Triazole Use in the Nursery: Fluconazole, Voriconazole, Posaconazole, and Ravuconazole

Abstract

Invasive fungal infections in infants admitted to the neonatal intensive care unit are common and often fatal. The mainstay of therapy against invasive fungal infections is antifungal agents. Over the last two decades, the development and approval of these drugs evolved tremendously, and the azole class emerged as important agents in the treatment and prevention of invasive fungal infections. Among the azoles, fluconazole has been used extensively due to its favorable pharmacokinetics, excellent activity against Candida spp, and safety profile. This drug has been well studied in children but data for its use in infants are largely limited to Candida prophylaxis studies. Voriconazole, a second generation triazole, has excellent activity against Candida and Aspergillus spp. However, data on its use in neonates are extremely limited. Posaconazole and Ravuconazole are the newest agents of the triazole family. The antimicrobial spectrum of posaconazole is similar to voriconazole, but with additional activity against zygomycetes. Experience with posaconazole in children is very limited, and there are no reports of its use in infants. Ravuconazole is not approved for use by the FDA but studies in animals and humans show that it is often fungicidal and has favorable pharmacokinetics. In conclusion, the management of invasive fungal infections has progressed greatly over the last two decades with the azole antifungals playing a significant role. Related to this class, future research is needed in order to better assess dosing, safety, schedules and areas of use of these agents in infants admitted to the neonatal intensive care unit.

Advances in the treatment of invasive neonatal candidiasis

“…The mechanism of action for triazole agents involves the fungal cytochrome P-450-dependent enzyme lanosterol 14-alpha-demethylase, causing accumulation of aberrant and toxic sterols in the cell membrane [52, 53]. …”

Dosing in neonates: special considerations in physiology and trial design

“…Fluconazole is a triazole antifungal that inhibits lanosterol 14-alpha-demethylase, an enzyme that is responsible for the formation of compounds essential for fungal cell membrane integrity (75). It exhibits time-dependent fungicidal activity and is used in the prophylaxis and treatment of systemic neonatal candidiasis (75, 76).…”

“…It exhibits time-dependent fungicidal activity and is used in the prophylaxis and treatment of systemic neonatal candidiasis (75, 76). Fluconazole exhibits low plasma protein-binding, demonstrates excellent cerebrospinal fluid penetration, and is predominantly eliminated through the renal system in unchanged form (75, 76).…”

“…It exhibits time-dependent fungicidal activity and is used in the prophylaxis and treatment of systemic neonatal candidiasis (75, 76). Fluconazole exhibits low plasma protein-binding, demonstrates excellent cerebrospinal fluid penetration, and is predominantly eliminated through the renal system in unchanged form (75, 76). Pediatric studies involving subjects aged 3 months and older showed that children and adolescents had higher fluconazole clearance, with a drug half-life of 22 hours compared with 30 hours in adults (75, 76).…”

“…Fluconazole exhibits low plasma protein-binding, demonstrates excellent cerebrospinal fluid penetration, and is predominantly eliminated through the renal system in unchanged form (75, 76). Pediatric studies involving subjects aged 3 months and older showed that children and adolescents had higher fluconazole clearance, with a drug half-life of 22 hours compared with 30 hours in adults (75, 76). To ensure 70% efficacy against fungal infections, a 24-hour area under the curve (AUC)-to-minimum inhibitory concentration (MIC) ratio of >50 is needed (76).…”