High-Dose Micafungin for Preterm Neonates and Infants with Invasive and Central Nervous System Candidiasis

Abstract

e High doses of micafungin are advocated in neonates with systemic candidiasis, but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, three of whom had meningitis, were treated for at least 14 days with 8 to 15 mg/kg of body weight/day of intravenous micafungin. Plasma micafungin concentrations (four measurements for each patient) were determined after the third dose, and the cerebrospinal fluid (CSF) micafungin concentrations in three patients were also obtained. Population PK analyses were used to identify the optimal model, and the model was further validated using external data (n ‫؍‬ 5). The safety of micafungin was assessed by measurement of the levels of liver and kidney function biomarkers. The mean age and weight at the initiation of treatment were 2.33 months (standard deviation [SD], 1.98 months) and 3.24 kg (SD, 1.61 kg), respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase concentration ratio. The CSF of three patients was sampled, and the observed concentrations were between 0.80 and 1.80 mg/liter. The model-predicted mean micafungin area under the concentration-time curve over 24 h was 336 mg · h/liter (SD, 165 mg · h/liter) with the 10-mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection, but 5 had neurologic impairments. Among the transaminases, alkaline phosphatase measurements were significantly higher posttreatment, with a geometric mean ratio of 1.17 (90% confidence interval, 1.01, 1.37). Furthermore, marked elevations in the gamma-glutamyltransferase (GGT) level were observed in three patients treated with 10-to 15-mg/kg/day doses, and improvement of the GGT level was noted after a dose reduction. Higher weight-based doses of micafungin were generally well tolerated in neonates and infants and achieved pharmacokinetic profiles predictive of an effect. Invasive candidiasis (IC) is a common infection in newborns and occurs in 7% to 20% of critically ill neonates (1-4). This risk increases progressively in low-birth-weight (LBW) infants (birth weight, Ͻ2,500 g), very-low-birth-weight (VLBW) infants (birth weight, Ͻ1,500 g), and extremely low-birth-weight (ELBW) infants (birth weight, Ͻ1,000 g) (1-4). Moreover, 50% to 64% of ELBW infants are susceptible to central nervous system (CNS) involvement early in the presentation of IC (1). CNS involvement is associated with a high rate of mortality (30 to 60%), and survivors can have significant long-term complications, including neuromotor developmental disorders, chronic lung disease, and severe retinopathy of prematurity (2-4).To date, most studies of antifungal drugs and clinical experience with such drugs in neonates have centered on older antifungal drugs, such as amphotericin B (AMB) deoxycholate, liposomal amphotericin B (L-AMB) and fluconazole. As a consequence, the current Infectious Diseases Society of America (IDSA) guidance supports the consideration o...

Treatment of invasive fungal diseases in cancer patients—Revised 2019 Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

“…The optimal AFT is likely a combination of L‐Amb combined with either flucytosine or fluconazole (CIII) 4 . Whether echinocandins (eg caspofungin or high dose micafungin) may be useful to treat Candida infections of the CNS is not fully explored 173‐175 . It need to be considered the poor CNS penetration of these agents—at least if the blood‐brain barrier is intact 58,175 .…”

Clinical Pharmacokinetics and Pharmacodynamics of Micafungin

“…Distribution into tissues throughout the body has not been extensively investigated and data mainly come from a limited number of case reports [ 28 – 38 ]. Furthermore, these data are often difficult to interpret because homogenate samples may show incorrect concentrations due to differences between intra- and extracellular concentrations.…”

“…In another patient, brain tissue was obtained which contained a T / P ratio for micafungin of 0.18 [ 30 ]. The most recent study measured micafungin concentrations in nine samples of three premature neonates after a 10 mg/kg dose and measured between 1 and 1.5 mg/L, corresponding with a CSF/ C 24h ratio of 0.16, and CSF/ C max ratio of 0.04 [ 38 , 48 ]. Although highly variable, these data might indicate that there is sufficient penetration of micafungin in these compartments for an antifungal effect, specifically in neonates with Candida meningoencephalitis treated with a high dose.…”

“…The plasma concentrations of micafungin and covariates influencing the concentration have been investigated in 15 population PK models (see Table 2 for details) [ 38 , 41 , 45 , 47 , 52 , 53 , 55 , 58 – 65 ]. In all cases, the plasma concentration was best described using a two-compartment model; additional compartments were used to explain tissue concentrations in two studies [ 41 , 47 ].…”

“…Interestingly enough, with the exception of BMI, no other weight-derived covariates such as fat-free mass, normalized fat mass, or lean body weight have been investigated to explain variability in CL or volume. Other covariates explaining variability in systemic CL were platelet count in Japanese adults and pediatric patients [ 52 ], alanine transferase and total bilirubin in pediatric patients [ 58 ], the ratio of aspartate transaminase and alanine transaminase in preterm neonates [ 38 ], and, finally, albumin and Sequential Organ Failure Assessment (SOFA) score in critically ill patients [ 61 ]. Variability in volume in distribution was explained by albumin concentrations in both postsurgical patients with peritonitis and critically ill patients [ 47 , 61 ].…”