Treatment

Empiric antibiotic therapy forms the cornerstone of treatment for febrile neutropenia and should be started immediately upon diagnosis. With such treatment, reductions in infection-related mortality have been observed over the past three decades. However, a mortality rate of 8 % among contemporary hospitalized cancer patients with febrile neutropenia would seem to indicate that this condition remains a serious threat to life (Crawford et al. 2004). It has become clear that patients with febrile neutropenia are not all alike, and treatment regimens may be individualized. The Infectious Diseases Society of America (IDSA) has published guide-

Table 13.6. Infectious Diseases Society of America (IDSA) recommended antibiotic regimens for empiric treatment of febrile neutropenia

Setting

Regimen

Low risk

Ciprofloxacin plus amoxicillin-clavulanate

High risk

Monotherapy

Cefepime or

Ceftazidime or

Imipenem or

Meropenem

Combination

Aminoglycoside plus

Antipseudomonal penicillin or

Cephalosporin (cefepime or ceftazidi-

me) or

Carbapenem

Combination

Cefepime or ceftazidime ± aminoglycoside

with vanco-

or

mycin

Carbapenem ± aminoglycoside or

Antipseudomonal penicillin + aminoglyco-

side

lines to facilitate the treatment of cancer patients with neutropenic fever (Table 13.6) (Hughes et al. 2002). A complete review of this complex topic is beyond the scope of this chapter; however, the treatment principles deserve discussion.

The IDSA treatment guidelines are based upon an individualized assessment of risk as determined by prognostic models. One such model, the Multinational Association of Supportive Care in Cancer (MASCC) Scoring Index, accurately predicts the risk of infection-related complications in neutropenic patients based upon seven clinical variables each with independent prognostic significance (Klastersky et al. 2000) (Table 13.7). Patients are generally divided into two groups: (1) low-risk (<5% risk of developing serious infection-related complications) and (2) high-risk (all other patients). Low-risk, compliant patients may be treated on an outpatient basis with oral antibiotics, the preferred agents being ciprofloxacin in combination with amoxicillin-clavulanate. In contrast, high-risk patients require hospitalization for i.v. antibiotics and close monitoring. The antibiotic of choice in high-risk patients is controversial and depends upon patient, cancer, and pathogen-related factors. Gram-negative bacilli and Gram-positive cocci are the predominant organisms involved and account for one-third and two-thirds of all cases, respectively (Table 13.8) (Hughes et al. 2002). Not only should the selected antibiotic regimen provide broad coverage of both groups, but it should also reflect the prevalence and susceptibility profiles of the individual institution. Historically, all patients received aminoglycoside-containing combination antibiotic therapy. The results of numerous contemporary studies have found that empiric antibiotic monotherapy provides similar efficacy to combination therapy in cases of uncomplicated neutropenic fever,

Table 13.7. TheMultinational Association ofSupportive Care in Cancer (MASCC) Risk Scoring Index for identification of low-risk febrile neutropenic patients at presentation

Characteristic Scorea

Extent of illnessb

No symptoms 5

Mild symptoms 5

Moderate symptoms 3

No hypotension 5

No chronic obstructive pulmonary disease 4

Solid tumor or no fungal infection 4

No dehydration 3

Outpatient at onset of fever 3

Age < 60 yearsc 2

a Highest theoretical score is 26. A risk index score of a 21 indicates that the patient is likely to be at low risk for complications and morbidity b Choose one item only c Does not apply to patients < 16 years of age

Table 13.8. Most common bacterial causes of febrile neutrope-nia

Gram-positive cocci Gram-negative bacilli

Staphylococcus species Escherichia coli

Coagulase-positive (S. aureus) Klebsiella species

Coagulase-negative (S. epider- Pseudomonas aeruginosa midis and others)

Streptococcus species

S. pneumoniae S. pyogenes Viridans group

Enterococcusfaecalis, E.faecium Corynebacterium species but with a lower rate of adverse reactions (De Pauw et al. 1994; Furno et al. 2002). This has led to a paradigm shift in treatment such that empiric antibiotic mono-therapy is now considered appropriate for the majority of patients. The IDSA currently recommends four antibiotics as appropriate empiric monotherapy: ceftazidi-me, cefepime, imipenem, and meropenem (Hughes et al. 2002). Piperacillin-tazobactam represents a fifth monotherapy option with proven efficacy (Bow et al. 2003). Combination antibiotic therapy remains the standard of care for low-risk cases treated with oral therapy, high-risk cases involving hemodynamic instability, and cases arising from institutions with a high-frequency of multidrug-resistant pathogens. Recommended combination regimens include an aminogly-coside with an antipseudomonal -lactam or cephalo-sporin (Table 13.6). The decision to add vancomycin is based upon a presumed risk of Gram-positive infection rather than routine practice. Indications for its empiric use include (1) apparent catheter-related infection; (2) positive blood culture for a Gram-positive bacterium; (3) colonization with methicillin-resistant Staphylococ-cus aureus; and (4) hemodynamic instability without an identifiable organism (Segal et al. 2005).

The response to treatment is evaluated after 2-3 days of therapy. If the causative organism is identified, antibiotics may be tailored accordingly. Unfortunately, the causative organism is confirmed in only one-third of patients (Bodey et al. 1978). In the event that the culture results are inconclusive, low-risk patients who remain afebrile and clinically stable may be switched to, or continued on, oral ciprofloxacin plus amoxicillin-clavulanate. Patients who demonstrate persistent fever after 3-5 days of empiric therapy are at risk for cryptic foci (e.g., abscess, endocarditis), resistant organisms, as well as fungal or viral infections (Sipsas et al. 2005). These patients require repeat evaluation and, most likely, modification of empiric antibiotic therapy. This should be done in consultation with an infectious disease specialist knowledgeable in the care of cancer patients. The recommended duration of antibiotic therapy for febrile neutropenia depends upon the absolute neutrophil count, presence or absence of fever on day 3, culture results, clinical course, and overall risk strata. The reader is referred to the 2002ID-SA guidelines in this regard (Hughes et al. 2002).

Antifungal therapy deserves appropriate consideration in cases of persistent neutropenic fever. Fungal infections account for 2 % -10 % of neutropenic infections overall, and up to 30 % of infections in patients with persistent neutropenic fever (Wisplinghoff et al. 2003; de Pauw et al. 1994). Furthermore, fungal septicemia carries with it a high mortality rate, which approaches 90 % in certain subgroups of patients (Sipsas et al. 2005). Based on the high prevalence and significant mortality of fungal infections, the IDSA recommends the empiric initiation of systemic antifungal therapy in neutropenic patients with fever persisting 5 days despite appropriate empiric antibiotic therapy (Hughes et al. 2002). Candida and Aspergillus species constitute the most common fungi identified. The drug of choice is amphotericin B, although fluconazole is an acceptable alternative. In contrast, there is no indication for empiric antiviral therapy in febrile neutropenic patients, nor are colony-stimulating factors routinely recommended. The use of antiviral agents is generally limited to cases of documented viral respiratory tract infection or documented herpes simplex or varicella-zoster cutaneous infection. Cutaneous viral infections, even if not the source of fever, require treatment since they are potential portals of entry for bacteria and fungi. Acyclovir, valacyclovir, or famciclo-vir are all appropriate antiviral treatment options.

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