.
Determine whether the patient is at low risk for com-
plications; determine whether vancomycin therapy is
Initial Antibiotic Therapy
acin plus amoxicillin-clavulanate.
Monotherapy with vancomycin not indicated.
For low-risk adults only; use ciproflox-
Received 7 December 2001; electronically published 13 February 2002.
These guidelines were developed and issued on behalf of the Infectious
Diseases Society of America.
Reprints or correspondence: Dr. Walter T. Hughes, St. Jude Children’s Research
Hospital, 332 North Lauderdale St., Memphis, TN 38105 (walter.hughes@
Clinical Infectious Diseases2002;34:730–51
? 2002 by the Infectious Diseases Society of America. All rights reserved.
Choose therapy with 1 of the followingagents:cefepime
or ceftazidime, or imipenem or meropenem.
Two drugs without vancomycin.
noglycoside plus antipseudomonal penicillin, cepha-
losporin (cefepime or ceftazidime), or carbapenem.
Vancomycin plus 1 or 2 antibiotics, if criteria for
use of vancomycin are met.
tazidime plus vancomycin, with or without an amino-
an aminoglycoside; or antipseudomonal penicillin plus
an aminoglycoside and vancomycin.
Choose an ami-
Choose cefepime or cef-
Modification of Therapy during the First Week
Patient becomes afebrile in 3–5 days.
agent is identified, adjust therapy to the most appro-
priate drug(s). If no etiologic agent is identified and if
the patient is at low risk initially, and oral antibiotic
treatment was begun with no subsequent complica-
tions, continue use of the same drugs. If the patient
was at low risk initially and therapy with intravenous
drugs was begun with no subsequent complications,
the regimen may be changed after 48 h to oral cipro-
floxacin plus amoxicillin-clavulanate for adults or ce-
fixime for children. If the patient is at high risk initially
with no subsequent complications, continue use of the
same intravenous drugs.
Persistent fever throughout the first 3–5 days. Reas-
sess therapy on day 3. If there is no clinical worsening,
continue use of the same antibiotics; stop vancomycin
use if cultures do not yield organisms. If there is pro-
gressive disease, change antibiotics. If the patient is feb-
rile after 5 days, consider adding an antifungal drug,
with or without a change in antibiotic regimen.
If an etiologic
Guidelines for Febrile Neutropenic Patients • CID 2002:34 (15 March) • 731
Duration of Antibiotic Therapy
Patient is afebrile by day 3.
is ?500 cells/mm3for 2 consecutive days, if there is no definite
site of infection, and if cultures do not yield positive results,
stop antibiotic therapy when the patient is afebrile for ?48 h.
If the patient’s neutrophil count is !500 cells/mm3by day 7,
if the patient was initially at low risk, and if there are no
subsequent complications, stop therapy when the patient is
afebrile for 5–7 days. If the patient was initially at high risk
and there are no subsequent complications, continueantibiotic
Persistent fever on day 3.
If the patient’s neutrophilcount
is ?500 cells/mm3, stop antibiotic therapy 4–5 days after the
neutrophil count is ?500 cells/mm3. If the patient’s neutrophil
count is !500 cells/mm3, reassess and continue antibiotic ther-
apy for 2 more weeks; reassess and consider stopping therapy
if no disease site is found.
If the patient’s neutrophilcount
Use of Antiviral Drugs
Antiviral drugs are not recommended for routine use unless
clinical or laboratory evidence of viral infection is evident.
Granulocyte transfusions are not recommendedforroutineuse.
Use of Colony-Stimulating Factors
Use of colony-stimulating factors is not routine but should be
considered in certain cases with predicted worsening of course.
Antibiotic Prophylaxis for Afebrile Neutropenic Patients
Use of antibiotic prophylaxis is not routinebecauseofemerging
antibiotic resistance, except for the use of trimethoprim-sul-
famethoxazole to prevent Pneumocystis carinii pneumonitis.
Antifungal prophylaxis with fluconazole and antiviral prophy-
laxis with acyclovir or ganciclovir are warranted for patients
undergoing allogenic hematopoietic stem cell transplantation.
This article, prepared by the IDSA Fever and Neutropenia
Guidelines Panel, updates guidelines established a decade ago
and revised in 1997  by the IDSA for the use of antimicrobial
agents to treat neutropenic patients withunexplainedfever.The
purpose is to assist internists, pediatricians, and family prac-
titioners in the treatment of febrile neutropenic patients who
have cancer and other underlying myelosuppressive diseases.
The guidelines were prepared by a panel of experts in oncology
and infectious diseases, peer-reviewed by an external group of
knowledgeable practitioners, reviewed and approved by the
Practice Guidelines Committee, and approved as published by
It is important to note that the guidelines are general and
must be applied wisely with respect to variations in individual
patients and types of infections, settings in which patients are
being treated, antimicrobial susceptibility patterns, underlying
causes of neutropenia, and expected time to recovery. The rec-
ommendations are based, whenever possible, on scientific
publications and peer-reviewed information that has been for-
mally presented at national and international meetings. When
firm recommendations cannot be made, usually because of in-
adequate scientific data, the Guidelines Panel of the IDSA has
offered suggestions based on the consensus of its members, all
of whom have extensive experience in the treatment of neutro-
from knowledge of and experience with hematopoietic and lym-
phoproliferative malignancies, but they can be applied in general
to febrile neutropenic patients with other neoplastic diseases.
Attempts have been made to estimate the validity of a partic-
ular recommendation or statement by use of the weighting sys-
tem described in the 1997 guidelines (table 1) . A ranking of
A–E indicates the strength of this recommendation, and the Ro-
man numerals I–III indicate the quality of evidence These rank-
ings are presentedinparenthesesafterspecificrecommendations.
We emphasize that no specific scheme, no specific drug or
combination of drugs, and no specific period of treatment can
be unequivocally applied to all febrile neutropenic patients.
When possible, it is advisable to involve an infectious diseases
specialist who is knowledgeable and interested in infections of
the immunocompromised host.
Most of the information and recommendations made in the
23-page 1997 guidelines  are still valid. In an attempt to
make the new guidelines more user-friendly, some of the back-
ground information and references from the 1997 version have
of drug-related allergies and other adverse effects from drugs
because of limited data specific for neutropenic patients. The
general principles of practice for nonneutropenic patients are
also reasonable for neutropenic patients.
OF THE NEUTROPENIC HOST
At least one-half of neutropenic patients who become febrile
have an established or occult infection, and at least one-fifth
of patients with neutrophil counts of !100 cells/mm3have bac-
teremia. The organisms that cause bacteremia are listed in table
2. Fungi are common causes of secondary infection among
neutropenic patients who have received courses of broad-spec-
trum antibiotics and may also cause primary infections.
The primary anatomic sites of infection often include the
alimentary tract, where cancer chemotherapy–inducedmucosal
damage allows invasion of opportunistic organisms. Similarly,
732 • CID 2002:34 (15 March) • Hughes et al.
System for ranking recommendations in clinical guidelines.
Infectious Diseases Society of America–United States Public Health Service Grading
Strength of recommendation
Quality of evidence
Good evidence to support a recommendation for use
Moderate evidence to support a recommendation for use
Poor evidence to support a recommendation
Moderate evidence to support a recommendation against use
Good evidence to support a recommendation against use
Evidence from ?1 properly randomized, controlled trial
Evidence from ?1 well-designed clinical trial, without randomiza-
tion; from cohort or case-controlled analytic studies (preferably
from 11 center); from multiple time-series; or from dramatic
results from uncontrolled experiments
Evidence from opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert committees
damage to the integument by invasive procedures, such as
placement of vascular access devices, often provides portals of
entry for infectious organisms.
constitutes a febrile state. In practice, a single oral temperature
measurement of ?38.3?C (101?F), in the absence of obvious
environmental causes, is usually considered to be a fever. A
temperature of ?38.0?C (100.4?F) for ?1 h indicates a febrile
When the neutrophil count decreases to
!1000 cells/mm3, increased susceptibility to infection can be ex-
pected, with the frequency and severity inversely proportionalto
the neutrophil count [2–4]. Patients with neutrophil counts of
!500 cells/mm3are at considerably greater risk for infectionthan
are those with counts of !1000 cells/mm3, and patients with
counts of ?100 cells/mm3are at greater risk than are those with
counts of !500 cells/mm3. In addition to the number of circu-
lating neutrophils, the duration of neutropenia is an important
determinant of infection. A low nadir in the neutrophil count
and protracted neutropenia (i.e., neutrophil count of !500 cells/
mm3for 10 days) are major risk factors for impending infection
[2, 5]. In addition to quantitative changes in neutrophil counts,
abnormalities of phagocytic function or other deficits in the im-
mune response may further increase the risk for infection in a
A temperature that is clearly greater than the normal
in the severely neutropenic patient, especially if accompanied
by anemia . Diminished or absent induration,erythema,and
pustulation in response to bacterial infection leave the patient
with a cutaneous infection without typical cellulitis, a pul-
monary infection without discernible infiltrateonaradiograph,
meningitis without pleocytosis in the CSF, and a urinary tract
infection without pyuria. Nevertheless, a search should be un-
dertaken for subtle symptoms and signs, including pain at the
sites that are most commonly infected. These sites are the peri-
odontium; the pharynx; the lower esophagus; the lung; the
perineum, including the anus; the eye (fundus); and the skin,
including bone marrow aspiration sites, vascularcatheteraccess
sites, and tissue around the nails.
Specimens should be obtained immediately for culture for
bacteria and fungi. If a central venous access device is in place,
some authorities, including the new “IDSA Guidelines for the
Management of Intravascular Catheter–RelatedInfections”,
recommend that ?1 set of blood samples be obtained for cul-
ture from the device lumen(s) as well as from a peripheralvein.
Other investigators believe that culture only of a blood sample
obtained from a central venous catheter is adequate [8, 9].
Quantitative blood cultures, although not necessarily recom-
mended routinely for all patients, may be helpful for those
suspected of having acatheter-relatedinfection,forwhomspec-
imens obtained from a central venous catheter and a peripheral
vein should be compared [7, 10]. High-grade bacteremia(1500
cfu/mL) is associated with greatermorbidityandmortalityrates
than is lower-grade bacteremia . The yield of bacterial and
fungal isolates is related to the culture systems used  and
the volume of the blood sample . Microbiology diagnostic
laboratories must stay abreast of new technological develop-
ments related to the causative organisms unique to the neu-
tropenic host. If a catheter entry site is inflamed or draining,
the fluid exuded should be examined by Gram staining and
culture for bacteria and fungi. If such lesions are persistent or
Guidelines for Febrile Neutropenic Patients • CID 2002:34 (15 March) • 733
chronic, stains and cultures for nontuberculous mycobacteria
should be performed .
Little clinically useful information is gained fromperforming
routine cultures of samples from the anterior nares, orophar-
ynx, urine, and rectum, when lesions or disease processes are
absent. However, for infection-control purposes, culture of an-
terior nasal samples can reveal colonization with methicillin-
resistant Staphylococcus aureus, penicillin-resistant pneumo-
cocci, or Aspergillus species, and culture of rectal samples can
yield Pseudomonas aeruginosa, multidrug-resistant, gram-neg-
ative bacilli, or vancomycin-resistant enterococci. Such results
may be useful collectively for infection control. Candida tro-
picalis in surveillance cultures has been associated with an in-
creased risk for subsequent infection due to this fungus .
Diarrhea believed to be of infectious etiology should be eval-
uated according the “IDSA Practice Guidelines for the Man-
agement of Infectious Diarrhea” . Culture of urine samples
is indicated if signs or symptoms of urinarytractinfectionexist,
a urinary catheter is in place, or the findings of urinalysis are
abnormal. Examination of CSF specimens is not recommended
as a routine procedure but should be considered if a CNS
infection is suspected and thrombocytopenia is absent or man-
ageable. Chest radiographs should be obtained whenever signs
or symptoms of respiratory tract abnormalityarepresent.Some
experts recommend chest radiography for persons who are to
be treated as outpatients, even without evidence of pulmonary
infection. A baseline radiograph is helpful for neutropenic pa-
tients who subsequently develop respiratory symptoms or ev-
idence of an infiltrate, but it is not cost-effective on a routine
basis. Of note, high-resolution CT will reveal evidence of pneu-
monia in more than one-half of febrile neutropenic patients
with normal findings on chest radiographs . Aspiration or
biopsy of skin lesions suspected of being infected should be
performed for cytologic testing, Gram staining, and culture
Complete blood cell counts and determination of the levels
of serum creatinine and urea nitrogen are needed to plan sup-
portive care and to monitor for the possible occurrence of drug
toxicity. These tests should be done at least every 3 days during
the course of intensive antibiotic therapy. The use of some
drugs, such as amphotericin B, will require more frequentmea-
suring of creatinine as well as electrolyte levels. Monitoring of
serum transaminase levels is advisable for patients with com-
plicated courses or suspected hepatocellular injury. Levels of
be affected by bacteremia in neutropenic patients with fever
[19–22] but the association is not sufficiently consistent to
warrant their use in clinical practice.
Recommendations for evaluation.
should consist of a thorough physical examination; a complete
blood cell count; measurement of serum levels of creatinine,
urea nitrogen, and transaminases; and culture of bloodsamples
(obtained from a peripheral vein and/or a catheter). A chest
radiograph is indicated for patients with respiratory signs or
symptoms or if outpatient management is planned (B-III).
INITIAL ANTIBIOTIC THERAPY
Because the progression of infection in neutropenic patients
can be rapid, and because such patients with early bacterial
infections cannot be reliably distinguished from noninfected
patients at presentation, empirical antibiotic therapy should be
administered promptly to all neutropenic patients at the onset
of fever (figure 1). Afebrile patients who are neutropenic but
who have signs or symptoms compatible with an infection
should also have empirical antibiotic therapy beguninthesame
manner as do febrile patients.
of microbiologically documented infections, although the rate
of gram-negative infections is increasing in some centers.Some
of the gram-positive organisms may be methicillin resistant
and, therefore, are susceptible only to vancomycin, teicoplanin
(which is not currently available in the United States), quinu-
pristin-dalfopristin, and linezolid. These are often more in-
dolent infections (e.g., infections due to coagulase-negative
staphylococci, vancomycin-resistant enterococci, or Coryne-
bacterium jeikeium), and a few days’ delay in administration of
specific therapy may not be detrimental to the patient’s out-
come, although it may prolong the duration of hospitalization.
Other gram-positive bacteria (S. aureus, viridans streptococci,
and pneumococci) may cause fulminant infections resulting in
serious complications or death, if not treated promptly [23,
24]. Gram-negative bacilli, especially P. aeruginosa, Escherichia
coli, and Klebsiella species (table 2), remain prominent causes
of infection and must be treated with selected antibiotics
[25–29]. Although fungal infections areusuallysuperinfections,
in some cases, Candida species or otherfungicancauseprimary
In the selection of the initial antibiotic regimen, one should
consider the type, frequency of occurrence, and antibiotic
susceptibility of bacterial isolates recovered from other pa-
tients at the same hospital. The use of certain antibiotics may
be limited by special circumstances, such as drug allergy or
organ (e.g., renal or hepatic) dysfunction. Such drugs as cis-
platin, amphotericin B, cyclosporine, vancomycin, and ami-
noglycosides should be avoided in combination, if possible,
because of their additive renal toxicity . Drug plasma
concentrations should be monitored when they are helpful in
predicting therapeutic success and toxicity (e.g., aminogly-
Vascular access devices (e.g., Hickman-Broviac catheters or
subcutaneous ports) may be left in placeduringantibiotictreat-
734 • CID 2002:34 (15 March) • Hughes et al.
Bacterial causes of febrile episodes in neutropenic
Gram-positive cocci and bacilli
Coagulase-positive (Staphylococcus aureus)
Coagulase negative (Staphylococcus epidermidis and others)
Gram-negative bacilli and cocci
Pseudomonas species (other than P . aeruginosa)
Table 2. (Continued.)
Anaerobic cocci and bacilli
aThe most common causes of bacteremia.
ment for most patients, even if infection of a local entry site
or catheter-related bacteremia is detected (A-II). S. aureus and
coagulase-negative staphylococci are the most common causes
of catheter-associated infections [31, 32], and these often re-
spond to treatment with parenteral antibiotics withoutremoval
of the catheter, unless a tunnel infectionhasbecomeestablished
(B-II) . Response to antibiotic therapy alone is most likely
and complications are least likely with coagulase-negative
staphylococcal catheter-related infections, but catheter removal
may be required for cure, regardless of the etiology, if the in-
fection is recurrent or response to antibiotics is not apparent
after 2 or 3 days of therapy. Evidence of a subcutaneous tunnel
or periport infection, septic emboli, hypotension associated
with catheter use, or a nonpatent catheter are indications for
removal, along with prompt administration of antibiotics (A-
II). Catheter removal combined with generous debridement of
infected tissue is also advisable for patients with atypical my-
cobacterial infection (A-II) . Bacteremia due to Bacillus spe-
cies, P. aeruginosa, Stenotrophomonas maltophilia, C. jeikeium, or
vancomycin-resistant enterococci, and fungemia due to Candida
species , often respond poorly to antimicrobialtreatment,and
prompt removal of the catheter is recommended, if possible (C-
III). Established infections with Acinetobacter species also often
require removal of the infected catheter.
The use of antibiotic-impregnated catheters, administration
of antibiotics through each lumen of the involved catheter,
rotation of antibiotic delivery through multilumen catheters,
and the use antibiotic-containing heparin lock solutions(“anti-
biotic lock therapy”) to supplement systemic therapyhavebeen
proposed by some investigators. Such practices are controver-
sial, and none can be recommended as a standard of practice
for all patients. For selected application, the reader is referred
to the 2001 guidelines for the management of intravascular
catheter–related infections, which were developed jointly by
Guidelines for Febrile Neutropenic Patients • CID 2002:34 (15 March) • 735
imipenem or meropenem.
Algorithm for initial management of febrile neutropenic patients. See tables 3 and 4 for rating system for patients at low risk.Carbapenem,
IDSA, the American College of Critical Care Medicine, and the
Society for Healthcare Epidemiology of America . Vanco-
mycin should not routinely be used prophylactically in cath-
eters. Insufficient data are available to recommend the routine
supplemental use of urokinase for management of catheter-
Despite extensive clinical studies since the 1970s, no single
empirical therapeutic regimen for the initialtreatmentoffebrile
patients with neutropenia can be recommended. The results
from study to study are often not comparable, because the
definitions of infectious diseases and the criteria used to assess
the response to therapy vary considerably [34, 35]. Although
it is generally agreed that many antibiotic regimens areeffective
in the control of infection with minimal toxicity, careful selec-
tion based on local patterns of infection and antibiotic sus-
ceptibilities may enhance efficacy while maintaining safety and
minimizing costs. For example, several studies have indicated
that not all b-lactam antibiotics are equally effective, at least at
certain institutions. Antibiotic resistance among gram-negative
bacilli may limit the efficiency of some b-lactams at some in-
Level of Risk for Oral Antibiotics and Outpatient Management
Treatment of carefully selected febrile neutropenicpatientswith
oral antibiotics alone appears to be feasible for adults at low
risk for complications (A-I) [39–53]. In general, the use of
antibiotics by the oral route may be consideredonlyforpatients
who have no focus of bacterial infection or symptomsandsigns
suggesting systemic infection (e.g., rigors, hypotension) other
than fever. Some patients may reliably receive their prescribed
therapy as outpatients, although many of the studies that have
supported treatment with oral antibiotics involvedhospitalized
patients [43, 45]. Vigilant observation and prompt access to
appropriate medical care must also be ensured 24 h per day,
7 days per week. For many patients and some institutions,
outpatient therapy may not be advisable. Patients with recov-
ering phagocyte counts are generally considered to be better
candidates for outpatient treatment than are patients with de-
creasing counts or no indication of marrow recovery.
Factors favoring low risk for serious infections among febrile
neutropenic patients, which have been identified in controlled
studies, are listed in table 3 [4, 42–53]. These characteristics
may serve as guidelines for the selection of patients for out-
patient therapy. A recent international collaborative study of
1139 febrile and neutropenic patients with malignancy estab-
lished and validated a scoring system to identify, at the time
of presentation with fever, those patients with low risk for
complications, including mortality.Factorsassociatedwith
lower risk for complications and a higher rate of favorable
outcome ( ) were as follows: age !60 years (children not
P ! .001
included), cancer in partial or complete remission, no symp-
toms or only mild to moderate symptoms of illness, outpatient
736 • CID 2002:34 (15 March) • Hughes et al.
among patients with neutropenia.
Factors that favor a low risk for severe infection
Absolute neutrophil count of ?100 cells/mm3
Absolute monocyte count of ?100 cells/mm3
Normal findings on a chest radiograph
Nearly normal results of hepatic and renal function tests
Duration of neutropenia of !7 days
Resolution of neutropenia expected in !10 days
No intravenous catheter–site infection
Early evidence of bone marrow recovery
Malignancy in remission
Peak temperature of !39.0?C
No neurological or mental changes
No appearance of illness
No abdominal pain
No comorbidity complicationsa
aConcomitant condition of significance (e.g., shock, hypoxia, pneu-
monia or other deep-organ infection, vomiting, or diarrhea).
Data are adapted from [4, 42–49, 51–53].
tropenic patients at time of presentation with fever.
Scoring index for identification of low-riskfebrileneu-
Extent of illnessa
No chronic obstructive pulmonary disease
Solid tumor or no fungal infection
Outpatient at onset of fever
Age !60 yearsb
that the patient is likely to be at low risk for complications and morbidity. The
scoring system is derived from .
aChoose 1 item only.
bDoes not apply to patients ?16 years of age. Initial monocyte count of
?100 cells/mm3, no comorbidity, and normal chest radiographfindingsindicate
children at low risk for significant bacterial infections .
Highest theoretical score is 26. A risk index score of ?21indicates
status atthetimeof onsetoffever,temperature!39.0?C,normal
findings on chest radiographs, absence of hypotension, respi-
ratory rate of ?24 breaths/min, absence of chronic pulmonary
diseases, absence of diabetes mellitus, absence of confusion or
other signs of mental status alteration, absence of blood loss,
absence of dehydration, no history of fungal infection, and no
receipt of antifungal therapy during the 6 months before pre-
sentation with fever. Integer weights were assigned for 7 char-
acteristics to develop a risk-index score (table 4), which was
subsequently tested for validation. A risk-index score of ?21
identified low-risk patients with a positive predictive value of
91%, specificity of 68%, and sensitivity of 71%. This study
generally supports the earlier studies of Talcott et al . The
database for this system did not include infants and children.
Recently, Klaassen et al.  prospectively derived and val-
idated a clinical prediction rule for pediatric oncology patients
with fever and neutropenia. Children presenting with an initial
absolute monocyte count of ?100 cells/mm3, with no co-
morbidity, and with a normal chest radiograph findings are at
lowest risk for significant bacterial infections.
As an alternative to initial outpatient therapy, earlydischarge
with continued outpatient therapy for selected patients may be
considered after a brief inpatient admission during which in-
travenous therapy is initiated, fulminant infection is excluded,
and the status of initial culture specimens is ascertained [52,
Treatment with Intravenous Antibiotics
The first step in antibiotic selection is to decide whether the
patient is a candidate for inpatient or outpatient management
with oral or intravenous antibiotics (figure 1).
Three general schemes of intravenous antibiotic therapies
with similar efficacy are considered here, with the caveat that
one may be more appropriate for certain patients andincertain
institutions than others. The schemes are as follows: single-
drug therapy (monotherapy), 2-drug therapy without a gly-
copeptide (vancomycin), and therapy with glycopeptide (van-
comycin) plus 1 or 2 drugs.
Single-drug therapy (monotherapy).
shown no striking differences betweenmonotherapyandmulti-
drug combinations for empirical treatment of uncomplicated
episodes of fever in neutropenicpatients(A-I)[54–71].Athird-
or fourth-generation cephalosporin (ceftazidime or cefepime)
or a carbapenem (imipenem-cilastatin or meropenem) may be
used successfully as monotherapy [68, 72, 73–78]. Physicians
should be aware that extended-spectrum b-lactamasesandtype
1 b-lactamases have reduced the utility of ceftazidime for
monotherapy . Cefepime, imipenem-cilastatin, and mero-
penem, unlike ceftazidime, have excellent activity against vir-
idans streptococci and pneumococci. Vancomycin was shown
to be required less frequently with cefepime than with cefta-
zidime monotherapy . A prospective double-blind study of
411 patients who had cancer showed that the rate of clinical
response was higher in febrile neutropenic patientstreatedwith
meropenem than it was in those treated with ceftazidime .
Elsewhere, similar results have been observed.Piperacillin-
tazobactam has also been found to be effective as monotherapy,
but its use has not been studied as extensively as that of the
other agents [64, 65].
The patient must be monitored closely for nonresponse,
emergence of secondary infections, adverse effects, and the de-
velopment of drug-resistant organisms. Addition of other anti-
Several studies have
Guidelines for Febrile Neutropenic Patients • CID 2002:34 (15 March) • 737
biotics may be necessary as the clinical course progresses. In
particular, the spectrum of these drugs does not usually cover
coagulase-negative staphylococci, methicillin-resistant S. au-
reus, vancomycin-resistant enterococci, some strains of peni-
cillin-resistant Streptococcus pneumoniae, and viridans strepto-
cocci. Cefepime or ceftazidime may be used in the presence of
mild or moderate renal dysfunction without dose modification
and for patients being treated with nephrotoxic drugs, such as
cisplatin, cyclosporin, or amphotericin B.
Quinolones, such as ciprofloxacin, also have been evaluated
for use as monotherapy in limited studies showing both fa-
vorable [77–79] and unfavorable results [80, 81]. The general
use of quinolones for prophylaxis among afebrile neutropenic
patients limits this class of drugs for initial therapy. Currently,
in comparison with the other antibiotics recommended for
for routine initial intravenous monotherapy.
Treatment with aminoglycosides alone is suboptimal, even
though the bacterial isolate may be susceptible in vitro.
Two-drug therapy without a glycopeptide antibiotic (van-
The most commonly used 2-drug therapy, ex-
cluding regimens with vancomycin,includesanaminoglycoside
(gentamicin, tobramycin, or amikacin) with an antipseudo-
monal carboxypenicillin or ureidopenicillin (ticarcillin-clavu-
lanic acid or piperacillin-tazobactam); an aminoglycoside with
an antipseudomonal cephalosporin, such as cefepime or cef-
tazidime; and an aminoglycoside plus a carbapenem (imipe-
nem-cilastatin or meropenem). Pertinent publications sum-
marized in the 1997 guidelines  show that, generally, the
different 2-drug combinations yield similar results when var-
iations in experimental design, definitions, end points, and un-
derlying primary diseases are taken into consideration. It is
important to note, in reviewing older studies, that the suscep-
tibility of isolates to antibiotics used at the time of the study
may be different from susceptibilities of some bacterial isolates
Advantages of combination therapy are potential synergistic
effects against some gram-negative bacilli  and minimal
emergence of drug-resistant strains during treatment [83, 84].
The major disadvantages are the lack of activity of these com-
binations, such as ceftazidime plus an aminoglycoside, against
some gram-positive bacteria, and the nephrotoxicity, ototox-
icity, and hypokalemia associated with aminoglycoside com-
pounds and carboxypenicillins. Limited studies show that a sin-
as multiple daily doses of these drugs  and as effective as
monotherapy with ceftazidime , but data are insufficient to
establish a practice standard. Serum levels of the aminoglycoside
should be monitored as needed in patients with impaired renal
function, and dosages should be adjusted until optimal thera-
peutic concentrations are achieved.
Quinolone-based combinations with b-lactams or glycopep-
tides are an option for initial therapy for patients not receiving
quinolone prophylaxis. Newer agents (gatifloxacin, moxiflox-
acin, and levofloxacin) have been used selectively to treat pa-
tients who have cancer, but their roles will need to be evaluated
further before recommendations canbemade[86–89].Arecent
large comparative trial showed that ciprofloxacin plus piper-
acillin-tazobactam is aseffectiveastobramycinandpiperacillin-
tazobactam . Any initial antibiotic regimen should include
drugs with antipseudomonal activity .
Therapy with glycopeptide (vancomycin) plus 1 or 2
Because of the emergence of vancomycin-resistant
organisms, especially enterococci, associated with excessive use
of vancomycin in the hospital, administration of vancomycin
the recommendations of the Hospital Infection Control Prac-
tices Advisory Committee of the Centers for Disease Control
and Prevention(CDC) forpreventingthespreadofvancomycin
resistance . The European Organization for Research and
Treatment of Cancer (EORTC)–National Cancer Institute of
Canada study showed that vancomycin is not in general a nec-
essary part of initial empirical antibiotictherapy,ifitisavailable
for subsequent treatment modifications [30, 93]. Atinstitutions
at which these infections are rare, vancomycin should be rou-
tinely withheld until the results of cultures indicate the need
for this antibiotic.
Infections caused by gram-positive bacteria are frequently
indolent, but some may be susceptible only to vancomycin and
can, on occasion, be serious, leading to death in !24 h if not
promptly treated. Although vancomycin has not been shown
to influence overall mortality due to gram-positive cocci as a
group, mortality due to viridans streptococci may be higher
among patients not initially treated with vancomycin [94, 95].
Some strains of viridans streptococci are resistant to or tolerant
of penicillin, but such antibiotics as ticarcillin, piperacillin, ce-
fepime (but not ceftazidime), and carbapenems all have ex-
cellent activity against most strains. At institutions at which
these gram-positive bacteria are common causes of serious in-
fections, vancomycin may be incorporated into initial thera-
peutic regimens of some high-risk patients but discontinued
24–48 h later if no such infection is identified. Someorganisms,
such as Bacillus species and C. jeikeium, are susceptible only to
vancomycin, but these infections are usually not severe. Inclu-
sion of vancomycin in initial empirical therapy may be prudent
for selected patients with the following clinical findings: (1)
clinically suspected serious catheter-relatedinfections(e.g.,bac-
teremia, cellulitis), (2) known colonization with penicillin-and
cephalosporin-resistant pneumococci or methicillin-resistantS.
aureus, (3) positive results of blood culture for gram-positive
bacteria before final identification and susceptibility testing, or
738 • CID 2002:34 (15 March) • Hughes et al.
(4) hypotension or other evidence of cardiovascular impair-
For some physicians in some medical centers, intensive che-
motherapy that produces substantial mucosal damage (e.g.,
high-dose cytarabine) or increases the risk for penicillin-resis-
tant streptococcal infections (e.g., infection with viridansstrep-
tococci), as well as prophylaxis with quinolones for afebrile
neutropenic patients before onset of fever, are also considered
indications for vancomycin to be included in the initial regi-
men. Sudden increase of temperature to 140?C has, to some
extent, been predictive of sepsis with viridans streptococci.
Several studies have evaluated vancomycin drug combina-
tions for the treatment of neutropenic patients with fever;these
combinations have included vancomycin plus any of the fol-
lowing antibiotics: imipenem [72, 96], cefepime , amikacin
and ticarcillin , meropenem , ciprofloxacin , az-
treonam [98, 99], ceftazidime [100–104], ceftazidime and ami-
kacin [30, 103], tobramycin and piperacillin [105, 106], ticar-
cillin , and ceftazidime and ticarcillin . Although the
combination of ceftazidime and vancomycin has been used
most extensively in the past, in some medical centers, the pos-
sible risk of emergence of resistance to ceftazidime may justify
the recommendation that vancomycin be preferentially used in
combination with cefepime or a carbapenem (imipenem-cilas-
tatin or meropenem).
Teicoplanin has been evaluated as an alternative to vanco-
mycin (see appendix 1 in the 1997 guidelines ) in limited
clinical trials [105, 106], but the drug has not receivedapproval
from the US Food and Drug Administration (FDA), and ad-
ditional studies are needed to place it in proper perspective.
Linezolid, the first FDA-approvedoxazolidinone,offersprom-
ise for treatment of drug-susceptible and-resistantgram-positive
bacterial infections, including those due to vancomycin-resistant
enterococci, although an associated myelosuppression may be
problematic . Quinupristin-dalfopristin, another drug that
has recently been approved by the FDA, is also effective against
vancomycin-resistant Enterococcus faecium. Further studies are
needed before guideline recommendations canbemadeforthese
Treatment with Oral Antibiotics
Several studies have evaluated oral absorbable broad-spectrum
antibiotics for use as initial empirical therapy for febrile, neu-
tropenic patients considered to be at low risk for bacterial in-
fection [39–53]. The outcomes for low-risk patients treated
with oral antibiotic therapy are generally equivalent to those
for similar patients treated with intravenous antibiotic therapy
when both treatment groups are managed in an inpatient set-
ting in controlled studies [43, 45]. Oral therapy has the ad-
and avoidance of catheter use, thereby reducing the possibility
of hospital- and catheter-related infection. Among the oral reg-
imens that have been most thoroughly evaluated are ofloxacin,
ciprofloxacin, and ciprofloxacin plus amoxicillin-clavulanate.
Quinolones are generally not as effective as cephalosporins or
carbapenems in treating gram-positive infections and may pre-
Quinolones are not currently approved for use in children !18
years of age, although toxicity has not been high in pediatric
trials . Although controlled studies of children have as-
sessed early switching from intravenous to oral antibiotics,
other than quinolones [52, 53], only a few children have been
included in studies of initial empirical oral therapy for febrile
neutropenia . At this time, there are insufficient data to
recommend initial empirical oral therapy for fever and neu-
tropenia in children. However, early discharge of patients while
they are receiving treatment with cefixime after ?48 h of in-
hospital observation of treatment with intravenous antibiotics
may be considered for selected children [52, 53].
Recommendations for Initial Regimen
Figure 1 shows an algorithm for initial management. First,
determine whether the patient is at low or high risk for serious
life-threatening infection on the basis of the criteria observed
at the time of presentation, which are presented in tables 3 and
4. If the risk is high, intravenous antibiotics must be used; if
risk is low, the patient may be treated with either intravenous
or oral antibiotics (A-II). Second, decide whether the patient
qualifies for vancomycin therapy. If the patient qualifies, begin
treatment with a 2- or 3-drug combination with vancomycin
plus cefepime, ceftazidime, or a carbapenem, with or without
an aminoglycoside. If vancomycin is not indicated, begin
monotherapy with a cephalosporin (cefepime or ceftazidime)
or a carbapenem (meropenem or imipenem-cilastatin)admin-
istered intravenously for uncomplicated cases. Two-drug com-
binations may be used for management of complicated cases
or if antimicrobial resistance is a problem. Adults selected for
oral therapy may receive ciprofloxacin plus amoxicillin-
clavulanate. Selection of patients for outpatient therapy must
be done carefully from the low-risk group, depending on the
capabilities of the medical center and doctor-patient relation-
ship. Initial therapy with oral antibiotics alone is not recom-
mended for children. Use current antibiotic susceptibility pat-
terns from your local hospital laboratory as an aid in antibiotic
MANAGEMENT OF THE ANTIBIOTIC REGIMEN
DURING THE FIRST WEEK OF THERAPY
Receipt of antibiotic treatment for at least 3–5 days is usually
required to determine efficacy of the initial regimen. From this
point, decisions regarding further treatment are made on the
Guidelines for Febrile Neutropenic Patients • CID 2002:34 (15 March) • 739
basis of whether the patient had bacteremia or pneumonia,
whether the fever has resolved, and whether the patient’s con-
dition has deteriorated. Some patients’ conditions may dete-
riorate rapidly in !3 days, necessitating reassessment of the
In several studies, the times to defervescence for febrile neu-
tropenic patients with cancer who receive antibiotic regimens
including cefepime, ceftazidime, ciprofloxacin, imipenem, and
piperacillin (with or without aminoglycosides) are 2–7 days
(median time, 5 days) [30, 85, 104, 109–111]. In a recent anal-
ysis of 488 episodes of fever and neutropenia, the median time
to clinical response was 5–7 days . The median time to
defervescence among low-risk patients has been 2 days[43, 45],
compared with 5–7 days for high-risk patients. When possible,
despite the fact that the patient remains febrile, the clinician
may wait 5 days to make any changes in antimicrobialregimen,
unless a change is mandated by clinical deterioration or the
results of a new culture.
Patient is Afebrile within 3–5 Days of Treatment
If a causative microbe is identified, the antibiotic regimen may
be changed, if necessary, to provide optimal treatment with
minimal adverse effects and lowest cost, but broad-spectrum
coverage should be maintained to prevent breakthrough bac-
teremia. Antibiotic treatment should be continued for a min-
imum of 7 days or until culture results indicate that the caus-
ative organism has been eradicated, infection at all sites has
resolved, and the patient is free of significant symptoms and
signs (figure 2). It is desirable for the neutrophil count to be
?500 cells/mm3before treatment is stopped. However, if the
neutropenia is prolonged and the aforementioned responses
have been achieved, consideration can be given to discontin-
uation of treatment before a neutrophil count of ?500 cells/
mm3is reached. This approach can be taken if the patient can
be carefully observed, the mucous membranes and integument
are intact (e.g., no mucositis, ulcerations, evidence of catheter
site infection, or bleeding sites are present), and no invasive
procedures or ablative chemotherapy are impending.
In the absence of discernible infectious disease (e.g., pneu-
monitis, enterocolitis, cecitis, endocarditis, catheter-associated
infection, or severe cellulitis) and of positive culture results,
treatment for compliant adults may be changed after ?2 days
of intravenous therapy to an oral antibiotic combination of
ciprofloxacin and amoxicillin-clavulanic acid [43, 45]. Among
children, 2 studies [52, 53] show that a change after 48–72 h
of intravenous antibiotics to oral cefixime alone provides ther-
apy that is as effective and safe as continuation of intravenous
antibiotics. Children who lack signs of sepsis (chills, hypoten-
sion, and requirement for fluid resuscitation) and severe mu-
cositis at the time of admission and throughout their courses,
who are afebrile for ?48 h, who have neutrophil counts of
?100 cells/mm3, and who are at low risk for complications
may have intravenous antibiotic treatment stoppedandtherapy
continued with oral cefixime. The controlled studies of adults
[43, 45] and children [52, 53] were done with inpatients, so
one cannot be assured that similar results will occur if patients
are discharged while receiving treatment with oral antibiotics.
Some investigators have advocated discontinuation of anti-
biotic therapy for patients without documented infections and
with signs of early marrow recovery before completing a 7-day
course [113–116]. At present, there is not enough evidence or
experience with this approach to endorse its use.
It is important to realize that the suggestions made here are
somewhat arbitrary, and a comprehensive assessment is essen-
tial for each patient. Antibiotic therapy alone, in the presence
of persistent neutropenia, may suppress but not eradicate the
Recommendations for afebrile patients.
a guide for treatment of patients who become afebrile within
3–5 days of starting treatment. Modify antibiotic therapy for
specific organisms, if identified, and continue use of broad-
spectrum antibiotics for ?7 days, until cultures are sterile and
the patient has clinically recovered. If the causative organism
is not found and the patient is receiving drugs intravenously
and was at low risk at the onset of treatment, treatment may
be changed to oral ciprofloxacin plus amoxicillin-clavulanate
for adults or cefixime for children after 48 h, if clinically pref-
erable. The same intravenous antibiotics should be continued
for high-risk patients (B-II).
Figure 2 presents
Persistent Fever throughout the First 3–5 Days of Treatment
Fever that persists for 13 days in patients for whom no infected
site or organism has been identified suggests that the patient
has a nonbacterial infection, a bacterial infection resistant to
the antibiotic(s) or slow to respond to the drug in use, the
emergence of a second infection, inadequate serum and tissue
levels of the antibiotic(s), drug fever, cell wall–deficient bac-
teremia , or infection at an avascular site (e.g., “abscesses”
or catheters). In reassessing the patient’s condition after 3 days
of treatment, the physician should attempt to identify factor(s)
that might account for nonresponsiveness (figure 3). However,
some patients with microbiologically defined bacterial infec-
tions, even when adequately treated, may require ?5 days of
therapy before defervescence occurs [30, 85, 104, 111, 112].
Reassessment includes a review of all previouscultureresults,
a meticulous physical examination, chest radiography, ascer-
taining the status of vascular catheters, culturing of additional
blood samples and specimens of specific sites of infection, and
diagnostic imaging of any organ suspected of having infection.
If possible, the determination of serum concentrations of an-
tibiotics, especially aminoglycosides, may be useful in assess-
ment of drug therapy. Ultrasonographyandhigh-resolutionCT
740 • CID 2002:34 (15 March) • Hughes et al.
system for patients at low risk.
Guide for management of patients who become afebrile in the first 3–5 days of initial antibiotic therapy. See tables 3 and 4 for rating
may be helpful, especially for patients with pneumonitis, si-
nusitis, and cecitis. Additional studies may be done to identify
relatively uncommon causes of fever. If reassessment yields a
cause of the fever or strongly suggests a cause not adequately
covered by the initial antibiotic regimen, a change should be
If the fever persists after 5 days of antibiotic therapy and
should be made (figure 3): (1) continuetreatmentwiththeinitial
antibiotic(s), (2) change or add antibiotic(s), (3) or add an anti-
fungal drug (amphotericin B) to the regimen, with or without
microbial drugs—will not be discussed as a valid option in these
general guidelines, although, in some highly individualizedcases
(such ascases inwhich thefeveristhoughttobeofnoninfectious
origin), physicians may elect to stop antibiotic therapy.
If no discernible changes in the patient’s condition have
occurred (i.e., the patient remains febrile but stable) during the
first 4–5 days of initial antibiotic treatment, and if reevaluation
yields no new information to the contrary, the initial antibiotic
regimen can be continued. This decision will be strengthened
if the neutropenia can be expected to resolve withintheensuing
If evidence of progressive disease or complication (such as
the onset of abdominal pain due to enterocolitis or cecitis, new
or worsening mucous membrane lesions, drainage or reactions
around catheter entry and/or exit sites, pulmonary infiltrates,
toxicity or other adverse effects caused by the drugs, or changes
in the bacteria in the mucous membranes [e.g., acquisition of
P. aeruginosa after admission samples for culture were taken])
becomes apparent during the initial antibiotic course, consid-
eration should be given to either the addition of appropriate
antibiotics or a change to different antibiotics. Whetherachange
is indicated will also depend on the initial antibiotic regimen.
If the initial antibiotic regimen is monotherapy or 2-drug
therapy without vancomycin, vancomycin may be considered
if any of the criteria for use of vancomycin mentioned above
have occurred (C-III). If a blood- or site-specific organism is
isolated, the most appropriate antibiotic should be used while
continuing broad-spectrum coverage.
If the initial treatment included vancomycin as a part of the
therapeutic regimen, consideration should be givento thewith-
drawal of vancomycin to minimize the development of anti-
bacterial resistance to this important drug. By day 3, the results
of admission cultures will be available to support a decision to
stop vancomycin therapy. The other initial antibiotics may be
continued if there is no evidence of disease progression, or, if
the patient is in a low-risk category (figure 2), an oral antibiotic
may be given, even if the patient is febrile (C-III).
The third choice to consider is the addition of antifungal
therapy. Amphotericin B is usually the drug of choice. Studies
in 1982  and 1989  suggested that up to one-third
of febrile neutropenic patients who do not respond to a 1-week
course of antibiotic therapy have systemic fungal infections
that, in most cases, are caused by Candida or Aspergillusspecies.
Although clinicians disagree as to when, and even if, ampho-
Guidelines for Febrile Neutropenic Patients • CID 2002:34 (15 March) • 741
Guide to treatment of patients who have persistent fever after 3–5 days of treatment and for whom the cause of the fever is not found.
tericin B therapy should beintroducedempirically,mostbelieve
that the patient who remains febrile and profoundly neutro-
penic for ?5 days, despite the administration of broad-spec-
trum antibiotics in adequate dosages, is a candidate for anti-
fungal therapy. Individual cases may have clinical features that
will direct use of amphotericin B earlier, later, or not at all.
Such an exception might be the patient who has no discernible
fungal lesion, has neither Candida nor Aspergillus species iso-
lated from any site, and is expected to have an increase in the
neutrophil count within a few days. In this case, treatmentwith
amphotericin B could be withheld and the patient should be
monitored carefully, if the patient is clinically stable. Every
effort should be made to determine whether systemic fungal
infection exists (e.g., biopsy of lesions should be performed;
radiographs of chest and sinuses should be obtained; nasal
endoscopy should be performed, if indicated, to investigate
sinusitis; and cultures and CT of the abdomen and chestshould
be done) before amphotericin B therapy is started. The em-
pirical decision to start use of the drug is not as difficult as the
decision to discontinue use of the drug. Much of the evaluation
at this time is to aid in a decision about when to stopantifungal
treatment later. It is noteworthy that a CT scan done after the
neutrophil count has recovered may show some enhancement
of earlier infection even with successful treatment.
Comparative trials have indicated that lipid formulations of
amphotericin B can be used as alternatives to amphotericin B
deoxycholate for empirical therapy. Although they do not ap-
pear to be substantially more effective, there is less drug-related
toxicity [119–122]. For example, in a clinical trial comparing
amphotericin B with liposomal amphotericin B (AmBisome;
Fujisawa Healthcare), the overall success rates were the same
for both preparations, although breakthrough fungal infections
occurred more frequently with amphotericin B and there was
a higher proportion of side effects with this preparation .
A double-blind comparative study showed that liposomal am-
photericin B (AmBisome) had superior safety to amphotericin
B lipid complex (Abelcet; Elan Pharmaceuticals) and a similar
therapeutic success rate . The investigators of a compar-
ative unblinded study concluded that Abelcet and AmBisome
are equally effective for the treatment of suspected and doc-
umented fungal infections in patients with leukemia; safety
related to severe adverse effects on the kidneys or liver was
similar, but the milder toxic reactions associated with acute
infusion-related reactions and increases in the creatinine level
were associated with Abelcet use, and more liver function test
abnormalities were associated with AmBisome use .
Two recent prospective randomized trials havedemonstrated
that fluconazole is an acceptable alternative to amphotericin B
for use as empirical antifungal therapy at institutions at which
mold infections (e.g., Aspergillus species) and drug-resistant
Candida species (Candida krusei and some strains of Candida
glabrata) are uncommon. Patients should not be considered
for empirical fluconazole treatment if they have symptoms of
sinusitis or radiographic evidence of pulmonary infection or
have received fluconazole as prophylaxis. Also,anypatientfrom
whom Aspergillus species were yielded on culture should not
be considered. Patients with pulmonary infection or sinusitis
have a high probability of infection with Aspergillus species or
742 • CID 2002:34 (15 March) • Hughes et al.
for patients at low risk. ANC, absolute neutrophil count.
Suggested scheme for estimating the duration of antibiotic administration under various conditions. See tables 3 and 4 for rating system
other molds. Amphotericin B still provides a broader spectrum
of activity than does fluconazole, although it does not appear
to prevent subsequent aspergillosis [123, 124]. A recent sys-
tematic meta-analytical review of lipid-based formulations of
amphotericin B and the azoles against amphotericin B deox-
ycholate in febrile neutropenic patients showed no consistent
treatment advantages associated with either formulation .
In a recent controlled study of 384 neutropenic patients with
cancer, itraconazole and amphotericin B were equivalent in
efficacy as empirical antifungal therapy, although itraconazole
was associated with less toxicity .
Caspofungin, an echinocandin, has recently been approved
by the FDA for the treatment of invasive aspergillosisrefractory
to amphotericin B and itraconazole. Data are not adequate for
recommendations regarding its use for treatmentof febrileneu-
Recommendations if fever persists for 13 days.
summarizes recommendations for patients with fever that per-
sists for 13 days. Begin diagnostic reassessment after 3 days of
treatment. By day 5, if fever persists and reassessment is un-
revealing, there are 3 options: (1) continue administration of
the same antibiotic(s) if the patient’s condition is clinically
stable, (2) change antibiotics if there is evidence of progressive
disease or drug toxicity, or (3) add an antifungal agent if the
patient is expected to have neutropenia for longer than 5–7
more days (B-II).
DURATION OF ANTIMICROBIAL THERAPY
The single most important determinant of successful discon-
tinuation of antibiotics is the neutrophil count. If no infection
is identified after 3 days of treatment, if the neutrophil count
is ?500 cells/mm3for 2 consecutive days, and if the patient is
afebrile for ?48 h, antibiotic therapy may be stopped at that
time (C-III) . If the patient becomes afebrile but remains neu-
tropenic, the proper antibiotic course is less well defined. Some
specialists recommend continuation of antibiotics, given intra-
venously or orally, until neutropenia is resolved (B-II) [108,
127, 128]. This approach may increase the risk for drug toxicity
and superinfection with fungi or drug-resistant bacteria .
It is reasonable for neutropenic patients who appear healthy
clinically, who were in a low risk category at onset of treatment,
who have no discernible infectious lesions, and who have no
radiographic or laboratory evidence of infection, to have their
use of systemic antibiotics stopped after 5–7 afebrile days, or
sooner, with evidence of hematologic recovery [44, 113, 127,
130, 131]. If use of antibiotics is stopped while the patient has
neutropenia, the patient must be monitored closely and intra-
venous antibiotics restarted immediately on the recurrence of
fever or other evidence of bacterial infection (figure 4) .
One should consider continuous administration of antibiotics
throughout the neutropenic period in patients with profound
neutropenia (!100 cells/mm3), mucous membrane lesions of
Guidelines for Febrile Neutropenic Patients • CID 2002:34 (15 March) • 743
the mouth or gastrointestinal tract, unstablevitalsigns,orother
identified risk factors (C-III). In patients with prolonged neu-
tropenia in whom hematologic recovery cannot be anticipated,
one can consider stopping antibiotic therapy after 2 weeks, if
no site of infection has been identified and the patient can be
observed carefully (C-III). Some experts suggest a change from
the therapeutic regimen to one of the prophylactic schemes
described below in the Antibiotic Prophylaxis for AfebrileNeu-
tropenic Patients section [128, 129, 133].
The duration of amphotericin B therapy varies. If a systemic
fungal infection has been identified, the course of antifungal
therapy will be determined bythecausativeagentandtheextent
of the disease. However, if no fungal infection is found, it is
not clear how long amphotericin B or other antifungal drugs
should be administered. Experience is limited predominantly
to amphotericin B. When neutropenia has resolved, the patient
is clinically well, and CT of the abdomen and chest reveals no
suspicious lesions, use of amphotericin B may be discontinued
[134, 135]. For clinically well patients with prolonged neutro-
penia, it is suggested that, after 2 weeks of receipt of daily doses
of amphotericin B, if no discernible lesions can be found by
clinical evaluation, chest radiography (or CT of the chest), and
CT of abdominal organs [136, 137], use of the drug can be
stopped. In the patient who appears ill or is at high risk, one
should consider continuation of therapy with antibiotics and
amphotericin B throughout the neutropenic episode, assuming
that hematologic recovery can be anticipated.
Another approach to clinically well patients with persistent
fever, which is preferred by other experts, is to terminate initial
antibiotic therapy after ∼4 days if no evidence of infection is
found and there is no response to therapy (C-III). Under these
conditions, which include very close, continuous monitoring
of patients, subsequently demonstrated infections may occur,
but most infections can be adequately treated . Empirical
amphotericin B administration should be considered for these
patients, despite discontinuation of antibiotic therapy, if fever
persists for 5–7 days after the start of initial therapy.
For patients who remain febrile after recovery of the neu-
trophil count to ?500 cells/mm3and despite receipt of broad-
spectrum antibacterial therapy, reassessment for undiagnosed
infection should be directed at fungal (especially chronic sys-
temic candidiasis, aspergillosis, histoplasmosis, and tricho-
sporonosis), mycobacterial, or viral infections . Antibiotic
therapy can generally be stopped despite persistent fever 4–5
days after the neutrophil count reaches ?500 cells/mm3if no
infectious lesions are identified. Ultrasonography (or, prefera-
bly, CT or MRI) of the abdomen maybe usefulforthedetection
of systemic fungal infections. Splenic, hepatic, and/or renal le-
sions may become apparent or enlarged as the neutrophilcount
Recommendations for duration of therapy.
dations for duration of therapy are summarized in figure 4.
THE USE OF ANTIVIRAL DRUGS
There is usually no indication for the empirical use of antiviral
drugs in the treatment of febrile neutropenic patients without
evidence of viral disease. However,ifskinormucousmembrane
lesions due to herpes simplex or varicella-zoster viruses are
present, even if they are not the cause of fever, treatment with
acyclovir is indicated. The intent is to enhance the healing of
these lesions, which provide portals of entry for bacteria and
fungi during the neutropenic period. In certain patients with
hematologic malignancies, fever, and neutropenia, the admin-
istration of acyclovir for the treatment or suppression of herpes
simplex virus infection has been associated with a more fa-
vorable febrile response than that in untreated patients .
Newer agents, such as valacyclovir and famciclovir, are better
absorbed after oral administration than is acyclovir and have
longer dosing intervals, and they might be preferred to oral
acyclovir. Systemic infections and disease due to cytomegalo-
virus are uncommon causes of fever in neutropenic patients,
with the exception of those who have undergone bone marrow
transplantation. Cytomegalovirus infection is treated with gan-
and fomivirsen are effective for the treatment cytomegalovirus
retinitis in patients with AIDS, but study among neutropenic
patients has been inadequate.
If certain viral respiratory tract infections are identifiedsoon
after onset in the febrile neutropenic patient, use of suitable
antiviral agents is usually warranted (e.g., ribavirin, for respi-
ratory syncytial virus infection, and zanamivir, oseltamivir, ri-
mantadine, or amantadine, for influenza virus infections).
Recommendations for use of antiviral drugs.
drugs are indicated only if there is clinical or laboratory evi-
dence of viral disease.
The routine use of granulocyte transfusions is not usually ad-
vocated. However, for certain patients with profound neutro-
penia in whom the microbiologically documented causative
bacteria cannot be controlled with optimal antibiotic therapy
or by administration of a granulocyte colony-stimulatingfactor
some investigators believe that granulocyte transfusions may
be useful [140–142]. Transfusion of high numbers of granu-
locytes obtained after administration of G-CSF, with orwithout
dexamethasone, to the donor is done by some clinicians, but,
at this time, there is no convincing evidence of its efficacy.
Significant toxicities in recipients include transmission of cy-
744 • CID 2002:34 (15 March) • Hughes et al.
tomegalovirus, alloimmunization associated with fever, graft-
versus-host reactions if granulocytes are not irradiated, pro-
gressive platelet refractoriness, and, possibly, respiratory
insufficiency associated with concomitant administration of
amphotericin B. The conclusion that granulocyte transfusion
therapy is currently an experimental clinical practice seems
There are no specific indications for
standard use of granulocyte transfusions (C-II).
USE OF COLONY -STIMULATING FACTORS
Hematopoietic growth factors have been studied as adjunctive
therapy to antimicrobial therapy for febrile neutropenic pa-
tients in several randomized, controlled trials [144–155]. These
studies show that G-CSF (filgrastim) or granulocyte-macro-
phage colony-stimulating factor (sargramostim) used as part
of the treatment of febrile neutropenic patientscanconsistently
shorten the duration of neutropenia, but these agents have not
consistently and significantly reduced other measures of febrile
morbidity, including duration of fever, use of anti-infectives,
or costs of management of the febrile neutropenic episode. No
study has demonstrated a decrease in infection-related mor-
tality rates. The 2001 update of the American Society of Clinical
Oncology guidelines recommends against the routine use of he-
matopoietic growth factor in uncomplicated cases of fever and
neutropenia . The IDSA panel agrees with these guidelines.
Under certain conditions in which worsening of the course
is predicted and there is an expected long delay in recovery of
the marrow, use of these agents may be indicated. Such con-
ditions include pneumonia, hypotensive episodes, severe cel-
lulitis or sinusitis, systemic fungal infections, and multiorgan
dysfunction secondary to sepsis. Therapy with colony-stimu-
lating factors could also be considered for patients who remain
severely neutropenic and have documented infections that do
not respond to appropriate antimicrobial therapy.
Recommendations for the use of colony-stimulating fac-
Colony-stimulating factors are not recommended for
routine use to treat febrile or afebrile neutropenic patients.The
IDSA panel supports and endorses the American Society of
Clinical Oncology guidelines (D-II) .
ANTIBIOTIC PROPHYLAXIS FOR AFEBRILE
Since the 1980s, several studies have shown that the frequency
of febrile episodes and infectious diseases can be reduced with
the administration of antibiotics duringtheearlyafebrileperiod
of neutropenia [1, 157–159]. Whatever benefit may come from
the administration of necessarily broad-spectrum antibiotics is
countered by deleterious effects from toxicity, emergence of
antibiotic-resistant bacteria, and fungal overgrowth. Of special
concern is the increasing prevalence of antibiotic-resistant
Afebrile patients who are expected to be profoundly neutro-
penic (!100 cells/mm3) are at greater risk for developing re-
sistant infections than are those with counts of 500 cells/mm3.
Additional significant risk factors include lesions that break the
mucous membranes and skin, use of indwelling catheters, use
of instruments (e.g., endoscopy), severe periodontal disease,
history of dental procedures,postobstructivepneumonia,status
of malignancy or organ engraftment, and compromise of other
immune responses. Personal factors, such as willingness to
comply with prescribed prophylaxis, personal hygiene habits,
and environmental (i.e., hospital or home) circumstances,must
also be considered.
Combinations of nonabsorbable drugs, such as aminoglyco-
sides, polymyxins, and vancomycin, have been used forinfection
prophylaxis in the past. Prospective, randomized trials havecon-
sistently shown that orally absorbable agents, such as trimeth-
oprim-sulfamethoxazole (TMP-SMZ) and quinolones, are more
effective and better tolerated for this purpose. In addition, the
increasing frequency of antibiotic resistance strongly recom-
mends against the use of prophylactic vancomycin.
Two types of oral absorbable antibiotics may be considered
for chemoprophylaxis. These are TMP-SMZ and the quinolones.
Studies of prophylaxis with TMP-SMZ were
reviewed in the 1997 report of the IDSA Fever and Neutropenia
Panel . In most of these studies, the infection rates for TMP-
SMZ–treated patients were significantly lower than were those
for placebo-treated control subjects, especially among patients
who had neutropenia for 12 weeks after reinduction of cytotoxic
therapy for leukemia. Adverse effects were few and insignificant,
but bacterial resistance has been noted. TMP-SMZ has proven
highly effective in the prevention of Pneumocystis carinii pneu-
monia in neutropenic and nonneutropenic patients .
Experts differ on recommendationsregardingtheroutineuse
of TMP-SMZ during periods of neutropenia. These differences
stem in great part from the overall lack of impactofprophylaxis
on patient mortality. In some studies, periods of granulocy-
topenia were prolonged and the rate of fungal colonizationwas
increased among patients receiving the antibiotics . In
patients at high risk for P. carinii pneumonitis (e.g., those with
leukemia, certain solid tumors, histiocytosis, or AIDS), TMP-
SMZ is indicated to prevent the pneumonitis and will second-
arily afford prophylaxis against some bacterial infections,
whether or not neutropenia occurs. Disadvantages of this reg-
imen include adverse reactions caused by sulfonamide drugs,
myelosuppression (in some cases), development of drug-resis-
tant bacteria, and oral candidiasis. Furthermore, the spectrum
of TMP-SMZ does not include P. aeruginosa.
Guidelines for Febrile Neutropenic Patients • CID 2002:34 (15 March) • 745
sively for prophylaxis in neutropenic patients [1, 157–159,
161–163], although they are ineffective against P. carinii. The
results of comparative studies of ofloxacin or ciprofloxacinver-
sus TMP-SMZ suggest that the effectiveness of the quinolones
is equal or superior to that of TMP-SMZ for the prevention
of febrile episodes of infectious origin . Unfortunately,most
of the studies have involved a number of patients that is in-
adequate for sound statistical analysis. However, 2 studies of
reasonable size are of interest. The study by Kern and Kurrle
 of 128 neutropenic patients who were randomized to
receive either ofloxacin or TMP-SMZ showed that gram-neg-
ative bacillary infections occurred significantly less frequently
in the ofloxacin group, but no difference in the frequency of
gram-positive bacterial and fungal infections was noted. Bac-
teremia due to methicillin-resistant staphylococci may occur
more frequently in neutropenic patients who receivequinolone
prophylaxis than it does in those who have not previously
received quinolone antibiotics . Thus, a disadvantage of
prophylaxis with quinolones is the inadequate coverage for
gram-positive bacterial infections. In another study, the addi-
tion of penicillin significantly reduced the number of episodes
of bacteremia, primarily via a reduction in the frequency of
streptococcal bacteremia in the penicillin group . The ad-
dition of rifampin to a quinolone resulted in more effective
prophylaxis in 2 studies [159, 163] but not in another .
Three reports in which meta-analysis had been applied to es-
timate efficacy found that quinolone-based prophylaxis sub-
stantially reduced the incidence of fever and microbiologically
documented infections in neutropenic patients [158, 166, 167].
The emergence of quinolone-resistant gram-negativebacillihas
been demonstrated in patients given quinolone prophylaxis
[168–171]. The quinolone drugs have not been approved by
the FDA for infants and children. These antibiotics should not
be used as prophylaxis routinely in medical centers in which
resistance has alreadybeenobservedor,ifparenteralquinolones
are part of empirical therapy, for febrileepisodesinneutropenic
patients. New fluoroquinolones with improved activity against
gram-positive bacteria have become available, but clinical ex-
perience with their use to treat neutropenic patients is limited.
The impact of the recent introduction of ciprofloxacin for an-
thrax prophylaxis on the development of resistance in other
bacteria is unknown.
Intravenous vancomycin has been used as
prophylaxis for catheter-related or quinolone-related gram-
positive infections. Although this approach may be effective, it
must be strongly discouraged because of the potentialforemer-
gence of vancomycin-resistant organisms. Furthermore, the
newer drugs, linezolid and quinupristin-dalfopristin, should
not be used for this purpose. Linezolid-related myelosuppres-
sion may occur.
The oral quinolones have been used exten-
increased substantially in recent years. Because these infections
are often difficult to diagnose and treat successfully, antifungal
prophylaxis may be appropriate in institutions in which the
infections are encountered frequently. Fluconazole has been
shown to reduce the frequency of both superficial and systemic
infections in patients who undergo bone marrow transplan-
tation [172–174]. Fluconazole’s efficacy is limited by its lack
of activity against C. krusei, some strains of C. glabrata, and
molds. Increased frequency of colonization with C. krusei and
C. glabrata has been reported in a few institutions in which
fluconazole has been used . A recent randomized, double-
blind trial of 274 adult neutropenic patients with cancer showed
that fluconazole prophylaxis reduced the incidence of both su-
perficial and invasive fungal infections and fungal-relateddeaths
. We agree with the 2000 guidelines from the CDC, IDSA,
and American Society of Blood and Bone Marrow Transplan-
tation , which recommends administration of fluconazole
at a dosage of 400 mg/day from the day of hematopoietic stem
cell transplantation until engraftment for the prevention of
Two large randomized, double-blind trials have shown that
itraconazole prophylaxis significantly reduced the frequency of
systemic fungal infection due to Candida species, and 1 trial
showed a decrease in the mortality rate associated with can-
didiasis [178, 179]. A systematic meta-analytical review of the
efficacy of antifungal prophylaxis among 17000 randomized
subjects observed reductions in the use of empirical antifungal
therapy, superficial fungal infection, invasive fungal infection,
and the fungal infection–related mortality rate .
Recommendations for antimicrobial prophylaxis.
SMZ therapy is recommended for all patients at risk for P.
carinii pneumonitis, regardless of whether they have neutro-
penia (A-I). However, there is no consensus to recommend
TMP-SMZ or quinolones for routine use for all afebrile neu-
tropenic patients. This lack of consensus is based, in great part,
on the current concern about the emergence of antibiotic-
resistant bacteria that has resulted from the overuse of anti-
biotics. In some special cases, for patients with profound and
prolonged neutropenia, a quinolone plus penicillin or TMP-
SMZ may be considered for critical periods of time, if the
potential for resistant organisms isappreciatedandoutweighed.
Routine use of fluconazole or itraconazole for all cases of
neutropenia is not recommended (D-II). However, in certain
circumstances in which the frequency of systemic infection due
to Candida albicans is high and the frequency of systemic infec-
tion due to other Candida species and Aspergillus species is low,
some physicians may elect to administer antifungal prophylaxis.
paradoxical. Data supporting the efficacy of prophylaxis with
TMP-SMZ, quinolones, fluconazole, and itraconazole in re-
The frequency of fungal infections has
746 • CID 2002:34 (15 March) • Hughes et al.
ducing the number of infectious episodes during the neutro-
penic period are adequate and would warrant a rating of A-I
from the standpoint of efficacy alone. However, concern about
the problem of emerging drug-resistant bacteria and fungi due
to extensive antibiotic use, plus the fact that such prophylaxis
has not been shown to consistently reduce mortalityrates,leads
to the recommendation that routine prophylaxis with these
drugs in neutropenic patients be avoided, with the exception
of use of TMP-SMZ for patients at risk for P. carinii pneu-
monitis. An axiom for prophylaxis is that the antibiotic used
should be administered for as short a period as possible and
to as few patients as possible.
Several approaches to reducing the cost of treating neutropenic
patients with unexplained fever have been explored [131, 132,
181–184]. Opportunities to reduce costs have proliferated be-
cause of an expanding armamentarium of oral and intravenous
antimicrobials, the emergence of hematopoietic colony-stim-
ulating factors, the advent of home antibiotic therapy services,
and data suggesting that empirical therapy can be discontinued
early in certain subsets of low-risk patients [113–115]. When
economic studies are conducted, it is essential that the welfare
of patients be paramount. It is not sufficient to simply dem-
onstrate statistically significant cost savings unless the impact
on morbidity and mortality is also considered.
Outpatient treatment of low-risk episodes of fever and neu-
tropenia is substantially less costly than inpatient care and is
preferred by most patients and families [185–187]. The panel
has attempted to encourage outpatient management when it is
safe and feasible. An assumption that hospitalization of a pa-
tient is the safest course to take is not necessarily correct, in
light of the Institute of Medicine’s recent report that 190,000
preventable deaths occur in hospitals in the United States each
The dosage of a drug should be considered with regard to
cost. Without question, the most effective dosage is basic for this
decision. However, thereisnoneedtoexceedtheoptimaldosage.
For example, the recommended dosage of ceftazidime is 2.0 g
given every 8 h for treatment of patients with severe, life-threat-
ening infections. However, in some studies, the lower dosage of
1.0 g given every 8 h has been used successfully to treat patients
with solid tumors who have expected short periods of neutro-
penia . Confirmation of such dosage schemes is needed
before a practice standard is established.
Duration of antibiotic treatment beyond the reasonable pe-
and, at this point, would not seem warranted, except in special
cases. The step-down from inpatient intravenous antibiotics to
outpatient oral antibiotics is usually cost-efficient.
The expensive colony-stimulating factors are frequentlyused
routinely, when they should be used according to well-thought-
out guidelines, such as those of the American SocietyofClinical
Oncology . Under some circumstances, such as high-dose
chemotherapy with either bone marrow or peripheral blood
stem cell support, colony-stimulating factors may be both clin-
ically and economically effective .
only for the FDA-approved indications: for cases of aspergillosis
that do not respond to the conventional amphotericin B prep-
aration and for patients who cannot tolerate the conventional
drug or who have or are at high risk for renal insufficiency.
Avoidance of the indiscriminate use of antifungal and antiviral
drugs during the febrile neutropenic episode requires adherence
to the policy of use only when adequate scientific data support
A simplified approach to performing marginal cost-effec-
tiveness analyses is detailed in a report from the Centers for
Disease Control and Prevention  and requires a descrip-
tion of the program and of the health outcomes averted and
the timing of these events; the rates of health outcomes and
the preventable fraction of the health outcomes averted; the
costs per unit of the intervention and the costs of the health
outcomes prevented; and the side effects incurred. Another
guide to decision analysis and economic evaluation is provided
by Haddix et al. . Because costs differ from location to
location, the cost-effectiveness of an intervention in the man-
agement of fever and neutropenia must be determined at the
physicians’ respective hospitals.
We acknowledge with appreciation the following expert con-
Cometta (Centre Hospitalier Universitaire Vaudois, Lausanne,
lottesville), Claudio Viscoli (University of Genova, Genova, It-
aly), and James C. Wade (Fred Hutchinson Cancer Research
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ERRATUM • CID 2003:36 (1 April) • 941 Download full-text
Clinical Infectious Diseases
? 2003 by the Infectious Diseases Society of America. All rights reserved.
E R R AT U M
An error appeared intheInfectiousDiseasesSocietyofAmer-
ica guidelines published in the 15 March 2002 issue of the
journal (Hughes WT, Armstrong D, Bodey GP, et al. 2002
Guidelines for the use of antimicrobial agents in neutropenic
patients with cancer. Clin Infect Dis 2002;34:730–51). The au-
thors listed in reference 41 should be “Hidalgo M, Hornedo J,
Lumbreras C, et al.” (not “Garcia-Carbonero R, Cortes-Funes
H”). The corrected version of reference 41 is as follows: “Hi-
dalgo M, Hornedo J, Lumbreras C, et al. Outpatient therapy
with oral ofloxacin for patients with low risk neutropenia and
fever: a prospective, randomized clinical trial. Cancer 1999;85:
213–9.” The authors regret this error.