Almost a decade has passed since our review on
the management of infectious problems encountered in the care of
patients with acute leukemia was published in Oncology. In
the interim, several studies have been published on that subject,
which, while contributing important new insights, have also served to
emphasize the fundamental principles of management first formulated
and proven in the setting of acute leukemia and intensive
antileukemia treatment almost 30 years ago (Table
1). These principles have informed the management of infections
in not only the neutropenic state but also the state of profound
immune suppression, as exemplified by graft-vs-host disease or the
acquired immune deficiency syndrome.
This article will describe recent developments relating to the
management of infectious illnesses in patients rendered neutropenic
by leukemia or its treatment. The discussion will focus on the
increasing repertoire of available antimicrobial drugs and adjunctive
agents, viewed against the background of newly emerging resistant
organisms and special problems, such as the increased use of
indwelling venous catheters.
Modern treatment approaches to neutropenic fever are all predicated
on the principle of prompt empiric initiation of broad-spectrum
antibiotics directed against potential pathogens, even in the absence
of a localizing inflammatory reaction or laboratory-based
documentation of infection. Indeed, this practice has been so
effective in reducing mortality that comparative studies that utilize
mortality as an end point currently require very large numbers of
patientsusually several hundred per arm.
Smaller studies that do not have sufficient power to detect mortality
differences have therefore focused on such end points as the duration
of fever, hospital stay, and treatment-related costs. In the United
States, this trend is driven, in part, by economic pressures imposed
by the recent cost-containment trends in delivery in general.
Although several meta-analyses have been performed to address the
issue of empiric antibiotic therapy, many are subject to the problems
inherent in the source studies, as well as the usual criticisms
relating to study selection and bias.[3,4] A particularly difficult
problem is the publication bias against studies with negative
results. All of these factors complicate the ability to in-terpret
the accumulated literature on the subject of infections in the
Anticipating some of these problems, the Immunocompromised Host
Society convened a consensus panel in 1988 to formulate guidelines
for the conduct and reporting of clinical trials in patients with
neutropenic fever. The report of that group, issued in 1990,
serves as a useful benchmark for the evaluation of clinical trials in
Prophylaxis Against Gram-Negative Infections
The gastrointestinal (GI) tract is a major source of bacteria in
patients who develop clinical or subclinical mucositis as a result of
cytotoxic therapy. Common organisms include Escherichia coli, Klebsiella
species, and Pseudomonas aeruginosa.
Oral GI prophylaxis has been advocated to combat the dissemination of
these organisms early in the course of profound cytotoxic
drug-induced neutropenia and to inhibit late-onset GI colonization
with drug-resistant pathogens. Such prophylaxis may be more important
in patients expected to have prolonged neutropenia or repetitive
cycles of myelosuppressive therapy, particularly if this is
associated with severe chemotherapy-induced mucositis.
Early studies using trimethoprim-sulfamethoxazole,[6,7] as well as
more recent studies using systemic quinolones, showed significant
reductions in the incidence of gram-negative infections, especially
in patients receiving more highly cytotoxic therapy and those with
more severe aplasia. However, the impact on other important outcomes
was limited in these studies, and prophylactic treatment with
trimetho-prim-sulfamethoxazole was found in some studies to be
associated with adverse events, including the emergence of resistant
bacteria and fungal infections.
Although the emergence of resistance with systemic fluoroquinolone
usage remains a concern, a meta-analysis of several trials in which
these agents had been used prophylactically concluded that the risk
was low. Trials comparing fluoroquinolones to
trimeth-oprim-sulfamethoxazole suggest greater efficacy for the
fluoroquinolones in preventing early-onset bacterial infections but
little effect on other end points.[9-11] However, oral norfloxacin
(Noroxin), which is not absorbed but reaches high concentrations in
the gut lumen, appears to spare anaerobic organisms and thus maintain
colonization resistance in the GI tract against fungal overgrowth or
the acquisition of new aerobic pathogens throughout the period of
prolonged profound chemotherapy-induced neutropenia.[11-14]
Empiric Treatment of First Fever
Fever in the neutropenic host must be interpreted as a sign of
infection, even in the absence of other localizing or systemic
symptoms, and must prompt the empiric institution of broad-spectrum
antibiotics. Numerous trials continue to validate this concept using
agents directed against aerobic and facultative gram-negative
bacteria, especially P aeruginosa.
To this end, the noncross-resistant combination of an
aminoglycoside and an antipseudomonal penicillin provides
complementary mechanisms of action and potential antibacterial
synergy. However, the renal, auditory, and vestibular toxicity that
may be associated with prolonged aminoglycoside use is substantial.
Therapeutic drug level monitoring, which is necessary to limit
aminoglycoside toxicity, adds to the cost of therapy. Many recent
studies, therefore, have focused on the identification of
nonaminoglycoside-containing regimens, with a distinct trend
toward the development of single-agent therapies.
Several beta-lactam and carbapenem antibiotics (eg, aztreonam
[Azactam], cefepime [Maxipime], ceftazidime, imipenem-cilastatin
[Primaxin], or meropenem [Merrem]) offer broad-spectrum activity
against gram-negative bacteria (including P aeruginosa) and
have therefore been assessed as single-agent therapies in patients
with neutropenic fever.[15-20] These drugs offer an attractive
alternative to penicillin- and aminoglycoside-containing regimens
because of their wide spectrum of activity against gram-negative
bacteria and their favorable toxicity profile.
For patients undergoing prolonged marrow aplasia, however, effective
coverage of P aeruginosa and prevention of late-onset
multidrug resistance are of paramount importance. Imipenem and
cefepime are, in addition, efficacious against some gram-positive
organisms and anaerobes. The post-antibiotic effect associated with
imipenem is particularly useful in the setting of profound
neutropenia because it provides continued antibacterial activity in
the absence of phagocytic cells.
Newer fluoroquinolones, including levofloxacin (Levaquin), show
moderate activity against anaerobes, as well as broad-spectrum
activity against aerobic gram-negative and gram-positive bacteria.
This, coupled with their ease of administration and favorable
toxicity profiles, makes them attractive candidates for empiric
treatment of febrile neutropenia. Unfortunately, bacteria that have
acquired resistance to other fluoroquinolones may be less susceptible
to these newer agents.
Gram-positive infections have increased in frequency among patients
with oncologic diseases, and now account for the majority of positive
blood cultures in many institutions. Factors responsible for this
increased incidence of gram-positive infections are listed in Table
2. These infections can be responsible for life-threatening
illness in neutropenic patients, as exemplified by recent reports of
overwhelming infections caused by viridans group strep-tococci (eg, Streptococcus
mitis and Streptococcus sanguis) in patients treated with
high-dose chemotherapy and/or radiation therapy, and fatal
outcomes in patients who received platelet transfusions contaminated
with gram-positive bacteria.
The dissemination of gram-positive organisms from possible sites of
barrier breakdown can be suppressed by effective prophylactic
therapy. Vancomycin, a cell wallacting glycopeptide antibiotic,
is efficacious against a broad range of gram-positive organisms
including many Staphylococcus isolates, Corynebacterium species,
and other bacteria that are resistant to beta-lactam antibiotics.
In prospective clinical trials at centers where gram-positive
infections are prevalent, vancomycin therapy begun empirically at the
time of first infectious fever results in prompt resolution of fever,
rapid clearance of local and/or disseminated gram-positive
infections, and prevention of late-onset gram-positive
infection.[23-24] In contrast, these benefits have not been realized
in centers that have a lower prevalence of gram-positive infections.[25,26]
In the latter setting, vancomycin has been effective in treating and
eradicating established infection in a timely fashion, whether it is
added empirically for prolonged fever or selectively based on the
suspicion or diagnosis of gram-positive infections (Table
3).[24,27,28] Prophylactic administration of vancomycin[29,30]
or teicoplanin (Targocid) to flush intravenous lines or for
indwelling fluid locks has been shown to reduce the risk of catheter
colonization and associated infections, although studies using
systemic administration of either drug have yielded conflicting results.[31-34]
Vancomycin-Resistant Bacterial InfectionsSince 1986,
vancomycin-resistant enterococci (VRE) have emerged as an
increasingly visible nosocomial problem, with epidemics reported
recently at several hospitals. Risk factors for the acquisition of
VRE include prolonged hospitalization, prior antibiotic
exposureparticularly to cephalosporins and vancomycinand
admission to an intensive care unit or ward where the prevalence of
VRE is high.
Isolates exhibiting the van A phenotype, including many strains of Enterococcus
faecalis and Enterococcus faecium, have been studied most
extensively at the level of genetic mechanisms. In these strains, an
inducible plasmid-borne genetic transposition results in synthesis of
cell wall peptide residues incapable of binding to peptidoglycan
antibiotics; these strains are thereby able to avoid cell wall
disruption by vancomycin or teicoplanin. The van B phenotype, also
found in strains of E faecalis and E faecium, exhibits
a somewhat lower level of resistance to vancomycin and is relatively
susceptible to teicoplanin.
Enterococci that have either phenotype also tend to be intrinsically
resistant to many other antibiotics, however, including beta-lactams
(due to the presence of penicillin-binding proteins with decreased
affinity), aminoglycosides, and quinolones.
Thus, therapeutic options for patients infected with these multiply
resistant enterococci are limited. This problem has launched a search
for newer antibiotic agents that might provide some activity against
VRE. Unfortunately, in vitro activity against VRE isolates,
identified in several classes of drugs (Table
4), has not readily translated into clinically effective
therapy. Thus, the establishment and maintenance of vigorous
infection control procedures remain the cornerstone of programs aimed
at controlling this group of organisms, not only to limit their
dissemination but also to prevent glycopeptide resistance in other,
more virulent gram-positive pathogens, such as Staphylococcus aureus.
The recent descriptions of vancomycin-resistant S aureus
arising in the setting of prolonged vancomycin treatment are a stark
reminder of this threat.[35-37] A combination of careful and
innovative antibiotic use and strict adherence to appropriate
infection control procedures are the only means for dealing with
the expanding problems of antibiotic resistance in nosocomially
Clostridium difficile InfectionsInfection
control procedures are also important in limiting the spread of Clostridium
difficile. This gram-positive anaerobic bacillus is
associated with colitis and diarrhea in patients with prolonged
exposure to broad-spectrum antibiotics or some forms of chemotherapy,
notably, cisplatin (Platinol) and high-dose cytarabine.[39-41] In the
patient rendered aplastic as a result of chemotherapy, infectious
diarrhea presents special problems because of the limited utility of
stool examination and the difficulty in distinguishing diarrhea due
to infection from diarrhea due to chemotherapy or mucositis.
In addition, fevers associated with C difficile are apt to be
mistaken for (or else obscured by) those associated with concurrent
bacterial, viral, or fungal infection. In one study, the risk of VRE
carriage was increased in patients who had previously contracted C difficile
colitis. Colitis also results in the hematogenous dissemination
of enteric organisms, including VRE.
Unfortunately, the discontinuation of antibiotics, clearly an
important measure in the treatment of C difficile diarrhea, is
infeasible in patients with febrile neutropenia. Recent research has
focused on methods for the more rapid and accurate diagnosis of these
infections, including tests based on the detection of bacterial toxin
in stool samples, polymerase chain reaction (PCR)based assays,
and newer methods for increasing the yield from stool cultures.
Anticlostridial antibodies are also being investigated for the
prevention and treatment of this disease.
Outpatient Antibiotic TherapyFebrile, neutropenic
patients are not all the same. The risk of adverse outcomes is
related to the depth and duration of neutropenia, severity of
mucositis, and/or the presence of indwelling vascular catheters. The
presence of fungal colonization by multiple species with invasive
potential, obvious sites of infection, positive blood cultures, or
severe comorbidities also portend a poor outcome. Conversely, the
risk of severe or life-threatening infections can be reduced by the
prophylactic use of oral quinolones or granulocyte growth factors.
Limited studies have demonstrated the safety of using oral or
once-daily intravenous antibiotics for the outpatient treatment of
neutropenic fever in cancer patients.[45,46] However, there are
insufficient data to recommend this approach for patients with acute
leukemia, who generally experience profound aplasia and extensive
treatment-induced oral and GI mucositis. Nevertheless, selected
afebrile neutropenic patients with acute leukemia who have intact
hematologic function (eg, during consolidation therapy) and who are
receiving moderate rather than intensive chemotherapy may be managed
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