429: Voriconazole prophylaxis in patients at high risk for invasive fungal infections following allogeneic hematapoetic stem cell transplantion

Voriconazole is a triazole antifungal agent with good activity against Aspergillus spp. Standard antifungal prophylaxis at NMH for recipients of allogeniec HSCT is itraconazole 200mg po bid. Voriconazole 200mg po bid is substituted on day0 of transplant if they have prior history of Aspergillus infection(secondary prophylaxis) or switched from itraconazole to voriconazole with receipt of high dose steroids(methylprednisolone 2mg/kg) for GVHD. Voriconazole is discontinued 30 days after immunosuppression is stopped. 80 allograft recipients who received voriconazole and in whom complete microbiologic and pharmacokinetic data were available were studied to determine the efficacy of voriconazole in preventing invasive fungal infections (IFI). 24 patients had no itraconazole prophylaxis. The remainder (n=56) received itraconazole for 1-161 days (median 7). The length of voriconazole therapy was 6-956 days (median 120). The total number of patient-days on voriconazole was >14,000d. A total of 10 IFIs were seen in patients on voriconazole: Candida glabrata (n=5), Candida krusei (n=1), Cunninghamella (n=1), Rhizopus (n=2), and Mucor (n=1).Although 4 cases of zygomycosis were seen, no case of Aspergillus infection was seen. The actuarial probability of zygomycosis or any invasive fungal infection is 7% and 18% respectively. Zygomycetes are not susceptible to voriconazole, and breakthrough infections are not surprising. In clinical trials C. glabrata and C. krusei were susceptible to voriconazole at MIC90=.5-2mcg and the majority of fluconazole resistant C.Glabrata isolates have MIC90s>1mcg.dose. Interestingly, steady-state trough voriconazole levels were <0.2, <0.2, 0.33, 0.55, 0.63, and 1.78 mcg/mL in the 6 candidiasis cases. C.Glabrata in patient with vori level=1.78 was fluconazole resistant(c/s not avaiable for other Candida specimens). All 6 candidiasis cases were seen amongst the 44 patients when voriconazole levels < 2 mcg and none amongst the 36 with levels of >2 mcg (P=0.061; Fishers exact test), consistent with a study correlating voriconazole levels and clinical success in aspergillosis (Smith et al. Antimicrob Agents Chemother 2006;50:1570-1572). Voriconazole is extremely effective in preventing aspergillus infections but Zygomycosis remains a concern in voriconazole-treated patients. Therapeutic drug monitoring with dose adjustment may be indicated in patients on voriconazole to avoid infections with fungi that are otherwise susceptible to the drug.Tabled 1breakthrough infectionsOrganismSiteDays of exposure to voriconazoleDays post transplantConcommitant infection/neutropeniaGVHDNumber of days of prior exposure to itraconazoleVoriconazole levelC.Kruseilung157183E.coli and VRE/noGI260.53C.Glabratalung136145VRE/yesGI90.63C.Glabratalung832837MRSE/yesGI/Skin70.20C.Glabratalung159179MRSA and Enterobacter/yesGI/Skin201.78C.Glabratalung56137MRSA and Strept/yesGI/Skin1220.33C.Glabratalung79VRE/yesGI/Skin70.33Rhizopussinus128135VRE/noSkin74.1Rhizopuslung755none/nonone1285.9Mucorlung7777E.coli/noSkin03.5Cunninghamellalung1790CONS/yesGI641.1 Open table in a new tab