Odio CM, Araya R, Pinto LE, et al. Caspofungin therapy of neonates with invasive candidiasis

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1 See discussions, stats, and author profiles for this publication at: Odio CM, Araya R, Pinto LE, et al. Caspofungin therapy of neonates with invasive candidiasis Article in The Pediatric Infectious Disease Journal January 2005 Impact Factor: 2.72 DOI: /01.inf a Source: PubMed CITATIONS 139 READS authors, including: Thomas J Walsh Cornell University, 812 PUBLICATIONS 51,664 CITATIONS SEE PROFILE Available from: Thomas J Walsh Retrieved on: 12 May 2016

2 ORIGINAL STUDIES Caspofungin Therapy of Neonates With Invasive Candidiasis Carla M. Odio, MD,* Roberto Araya, MD, Luis E. Pinto, MD, Carlos E. Castro, MD, Sergio Vasquez, MD, Braulio Alfaro, MD, Alberto Sàenz, MD, Marco L. Herrera, MSQ, and Thomas J. Walsh, MD Background: Invasive candidiasis is an increasing problem in neonatal intensive care units worldwide and is an important cause of morbidity, mortality and prolongation of hospital stay. Despite administration of amphotericin B, invasive candidiasis in neonates is sometimes complicated by persistent fungemia and refractory invasive candidiasis. The problem has been augmented by the increasing prevalence of non-albicans species that often are resistant to fluconazole and to amphotericin B. Population and Methods: The population consisted of 1 term and 9 premature neonates with invasive candidiasis caused by Candida albicans (n 4), Candida parapsilosis (n 3), Candida tropicalis (n 2) and Candida glabrata (n 1). Despite initial therapy with deoxycholate amphotericin B, blood cultures remained positive in all patients for days. Invasive candidiasis progressed to meningitis and enlarging renal Candida bezoars in the kidney of one patient and an enlarging atrial vegetation in another. Another patient developed severe hypokalemia refractory to potassium supplementation. Two of the C. albicans and all of the non-albicans Candida isolates were resistant to fluconazole; the C. glabrata isolate was resistant to amphotericin B. Amphotericin B was discontinued and caspofungin initiated in all patients in a dosage of 1 mg/kg/d for 2 days followed by 2 mg/kg/d. Results: All positive blood cultures cleared between 3 and 7 days after initiation of caspofungin, the atrial vegetation resolved and the renal Candida bezoars disappeared. Renal and hepatic function tests did not show any values above normal throughout caspofungin therapy. There were no attributable clinical adverse events during the administration of caspofungin in any of the patients. Accepted for publication July 12, From *Infectious Diseases, Neonatology and Microbiology, Hospital Nacional de Niños, and The School of Medical Sciences, San Jose, Costa Rica; and the Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD Address for reprints: Carla M. Odio, MD, Division of Infectious Diseases and Neonatology, Hospital Nacional de Niños Dr. Carlos Saenz Herrera, Apartado , San Jose, Costa Rica. Fax (506) ; Codio@hnn.sa.cr. Copyright 2004 by Lippincott Williams & Wilkins ISSN: /04/ DOI: /01.inf a Conclusions: Caspofungin was effective, safe and well-tolerated as an alternative therapy for persistent and progressive candidiasis in those neonates who were unresponsive to or intolerant of deoxycholate amphotericin B. Key Words: caspofungin, amphotericin B, neonatal, candidiasis, candidemia, endocarditis, meningitis, neonatal intensive care unit, prematures (Pediatr Infect Dis J 2004;23: ) Bloodstream infections caused by Candida species are an increasingly important infectious complication in patients in the neonatal intensive care unit (NICU). 1 3 Candidemia has a significant impact on overall and causespecific mortality rates and morbidity. 4,5 These events have developed concurrently with a recent shift from Candida albicans to non-albicans species of Candida. 6 9 However, C. albicans remains the dominant species in most NICUs. Antifungal therapy also has evolved during the past decade, and a number of clinical treatment trials have been completed, albeit not in neonates Accordingly therapeutic guidelines 16 for the management of candidemia have been recently formulated on the basis of results of these trials. Although amphotericin B is considered the mainstay of antifungal therapy in NICUs, it has been associated with adverse reactions. 17 Fluconazole is active against most Candida spp. but is limited by emergence of resistance, particularly in non-albicans species of Candida. Caspofungin belongs to the group of novel antifungal agents known as echinocandins that are highly selective, irreversible inhibitors of 1,3- -D-glucan synthesis Caspofungin is fungicidal against Candida spp., including many strains that are resistant to amphotericin B and triazoles. To our knowledge, this report represents the first published case series that evaluate the tolerability and effectiveness of caspofungin in neonates with refractory invasive candidiasis. The Pediatric Infectious Disease Journal Volume 23, Number 12, December

3 Odio et al The Pediatric Infectious Disease Journal Volume 23, Number 12, December 2004 SUBJECTS AND METHODS Serving as a referral center for the entire country of Costa Rica, the NICU at Hospital Nacional de Niños has 33 beds. From January 2001 through December 2003, there were 2533 admissions (2001, 756; 2002, 845; 2003, 932) which represents a mean of 70 monthly admissions. Caspofungin was approved for use in Costa Rica in October 2001 (Cancidas; Merck Sharp and Dohme) for patients older than 16 years, with invasive Candida spp. or Aspergillus spp. that fail to respond or develop intolerability to deoxycholate amphotericin B or to azoles. Written informed consent from the parents or legal guardians was obtained before caspofungin administration, because this drug is not approved for use in infants in Costa Rica or elsewhere. All patients developed severe refractory invasive candidiasis that failed to respond to amphotericin B in 10 cases and/or fluconazole in 2 cases. Eight (C. albicans, 2; nonalbicans, Candida, 6) isolates were resistant in vitro to fluconazole, and 1 of the non-albicans isolates (C. glabrata) was resistant to both drugs. Data were collected prospectively with respect to demographic information, potential risk factors for invasive candidiasis, use of previous antifungal agents and reasons that prompted use of caspofungin. To assess toxicity, serum biochemistry profiles, which included urea nitrogen, potassium, creatinine, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, were obtained immediately before, weekly during and within 3 days after discontinuation of therapy with caspofungin. Other data collected prospectively included cumulative doses of amphotericin B and of caspofungin, as well as time of follow-up of patients after discontinuation of therapy. Clinical follow-up of the patients was performed daily while hospitalized and weekly after discharge until submission of this report. To assess tolerability, heart and respiratory rate, mean arterial blood pressure and oxygen saturation were monitored during each infusion of caspofungin. Caspofungin was administered once daily as a 1-hour infusion in a dosage of 0.5 mg/kg for 3 days followed by 1 mg/kg daily for 28 days in one patient; all other patients received 1 mg/kg/d for the first 2 days followed by 2 mg/kg/d for days. Susceptibility Testing. Susceptibility testing of Candida isolates to amphotericin B and fluconazole was performed at the Microbiology Laboratory of Hospital Nacional de Niños by the ATB FUNGUs, biomèrieux procedure. 24 Resistance to amphotericin and to fluconazole was defined by a minimal fungicidal concentration (MFC) of 8 and of 64 g/ml, respectively. RESULTS Patient Characteristics. From January through December of 2001, 2002 and 2003, there were were 17, 16 and 10 patients with candidemia, respectively. C. albicans, Candida parapsilosis, Candida tropicalis and Candida glabrata accounted for 58% (25 of 43), 35% (15 of 43)%, 5% (2 of 43) and 2% (1 of 43) of all cases of invasive candidiasis, respectively. In these 3 years 9 of 42 (21%) of the patients were unresponsive and 1 of 43 was intolerant to deoxycholate amphotericin B. During these past 3 years, our NICU has managed invasive candidiasis caused b y C. albicans (n 4), and C. parapsilosis (n 3), C. tropicalis (n 2) and C. glabrata (n 1) in 9 premature neonates and 1 term neonate with caspofungin. All but 1 were premature with mean gestational and chronologic ages of the 9 prematures of 33 weeks and 44 days, respectively; mean birth weight was 1500 g (Table 1). All had central venous catheters that were removed as soon as the results of the blood culture were known (mean time from TABLE 1. Characteristics of Neonates With Invasive Candidiasis Treated with Caspofungin Patient GA (wk) CA (Days) Wt (kg) Isolate Sites of Infection Cumulative Dose (mg/kg) Outcome Ampho* Caspo Cure Relapse Death Months of Follow-up and Status Candida parapsilosis Blood, heart X C. parapsilosis Blood X Candida albicans Blood, CSF, urine, kidney x NA C. albicans Blood X C. albicans Blood X C. albicans Blood X C. parapsilosis Blood X Candida tropicalis Blood X C. tropicalis Blood 5 30 X Candida glabrata Blood 7 30 X 3 *Cumulative amount of amphotericin B (Ampho) administered before caspofungin. Died from Klebsiella pneumoniae septicemia, after negative cultures for candida in blood, CSF, urine Not applicable Toxicity to amphotericin B Relapsed four days after discontinuation of caspofungin; sterilized blood culture after the 3 rd dose of a 2 nd course of caspofungin GA indicates gestational age; CA, chronologic age; Caspo, caspofungin Lippincott Williams & Wilkins

4 The Pediatric Infectious Disease Journal Volume 23, Number 12, December 2004 Caspofungin Therapy clinical onset, 1.7 days) before or at the time of the start of amphotericin B. All patients were receiving total parenteral nutrition at the start of caspofungin, and 5 received it during the entire treatment. Candida spp. were recovered from blood in all patients. Among the 10 patients, the reasons for changing therapy from deoxycholate amphotericin B to caspofungin were persistently positive peripheral blood cultures in the absence of a central venous or arterial catheter, after cumulative doses of deoxycholate amphotericin B ranging from 9 to 38 mg/kg in 6 patients to progressive disseminated disease with persistence of candidemia after cumulative doses of 42 and 37 mg/kg in 1 patient each, respectively, toxicity (hypotension, bradycardia and hypokalemia refractory to potassium supplementation) from amphotericin B after a cumulative dose of 9 mg/kg in one patient and resistance of the isolate (C. glabrata) to amphotericin B and fluconazole in another. The latter had received a cumulative dose of amphotericin B of 10.5 mg/kg when switched to caspofungin; the blood cultures were still positive. Sites of Presumed or Documented Infection and of Isolation of the Candida spp. In 8 patients, Candida (C. albicans, 3;C. parapsilosis, 3;C. tropicalis, 2;C. glabrata, 1) was recovered from peripheral blood and central venous catheter blood at the time of diagnosis of the infection and from peripheral blood thereafter while receiving amphotericin B; 1 of these patients with C. parapsilosis recovered from blood developed a vegetation on the left atrium that continued to enlarge while receiving amphotericin B. In 1 patient, C. albicans was recovered from peripheral and central venous catheter blood, urine and cerebrospinal fluid (CSF) while receiving amphotericin B; this patient showed ultrasonographic changes compatible with ventriculitis and kidney bezoars on the brain and abdominal ultrasounds, respectively. The cultures from peripheral blood, urine and CSF continued to yield C. albicans during amphotericin B therapy (Table 1) The duration of positive blood cultures after initiation of amphotericin was 28, 21, 25, 12, 23, 22, 24, 19, 7 and 9 days in patients 1 through 10, respectively. Susceptibility Results. Eight (C. albicans, 2; non-albicans Candida, 6) isolates were resistant (MFC 64 g/ml) in vitro to fluconazole; all of the C. albicans isolates were susceptible (MFC 4 g/ml) to amphotericin B in vitro, and the C. glabrata isolate was resistant to both drugs. Dose of Caspofungin. The dosage of caspofungin was estimated based on the body weight at the time of initiation of therapy. One patient (Table 1, patient 1) received 0.5 mg/kg for the first 3 days and 1 mg/kg thereafter. The other 9 patients received 1 mg/kg for the first 2 days and 2 mg/kg in the following days. In milligrams per m 2, the patients received mg (mean, 10.5 mg) the first 2 days, followed by mg (mean, 23.3 mg) thereafter. Response to Caspofungin. C. albicans was recovered from blood and CSF in in 1 patient, as well as from a urine sample obtained via aseptic in and out catheterization. This patient had renal Candida bezoars visualized by ultrasound in 1 kidney. Blood, urine and CSF cultures were sterile after 5, 3 and 7 days of caspofungin, respectively. The renal Candida bezoars resolved after 19 days of caspofungin therapy. This patient died on day 19 of caspofungin therapy for overwhelming Klebsiella pneumoniae septicemia; an autopsy was not performed. In second patient with disseminated candidiasis C. parapsilosis was recovered from the blood, and a mm atrial vegetation was visualized by echocardiography. After 7 weeks of amphotericin B administration, the lesion showed enlargement, and the blood cultures were still positive. Amphotericin B was discontinued. After initiation of caspofungin, blood cultures were sterile after 4 doses and the vegetation resolved by sonography after the 9th day of therapy. The other 8 patients had persistent candidemia (C. albicans, 3;C. parapsilosis, 2;C. tropicalis, 2;C. glabrata, 1). All cases of persistent candidemia resolved on caspofungin therapy. One patient with C. albicans fungemia had recurrent candidemia 4 days after completion of a course of caspofungin of 2 mg/kg administered during 15 days. Caspofungin in this patient was administered again for a second course of 15 days. Candidemia resolved after 3 doses, and the patient remained relapse-free after 11 months of follow-up. Safety and Tolerability of Caspofungin There were no clinical or laboratory adverse events related to caspofungin administration. Heart and respiratory rates, mean arterial blood pressure and oxygen saturation remained stable during each infusion of caspofungin in the 10 neonates. Serum transaminases, bilirubin, blood urea nitrogen, sodium, potassium and creatinine remained within normal limits during caspofungin therapy. Concomitant Therapy. During caspofungin administration, 4 patients received 2 concomitant 48-hour courses of amikacin plus oxacillin (n 3) and amikacin plus clindamycin (n 1) for suspected sepsis; 1 patient received 7 days of vancomycin for treatment of Staphylococcus simulans septicemia, 1 received 4 days of meropenem before death caused by K. pneumoniae septicemia and 6 received aminophylline or theophylline. DISCUSSION Invasive candidiasis is a major cause of attributable morbidity and mortality in newborn infants, particularly in very low birth weight infants. For example, from 1981 to 1995, the incidence of candidemia in 1 NICU increased to 11%. 4 Moreover the prevalence of Candida spp. that cause invasive candidiasis is shifting from C. albicans to nonalbicans Candida species, particularly C. parapsilosis, C. tropicalis and C. glabrata. 25,26 Six of our 10 patients were infected with non-albicans Candida species Lippincott Williams & Wilkins 1095

5 Odio et al The Pediatric Infectious Disease Journal Volume 23, Number 12, December 2004 Invasive candidiasis in neonates may continue to progress despite treatment with conventional amphotericin B, 27 as was the case in 9 of our patients with persistently positive blood cultures. Intolerance may also mandate discontinuation of this drug, as occurred in 1 of our patients receiving deoxycholate amphotericin B. Dose-limiting nephrotoxicity, including intractable hypokalemia, may be a serious problem with amphotericin B in very low birth weight infants. 17 Lipid formulations of amphotericin B have been used for invasive neonatal candidiasis. The majority of the neonatal experience has been accumulated with amphotericin B lipid complex (Abelcet) 28,29 and liposomal amphotericin B (AmBisome). 30,31 Given that lipid formulations of amphotericin B are not available in Costa Rica, another alternative was sought for our patients. As preclinical and clinical data have demonstrated that caspofungin is as or more effective and safer than deoxycholate amphotericin B in adult patients, 32 we considered that caspofungin was an appropriate alternative to deoxycholate amphotericin B in neonates. Our patients cleared C. albicans from blood in a mean of 4.3 days of therapy with caspofungin. One patient relapsed 4 days after the last dose of caspofungin; however, on readministration of caspofungin, the blood culture was sterile after 3 doses. This patient remained relapse-free during 11 months of follow-up. Two of our patients had documented disseminated candidiasis, which responded to caspofungin within 9 19 days of therapy. One could hypothesize that the atrial vegetation of the patient with Candida endocarditis embolized and that this accounted for the echocardiographic changes after 9 doses of caspofungin. However, a pulmonary embolus of this magnitude would have likely caused severe pulmonary or hemodynamic deterioration, which did not occur. Caspofungin was useful for this patient, because surgical excision of such vegetations in small premature infants is associated with high mortality. 33 None of our patients experienced clinical adverse events during or at the end of therapy with caspofungin therapy, nor were there abnormalities in parameters of hepatic or renal function. Recently Franklin et al 34 reported their experience with the safety and tolerability of caspofungin in 25 pediatric oncology patients. 34 They concluded that caspofungin was safe and well-tolerated in this population. However, these investigators did not evaluate the efficacy of caspofungin for 2 reasons: a large number of patients were receiving concomitant antifungal agents; and caspofungin was administered in some patients for only 1 day. Recent results of a study from Walsh et al 35 on the pharmacokinetics of caspofungin in pediatric patients demonstrated that a 1-mg/kg dose resulted in a lower area under the concentration-time curve relative to that of adults receiving the standard regimen of 50 mg/d. They further found that a dosage of 50 mg/m 2 /d provided comparable concentration-time curves 1096 in pediatric patients between 2 and 12 years of age as those achieved with the 50-mg/d dosage in adult patients. Nine of our 10 patients received 2 mg/kg/d, and all but 1 attained sustained cure; however, the optimal dose for neonates is unknown. Although the dosage of 2 mg/kg was effective and well-tolerated in these neonates, studies of the plasma pharmacokinetics of caspofungin in this population are warranted to define the optimal dose and to proceed with randomized trials to assess its clinical efficacy and safety. In summary, caspofungin was successful in the treatment of invasive candidiasis in 10 neonates who were refractory to, resistant to or intolerant of therapy with deoxycholate amphotericin B. There was no evidence of caspofunginrelated laboratory or clinical toxicity in these 10 patients. Caspofungin is an appropriate alternative for the treatment of invasive candidiasis in premature neonates when there is lack of response, resistance or toxicity to other antifungal agents such as deoxycholate amphotericin B or fluconazole. REFERENCES 1. Makhoul IR, Kassis I, Smolkin T, Tamir A, Sujov P. Review of 49 neonates with acquired fungal sepsis: further characterization. Pediatrics. 2001;107: Butler KM, Baker CJ. Candida: an increasingly important pathogen in the nursery. Pediatr Clin North Am. 1988;35: Benjamin DK Jr, Poole C, Steinbach WJ, Rowen JL, Walsh TJ, Neonatal candidemia and end-organ damage: a critical appraisal of the literature using meta-analytic techniques. 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