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.

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.

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.

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.

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).

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.