Patients with profound neutropenia due to hematologic malignancies or
associated treatment(s) are at risk for severe morbidity and for
developing fatal bacterial infection. When patients with neutropenia
also present with feveran early sign of infection among these
patientsit is a standard of care to initiate empiric antibiotics.
Such treatment is generally administered to prevent the rapid
progression of infection that may result in septic shock or death.
However, the overuse of antimicrobials over time may result in
antimicrobial resistance and development of cross-resistance among pathogens.
Given the benefits of antibiotic treatment, are we reducing the
incidence of serious infections in the setting of febbrile
neutropenia? Conversely, given the drawbacks of inappropriate
antimicrobial therapy, are there instances of excessive use of
antimicrobials in treatment? Can we minimize the use of antibiotics
without compromising the health and well-being of our patients? These
are important questions to answer, particularly as we encounter
changing patterns of bacterial infection and antibiotic resistance.
The purpose of this article is to examine the characteristics that
define those patients requiring antimicrobial therapy. Current
therapeutic practices will be reviewed, as well as measures that can
improve patient outcome. An evaluation of risk for serious bacterial
infection will be examined as a refinement of treatment strategy for
In neutropenic patients, the signs and symptoms of infection are
often blunted or absent. Fever is an early warning sign. Current
National Comprehensive Cancer Network (NCCN) Guidelines recommend
that all patients who present with a temperature greater than 38°
C orally and who have a neutrophil count < 500/µL, or <
1,000/µL with a predicted decline to < 500/µL over the
following 48 hours, be treated with initial empiric antibiotic
therapy. Absence of noninfectious causes of fever, such as underlying
malignancy, transfusion of blood products, or drug reactions (eg,
cytokines, antimicrobial agents), should be confirmed prior to
initiating antibiotic therapy.
An initial evaluation of such patients should focus on identifying
the causative pathogen(s) and potential sites of infection (eg,
catheter site; specific lesions in areas such as the alimentary
canal, skin, and lungs) by thorough medical examination and
laboratory and microbiological evaluations. While empiric therapy is
usually initiated without microbiological evidence, pathogen
identification should direct secondary treatment modifications.
Patient stratification for risk of infection-associated morbidity and
mortality is essential to facilitate treatment decisions.
While high-risk patients[4,5] require hospital-based intravenous (IV)
therapy, low-risk patients may be effectively and safely treated as
inpatients and outpatients on a sequential basis. Low-risk patients
may even be treated on a completely outpatient basis, if risk
stratification is accurate and an ambulatory treatment infrastructure
The choice of antibiotic, mode of administration, and duration of
treatment varies from patient to patient, with empiric parenteral,
broad-spectrum antimicrobial drugs being indicated for patients who
are febrile and neutropenic and considered at high risk. Low-risk
subgroups may be administered as intravenous (IV) therapy, oral
therapy, or sequential IV/oral therapy. Other treatment variables
include the number of antibiotics (monotherapy vs combination
therapy), dosage, and duration of treatment.
Choice of antibiotics is wide and the selection of an initial agent
should be based on the patients history. This includes a
history of prior antibiotic regimens, resistant bacterial
infections/colonization, duration and severity of current febrile
episode and neutropenia, comorbid disease, catheter-site infection,
drug allergies, and geographic (institutional and community) patterns
of antibiotic susceptibilities among bacteria most commonly
encountered in patients with similar infections. Current
recommendations of the NCCN for initial therapy of fever and
neutropenia are summarized in Table 1.
A review of nearly 100 studies (1990-1995) of various initial empiric
regimens among patients with fever and neutropenia found no single
regimen to be clearly superior. Although most studies have
recommended the use of combination therapy (eg, ß -lactam plus
aminoglycoside or double ß-lactams), no relevant differences
have been demonstrated between combination therapy and monotherapy
with newer extended-spectrum antibiotics.[6-8] Monotherapy seems
prudent for short duration neutropenia (less than 1 week), while
combination therapy could prevent breakthrough of resistant
infections with long duration neutropenia (greater than 1 week).
Response rates to treatment with ß-lactams, with or without
aminoglycosides, have varied between 50% and 60%.
One of the major problems associated with comparison studies is the
difficulty in interpretation caused by variability in study designs
and efficacy or outcome measures.[9,10] Furthermore, many patients
with neutropenia have complex medical profiles, leading to increased
physician concern and a tendency to modify regimens during the
treatment course of febrile episodes. Such modifications generally
are made in a setting of inadequate diagnostic information. It has
been estimated that empiric regimens may be modified in 40% to 60% of cases.
Data from a series of French studies conducted between 1987 and 1992,
involving 591 evaluable febrile episodes, indicate that the mortality
rate among patients with neutropenia and fever has not improved
despite improved control of gram-positive and gram-negative
microorganisms. This outcome has been attributed to an increase
in disseminated fungal infections, thereby resulting in the addition
of antifungal agents to some treatment regimens. Thus, while empiric
therapy is sufficient in controlling infections for many patients,
others need additional antibiotics or antifungal agents for fever resolution.
It has been greatly debated whether a glycopeptide antibiotic, such
as vancomycin or teicoplanin (Targocid), should be added to standard
empiric therapy. Initial advocacy for the up-front addition of
vancomycin was based on the detection of superinfections during
ß-lactam monotherapy and the efficacy of vancomycin
addition in preventing such superinfections.
A study by the European Organization for Research and Treatment of
Cancer (EORTC) and the National Cancer Institute (NCI-C), Canada, has
shown that vancomycin is not an essential component of initial
empiric therapy for fever in granulocytopenic cancer patients.
Widespread use of vancomycin has resulted in the emergence of
glycopeptide resistance in enterococci, and therefore, initial
therapy with vancomycin should be restricted to select groups of
patients who may be at a high risk for serious gram-positive infections.
Patients at high risk for serious infections, and in whom vancomycin
use is justified, include those with skin or venous-access infections
that are clinically apparent and serious, and those subjected to
intensive mucositis-producing chemotherapy. Also at high risk are
patients colonized with antibiotic-resistant gram-positive
pathogens. Patients with prior quinolone prophylaxis are also at
high risk for bacteremia due to viridans streptococci.
Patients with gram-positive blood cultures, known colonization with
penicillin, or cephalosporin-resistant pneumococci or
methicillin-resistant Staphylococcus aureus (MRSA), and those
patients with hypotension or septic shock (even in the absence of
identified pathogen) may be considered as candidates for empiric
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