Emerging Therapies



The principal azoles are fluconazole (FZ) and itraconazole (IZ), with each having advantages. New developments are the introduction of IZ in cyclodextrin solution for oral use, and IZ in cyclodextrin for IV. While these can no longer be considered investigational, their place is only presently being determined. The solution enhances bioavailability, this is of interest with patients for whom absorption of capsules was problematic, e.g., with hypochlorhydria and enteropathy. Side effects of the oral cyclodextrin are sometimes seen, largely gastrointestinal. The IV preparation offers the possibility of sufficient antifungal serum levels from the outset of therapy, even in patients unable to take oral medications or likely to have absorption problems, avoiding the 2 week progression to steady state with oral forms. Nearest on horizon are developments of triazoles. Voriconazole, structurally related to FZ, expands the spectrum of FZ to include Aspergillus, thus achieving a spectrum similar to IZ. It acts synergistically with host effector cells. Its oral bioavailability is ?80%. Tablets and an IV formulation in sulfobutylcyclodextrin are under study. The half-life is 6 hours in most subjects, but blood levels are variable among patients, presumably related to pharmacogenetic differences, similar to IZ. The drug is metabolized in the liver, and no significant amounts are found in urine, unlike FZ and like IZ. It penetrates into CSF, like FZ and unlike IZ. There are significant drug interactions with rifampin, rifabutin, phenytoin, cyclosporine, some antiretrovirals, omeprazole, and prednisolone, all reminiscent of IZ. The most notable toxicity has been transient ocular symptoms; elevated liver function tests, skin reactions have also been noted. Clinical trials in empirical treatment of fever in neutropenia and of invasive aspergillosis are in progress. Posaconazole (SCH 56592) is a triazole less far along in development. More structurally similar to IZ than FZ, its preclinical toxicity and drug interaction profiles are similar to IZ, and it has promising in vitro and in vivo activity against Aspergillus. The serum half-life is 15-25 hrs., and is dose-dependent. It is highly protein bound. Penetration into CSF is poor, though there is activity against CNS infection, a picture similar to IZ. Serum drug levels are improved by co-administration with food. A prodrug is under study for IV. In animals, it is the most cidal drug against coccidioidomycosis and has demonstrated efficacy against cerebral phaeohyphomycosis. An initial trial in human coccidioidomycosis showed promise. Headache, dry mouth, somnolence, dizziness have been seen. Ravuconazole (BMS 207147) is less far along. Of interest is its activity in vitro against the endemic pathogens Coccidioides, Histoplasma, Blastomyces and Paracoccidioides, even superior to IZ, Fusarium, and Aspergillus, and against Candida krusei and fungi containing the MDR-1 resistance gene, both resistance problems particularly for FZ. The drug is metabolized by the liver. It has the longest half-life of the currently studied azoles, drug levels are improved by food, and little active drug appears in urine. In a model of orogastrointestinal candidiasis, it was orally more active even than FZ. &

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Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 40th