Download The Infectious Diseases Society of America 2002 Guidelines for the

The Infectious Diseases Society of America
2002 Guidelines for the Use of Antimiaobial
Agents in Patients with Cancer and Neutropenia:
Salient Features and Comments
Kenneth V. I. Rolston
University of Texas M D. Anderson Cance' Center, Houston, Texas
Infection remains the most common complication of chemotherapy-induced neutropenia. Bacterial infections
predominate initially. Invasive fungal infections occur in patients with prolonged neutropenia. Chemoprophylaxls is recommended only for patients at high risk. Initial empirical therapy is based on local epidemiology
and drug-susceptibility patterns. Patients at low risk can be treated as outpatients. Other patients need hospitalbased, parenteral therapy. Several options are available, including combination regimens or monotherapy.
Initial antimicrobial coverage against Pseudomonas species is necessary. Subsequent management depends on
the nature of the febrile episode. If defervescence occurs within 3-5 days and no pathogen has been identified,
the initial regimen or a suitable oral regimen can be used to complete a 7- to 10-day course. If the etiology
has been established, therapy can be adjusted for optimal coverage (activity against gram-negative organisms
must be maintained). If fever persists for longer than 3-5 days, assessment for a fungal infection, a resistant
organism, or a new infectious focus should be conducted and empirical antifungal therapy instituted.
Itifectioti i,s the most comtnon complication associated
with tieutropetita and accounts tor substantial morbidtty atid nitirtality. The pt•it^ciple^s that guide the matiagertient of patietits with ticutropenia are differetit from
those for itTsmutnocompetetit patients. The Infectious
Diseases Society of America (IDSA) initially developed
guidelities for the use of antitrticrobial agents in to treat
neutropenic patients with cancer more than a decade
ago and has prodticed 2 subsequent revisions [1-3].
Here I highlight the salient featutes of the IDSA guidelities and also synthesize iiifortnation presented in the
preceding 3 articles iti this suppletnent issue of Clinical
Infectious Diseases |4-6 .
DEFINITIONS
Fever.
Fever has been defined as an oral temperature
of ^3B.3°C. Rectal temperature measurement is not
recommended, because it may precipitate bacteremia,
particularly in patients with mucositis, hemorrhoids,
anai fissures, or other localized lesions. Occasionally,
neutropenic patients with infectiort may be afebrile or
even hypothermic. This includes patients infected by
certain organisms (e.g., Cloitridium septicum, Pseudo)iioi!as acriigiuosa, and Acinetohacter species), patients
with septic shock, and patients who are receiving corticosteroids or other immunosuppressive agents known
to blunt the inflammatory response.
Neutropenia.
Neutropenia is defined as an abso-
lute neutropbil count of eitber S500 cells/mm' or
Reprint; o- CDrrespnricterir.e Dr. KeriKtn V I Rolston. Deaartment ot Intecliojs
Diseases, inteclion Carttal and Enalovee Health, Ui'ivesi'v of Texas, M. C
^1000 cells/mm' witb a predictable decline to ^500
Anderson Cancer C^n-ei, I3I5 Halccnbe Bculei'arri [BnK 4C2I, .-teLS-.uii *X 77030
celts/tntn' in 24—48 h. The incidence and severity of
ikrolstonSiTuJa'idn'SC'ii nrg;
infection is inversely proportional to the number of
Clinical Infectious Diseases
2004; 39:S44-4
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S44 • CID 2004:39 (Suppl 1) • Rnlston
All rKjIits rEistirvsn
circulating neutrophils. The duration of neutropenia is
another important determinant of the risk of infec-
tion—the more protracted the neutropenic state, the greater
the risk of infection [7, 8].
SPECTRUM OF INFECTION
Currently, gram-positive organistns cause bacteremia in patients with neutropenia more often than do gram-negative organisms [9, 10]. However, bacteremia occurs in only 15%-20%
of neutropenic patients with documented infections [ l l j .
Gram-negative organisms are isolated jnore frequently from
other sites of infection, such as the urijtary tract, respiratory
tract, and gastrointestinal tract (irt cases of enterocolitis or pcrirectal infection). These sites of infection should also be considered to achieve a more accurate picture of the spectrum of
bacterial infectioii.s. In addition, ~25'Mi-30% of infections are
polymicrobial, and ~80% of these have a gram-negative organism as a component [12]. When these are taken into account, gram-positive organisms are not as predominant as they
appear to be. For reasons that are poorly understood, anaerobic
bacteria are isolated infrequently front patients with neutropenia. Invasive fungal infections, particularly those caused by
molds such as Asptrgilliis species, tend to occur latet in the
course of neutropenia than do bacterial infections. The herpes
group of viruses (herpes simplex virus, varicella-zoster virus,
cytomegalovirus, Epstein-Barr virus, and human herpesvirus
6), and community-acquired respiratory viruses (respiratory
syncytial virus, influenza virus, and parainfluenza virus) have
emerged as important pathogens in selected subsets of patients
(hematopoietic stem cell transplant recipients}, and some of
these infections have a seasonal distribution [13 .
INITIAL EVALUATION OF FEBRILE
NEUTROPENIC PATIENTS
A thorough history and physical examination is of paramount
importance. Useful bits of historical information include the
nature and duration of anlineoplastic therapy (some regimens
are more myelosuppressive or immunosuppressive than others
and maybe associated with infection with different pathogens),
administration of prophylactic or broad-spectrum antibiotics
(because thc.se are likely to alter the patient's niicioflora), previous infections, medical procedtires, allergies, and/or drugdrug interactions. The physical e.^iLamination should entail a
careful search for potentially infected sites, including the gastrointestinal tract (oropharynx, esophagus, and perineum),
skin, nails and nailbed, eyes, lungs, vascular access sites, and
bone marrow or other biopsy sites.
Laboratory evaluation recommended for all febrile neutropenic patients includes 2 set.s of blood samples for culture for
bacteria and fungi, 1 from peripheral blood and 1 from each
catheter lumen, if present. Although quantitative cultures with
lysis centrifugation techniques are not done in most institu-
tions, they might provide useful information regarding the severit)' of infection arid might help determine the duration of
therapy [14|. (Chemical analysis, including a complete blood
cell count, an electrolyte panel, and liver and renal function
panels, should be done at baseline and every 2 or 3 days as
needed.
!Studies that provide useful information but are not necessary
lor all febrile neutropenic patients include chest radiography,
if symptoms are present or outpatient management is being
considered; culture of urine, if patients are catheterized or
symptomatic; and culture of stool and screening for Clostridium
dlfficUe toxin in patients with diarrhea. Testing of CSF and joint
fluid should be done only when signs of local infection are
present. All drainage materials should be subjected to appropriate smears and cultures (including for detection of acid-fast
bacilli and fungi). Screening for resistant organisms (e.g., methicillin-resistant Staphylococcus aureus and vancomycin-resistant
enterococci) is recommended only for infection control purposes. Measurements of levels of C-reactive protein, procakitonin, and otber cytokines may occasionally provide useful information but are not routinely recommended.
INITIAL ANTIBIOTIC THERAPY
The prompt administration of empirical antibiotic therapy
based on local epidemiology and drug-susceptibility patterns
is essential, because infections may progress rapidly in patients
with neutropenia [3]. Initial therapy is directed primarily at
bacterial pathogens, because fungal, viral, or protozoa! organisms rarely cause tbo initial infection. Not all febrile neutropenic
patients have tbe same risk of developing medical morbidity
or serious complications during a febrile episode. A "low-risk"
subset can be identified at the onset of the febrile episode by
means of various risk prediction rules [15, 16]. These patients
arc candidates for outpatient management with oral or intravenous antibiotics [17[. Mast outpatient regimens are quinolone-based combinations (e.g., ciprofloxacin plus amoxicillin-claviilanate or clindamycin), Monotberapy with newer,
broad-spectrum quinolones (gatifloxacin and moxifloxacin) is
being evaluated but cannot yet be recommended [IK],
Patients not identified as being at low risk of serious complications need hospital-based, parenteral, broad-spectrum antibiotic therapy. When selecting empirical regimens, several factors need to be considered in addition to local epidemiology
and drug-susceptibility patterns. Potential toxicities and allergies might limit the use of certain agents. The use of multiple
nephrotoxic agents (e.g., cisplatin, cyclosporine, aminogiycosides, and polyenes) to treat the same patient should be avoided
if possible. Blood levels of potentially toxic agents should be
monitored to preempt toxicity. Most febrile neutropenic patients wiil have indwelling catheters in place for vascular access.
inos lor Febrile NeutropcnJL- l\itients " CID 2004:39 (Suppl 1) • S45
In general, these may be left in place unless there is evidence
of tunnel infection or documented infection caused by Bacillus
species, Corynebacterium jeikeium, S. aureus, P. aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, or Candida
species. Rotation of parenteral therapy through all lumens of
multilumen catheters is also recommended.
Two general schemes of intravenous antibiotic therapy are
used: monotherapy or combination therapy. Combination therapy is subdivided into regimens that do or do not contain a
glycopeptide (i.e., vancomycin, or teicoplanin when available).
Inclusion of agents such as linezolid or quinupristin-dalfopristin in empirical regimens has not been well studied and is
not recommended.
Combination therapy.
When combination regimens are
being chosen, a decision regarding the initial inclusion of a
glycopeptide needs to be made. If a glycopeptide is not deemed
necessary, a combination regimen will usually consist of an
aminoglycoside (amikacin, gentamicin, or tobramycin) plus an
extended-spectrum cephalosporin (cefepime or ceftazidime),
an antipseudomonal penicillin (piperacillin-tazobactam or ticarcillin-clavulanate), or a carbapenem (imipenem or meropenem). Combinations of 2 /S-lactam agents have been used
but have fallen out of favor because of increased potential for
the emergence of resistance. When vancomycin is deemed necessary, any of the agents listed above can be combined with it,
with or without an aminoglycoside. Combinations that include
a quinolone should be used only for patients who have not
received quinolone prophylaxis.
The advantages of combination therapy include potential
synergistic activity against some organisms and a reduction in
the emergence of drug-resistant strains during therapy, although data regarding this issue are conflicting. The major
disadvantages are increased toxicity (e.g., nephrotoxicity, ototoxicity, and rashes) and drug-drug interactions.
Monotherapy.
Comparative studies have shown no significant differences between the outcomes of monotherapy and
combination regimens when used empirically [3]. Agents recommended for monotherapy include cefepime and ceftazidime,
among the cephalosporins (although resistance to ceftazidime
has increased considerably at many institutions), and the carbapenems imipenem and meropenem (but not ertapenem)
[19-21]. The quinolones are not recommended for monotherapy, although the potential of some newer quinolones (gatifloxacin and moxifloxacin) for monotherapy for low-risk
febrile neutropenic patients is being evaluated [18]. Aminogiycosides should not be used as single agents to treat patients
with neutropenia under any circumstances [22]. The fixed combination piperacillin-tazobactam administered as a single agent
has been less well evaluated but might be potentially useful for
some patients [23-25]. Patients receiving monotherapy should
be closely monitored for treatment response, adverse events.
S46 • CID 2004:39 (Suppl 1) • Rolston
superinfections with organisms such as methicillin-resistant S.
aureus and methicillin-resistant Staphylococcus epidermidis,
vancomycin-resistant enterococci, and S. maltophilia, and the
development of resistance while undergoing therapy [26]. lt
may be prudent to administer combination therapy to patients
with complex, tissue-based infections and those with polymicrobial infections (pneumonia, perirectal infections, or enterocolitis) and monotherapy to patients with unexplained fever
or simple infections [27].
MANAGEMENT DURING THE FIRST
WEEK OF THERAPY
To determine the efficacy of the initial regimen, it is generally
necessary to administer it for 3-5 days. Subsequent treatment
and its duration will depend on the nature of the infection
(i.e., whether it is pneumonia, bacteremia, or unexplained fever) and on whether the patient is in a low-risk or high-risk
subset. Modification of the initial regimen before completion
of 3 days of treatment is indicated if there is clinical deterioration or if it is mandated by microbiological information from
a positive culture result.
If defervescence is achieved within 3-5 days, but no specific
etiology has been established, low-risk patients can be discharged with treatment with an oral fluoroquinolone. Highrisk patients should receive the initial regimen for at least 7
days before discontinuation of therapy. If a causative pathogen
is identified, therapy can be adjusted to provide optimal coverage, but broad-spectrum coverage needs to be maintained to
avoid breakthrough infections. Antibiotic treatment should be
continued for a minimum of 7 days and/or until culture results
indicate a microbiological response, infection has resolved at
all sites, and the patient is asymptomatic. For documented
infections, it is desirable for the neutrophil count to have risen
to >500 cells/mm^ before therapy is stopped. Careful monitoring is necessary if antibiotic therapy is stopped for patients
with persistent neutropenia.
If fever persists for >3-5 days, the patient needs to be reassessed for the development of a drug-resistant organism or a
new site of infection (e.g., an abscess or at a catheter site).
Various tests, including additional cultures, radiographic studies, and, on occasion, invasive procedures, ought to be part of
the reassessment. If this reassessment reveals a cause of the
fever, a change in therapy should be made accordingly (e.g.,
strengthening antimicrobial coverage against gram-negative,
gram-positive, or anaerobic organisms). If reassessment does
not yield a cause, the addition of empirical antifungal therapy
with or without modification of the antibacterial regimen is
generally appropriate. This generally consists of a polyene (a
standard or a lipid formulation of amphotericin B), particularly
if a mold infection is suspected and for patients who received
azole antifungal prophylaxis. Newer agents (i.e., voriconazole)
are being evaluated for empirical antifungal therapy but have
not yet received US Food and Drug Administration approval
for this indication [28, 29].
SUBSEOUENT MANAGEMENT ANO DURATION
OF THERAPY
Recovery from neutropenia is the most important factor influencing the duration of therapy, in the opinion of most (but
not all) authorities [7, 30]. Therapy can be stopped if no specific
infection has been documented, the neutrophil count has increased to ^500 cells/mm' for 2 consecutive days, and the
patient has been afebrile for at least 48 h. Therapy can also be
discontinued if the patient is afebrile but still neutropenic, provided that close monitoring can be ensured. When a specific
infection has been documented, appropriately adjusted therapy
should be continued until the neutrophil count has recovered
or improved, the patient has been afebrile for ~4 days, and
there is clinical, microbiological, and radiographic evidence of
resolution. Patients with persistent neutropenia should be
treated for at least 2 weeks. Empirical antifungal therapy can
be discontinued according to the same rationale mentioned
above. Treatment of documented or strongly suspected fungal
infections will depend on the specific fungal pathogen and the
nature and the site of the infection. Empirical antiviral therapy
is not recommended. The choice of specific therapy or preemptive therapy will depend on the specific pathogen being
targeted. The antiviral armamentarium is expanding and includes newer agents such as cidofovir, valganciclovir, and fomiversen. During winter months, infections with respiratory syncytial virus and influenza or parainfluenza viruses can put
hematopoietic stem cell transplant recipients and some patients
with hematologic malignancies at serious risk. These infections
can be prevented or treated with suitable agents, such as ribavirin, zanamivir, oselfamivir, rimantidine, or amantidime.
These strategies have been shown to have an impact on overall
morbidity and mortality [31, 32].
The evaluation of patients who remain febrile after the resolution of neutropenia should focus on occult or undiagnosed
infections of a fungal (e.g., chronic systemic infections with
Cattdida or Aspergillus species or other molds, or histoplasmosis), mycobacterial, or viral nature, particularly for patients
who have deficiencies in cell-mediated immunity and/or who
are receiving immunosuppressive therapy.
OTHER CONSIDERATIONS
Colony-stimulating factors (i.e., granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor) and granulocyte transfusions are not recommended for
routine use. Situations in which they might be helpful include
documented infections refractory to appropriate therapy, severe
uncontrollable fungal infections, and specific infections, such
as pneumonia [33, 34]. Human activated protein C (i.e., drotrecogin alfa) is indicated for the reduction of mortality among
patients with severe sepsis associated with acute and multiple
organ dysfunction [35]. It has, however, not been fully evaluated in patients with neutropenia or thrombocytopenia and
can increase the risk of bleeding. Routine antibacterial and
antifungal prophylaxis for all patients with neutropenia is not
recommended. High- risk patients may benefit from antibacterial prophylaxis, usually with a fluoroquinolone, and antifungal prophylaxis with fluconazole or itraconazole. Prophylaxis with trimethoprim-sulfamethoxazole (or an alterative
agent in patients allergic to this agent) is recommended for all
patients at risk for infection with Pneumocystis jiroveci. All prophylaxis should be given for the shortest duration possible.
CONCLUSIONS
Guidelines provide recommendations based on the best available evidence. They are not absolute or mandatory. They should
not be considered to be legally binding. Finally, they should be
revised at appropriate intervals, as new data become available.
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