2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer.
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ABSTRACT: The use of oral prophylactic antibiotics in patients with neutropenia is controversial and not recommended by this group because of a lack of evidence showing a reduction in mortality and concerns that such practice promotes antimicrobial resistance. Recent evidence has demonstrated non-significant but consistent, improvement in all-cause mortality when fluoroquinolones (FQs) are used as primary prophylaxis. However, the consensus was that this evidence was not strong enough to recommend prophylaxis. The evidence base for FQ prophylaxis is presented alongside current consensus opinion to guide the appropriate and judicious use of these agents. Due consideration is given to patient risk, as it pertains to specific patient populations, as well as the net effect on selective pressure from antibiotics if FQ prophylaxis is routinely used in a target population. The potential costs and consequences of emerging FQ resistance, particularly among Escherichia coli, Clostridium difficile and Gram-positive organisms, are considered. As FQ prophylaxis has been advocated in some chemotherapy protocols, specific regard is given to whether FQ prophylaxis should be used to support these regimens. The group also provides recommendations for monitoring and surveillance of emerging resistance in those centres that have adopted FQ prophylaxis.Internal Medicine Journal 01/2011; 41(1b):102-9. · 1.82 Impact Factor
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ABSTRACT: Administration of empiric antimicrobial therapy is standard practice in the management of neutropenic fever, but there remains considerable debate about the selection of an optimal regimen. In view of emerging evidence regarding efficacy and toxicity differences between empiric treatment regimens, and strong evidence of heterogeneity in clinical practice, the current guidelines were developed to provide Australian clinicians with comprehensive guidance for selecting an appropriate empiric strategy in the setting of neutropenic fever. Beta-lactam monotherapy is presented as the treatment of choice for all clinically stable patients while early treatment with combination antibiotic therapy is considered for patients at higher risk. Due consideration is given to the appropriate use of glycopeptides in this setting. Several clinical caveats, accounting for institution- and patient-specific risk factors, are provided to help guide the judicious use of the agents described. Detailed recommendations are also provided regarding time to first dose, timing of blood cultures, selection of a first-line antibiotic regimen, subsequent modification of antibiotic choice and cessation of therapy.Internal Medicine Journal 01/2011; 41(1b):90-101. · 1.82 Impact Factor
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ABSTRACT: Endothelial barrier breakdown is a hallmark of septic shock, and proteins that physiologically regulate endothelial barrier integrity are emerging as promising biomarkers of septic shock development. Patients with cancer and febrile neutropenia (FN) present a higher risk of sepsis complications such as septic shock. Nonetheless, these patients are normally excluded or under-represented in sepsis biomarker studies. The aim of our study was to validate the measurement of a panel of microvascular permeability modulators as biomarkers of septic shock development in cancer patients with chemotherapy-associated FN. This was a prospective study of diagnostic accuracy, performed in two distinct in-patient units of a University Hospital. Levels of vascular endothelial growth factor A (VEGF-A), soluble fms-like tyrosine kinase-1 (sFlt-1) and angiopoietin (Ang) 1 and 2 were measured after the onset of neutropenic fever, in conditions designed to mimic the real-world use of a sepsis biomarker, based on our local practice. Patients were categorized based on the development of septic shock by 28 days as an outcome. 99 consecutive patients were evaluated in the study, of which 20 developed septic shock and 79 were classified as non-complicated FN. VEGF-A and sFlt-1 levels were similar between both outcome groups. In contrast, Ang-2 concentrations were increased in patients with septic shock, whereas an inverse finding was observed for Ang-1, resulting in a higher Ang-2/Ang-1 ratio in patients with septic shock (5.29, range 0.58-57.14) compared to non-complicated FN (1.99, range 0.06-64.62; P = 0.01). After multivariate analysis, the Ang-2/Ang-1 ratio remained an independent factor for shock septic development and 28-day mortality. A high Ang-2/Ang-1 ratio can predict the development of septic shock in cancer patients with febrile neutropenia.Critical care (London, England) 08/2013; 17(4):R169. · 4.72 Impact Factor
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
Category, grade Definition
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