Anti fungal agents; types

The discovery of sulfa drugs in 1932 and the first clinical use of penicillin in 1941 ushered in the modern antibiotic era. The introduction of each new antibiotic, however, has been followed by the development of microbial resistance to that antibiotic. Many bacteria are now resistant to multiple classes of antibiotics. It is important for clinicians to use antibiotics appropriately and prudently, as unnecessary antibiotic use contributes to the selection of increasingly resistant organisms.

Anti fungal


Antifungal Agents

Fungal infections are generally divided into yeast infections and mold infections. Most yeast infections in otolaryngology are due to Candida species. Mold infections, such as those due to  Aspergillus and the agents of mucormycosis, are much more difficult to treat than Candida infections. In general, antifungal antibiotics with activity against molds also treat Candida, while the reverse is not true. Results of antifungal susceptibility testing for Candida species are clinically  meaningful (correlate with response to therapy), but the same is not true for molds. For treatment of invasive mold infections, results of clinical trials using various antifungal agents have proven to be most reliable in guiding therapy.

Amphotericin

 Amphotericin B treats nearly all molds and Candida species but has significant toxicities, including renal. Liposomal amphotericin is at least as effective as amphotericin B and has significantly less renal toxicity, but is much more expensive. Both the agents are only available intravenously.

Azoles

The major azoles available in the U.S. are fluconazole, itraconazole, voriconazole, posaconazole, and most recently isavuconazonium sulfate (metabolized to isavuconazole). Azoles have high bioavailability so oral and intravenous formulations often achieve similar serum levels. Fluconazole achieves excellent tissue penetration and is effective against nearly all strains of Candida albicans, although some other Candida species may be resistant. Fluconazole is not effective against molds. Itraconazole has some activity against molds but therapeutic serum drug levels are difficult to achieve, and itraconazole is less effective against Aspergillus than voriconazole. Voriconazole, available orally and intravenously, is the treatment of choice for invasive Aspergillus infections. It also has activity against some other molds (e.g., Fusarium) although not against the molds that cause mucormycosis (e.g., Rhizopus, Mucor). Oral voriconazole has excellent bioavailability. Posaconazole has activity against fungi that cause mucormycosis and is available orally and intravenously. Posaconazole is FDA-approved only for the treatment of refractory oropharyngeal candidiasis and for prophylaxis of invasive Aspergillus and Candida infections in high-risk patients, such as immunocompromised hosts. Posaconazole is frequently used as step-down oral therapy in invasive mold infections such as mucormycosis after an initial course of treatment with amphotericin or liposomal amphotericin. Isavuconazonium sulfate (metabolized to isavuconazole) is available both intravenously and orally and has broad-spectrum antifungal activity, including against both Aspergillus and the agents of mucormycosis.

Hepatotoxicity is an important side effect of azoles and liver function tests should be monitored. All azoles, except for isavuconazonium sulfate, can prolong the QTc interval and this should be monitored closely while on therapy. Isavuconazonium sulfate can shorten the QTc interval. Azoles are metabolized through the CYP3A4 pathway of the liver and therefore have many drug-drug-interactions. Healthcare providers should evaluate potential interactions with a patient’s other medications before prescribing azoles.

Echinocandins

 Echinocandins, including caspofungin and micofungin, are primarily used to treat serious infections due to Candida species that are resistant to fluconazole. Echinocandins are generally well tolerated but are available only intravenously.

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