Pharmacokinetic, efficacy, and safety considerations for the use of antifungal drugs in the neonatal population

ABSTRACT

Introduction

Invasive fungal infections are an important cause of morbidity and mortality in infants, particularly in extreme prematurity. Successful systemic treatment requires consideration of antifungal efficacy, safety, and pharmacokinetics, including optimization of dosing in this population.

Areas covered

This review summarizes published pharmacokinetic data on four classes of antifungal agents used in the neonatal population. Alterations in absorption, distribution, drug metabolism and clearance in infants compared to adult populations are highlighted. Additionally, pharmacodynamics, safety, and therapeutic drug monitoring are discussed. Recent advancements in neonatal antifungal pharmacotherapies are examined, with emphasis on clinical application.

Expert opinion

Over the last two decades, published studies have provided increased knowledge on pharmacokinetic considerations in the neonatal population. Future research should focus on filling in the knowledge gaps that remain regarding the benefits and risks of combination antifungal therapy, the rising use of micafungin for invasive candidiasis given its fungicidal activity against polyene and azole-resistant Candida species and its minimal adverse effect profile, and the need for pharmacokinetic and safety data of broad spectrum triazoles, like voriconazole and posaconazole, in infants. Furthermore, efforts should focus on well-designed trials, including population pharmacokinetic studies, to develop dosing recommendations with subsequent implementation into clinical practice.

KEYWORD:

• Amphotericin B deoxycholate
• anidulafungin; caspofungin
• fluconazole
• flucytosine
• infant
• invasive fungal infection
• micafungin
• pharmacokinetics
• voriconazole

Article highlights

• Preterm infants, particularly extremely low birth weight infants, are at risk of developing invasive fungal infections due to central vascular catheterization, endotracheal tubes, parenteral nutrition, exposure to broad-spectrum antibiotics, and their immature immune systems. Most fungal infections result from Candida species and are associated with significant morbidity and mortality. Meningo-encephalitis should be presumed in infants with candidemia.

• Well-powered trials are lacking to guide treatment in neonatal populations; therefore, antifungal efficacy is largely extrapolated from adult studies.

• Current Infectious Diseases Society of America guidelines recommend amphotericin B deoxycholate as first-line©therapy for neonatal invasive candidiasis, although clinical application is limited by uncertainties surrounding safety and appropriate dosing.

• European Society of Clinical Microbiology and Infectious Diseases guidelines recommend either amphotericin B deoxycholate, liposomal amphotericin B, fluconazole or micafungin as treatment options for neonatal invasive candidiasis.

• A wide spectrum of pharmacokinetic and efficacy data exist for agents such as liposomal amphotericin B, fluconazole, and micafungin - all of which appear safe – and with further studies, have potential for use as alternative first-line©treatment options for invasive candidiasis.

• Given concerns or paucity of data on safety, resistance, or efficacy, agents such as flucytosine, voriconazole, posaconazole, caspofungin©, and anidulafungin should generally be limited to salvage therapy for invasive candidiasis. However, efforts to collect infant-specific pharmacokinetic and safety data are urgently needed given emerging aspergillus and mucormycosis infections in the neonatal population.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.