MANAGEMENT OF FEBRILE NEUTROPENIA IN LEUKEMIA/LYMPHOMA PATIENTS (FOR PHYSCICIANS)

Guidelines of the Infectious Disease Society of America (IDSA)

INTRODUCTION

Patients undergoing cytotoxic chemotherapy and bone marrow transplantation for treatment of malignant diseases are at high risk for hematological toxicities, including neutropenia. Neutropenia and other immunological impairments increase susceptibility to infection in these patients.

The rate and degree of neutrophil decline, as well as the duration of neutropenia, have been shown to influence the risk of infection in patients with acute leukemia. The risk of infection is most significant for patients who have an absolute neutrophil count of less than 0.5 x 109/L. The incidence of bacteremia and death is greatest among patients with a granulocyte count of less than 0.5 x 109/L. The incidence of bacteremia and death is greatest among patients with a granulocyte count of less than 0.1 x 10o L. Infection remains a leading cause of morbidity and mortality for patients undergoing cancer chemotherapy and bone marrow transplantation. Infection in a neutropenic patient is difficult to evaluate because the normal inflammatory response to the infecting microorganism is blunted. Fever may be the only presenting sign of infection, and it is considered to be of infectios origin unless proven otherwise. The onset of fever in an neutropenic patient is an indication for empiric initiation of high-dose, parenteral , broad-spectrum antibiotic therapy to reduce illness and death due to infection.

Many single and multiple-agent regimens for treating febrile neutropenia have been studied.

The Infectious Diseases Society of America (IDSA) has published evidence-based, peer-reviewed guidelines for the treatment of unexplained fever in neutropenic patients. The guidelines are concerned primarily wit the choice and duration of empiric antibiotic therapy in patients with neutropenia secondary to cancer chemotherapy in the hospital setting.

The Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guidelines Panel updates guidelines established a decade ago by the Infectious Disease Society of America for the use of antimicrobial agents to treat neutropenic patients with unexplained fever in 2002.

The guidelines were prepared by a panel of experts in oncology and infectious diseases, peer-reviewed by an external group of knowledgeable practitioners, reviewed and approved by the Practice Guidelines Committee, and approval as published by the IDSA.

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 scientific publications and peer-reviewed information that has been formally presented at national and international meetings. When firm recommendations cannot be made, usually because of inadequate scientific 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 hematopietic and lymphoproliferative malignancies, but they can be applied in general to febrile neutropenic patients with other neoplastic diseases.

INITIAL ANTIBIOTIC THERAPY

Because the progression of infection in neutropenic patients can be rapid, and because such patients with early bacterial infections cannot be reliably distinguished from noninfected patients at presentation, empirical antibiotic therapy should be administered promptly to all neutropenic patients at the onset of fever.

A febrile patients who are neutropenic but who have signs or symptoms compatible with an infection should also have empirical antibiotic therapy begun in the same manner as do febrile patients.

Gram-positive bacteria now account for ~ 60%-70% of microbiologically documentation infections, although the rate of gram-negative infections is increasing in some centers. Some of the gram-positive organisms may be Methicillin resistant and, therefore, are susceptible only to vancomycin, teicoplanin quinupristin-dalfopristin and linezolid.. These are often more indolent infections (e.g. infections due to coagulase-negative staphylococci, vancomycin-resistant enterococci or Corynebacterium jeikeium), and a few days' delay in administration of specific therapy may not be detrimental to the patient's outcome, although it may prolong the duration of hospitalization. Other gram-positive bacteria (S. aureus, viridans streptococci, and pneumococci) maycause fulminant infections resulting in serious complications or death, if not treated promptly. Gram-negative bacilli, especially P. aeruginosa, Escherichia coli, and Klebsiella species, remain prominent causes of infection and must be treated with selected antibiotics. Although fungal infections are usually superinfections, in some cases, Candida species or other fungi can cause primary infections.

In the selection of the initial antibiotic regimen, one should consider the type, frequency of occurrence, and antibiotic susceptibility of bacterial isolates recovered from other patients at the same hospital. The use of certain antibiotics may be limited by special circumstances, such as drug allergy or organ (e.g. renal or hepatic) dysfunction. Such drugs as cisplatin, amphotericin B, cyclosporine, vancomycin and aminoglycosides should be avoided in combination because of their additive renal toxicity.

Drug plasma concentrations should be monitored when they are helpful in predicting therapeutic success and toxicity (e.g. aminoglycosides).

Because the progression of infection in neutropenic patients can be rapid, and because such patients with early bacterial infections cannot be reliably distinguished from noninfected patients at presentation, empirical antibiotic therapy should be administered promptly to all neutropenic patients at the onset of fever. A febrile patients who are neutropenic but who have signs or symptoms compatible with an infection should also have empirical antibiotic therapy begun in the same manner as do febrile patients.

Gram-positive bacteria now account for ~ 60%-70% of microbiologically documentation infections, although the rate of gram-negative infections is increasing in some centers. Some of the gram-positive organisms may be Methicillin resistant and, therefore, are susceptible only to vancomycin, teicoplanin quinupristin-dalfopristin and linezolid.. These are often more indolent infections (e.g. infections due to coagulase-negative staphylococci, vancomycin-resistant enterococci or Corynebacterium jeikeium), and a few days' delay in administration of specific therapy may not be detrimental to the patient's outcome, although it may prolong the duration of hospitalization. Other gram-positive bacteria (S. aureus, viridans streptococci, and pneumococci) maycause fulminant infections resulting in serious complications or death, if not treated promptly. Gram-negative bacilli, especially P. aeruginosa, Escherichia coli, and Klebsiella species, remain prominent causes of infection and must be treated with selected antibiotics. Although fungal infections are usually superinfections, in some cases, Candida species or other fungi can cause primary infections.

In the selection of the initial antibiotic regimen, one should consider the type, frequency of occurrence, and antibiotic susceptibility of bacterial isolates recovered from other patients at the same hospital. The use of certain antibiotics may be limited by special circumstances, such as drug allergy or organ (e.g. renal or hepatic) dysfunction. Such drugs as cisplatin, amphotericin B, cyclosporine, vancomycin and aminoglycosides should be avoided in combination because of their additive renal toxicity. Drug plasma concentrations should be monitored when they are helpful in predicting therapeutic success and toxicity (e.g. aminoglycosides).

Catheter removal combined with generous debridement of infected tissue is also advisable for patients with atypical mycobacterial infection.

Bactermia due to Bacillus species, P. aeruginosa, Stenotropohomonas maltophilia, C. jeikeium, or vancomycin resistant enterococci, and fungemia due to Candida species, often respond poorly to antimicrobial treatment, and prompt removal of the catheter is recommended, if possible. Established infections with Acinetobacter species also often require removal of the infected catheter. The use of antibiotic-impregnated catheters, administration of antibiotics through each lumen of the involved catherter, rotation of antibiotic delivery through multilumen catheters, and the use antibiotic-containing heparin lock solutions ("antibiotic lock therapy") to supplement systemic therapy have been proposed by some investigators. II. 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. 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 infections (e.g. rigors, hypotension) other than fever.

TREATMENT WITH INTRAVENOUS ANTIBIOTICS

The first step in antibiotic selection is to decide whether the patient is a candidate for patient or outpatient management with oral or intravenous antibiotics.

Three general schemes of intravenous antibiotic therapies with similar efficacy are considered here, with the caveat that one may be more appropriate for certain patients and in certain institutions than others. The schemes are as follows: single-drug therapy (monotherapy), 2-drug therapy without a glycopeptide (vancomycin), and therapy with glycopeptide (vancomycin) plus 1 or 2 drugs.

Three general schemes of intravenous antibiotic therapies with similar efficacy are considered here, with the caveat that one may be more appropriate for certain patients and in certain institutions than others. The schemes are as follows: single-drug therapy (monotherapy), 2-drug therapy without a glycopeptide (vancomycin), and therapy with glycopeptide (vancomycin) plus 1 or 2 drugs.

Single-drug therapy (monotherapy)

Several studies have shown no striking differences between monotherapy and multidrug combinations for empirical treatment of uncomplicated episodes of fever in neutropenic patients. A third-or fourth-generation cephalosporin (ceftazidime or cefepime) or a carbapenem (imipenem-cilastatin or meropenem) may be used successfully as monotherapy). Physicians should be aware that extended spectrum -lactamases and type 1- lactamases have reduced the utility of ceftazidime for monotherapy. Cefepime, imipenem-cilastatin, and meropenem, unlike ceftazidime, have excellent activity against viridans streptococci and pneumococci. Vancomycin was shown to be required less frequently with cefepime than with ceftazidime monotherapy.

Piperacillin-tazobactam has also been found to be effective as monotherapy.

The patient must be monitored closely for nonresponse, emergence of secondary infections, adverse effects, and the development of drug-resistant organisms. In particular, the spectrumof drugs usually used as monotherapy does not usually cover coagulase-negative staphylococci, methicillin-resistant S. aureus, vancomycin-resistant enterococci, some strains of penicillin-resistant Streptococcus pneumoniae, and viridans streptococci.

Two-drug therapy without a glycopeptide antibiotic (vancomycin)

1. The most commonly used 2-drug therapy, excluding regimens with vancomycin, includes an aminoglycoside (gentamicin, tobramycin, or amikacin) with an antipseudomonal carboxypenicillin or ureidopenicillin (ticarcillin-clavulanic acid or piperacillin-tazobactam.

2. An aminoglycoside with an antipseudomonal cephalosporin, such as cefepime or ceftazidime

3. An aminoglycoside plus a carbapenem (imipenem-cilastatin or meropenem)

Advantages of combination therapy are potential synergistic effects against some gram-negative bacilli and minimal emergence of drug-resistant strains during treatment. The major disadvantages are the lack of activity of these combinations, such as ceftazidime plus an aminoglycoside compounds and carboxypenicillin like (ticarcillin-clavulanate).

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 specific 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. 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.

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 influence 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. Some strains of viridans streptococci are resistant to or tolerant of penicillin, but such antibiotics as ticarcillin, piperacillin, cefepime (but not ceftazidime), andcarbapenems all have excellent activity against most strains.

Teicoplanin has been evaluated as an alternative to vancomycin. Linezolid, the first FDA approved oxazolidinone, offers promise for treatment of drug-susceptible and resistant gram-positive bacterial infections, including those due to vancomycin-resistant enterococci. Quinupristin-dalfopristin, another drug that has recently been approved by the FDA, is also effective against vancomycin-resistant Enterococcus faecium.

MANAGEMENT OF THE ANTIBIOTIC REGIMEN DURING THE FIRST WEEK OF THE THERAPY

Receipt of antibiotic treatment for at least 3-5 days is usually required to determine efficacy of the initial regimen. From this point, decisions regarding further treatment are made on the basis of whether the patient had bacteremia or pneumonia, whether the fever has resolved, and whether the patient's condition has deteriorated. Some patients' conditions may deteriorate rapidly in < 3 days, necessitating reassessment of the empirical regimen.

PATIENT IS AFEBRILE WITHIN 3-5 DAYS OF TREATMENT

If a causative microbe is identified, the antibiotic regimen may be changed, if necessary, to provide optimal treatment with minimal adverse effects and lowest cost, but broad-spectrum coverage should be maintained to prevent breakthrough bacteremia. Antibiotic treatment should be continued for a minimum of 7 days or until culture results indicate that the causative organism has been eradicated, infection at all sites has resolved, and the patient is free of significant symptoms and signs.

PERSISTENT FEVER THROUGHOUT THE FIRST 3-5 DAYS OF TREATMENT

Fever that persists for > 3 days in patient for whom no infected site or organism has been identified 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) 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 wall-deficient bacteremia, or infection at an avascular site (e.g. "abscesses"or catheters). In reassessing the patient's condition after 3 days of treatment, the physician should attempt to identify factor (s) that might account for nonresponsiveness. However, some patients with microbiologically defined bacterial infections, even when adequately treated, may require > 5 days of therapy before defervescence occurs.

If the fever persists after 5 days of antibiotic therapy and reassessment does not yield a cause, 1 of 3 choices of management should be made.

1. Continue treatment with the initial antibiotic(s

2. Change or add antibiotic(s)

3. or add an antifungal drug (amphotericin B) to the regimen, with or without changing the antibiotics. A fourth choice - withdrawal of all antimicrobial drugs - will not be discussed as a valid option in these general guidelines, although, in some highly individualized cases (such as cases in which the fever is thought to be of noninfectious origin), physicians may elect to stop antibiotic therapy.

RECOMENDATION IF FEVER PRESIST FOR > 3 DAYS

Figure 3 summarizes recommendations for patients with fever that persists for > 3 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 patient's 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 5-7 more days (B-II).

DURATION OF ANTIMICROBIAL THERAPY

The single most important determinant of successful discontinuation of antibiotics is the neutrophil count. If no infection is identified after 3 days of treatment, if the neutrophil count is > 500 cells/mm3 for 2 consecutive days, and if the patient is a febrile for > 48 h, antibiotic therapy may be stopped at that time (C-III). If the patient becomes a febrile but remains neutropenic, the proper antibiotic course is less well defined. Some specialists recommend continuation of antibiotics, given intravenously or orally, until neutropenia.

This approach may increase the risk for drug toxicity and superinfection with fungi or drug-resistant bacteria. 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 discernible infections lesions, and who have no radiographic or laboratory evidence of infection, to have their use of systemic antibiotics stopped after 5-7 afebrile days, or sooner, with evidence of hematologic recovery. 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. One should consider continuous administration of antibiotics throughout the neutropenic period in patients with profound neutropenia (< 100 cells/mm3), mucous membrane lesions of the mouth or gastrointestinal tract, unstable vital signs, or other identified risk factors. In patients with prolonged neutropenia in whom hematologic recovery cannot be anticipated, one can consider stopping antibiotic therapy after 2 weeks, if no site of infection has been identified and the patient can be observed carefully.

ANTIBIOTIC PROPHYLAXIS FOR AFEBRILE NEUTROPENIC PATIENTS

Since the 1980s, several studies have shown that the frequency of febrile episodes and infectious diseases can be reduced with the administration during the early afebrile period of neutropenia.

Afebrile patients who are expected to be profoundly neutropenic (< 100 cells/mm3) are at greater risk for developing resistant infections than are those with counts of 500 cells/mm3. Additional significant risk factors include lesions that break the mucous membranes and skin, use of indwelling catheters, use of instruments (e.g. endoscopy), severe periodontal disease, history of dental procedures, postobstructive pneumonia, status of malignancy or organ engraftment, and compromise of other immune responses.

Combinations of nonabsorbable drugs, such as aminoglycosides, polymxins, and vancomycin, have been used for infection prophylaxis in the past. Prospective, randomized trials have consistently shown that orally absorbable agents, such as trimethoprim-sulfamethoxazole (TMP-SMZ) and quinolones, are more effective and better tolerated for this purpose. In addition, the increasing frequency of antibiotic resistance strongly recommends against the use of prophylactic vancomycin.

Two types of oral absorbable antibiotics may be considered for chemoprophylaxis. These are TMP-SMZ and the quinolones.

VANCOMYCIN

Intravenous vancomycin has been used as prophylaxis for catheter-related or quinolone-related gram-positive infections. Although this approach may be effective, it must be strongly discouraged because of the potential for emergence of vancomycin-resistant organisms.

ANTIFUNGAL DRUGS

Recommendations for antimicrobial prophylaxis

TMP-SMZ therapy is recommended for all patients at risk for P. carinii pneumonitis, regardless of whether they have neutropenia. However, there is no consensus to recommend TMS-SMZ or quinolones for routine use for all afebrile neutropenic patients.

Routine use of fluconazole or itraconazole for all cases of neutropenia is not recommended. However, in certain circumstances in which the frequency of systemic infection due to Candida albicans is high and the frequency of systemic infection due to other Candida species and Aspergillus species is low, some physicians may elect to administer antifungal prophylaxis

 
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