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 recommendations are based, whenever possible, on scientic publications and peer-reviewed information that has been formally presented at national and international meetings. When rm recommendations cannot be made, usually because of inadequate scientic 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 neutropenic patients. These guidelines have been derived predominantly from knowledge of and experience with hematopoietic and lymphoproliferative 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 particular recommendation or statement by use of the weighting system described in the 1997 guidelines (table 1) [1]. A ranking of AE indicates the strength of this recommendation, and the Roman numerals IIII indicate the quality of evidence These rankings are presented in parentheses after specic recommendations. We emphasize that no specic scheme, no specic drug or combination of drugs, and no specic 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 [1] are still valid. In an attempt to make the new guidelines more user-friendly, some of the background information and references from the 1997 version have not been included here. We have not addressed the management of drug-related allergies and other adverse effects from drugs because of limited data specic for neutropenic patients. The general principles of practice for nonneutropenic patients are also reasonable for neutropenic patients.
CLINICAL FEATURES OF THE NEUTROPENIC HOST At least one-half of neutropenic patients who become febrile have an established or occult infection, and at least one-fth of patients with neutrophil counts of !100 cells/mm3 have bacteremia. 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-spectrum antibiotics and may also cause primary infections. The primary anatomic sites of infection often include the alimentary tract, where cancer chemotherapyinduced mucosal damage allows invasion of opportunistic organisms. Similarly,

Guidelines for Febrile Neutropenic Patients CID 2002:34 (15 March) 731
Table 1. Infectious Diseases Society of AmericaUnited States Public Health Service Grading System for ranking recommendations in clinical guidelines.
Category, grade Strength of recommendation A B C D E Quality of evidence I II Evidence from 1 properly randomized, controlled trial Evidence from 1 well-designed clinical trial, without randomization; 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 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 Denition
damage to the integument by invasive procedures, such as placement of vascular access devices, often provides portals of entry for infectious organisms.
Fever. A temperature that is clearly greater than the normal constitutes a febrile state. In practice, a single oral temperature measurement of 38.3C (101F), in the absence of obvious environmental causes, is usually considered to be a fever. A temperature of 38.0C (100.4F) for 1 h indicates a febrile state. Neutropenia. When the neutrophil count decreases to !1000 cells/mm3, increased susceptibility to infection can be expected, with the frequency and severity inversely proportional to the neutrophil count [24]. Patients with neutrophil counts of !500 cells/mm3 are at considerably greater risk for infection than are those with counts of !1000 cells/mm3, and patients with counts of 100 cells/mm3 are at greater risk than are those with counts of !500 cells/mm3. In addition to the number of circulating 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/ mm3 for 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 decits in the immune response may further increase the risk for infection in a neutropenic host. EVALUATION Symptoms and signs of inammation may be minimal or absent in the severely neutropenic patient, especially if accompanied by anemia [6]. Diminished or absent induration, erythema, and

734 CID 2002:34 (15 March) Hughes et al.
Figure 1. Algorithm for initial management of febrile neutropenic patients. See tables 3 and 4 for rating system for patients at low risk. Carbapenem, imipenem or meropenem.
IDSA, the American College of Critical Care Medicine, and the Society for Healthcare Epidemiology of America [7]. Vancomycin should not routinely be used prophylactically in catheters. Insufcient data are available to recommend the routine supplemental use of urokinase for management of catheterrelated infection. Despite extensive clinical studies since the 1970s, no single empirical therapeutic regimen for the initial treatment of febrile patients with neutropenia can be recommended. The results from study to study are often not comparable, because the denitions of infectious diseases and the criteria used to assess the response to therapy vary considerably [34, 35]. Although it is generally agreed that many antibiotic regimens are effective in the control of infection with minimal toxicity, careful selection based on local patterns of infection and antibiotic susceptibilities may enhance efcacy while maintaining safety and minimizing costs. For example, several studies have indicated that not all b-lactam antibiotics are equally effective, at least at certain institutions. Antibiotic resistance among gram-negative bacilli may limit the efciency of some b-lactams at some institutions [3638].
Level of Risk for Oral Antibiotics and Outpatient Management
Treatment of carefully selected febrile neutropenic patients with oral antibiotics alone appears to be feasible for adults at low risk for complications (A-I) [3953]. In general, the use of
antibiotics by the oral route may be considered only for patients who have no focus of bacterial infection or symptoms and signs suggesting systemic infection (e.g., rigors, hypotension) other than fever. Some patients may reliably receive their prescribed therapy as outpatients, although many of the studies that have supported treatment with oral antibiotics involved hospitalized patients [43, 45]. Vigilant observation and prompt access to appropriate medical care must also be ensured 24 h per day, 7 days per week. For many patients and some institutions, outpatient therapy may not be advisable. Patients with recovering phagocyte counts are generally considered to be better candidates for outpatient treatment than are patients with decreasing counts or no indication of marrow recovery. Factors favoring low risk for serious infections among febrile neutropenic patients, which have been identied in controlled studies, are listed in table 3 [4, 4253]. These characteristics may serve as guidelines for the selection of patients for outpatient therapy. A recent international collaborative study of 1139 febrile and neutropenic patients with malignancy established and validated a scoring system to identify, at the time of presentation with fever, those patients with low risk for complications, including mortality [50]. Factors associated with lower risk for complications and a higher rate of favorable outcome (P !.001) were as follows: age !60 years (children not included), cancer in partial or complete remission, no symptoms or only mild to moderate symptoms of illness, outpatient

Quinolone-based combinations with b-lactams or glycopeptides are an option for initial therapy for patients not receiving quinolone prophylaxis. Newer agents (gatioxacin, moxioxacin, and levooxacin) have been used selectively to treat patients who have cancer, but their roles will need to be evaluated further before recommendations can be made [8689]. A recent large comparative trial showed that ciprooxacin plus piperacillin-tazobactam is as effective as tobramycin and piperacillintazobactam [90]. Any initial antibiotic regimen should include drugs with antipseudomonal activity [91]. Therapy with glycopeptide (vancomycin) plus 1 or 2 drugs. Because of the emergence of vancomycin-resistant organisms, especially enterococci, associated with excessive use of vancomycin in the hospital, administration of vancomycin should be limited to specic indications. Hospitals should adopt the recommendations of the Hospital Infection Control Practices Advisory Committee of the Centers for Disease Control and Prevention (CDC) for preventing the spread of vancomycin resistance [92]. The European Organization for Research and Treatment of Cancer (EORTC)National Cancer Institute of Canada study showed that vancomycin is not in general a necessary part of initial empirical antibiotic therapy, if it is available for subsequent treatment modications [30, 93]. At institutions at which these infections are rare, vancomycin should be routinely withheld until the results of cultures indicate the need for this antibiotic. Infections caused by gram-positive bacteria are frequently indolent, but some may be susceptible only to vancomycin and can, on occasion, be serious, leading to death in !24 h if not promptly treated. Although vancomycin has not been shown to inuence overall mortality due to gram-positive cocci as a group, mortality due to viridans streptococci may be higher among patients not initially treated with vancomycin [94, 95]. Some strains of viridans streptococci are resistant to or tolerant of penicillin, but such antibiotics as ticarcillin, piperacillin, cefepime (but not ceftazidime), and carbapenems all have excellent activity against most strains. At institutions at which these gram-positive bacteria are common causes of serious infections, vancomycin may be incorporated into initial therapeutic regimens of some high-risk patients but discontinued 2448 h later if no such infection is identied. Some organisms, such as Bacillus species and C. jeikeium, are susceptible only to vancomycin, but these infections are usually not severe. Inclusion of vancomycin in initial empirical therapy may be prudent for selected patients with the following clinical ndings: (1) clinically suspected serious catheter-related infections (e.g., bacteremia, cellulitis), (2) known colonization with penicillin- and cephalosporin-resistant pneumococci or methicillin-resistant S. aureus, (3) positive results of blood culture for gram-positive bacteria before nal identication and susceptibility testing, or

Guidelines for Febrile Neutropenic Patients CID 2002:34 (15 March) 737
(4) hypotension or other evidence of cardiovascular impairment [92]. For some physicians in some medical centers, intensive chemotherapy that produces substantial mucosal damage (e.g., high-dose cytarabine) or increases the risk for penicillin-resistant streptococcal infections (e.g., infection with viridans streptococci), as well as prophylaxis with quinolones for afebrile neutropenic patients before onset of fever, are also considered indications for vancomycin to be included in the initial regimen. Sudden increase of temperature to 140C has, to some extent, been predictive of sepsis with viridans streptococci [95]. Several studies have evaluated vancomycin drug combinations for the treatment of neutropenic patients with fever; these combinations have included vancomycin plus any of the following antibiotics: imipenem [72, 96], cefepime [60], amikacin and ticarcillin [94], meropenem [74], ciprooxacin [97], aztreonam [98, 99], ceftazidime [100104], ceftazidime and amikacin [30, 103], tobramycin and piperacillin [105, 106], ticarcillin [93], and ceftazidime and ticarcillin [38]. Although the combination of ceftazidime and vancomycin has been used most extensively in the past, in some medical centers, the possible risk of emergence of resistance to ceftazidime may justify the recommendation that vancomycin be preferentially used in combination with cefepime or a carbapenem (imipenem-cilastatin or meropenem). Teicoplanin has been evaluated as an alternative to vancomycin (see appendix 1 in the 1997 guidelines [1]) in limited clinical trials [105, 106], but the drug has not received approval from the US Food and Drug Administration (FDA), and additional studies are needed to place it in proper perspective. Linezolid, the rst FDA-approved oxazolidinone, offers promise for treatment of drug-susceptible and -resistant gram-positive bacterial infections, including those due to vancomycin-resistant enterococci, although an associated myelosuppression may be problematic [107]. Quinupristin-dalfopristin, another drug that has recently been approved by the FDA, is also effective against vancomycin-resistant Enterococcus faecium. Further studies are needed before guideline recommendations can be made for these drugs.
of hospital- and catheter-related infection. Among the oral regimens that have been most thoroughly evaluated are ooxacin, ciprooxacin, and ciprooxacin plus amoxicillin-clavulanate. Quinolones are generally not as effective as cephalosporins or carbapenems in treating gram-positive infections and may predispose to the development of viridans streptococcal sepsis [95]. Quinolones are not currently approved for use in children !18 years of age, although toxicity has not been high in pediatric trials [101]. Although controlled studies of children have assessed early switching from intravenous to oral antibiotics, other than quinolones [52, 53], only a few children have been included in studies of initial empirical oral therapy for febrile neutropenia [108]. At this time, there are insufcient data to recommend initial empirical oral therapy for fever and neutropenia in children. However, early discharge of patients while they are receiving treatment with cexime after 48 h of inhospital observation of treatment with intravenous antibiotics may be considered for selected children [52, 53].

100 cells/mm3, and who are at low risk for complications may have intravenous antibiotic treatment stopped and therapy continued with oral cexime. The controlled studies of adults [43, 45] and children [52, 53] were done with inpatients, so one cannot be assured that similar results will occur if patients are discharged while receiving treatment with oral antibiotics. Some investigators have advocated discontinuation of antibiotic therapy for patients without documented infections and with signs of early marrow recovery before completing a 7-day course [113116]. At present, there is not enough evidence or experience with this approach to endorse its use. It is important to realize that the suggestions made here are somewhat arbitrary, and a comprehensive assessment is essential for each patient. Antibiotic therapy alone, in the presence of persistent neutropenia, may suppress but not eradicate the infection. Recommendations for afebrile patients. Figure 2 presents a guide for treatment of patients who become afebrile within 35 days of starting treatment. Modify antibiotic therapy for specic organisms, if identied, and continue use of broadspectrum antibiotics for 7 days, until cultures are sterile and the patient has clinically recovered. If the causative organism is not found and the patient is receiving drugs intravenously and was at low risk at the onset of treatment, treatment may be changed to oral ciprooxacin plus amoxicillin-clavulanate for adults or cexime for children after 48 h, if clinically preferable. The same intravenous antibiotics should be continued for high-risk patients (B-II).
Persistent Fever throughout the First 35 Days of Treatment
Fever that persists for 13 days in patients for whom no infected site or organism has been identied suggests that the patient has a nonbacterial infection, a bacterial infection resistant to the antibiotic(s) or slow to respond to the drug in use, the emergence of a second infection, inadequate serum and tissue levels of the antibiotic(s), drug fever, cell walldecient bacteremia [117], or infection at an avascular site (e.g., abscesses or catheters). In reassessing the patients condition after 3 days of treatment, the physician should attempt to identify factor(s) that might account for nonresponsiveness (gure 3). However, some patients with microbiologically dened bacterial infections, even when adequately treated, may require 5 days of therapy before defervescence occurs [30, 85, 104, 111, 112]. Reassessment includes a review of all previous culture results, a meticulous physical examination, chest radiography, ascertaining the status of vascular catheters, culturing of additional blood samples and specimens of specic sites of infection, and diagnostic imaging of any organ suspected of having infection. If possible, the determination of serum concentrations of antibiotics, especially aminoglycosides, may be useful in assessment of drug therapy. Ultrasonography and high-resolution CT

Figure 3.

Guide to treatment of patients who have persistent fever after 35 days of treatment and for whom the cause of the fever is not found.
tericin B therapy should be introduced empirically, most believe that the patient who remains febrile and profoundly neutropenic for 5 days, despite the administration of broad-spectrum antibiotics in adequate dosages, is a candidate for antifungal therapy. Individual cases may have clinical features that will direct use of amphotericin B earlier, later, or not at all. Such an exception might be the patient who has no discernible fungal lesion, has neither Candida nor Aspergillus species isolated from any site, and is expected to have an increase in the neutrophil count within a few days. In this case, treatment with amphotericin B could be withheld and the patient should be monitored carefully, if the patient is clinically stable. Every effort should be made to determine whether systemic fungal infection exists (e.g., biopsy of lesions should be performed; radiographs of chest and sinuses should be obtained; nasal endoscopy should be performed, if indicated, to investigate sinusitis; and cultures and CT of the abdomen and chest should be done) before amphotericin B therapy is started. The empirical decision to start use of the drug is not as difcult as the decision to discontinue use of the drug. Much of the evaluation at this time is to aid in a decision about when to stop antifungal treatment later. It is noteworthy that a CT scan done after the neutrophil count has recovered may show some enhancement of earlier infection even with successful treatment. Comparative trials have indicated that lipid formulations of amphotericin B can be used as alternatives to amphotericin B deoxycholate for empirical therapy. Although they do not appear to be substantially more effective, there is less drug-related toxicity [119122]. For example, in a clinical trial comparing
amphotericin B with liposomal amphotericin B (AmBisome; Fujisawa Healthcare), the overall success rates were the same for both preparations, although breakthrough fungal infections occurred more frequently with amphotericin B and there was a higher proportion of side effects with this preparation [120]. A double-blind comparative study showed that liposomal amphotericin B (AmBisome) had superior safety to amphotericin B lipid complex (Abelcet; Elan Pharmaceuticals) and a similar therapeutic success rate [121]. The investigators of a comparative unblinded study concluded that Abelcet and AmBisome are equally effective for the treatment of suspected and documented fungal infections in patients with leukemia; safety related to severe adverse effects on the kidneys or liver was similar, but the milder toxic reactions associated with acute infusion-related reactions and increases in the creatinine level were associated with Abelcet use, and more liver function test abnormalities were associated with AmBisome use [122]. Two recent prospective randomized trials have demonstrated that uconazole is an acceptable alternative to amphotericin B for use as empirical antifungal therapy at institutions at which mold infections (e.g., Aspergillus species) and drug-resistant Candida species (Candida krusei and some strains of Candida glabrata) are uncommon. Patients should not be considered for empirical uconazole treatment if they have symptoms of sinusitis or radiographic evidence of pulmonary infection or have received uconazole as prophylaxis. Also, any patient from whom Aspergillus species were yielded on culture should not be considered. Patients with pulmonary infection or sinusitis have a high probability of infection with Aspergillus species or

Guidelines for Febrile Neutropenic Patients CID 2002:34 (15 March) 741
Figure 4. Suggested scheme for estimating the duration of antibiotic administration under various conditions. See tables 3 and 4 for rating system for patients at low risk. ANC, absolute neutrophil count.
other molds. Amphotericin B still provides a broader spectrum of activity than does uconazole, although it does not appear to prevent subsequent aspergillosis [123, 124]. A recent systematic meta-analytical review of lipid-based formulations of amphotericin B and the azoles against amphotericin B deoxycholate in febrile neutropenic patients showed no consistent treatment advantages associated with either formulation [125]. In a recent controlled study of 384 neutropenic patients with cancer, itraconazole and amphotericin B were equivalent in efcacy as empirical antifungal therapy, although itraconazole was associated with less toxicity [126]. Caspofungin, an echinocandin, has recently been approved by the FDA for the treatment of invasive aspergillosis refractory to amphotericin B and itraconazole. Data are not adequate for recommendations regarding its use for treatment of febrile neutropenic patients. Recommendations if fever persists for 13 days. Figure 3 summarizes recommendations for patients with fever that persists for 13 days. Begin diagnostic reassessment after 3 days of treatment. By day 5, if fever persists and reassessment is unrevealing, there are 3 options: (1) continue administration of the same antibiotic(s) if the patients condition is clinically stable, (2) change antibiotics if there is evidence of progressive disease or drug toxicity, or (3) add an antifungal agent if the patient is expected to have neutropenia for longer than 57 more days (B-II).
742 CID 2002:34 (15 March) Hughes et al.
DURATION OF ANTIMICROBIAL THERAPY The single most important determinant of successful discontinuation of antibiotics is the neutrophil count. If no infection is identied after 3 days of treatment, if the neutrophil count is 500 cells/mm3 for 2 consecutive days, and if the patient is afebrile for 48 h, antibiotic therapy may be stopped at that time (C-III). If the patient becomes afebrile but remains neutropenic, the proper antibiotic course is less well dened. Some specialists recommend continuation of antibiotics, given intravenously or orally, until neutropenia is resolved (B-II) [108, 127, 128]. This approach may increase the risk for drug toxicity and superinfection with fungi or drug-resistant bacteria [129]. It is reasonable for neutropenic patients who appear healthy clinically, who were in a low risk category at onset of treatment, who have no discernible infectious lesions, and who have no radiographic or laboratory evidence of infection, to have their use of systemic antibiotics stopped after 57 afebrile days, or sooner, with evidence of hematologic recovery [44, 113, 127, 130, 131]. If use of antibiotics is stopped while the patient has neutropenia, the patient must be monitored closely and intravenous antibiotics restarted immediately on the recurrence of fever or other evidence of bacterial infection (gure 4) [132]. One should consider continuous administration of antibiotics throughout the neutropenic period in patients with profound neutropenia (!100 cells/mm3), mucous membrane lesions of

746 CID 2002:34 (15 March) Hughes et al.
The expensive colony-stimulating factors are frequently used routinely, when they should be used according to well-thoughtout guidelines, such as those of the American Society of Clinical Oncology [156]. Under some circumstances, such as high-dose chemotherapy with either bone marrow or peripheral blood stem cell support, colony-stimulating factors may be both clinically and economically effective [189]. Liposomal and lipid-complex amphotericin B cost 1060 times more than does amphotericin B deoxycholate and should be used only for the FDA-approved indications: for cases of aspergillosis that do not respond to the conventional amphotericin B preparation and for patients who cannot tolerate the conventional drug or who have or are at high risk for renal insufciency. Avoidance of the indiscriminate use of antifungal and antiviral drugs during the febrile neutropenic episode requires adherence to the policy of use only when adequate scientic data support the indication. A simplied approach to performing marginal cost-effectiveness analyses is detailed in a report from the Centers for Disease Control and Prevention [190] and requires a description of the program and of the health outcomes averted and the timing of these events; the rates of health outcomes and the preventable fraction of the health outcomes averted; the costs per unit of the intervention and the costs of the health outcomes prevented; and the side effects incurred. Another guide to decision analysis and economic evaluation is provided by Haddix et al. [191]. Because costs differ from location to location, the cost-effectiveness of an intervention in the management of fever and neutropenia must be determined at the physicians respective hospitals.

Acknowledgments

We acknowledge with appreciation the following expert consultants who made valuable suggestions for the guidelines: Alain Cometta (Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland), Gerald R. Donowitz (University of Virginia, Charlottesville), Claudio Viscoli (University of Genova, Genova, Italy), and James C. Wade (Fred Hutchinson Cancer Research Center, Seattle).

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