Antifungal agents in neonatal systemic candidiasis.

Abstract

Neonatal systemic candidiasis is increasingly being recognized as a cause of septicemia in the neonatal intensive care unit (2, 19, 26, 36, 59). Predisposing factors for candidemia and subsequently invasive infections include prematurity, prolonged exposure to broad-spectrum antibiotics, the use of intravenous fat emulsions, the presence of necrotizing enterocolitis, prolonged intravascular catheterization, and tracheal intubation (33, 49, 50, 51, 63). Moreover, the immune functions of the newborn, especially in the preterm infant, are suboptimal, manifested as a decreased T-cell and granulocyte function (6, 22, 65). Additionally, it has been shown that lung macrophages of newborns have reduced anti-Candida activity (16). Infection is preceded generally by colonization of the gastrointestinal tract and the skin shortly after delivery (1, 27). Clinical evidence suggests that heavy colonization at multiple sites is a predisposing factor for clinical disease (27, 41), although this is still controversial (40). Most fungal infections in newborns are caused by Candida albicans, Candida parapsilosis, and more rarely, Candida tropicalis (1, 20, 42, 48). The symptoms of systemic candidal infection in the newborn are not specific. In several studies deterioration of respiratory function and apnea were the most common presenting signs, occurring in 70% of infants (2, 10, 26). Temperature instability, irritability, abdominal distension, carbohydrate intolerance, rash, and lethargy were also commonly observed. Similar symptoms are noted in newborns with bacterial infections, which occur frequently or coincidentally with systemic candidiasis. Therefore, most fungemic newborns are presumptively treated for bacterial infection. Since the signs, symptoms, and results of hematologic studies for infants suspected of having candidiasis are not specific, positive cultures are the mainstay in the diagnosis of invasive candidiasis. However, in newborn patients most antifungal therapy is started when fungal elements are seen on Gram stain or yeasts are isolated from some body fluid. On occasion it is even begun empirically or on the basis of the presence of a suggestive rash. Amphotericin B with or without flucytosine is still the treatment of choice for newborns with systemic candidiasis. However, since the introduction of ketoconazole in 1981, fluconazole in 1990, and intraconazole in 1992, these antifungal azoles, which unlike amphotericin B can be given orally, there has been a tendency to use these drugs as alternative therapies. Physicians have been influenced by the efficacy, safety, and ease of the administration of the azoles, despite the lack of direct comparisons of the efficacies of these drugs and amphotericin B. Our purpose here is to present an overview of the available pharmacokinetic data for amphotericin B, flucytosine, and this new group of azole drugs in the newborn. Dosage recommendations, recommendations for dosage adjustments in the face of organ system failure, and recommendations for monitoring toxicity will be suggested.