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When and If to Initiate Empirical Therapy
The clinician assessing the febrile neutropenic patient for antifungal therapy should be aware that the first neutropenic fever is rarely caused by fungi; the fever should be regarded as bacterial in origin and treated with antibiotics.95 Persistent fever with negative cultures despite broad-spectrum antibiotic use is, however, quite common. Most episodes of neutropenic fever are never explained; however, postmortem examination reveals unrecognized IFI in many patients.96,97
The decision whether or not to use empirical therapy can be guided by consideration of well-documented indicators that heighten one's suspicion for fungal infection.98 For example, persistent fever in a patient receiving fluconazole prophylactically is less likely to be caused by IFI than if prophylaxis had not been given.66 When fluconazole prophylaxis is used, the clinician can afford to delay the start of empirical antifungal therapy with increasing confidence that candidal infections arising early in the neutropenic period will be adequately suppressed by fluconazole prophylaxis. Knowledge that Aspergillus infection occurs later in the neutropenic period gives the clinician time to monitor the patient for the discriminating symptoms of Aspergillus infection and the results of cultures that have been performed.
The results of early clinical trials23, 36, 99-103 suggest that empirical antifungal therapy results in lower frequency of morbidity and mortality due to IFI, and the practice is endorsed in recent consensus practice guidelines. 29, 104
Choice of Antifungal Agent
Choice of therapeutic intervention in suspected invasive fungal infection depends on the characteristics of the targeted fungal pathogen and its susceptibility to specific antifungal agents. Amphotericin B is effective for empirical therapy. Most Candida species can be treated with daily doses of between 0.5 and 0.7 mg/kg, whereas Aspergillus and other moulds require higher doses of 1.0 to 1.5 mg/kg/day. Higher doses should be reserved for patients in whom the index of suspicion of infection is high, as these doses can be associated with considerable toxicity. The nephrotoxic potential is increased when AmB is given in combination with other nephrotoxic drugs, such as cyclosporine, tacrolimus, aminoglycosides, and foscarnet. It has been reported that 10% to 20% of patients receiving high doses of AmB for prolonged periods in combination with these drugs will require hemodialysis.105
Lipid formulations of AmB (amphotericin B lipid complex – ABLC; amphotericin B colloidal dispersion – ABCD; and liposomal amphotericin B – L-AmB) have been evaluated as empirical therapy in neutropenic patients, but only a small number of prospective, randomized, double-blind trials have compared these formulations (doses of 1 to 5 mg/kg/day) with amphotericin B deoxycholate (doses of 0.3 to 1.0 mg/kg/day). Both ABCD and L-AmB showed efficacy comparable to AmB, but nephrotoxicity was significantly less with the lipid formulations.106,107 In a recent controlled trial, febrile neutropenic patients were randomized to receive either L-AmB 3 mg/kg/day or 5 mg/kg/day, or ABLC 5 mg/kg/day. The incidence of nephrotoxicity was significantly lower in patients given L-AmB compared with those given ABLC (L-AmB 3 mg/kg/day, 14%; 5 mg/kg/day, 15%; ABLC, 42%).108
The incidence of infusion-related adverse events also varies among the lipid formulations.109 Estimates are imprecise due to lack of comparability of dosing, variability in premedications before dosing, and little standardization of definitions of adverse events. However, infusion-related reactions with ABCD and ABLC appear to be more common than those associated with L-AmB. One prospective randomized trial reported a higher incidence of infusion-related reactions with ABCD compared with conventional AmB.106 In contrast, L-AmB-treated patients experienced significantly fewer infusion-related reactions compared with those treated with conventional amphotericin B (chills, 18% versus 54% of patients; fever, 17% versus 44%),106 or those treated with ABLC (chills, 21% versus 79% of patients; and fever, 22% versus 58%).108
Fluconazole is also effective for empirical antifungal therapy when the suspected pathogens are yeasts,110-112 but is not effective against Aspergillus and other moulds.113 Itraconazole has a broader spectrum of activity, including Aspergillus. Comparison of the IV preparation followed by the oral solution of itraconazole with conventional AmB as empirical therapy during neutropenia showed equivalent efficacy and significantly less toxicity in patients treated with itraconazole.114
Voriconazole is now available and has been shown in one study to perhaps be a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever. However, the FDA did not grant approval for this indication because the study failed to meet its stated primary endpoint.
Other options for empirical therapy, including new triazoles and echinocandins, may prove effective.
Course Number: V035D
This CME Expires on July 1, 2005; no tests will be accepted after this date.
This course is accredited by
The University of Pittsburgh School of Medicine, Center for Continuing Education and The International Immunocompromised Host Society
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