Hepatitis associated with micafungin use in a preterm infant

Abstract

Micafungin is an echinocandin-class antifungal agent licensed for treatment of invasive disease in adults. The optimal dosing regimens have not been established for infants. We describe a premature infant who developed hepatitis and cholestasis during micafungin therapy initiated for protracted candidemia. Practitioners should be aware of this potential adverse effect if using micafungin in young patients. Journal of Perinatology (2009) 29, 320-322; doi:10.1038/jp.2008 Keywords: micafungin; hepatitis; infant; candidemia Introduction Optimal treatment of invasive fungal infection is an ongoing challenge for neonatologists, especially as the number of immunosuppressed and premature patients increases. Micafungin is a member of the echinocandin family of antifungals recently licensed for adults as an alternative or complement to traditional agents such as azoles and amphotericin B. 1 Optimal dosing and safety of this agent have not been established for infants and children.Case report A 44-day-old 2400 g former 28 week human immunodeficiency virus (HIV) and hepatitis C-exposed premature female was in her fourth week of nafcillin therapy for methicillin-susceptible Staphylococcus aureus bacteremia and right femoral osteomyelitis when she developed a new illness manifested as apnea requiring bag-mask ventilation. Blood, urine and cerebrospinal fluid (CSF) cultures were sent, and empirical treatment was initiated with vancomycin and gentamicin. After 1 day, her blood culture grew Candida albicans. The CSF and urine cultures were sterile. Therapy was changed to conventional amphotericin B (1 mg kg À1 per day) and her peripherally inserted central catheter (PICC) was removed. Head and renal ultrasounds were obtained and were normal. An echocardiogram showed a linear echodensity in the left innominate vein consistent with a cast at the location of the previous PICC line, and an ophthalmologic examination showed lesions consistent with Candida in the superior macula of the retina.Candidemia persisted, and on the seventh day of amphotericin B therapy, micafungin was added to the regimen at a dose of 8 mg kg À1 daily. The dose was chosen based on preliminary pharmacokinetic work by Heresi et al. 1 and expert opinion. Blood cultures became sterile 3 days later, and an ophthalmologic exam on day 7 of micafungin showed improvement in the retinal lesions.Before initiation of micafungin, the patient's serum aspartate aminotransaminase (AST) was 21 IU l À1 , serum alanine aminotransaminase (ALT) was 20 IU l À1 , total bilirubin was 1 mg per 100 ml and alkaline phosphatase was 268 IU l À1 . On day 2 of micafungin administration, the total bilirubin was 11.7 mg per 100 ml with direct bilirubin of 10.1 mg per 100 ml, but the AST and ALT were 25 and 28 IU l À1 , respectively ( Figure 1). On day 8 of micafungin administration, the AST had increased to 79 IU l À1 and the ALT to 39 IU l À1 . The total bilirubin was 12 mg per 100 ml and the conjugated bilirubin was 8.3 mg per 100 ml. The patient was transferred to our care on day 14 of m...

The Use of Antifungal Therapy in Neonatal Intensive Care

“…89,94 King et al presented a case of hepatitis related to micafungin in a 44–day-old infant. 98 Micafungin doses from 0.75–15 mg/kg/day have been studied in children. 21,96,99 …”

Challenging issues in neonatal candidiasis

“…Regarding caspofungin dosing, neonatal clinical studies had used 1 to 2 mg/kg, but pharmacokinetic data indicate that 2.5 mg/kg should be used. For micafungin dosing, pharmacokinetic data suggest a dose of 10 mg/kg [21][22][23]29,30 . A micafungin RCT is currently suspended for further pharmacodynamic studies (www.Clinicaltrials.gov Identifier: NCT00815516).…”

“…Pharmacokinetic data have recently been published for fluconazole, micafungin, and caspofungin [14][15][16][17][18][19][20][21][22][23] . With studies examining pharmacokinetic data targeting comparable levels in adults, neonatal data are needed regarding safety.…”

Antifungal therapy for newborn infants with invasive fungal infection

“…Echinocandin resistance a er prolonged use selects fungi with a mutation in the 1,3-β-D-glucan synthase gene has been described (Krogh-Madsen 2006;Laverdiere 2006;Baixench 2007). Reported side e ects are generally mild and transient but acute hepatitis has been associated with micafungin use (King 2009).…”