Journal of Perinatology (2007) 27, 127–129 r 2007 Nature Publishing Group All rights reserved. 0743-8346/07 $30 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Caspofungin for the treatment of resistant candidemia in a premature infant

PB Smith1,2, WJ Steinbach1,3, CM Cotten1, WA Schell4, JR Perfect3,4, TJ Walsh5 and DK Benjamin Jr1,2 1Department of Pediatrics, Duke University, Durham, NC, USA; 2Duke University Clinical Research Institute, Durham, NC, USA; 3Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA; 4Department of Medicine, Duke University, Durham, NC, USA and 5National Cancer Institute, Bethesda, MD, USA

creation of ostomies and necrotizing enterocolitis. Antimicrobial Candidemia is common in extremely low birth weight infants and is exposure preceding the fungal infection included 26 days of associated with substantial mortality and morbidity. Treatment options have ampicillin, 32 days of gentamicin, 10 days of metronidazole, traditionally been limited to deoxycholate or fluconazole. 15 days of vancomycin and 5 days of amphotericin B deoxycholate. We present a case of a premature infant with persistent candidemia despite The development of a conjugated hyperbilirubinemia on day of life treatment that responded to therapy with caspofungin, an (DOL) 80 prompted an abdominal ultrasound demonstrating antifungal. The infant’s Candida isolate developed resistance debris within the right consistent with and a to during fluconazole administration and also suffered from severe culture positive for . Two days later, blood hypercalcemia during the initiation of caspofungin therapy. cultures were positive for C. albicans; however, cerebrospinal fluid Journal of Perinatology (2007) 27, 127–129. doi:10.1038/sj.jp.7211637 cultures were negative with unremarkable cell and chemistry Keywords: caspofungin; candidiasis; hypercalcemia parameters. Echocardiogram, head ultrasounds and ophthalmologic examinations were also unremarkable. The infant was initially placed on amphotericin B deoxycholate, Introduction but was changed to amphotericin B lipid complex owing to Candidemia is common in the neonatal intensive care unit.1 substantially reduced urine output and elevated Extremely premature infants are most at risk for infection. (Figure 1). Despite the addition of fluconazole and removal of Clinicians are often faced with persistent Candida infections in central venous catheters, blood cultures remained persistently this population despite antifungal therapy and optimal central positive with C. albicans for 41 days. Serial ultrasounds revealed catheter management. Caspofungin is a fungicidal antifungal that increasing debris in both kidneys and dilation of the collecting has seen limited use in the neonatal population owing to a paucity system of the right kidney necessitating nephrostomy tube of data on and few reports of use in this placement. After this procedure, the patient clinically deteriorated population. We report the successful treatment of an infant with and required ionotropic support and high-frequency ventilation. At persistent candidemia using caspofungin. this point, the infant had received 30 days of fluconazole and 32 days of amphotericin B deoxycholate (1 mg/kg), amphotericin B lipid complex (5 mg/kg) or liposomal amphotericin B (7 mg/kg). Caspofungin therapy was initiated with a loading dose of Case report 100 mg/m2 (8 mg/kg) followed by a maintenance dose of 2 The patient was an 810 g quadruplet male born via 70 mg/m /day (6 mg/kg/day). The patient experienced dramatic Caesarian-section at 25 weeks gestation. The patient received oral clinical improvement, and renal ultrasounds demonstrated a for fungal prophylaxis. The clinical course was remarkable decreasing amount of debris within the collecting system of the for multiple complications including grade IV intraventricular kidneys. Blood and urine cultures were negative 8 days after hemorrhages, pneumothorax, patent ductus arteriosus requiring institution of caspofungin therapy. surgical ligation, spontaneous ileal perforation necessitating the On routine laboratory testing, the infant’s serum calcium was found to be elevated at 16.8 mg/dl on day 14 of caspofungin Correspondence: Dr PB Smith, Duke University Medical Center, Durham, Box 3179, NC therapy. The serum phosphorus and magnesium were also elevated 27710, USA. E-mail: [email protected] at 9.3 and 3.6 mg/dl, respectively. The infant was tolerating small Received 14 August 2006; revised 9 October 2006; accepted 31 October 2006 amounts of enteral feeds of Neocate, and no major changes to the Caspofungin for candidemia in a premature infant PB Smith et al 128

by 2 mg/kg/day. One infant died of Klebsiella pneumoniae after 19 days of caspofungin therapy, but the remaining nine infants survived. A second report of 13 infants with persistent candidemia demonstrated sterilization of blood cultures in 11 infants given a 1 mg/kg/day dosing regimen of caspofungin.5 However, only six of the infants survived. It is unclear if the doses utilized in those two previous reports were optimal, especially given the disparate survival results. Hypercalcemia associated with caspofungin use has not been Figure 1 Timeline of antifungal dosing: caspofungin dose: loading: previously described, but has been noted in the setting of 100 mg/m2 followed by 70 mg/m2/day. Restarted at 35 mg/m2/day. disseminated candidiasis and other infections, including coccidioidomycosis, histoplasmosis and pneumocystosis.6 Hypercalcemia is thought to be caused by extrarenal 1a-hydroxylation of 25-hydoxy-vitamin D by cytokine-stimulated Table 1 MIC80 mg/ml (MIC100 for amphotericin) of Candida albicans macrophages. Although no vitamin D levels or urine electrolytes 8 isolated from patient according to CLSI M-27A2 criteria were determined in our patient, parathyroid hormone levels were Isolate Amphotericin B Caspofungin depressed (5 pg/ml). No adverse events were noted in the cohort of infants presented by Odio et al.4 Natarajan et al.5 observed Day of life 80 0.5 0.25 <0.015 <0.03 thrombophlebitis in one patient, hypokalemia in two patients, Day of life 107 0.5 >64 >8 0.06 elevated in four patients and isolated direct hyperbilirubinemia in one patient in their cohort of infants. Administration of fluconazole leading to azole resistance has parenteral nutrition composition had been made in the days before been noted in neonatal intensive care units, as occurred in our the episode of hypercalcemia. No etiology for these findings was patient. However, we believe this is the first reported instance of determined; however, caspofungin therapy was discontinued for cross-resistance to voriconazole in an infant. Voriconazole use is 72 h, and the laboratory values were normalized. Voriconazole also limited in infants due to concerns with retinal side effects seen therapy was begun during the interim, but in vitro susceptibility in older patients and the possible yet unknown interaction with testing of the most recent C. albicans isolate demonstrated retinopathy of prematurity. Although voriconazole has been shown resistance to voriconazole as well as fluconazole (Table 1). to be active against Candida isolates such as C. glabrata and Caspofungin was restarted at a dose of 35 mg/m2/day (3 mg/kg). C. krusei that are often resistant to fluconazole, some authors The patient’s calcium levels remained normal throughout the caution its use in situations where fluconazole resistance is additional 48 days of therapy, and the patient was discharged home suspected.7 on DOL 211. This case illustrates the therapeutic potential of for neonatal candidiasis.4 However, understanding of echinocandin pharmacokinetics and safety in this patient group are required Discussion before widespread use. Caspofungin, an echinocandin, irreversibly inhibits 1,3 b-D glucan 2 synthase in the fungal cell wall. Lack of 1,3 b-D glucan decreases the integrity of the fungal cell wall leading to yeast cell lysis. References Caspofungin is fungicidal in vitro for all medically important Candida species. 1 Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA et al. A study of 39 pediatric patients (ages 2–17 years) determined Late-onset sepsis in very low birth weight neonates: the experience of the that weight-based dosing (1 mg/kg/day) yielded suboptimal serum NICHD Neonatal Research Network. Pediatrics 2002; 110: 285–291. levels.3 A scheme based on body-surface area dosing (maintenance 2 Franklin JA, McCormick J, Flynn PM. Retrospective study of the safety of dose of 50 mg/m2/day) was found to better approximate levels of caspofungin in immunocompromised pediatric patients. Pediatr Infect Dis J 2003; 22: 747–749. adults given 50 mg/day. Unfortunately, pharmacokinetic data for 3 Walsh TJ, Adamson PC, Seibel NL, Flynn PM, Neely MN, Schwartz C et al. caspofungin in infants are nonexistent as of this writing. Pharmacokinetics, safety, and tolerability of caspofungin in children and Clinical experience with caspofungin as a therapeutic agent in adolescents. Antimicrob Agents Chemother 2005; 49: 4536–4545. 4 infants is also limited. Odio et al. reported 10 candidemic infants 4 Odio CM, Araya R, Pinto LE, Castro CE, Vasquez S, Alfaro B et al. Caspofungin treated with caspofungin after failure of therapy with amphotericin therapy of neonates with . Pediatr Infect Dis J 2004; 23: B. The infants were given a dose of 1 mg/kg/day for 2 days followed 1093–1097.

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5 Natarajan G, Lulic-Botica M, Rongkavilit C, Pappas A, Bedard M. Experience isolates from HIV-infected children with oropharyngeal candidosis. with caspofungin in the treatment of persistent in neonates. J Antimicrob Chemother 2000; 46: 338–340. J Perinatol 2005; 25: 770–777. 8 Pfaller MA, Chaturvedi V, Espinel-Ingroff A, Ghannoum MA, Gosey LL, 6 Kantarjian HM, Saad MF, Estey EH, Sellin RV, Samaan NA. Hypercalcemia in Odds FC et al. Reference Method for Broth Dilution Antifungal Susceptibility disseminated candidiasis. Am J Med. 1983; 74: 721–724. Testing of Yeasts; Approved Standard M27-A2National Committee for 7 Muller FM, Weig M, Peter J, Walsh TJ. Azole cross-resistance to , Clinical Laboratory Standards. National Committee for Clinical Laboratory fluconazole, and voriconazole in clinical Candida albicans Standards: Wayne, Pennsylvania, 2002.

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