Prophylaxis And Therapy

Routine decontamination of the gut is not recommended for HSCT candidates.2 The use of oral fluoroquinolones and an agent active against Gram-positive cocci in asymptomatic neutropenic patients reduces the occurrence of Gram-positive and Gram-negative bacteremias, but has no impact on fever-related morbidity or infection-related mortality.33 A novel strategy to reduce the occurrence of oral mucositis after intensive chemotherapy using palifermin (recombinant human keratinocyte growth factor) has demonstrated promise. In a double-blind, placebo-controlled trial involving patients with hematologic malignancies, palifermin recipients had less severe mucositis, a shorter duration of mucositis, and a lower incidence of fever during neutropenia and bacteremia compared with placebo recipients.34

Acyclovir prophylaxis is indicated for all HSV-seropositive HSCT candidates and has been shown to reduce the occurrence of viral reactivation.35 Prophylaxis should commence at the initiation of the preparative regimen and continue to engraftment or to the resolution of mucositis.2 Valacyclovir has not been FDA-approved for this indication.

Antifungal prophylaxis is indicated during neutrope-nia in all allogeneic and most autologous HSCT recipients. Fluconazole has been recommended by the Centers for Disease Control and Prevention, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation,2 but is not effective in the prevention of infections due to Aspergillus species, C. krusei, and C. glabrata. This has led some centers to use other agents for antifungal prophylaxis, including low or moderate dose ampho-tericin B, liposomal amphotericin B, inhaled or nasal amphotericin B, and voriconazole. Unfortunately, the efficacy of these various prophylactic strategies has not been demonstrated in well designed clinical trials. Moreover, the zygomycetes have emerged as important pathogens in patients receiving voriconazole prophylaxis or therapy.29 30 Oral itraconazole should not be used because of its variable absorption; its interactions with other agents such as cyclosporine, methyl-prednisolone, rifampin, antiepileptics, and warfarin; and the prolonged time required to achieve steady state concentrations in the blood.2 New antifungals are in development and may have a future role in prophylaxis against fungal infections in HSCT recipients. A recent large, randomized, double-blind, multicenter, prospective phase 3 clinical trial compared flu-conazole with micafungin, a new echinocandin, for prophylaxis against invasive fungal infections in neu-tropenic patients undergoing autologous and allo-geneic HSCT.36 Micafungin was superior to fluconazole across treatment groups and was associated with a lower incidence of aspergillosis and colonization with C. glabrata.

Empiric antibacterial therapy in febrile HSCT recipients should be guided by the suspected site of infection and by knowledge of antimicrobial susceptibility profiles of institutional isolates as well as by organisms previously infecting or colonizing the patient. Catheter-related infections can often be cured without device removal, except in those with tunnel, fungal, or mycobacterial infections and in those who are hemodynamically unstable. Empiric antifungal therapy in persistently febrile neutropenic patients has traditionally been amphotericin B. A recent randomized, double-blind, multicenter study compared the echinocandin caspofungin with liposomal ampho-tericin B for empiric therapy in 1095 persistently febrile neutropenic patients, of whom 75 were HSCT recipients.37 Caspofungin was as effective and better tolerated than amphoterin B, with lower incidences of nephro-toxicity and infusion-related side effects.

For decades amphotericin B has been the treatment of choice for invasive aspergillosis and other filamentous fungi; however, response rates have been disappointing, and as low as 10-15% in allogeneic HSCT recipients.38 Several alternative agents have recently become available with superior efficacy. Voriconazole is a broad-spectrum triazole with activity against most Candida and Aspergillus species. In a randomized, unblinded trial comparing high-dose amphotericin B with voriconazole for primary therapy in 277 patients with suspected or proven invasive aspergillosis, many of whom were HSCT recipients, voriconazole had superior efficacy and fewer serious side effects compared with amphotericin B. After 12 weeks, 52.8% of voriconazole recipients versus 31.6% in the ampho-tericin B group had responded to therapy, though transient visual disturbances occurred in nearly half of voriconazole recipients.39

While superior to amphotericin B, voriconazole is not uniformly effective and many patients require salvage therapy. Several recent studies have examined alternative strategies. The utility of the echinocandin caspofungin was examined in 83 patients with invasive aspergillosis who were refractory to or intolerant of conventional therapy; 79.5% had failed conventional therapy with formulations of amphotericin B and 25% were HSCT recipients.40 Forty-five percent responded to caspofungin, including 50% with pulmonary aspergillosis and 23% with disseminated disease; however, HSCT recipients had a poorer response compared with those with hematologic malignancies. In a small, single center observational study, HSCT recipients with refractory invasive aspergillosis were treated with a combination of voriconazole and caspofungin, and compared with an earlier group treated with voriconazole alone.41 In this nonran-domized study, patients who received combination therapy had improved survival at 3 months compared with historical controls who received voricona-zole monotherapy.

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