Many hospitals and cancer treatment centers in the United States and
Europe are now routinely reporting an increase in the proportion of
bloodstream infections caused by gram-positive bacteria.[1-4]
Gram-negative pathogens were previously the most frequently isolated
organisms causing infections among cancer patients, but in recent
years there has been a progressive increase in the isolation of
gram-positive species. Gram-negative species, although less
frequently isolated, remain a significant source of infection.
The shift to a gram-positive pathogen dominance is in part the result
of changes in treatment practices and in the patient populations. For
example, the practice of using quinolones prophylactically has been
noted to increase the occurrence of infections due to gram-positive
pathogens. The use of indwelling central venous catheters for drug
delivery is also associated with an increased incidence of
gram-positive infection among immunocompromised patients.
Centers across the United States now routinely report increasing
antimicrobial resistance among many pathogens, including those most
often implicated in bloodstream infections of immunocompromised
patients. Geographic variation in resistance levels and patterns do
exist, but the overall trend confirms the increasing ability of
bacteria to evolve new resistant species. Antimicrobial resistance is
a local phenomenon and also a class of treatment phenomenon. Several
strains are now partially or fully resistant to standard,
broad-spectrum antibiotics, and to newer drugs in the same classes.
Resistance is also emerging to relatively new drugs representing
novel structural classes, such as the streptogramin combination,
In the United States, methicillin resistance among Staphylococcus
aureus was reported to average 29% nationwide in 1999, and almost
80% for coagulase-negative species of staphylococci. Whereas
vancomycin was able to control staphylococcal, streptococcal, and
enterococcal infections a decade ago, the average nosocomial
resistance among enterococcal species in the United States in 1999
has risen to 18% and is higher (30%) among hematology/oncology patients.
Enterococcal infections in immunocompromised patients are of
especially grave concern because these species are relatively poorly
controlled by other drugs that are currently available. Antimicrobial
resistance rates in Europe are generally lower than the rates of
resistance reported for hospitalized patients in several studies from
the United States. In contrast, colonization of nonhospitalized,
healthy individuals in Europe with glycopeptide-resistant enterococci
has been reported to range from 2% to 12%, compared to a virtual
absence of such resistance in the community sector in the United States.
The likelihood that attempts to combat bacteria have inadvertently
become the source of selection for resistance mechanisms emphasizes
the fact that drug choice and therapeutic regimen design must be made
with a knowledge of antibiotic resistance patterns, and that efforts
to minimize unnecessary antibiotic exposure must be redoubled.
Patients with neutropenia and presumed or documented infection
require immediate antimicrobial treatment. Empiric antibiotics remain
the standard of practice, and will continue to be until
identification and characterization of bloodstream isolates become
readily available. Ideally, the choice of antibiotics would be
pathogen-specific; empiric choices must be based on knowledge of
current, institution-specific patterns of microbial prevalence and
resistance and the pathogens most likely to cause infection.
Many institutions provide care for patients from a wide geographic
area and are less able to rely on nosocomial patterns alone to
predict antimicrobial susceptibility patterns of the possible
causative pathogens in a given individual. Antibiotic pressures from
communities also contribute to the resistance pattern.
Each patient presents his or her own unique history of previous
antibiotic exposures, co-morbidities, pathogen colonizations, risk
factors, and medication intolerances. The design of a regimen should
take into account as many of these variables as possible. For
example, glycopeptides (ie, vancomycin) generally are not used as
initial treatment for a febrile episode. Beta-lactams are the
preferred agents, unless the patient has a history of
methicillin-resistant S aureus (MRSA), is known to be
colonized by antibiotic-resistant streptococci or enterococci, is
receiving high-dose mucositis-inducing chemotherapy, or has a
clinically significant catheter-site infection.
Traditionally, patients with fever and neutropenia have been
hospitalized to receive intravenous antibiotics and then discharged
at the completion of a successful treatment course. Patients remained
hospitalized even when their fever had quickly resolved (within a few
days). It is now considered possible to discharge patients who
experience rapid defervescence, especially those with resolving
neutropenia, to continue their antibiotic regimen on an outpatient
basis. Studies that have evaluated an outpatient treatment approach
find this a safe and effective alternative for low-risk
patients.[7-9] Low-risk patients are usually those who
are clinically stable, have no major co-morbidities and have
responding cancer. When such low-risk patients have
received ambulatory treatment, the risk of infection-associated
complications and deaths has been low.[7-9]
The success of ambulatory therapy depends on being able to accurately
identify low-risk patients and having an effective ambulatory
infrastructure to care for patients 24 hours per day, 7 days a week.
Also important is the ability of the patients to get to the emergency
center easily and quickly, should their clinical condition change.
Thus, while this practice is theoretically appealing and is supported
by a small number of clinical trials, successful implementation at
most institutions will require development of the appropriate
infrastructure for emergency outreach and management. Treatment
centers or clinics that currently provide such highly accessible
outpatient services appear to be very successful and patient
satisfaction seems high.
The perceived cost-effectiveness of ambulatory treatment of fever and
neutropenia has yet to be demonstrated in practice. A single
week-long hospital stay may turn out to be less expensive than
outpatient care if the latter requires emergency room visits for
poorly controlled infection. Finally, the availability of orally
active antibiotics with good gram-positive and gram-negative pathogen
coverage is important for the success of ambulatory antibiotic
therapy in the febrile hematologic/oncologic patient.
Although patients may be discharged on parenteral antibiotics, the
benefits of orally active agents are obvious. In this regard,
linezolid (Zyvox) appears to be the first option of an antibiotic
that is active following both parenteral and oral administration, and
has excellent activity against gram-positive infections. The
bioavailability of linezolid in the setting of mucosal disruption
caused by chemotherapy-induced mucositis must still be investigated.
Empiric antibiotic treatment for most patients with fever and
neutropenia is with high-dose, broad-spectrum monotherapy or
antibiotic combinations. Individual practitioners
preferences as to specific drug choice vary widely. Three recommended
approaches are: monotherapy with either a carbapenem or an
extended-spectrum antipseudomonal cephalosporin; combination therapy
using an aminoglycoside and an antipseudomonal penicillin or
cephalosporin, or a combination of ciprofloxacin (Cipro) with
piperacillin (Pipracil). Any of the preceding regimens may be
combined with intravenous vancomycin in select clinical
In many cases, such treatment adequately manages febrile episodes,
even in cases in which in vitro resistance of a strain would indicate
a lack of drug efficacy. If fever does not resolve early (within
about 48 hours), changes in the initial regimen may be effective.
Antimicrobial resistance is of concern and limits the efficacy of
antibiotics that have been used in the past. For example, the growing
resistance to glycopeptides (ie, vancomycin) among enterococcal
strains, and the potential fatality associated with such resistant
infections, has alerted most clinicians to the need to use care in
prescribing this class of antibiotics. Fortunately, new drugs are
being developed that have excellent activity among many gram-positive
pathogens, with minimal or no inherent resistance.
The streptogramin drug combination quinupristin/dalfopristin still
has relatively high activity in most bacterial species, although
resistance is emerging, and its activity against Enterococci faecalis
is poor. Glycylcycline derivatives (tetracycline class), and new
drugs in the macrolide/ketolide and carbapenem classes, are being
tested as possible additions to the antibiotic armamentarium.
Another new class of drugs, the oxazolidinones, which includes
linezolid, has shown excellent early activity, including activity
among multidrug-resistant gram-positive species.[12, 13, 14] The fact
that the oxazolidinones are synthetic agents unrelated to any known
class of available antibiotics suggests that the development of
resistance may be retarded. Linezolid has been found to be active
against clinically significant gram-positive species, including
methicillin-resistant S aureus, vancomycin-resistant
enterococci, and even penicillin-resistant Streptococcus pneumoniae,
with no evidence of in vitro resistance or cross-resistance with
other antibiotic classes.
It now is clear that antibiotic usage can exacerbate resistance among
bacteria. Greater exposure to antibiotics, particularly among
hospitalized populations, is associated with the emergence of
resistance to specific antibiotics and to other agents in the same
antibiotic class. The practice of prophylactic antibiotic use also
may alter pathogen species mix and influence the emergence of
resistant strains. While prophylactic treatment is important in some
cases (eg, transplant recipients), it should be administered with a
recognition of the risk of resistance.
Balancing the need for adequate antibiotic use, control of
bloodstream infections, the prevention of antibiotic overuse, and
associated facilitation of resistance is an ongoing struggle. One way
to reduce the incidence of resistance is to reduce the use of
specific antibiotics, particularly glycopeptides. This can be
accomplished with an awareness of the problem and determination
within the institution and practitioners to limit these drugs for
only those cases in which they are specifically indicated.
Recent trials have shown that using drug combinations that include
piperacillin/tazobactam (Zosyn) as empiric therapy can reduce the
need for glycopeptides and decrease glycopeptide resistance.  A
switch in treatment away from glycopeptides or cephalosporins can
also reduce the incidence of resistant strains.[17,18] The use of
alternate new antibiotics, such as quinupristin/dalfopristin (a
streptogramin antibiotic), linezolid (an oxazolidinone), and
glycylcyclines (new derivatives of tetracycline), may be other
clinically important options.
Standard infection control measures are other strategies that must
not be overlooked, and include careful hand-washing by all staff who
come into contact with patients, meticulous catheter insertion and
maintenance care, and isolation techniques (for example, through the
food chain) for patients known to harbor antibiotic-resistant
pathogens (ie, MRSA, VRE, etc.).
Because empiric therapy is still the mainstay for treatment of fever
and neutropenia in immunocompromised cancer patients, knowledge of
pathogen prevalence and resistance patterns will continue to be
essential. The accumulation of antimicrobial resistance via multiple
mechanisms will require the implementation of consistent infection
control measures, appropriate antibiotic usage, plus the continued
development of novel antibiotics. In the foreseeable future, this
avenue of treatment will be the only reliable protection against
fatal infection for high-risk, neutropenic patients. Careful risk
assessment and, when possible, patient-specific and pathogen-specific
treatment can reduce excessive antimicrobial use and inhibit the
development of resistance.
Although most patients with fever and neutropenia will continue to
receive empiric antibiotics in a hospital setting, there is a trend,
particularly in the United States, to treat low-risk
patients who are expected to have a low incidence of complications in
an outpatient setting. Once-daily dosing, the availability of
antibiotics with long biological half-lives, and antibiotics with
both oral and parenteral formulations facilitate both inpatient and
outpatient therapy. The desire of many patients to return to a home
setting as soon as possible is one factor that is fueling the shift
to ambulatory care for low-risk patients. However, there are a number
of considerations before ambulatory antibiotic therapy can become a
successful strategy in the management of such patients, including an
infrastructure to provide 24-hour emergency treatment as needed, and
the ability of ambulatory patients to reach such centers quickly.
In the future, our attention must continue to be focused on
minimizing inappropriate antibiotic use, while maintaining (and
improving) our awareness of pathogen prevalence and resistance
patterns. The value of standard infection control measures cannot be
underestimated as a very effective means to reduce the need for
treatment and transmission of resistant strains (Table
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