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Antifungal therapy for candidemia: Outcomes
Abstracts / Early Human Development 85 (2009) S93–S100 h
CHOC, Orange, United States University of Utah, Salt Lake City, United States j University of Michigan, Ann Arbor, United States k CHOP, Philadelphia, United States l Case Western Reserve University, Cleveland, United States m University of Manchester, Manchester, United States i
Background: Meropenem is approved for treatment of complicated abdominal infections in pediatric patients and adults. The primary objective of this study is to characterize meropenem multiple-dose PK and preliminary safety in young infants. Design and population: Infants <91 days of age with suspected or documented complicated intra-abdominal infections were eligible for the study. Infants with renal dysfunction or history of seizures were excluded. Material and methods: Population and individual subject (Bayesian) PK parameters were estimated using NONMEM. Results: Data including 99 meropenem concentrations on the first 22 infants enrolled are presented. Dosing was based on both gestational age and postnatal age: 3 infants received 20 mg/kg q12 h, 13 received 20 mg/kg q8 h, 1 received 30 mg/kg q8 h, and 1 received 40 mg/kg q8 h. Median gestational age at birth and post-natal age were 27 weeks and 18 days, respectively. Median plasma clearance (CL), volume of distribution, and elimination T½ were 0.12 L/kg/h, 0.54 L/kg, and 2.9 h, respectively. A significant, positive association was observed between CL and postconceptional age. All infants had predicted meropenem concentrations above an MIC of 2 µg/mL for >75% of the dosing interval. No serious adverse events related to meropenem were observed. Conclusions: Meropenem doses of 20 mg/kg q12 h to 40 mg/kg q8 h were well tolerated and produced drug plasma concentrations above an MIC that inhibits most susceptible pathogens.
doi:10.1016/j.earlhumdev.2009.08.038
Safety and pharmacokinetics of multiple-dose anidulafungin in infants Michael Cohen-Wolkowieza, Brian Smitha,⁎, Lauren Pipera, Cassie Morana, Ping Liub, Angela Kashubac, Edmund Capparellid, Thomas Walshe, William Hopef, Daniel K. Benjamin Jr.a a Duke University, Durham, United States b Pfizer, Inc., New London, United States c University of North Carolina, Chapel Hill, United States d University of California at San Diego, San Diego, United States e National Cancer Institute, Bethesda, United States f University of Manchester, Manchester, United States
Background: Disseminated candidiasis and hematogenous Candida meningoencephalitis (HCME) cause substantial morbidity and mortality in premature infants. The echinocandins are attractive products for this population given their safety profiles. Experimental models of HCME suggest that high echinocandin weight-based dosages are required for successful therapy. The PK of anidulafungin in infants remains uncharacterized. The objective of this open-label study was to determine the safety and PK of multiple dose intravenous anidulafungin in infants <24 months of age at risk of invasive fungal infections. Design and population: Subjects received a 3 mg/kg loading dose followed by a maintenance dose of 1.5 mg/kg every 24 h for 3–5 consecutive days. A total of 4–5 plasma samples were obtained from each subject at steady state (doses 3–5). Material and methods: PK parameters were generated using NCA analysis in WinNonlin v5.
S97
Results: Data from 34 steady state anidulafungin concentrations in 7 infants are presented (Table). No drug related adverse events were seen during therapy. One death occurred upon discontinuation of extracorporeal membrane oxygenation per standard of care.
Subject
Clearance (L/kg/h)
AUCss (µg h/mL)
Cmax (µg/mL)
Estimated gestational age (wks)
Postnatal days
1 2 3 4 5 6 7 Mean SD
0.049 0.016 0.016 0.015 0.018 0.013 0.027 0.022 0.013
30.5 94.1 92.3 101.8 82.0 113.6 54.6 81.3 28.9
2.2 5.4 4.1 5.8 4.7 7.2 3.6 4.7 1.7
36 38 35 37 37 39 24 35.1 5.1
24 28 50 68 104 169 197 91.4 68.5
AUC: area under the curve; Cmax: maximum concentration.
Conclusions: Anidulafungin 1.5 mg/kg/day (loading dose 3 mg/kg) was well tolerated in these infants. The total exposure (AUCss) at this dosage was within 20% of that observed in older children given the same weight-based dosage and adults receiving 100 mg/day. Optimal dosing for Candida meningoencephalitis remains to be determined. doi:10.1016/j.earlhumdev.2009.08.039
Antifungal therapy for candidemia: Outcomes Cassie Morana, Daniel K. Benjaminb, Brian Smitha,⁎, Michael Cohen-Wolkowieza, Clark Reesec, Daniel K. Benjamin Jr.a a Duke University, Durham, United States b Clemson University, Clemson, United States c Pediatrix–Obstetrix Center for Research and Education, Sunrise, United States
Background: Candidiasis is a leading cause of morbidity and mortality in neonates. Although several antifungal agents are used in this population, safety and efficacy data are limited. We sought to determine the mortality, length of hospital stay, and time to infection clearance for neonates treated with different antifungal regimens. Design and population: This was a retrospective cohort study of neonates <120 days of age admitted to 248 neonatal intensive care units managed by the Pediatrix Medical Group in the United States between 1996 and 2007. Material and methods: We collected data for 1277 neonates who had a blood, urine, or cerebrospinal fluid culture positive for Candida and were treated with an antifungal agent. We compared outcomes for each antifungal agent. Results: The mean gestational age and birth weight were 27 weeks and 1108 g. Overall mortality was 19%; time to discharge 62 days; and duration of infection 5 days. Controlling for gestational age, birth weight, race, sex, and maternal age, there was no difference in mortality, time to discharge, or time to clear infection in patients treated with fluconazole alone versus those treated with amphotericin B deoxycholate or liposomal amphotericin alone. There was no difference in outcome for patients who received antifungal prophylaxis, compared to those that did not receive prophylaxis. Conclusions: Outcomes were not dependent upon the antifungal agent or the use of prophylaxis.
doi:10.1016/j.earlhumdev.2009.08.040
CHOC, Orange, United States University of Utah, Salt Lake City, United States j University of Michigan, Ann Arbor, United States k CHOP, Philadelphia, United States l Case Western Reserve University, Cleveland, United States m University of Manchester, Manchester, United States i
Background: Meropenem is approved for treatment of complicated abdominal infections in pediatric patients and adults. The primary objective of this study is to characterize meropenem multiple-dose PK and preliminary safety in young infants. Design and population: Infants <91 days of age with suspected or documented complicated intra-abdominal infections were eligible for the study. Infants with renal dysfunction or history of seizures were excluded. Material and methods: Population and individual subject (Bayesian) PK parameters were estimated using NONMEM. Results: Data including 99 meropenem concentrations on the first 22 infants enrolled are presented. Dosing was based on both gestational age and postnatal age: 3 infants received 20 mg/kg q12 h, 13 received 20 mg/kg q8 h, 1 received 30 mg/kg q8 h, and 1 received 40 mg/kg q8 h. Median gestational age at birth and post-natal age were 27 weeks and 18 days, respectively. Median plasma clearance (CL), volume of distribution, and elimination T½ were 0.12 L/kg/h, 0.54 L/kg, and 2.9 h, respectively. A significant, positive association was observed between CL and postconceptional age. All infants had predicted meropenem concentrations above an MIC of 2 µg/mL for >75% of the dosing interval. No serious adverse events related to meropenem were observed. Conclusions: Meropenem doses of 20 mg/kg q12 h to 40 mg/kg q8 h were well tolerated and produced drug plasma concentrations above an MIC that inhibits most susceptible pathogens.
doi:10.1016/j.earlhumdev.2009.08.038
Safety and pharmacokinetics of multiple-dose anidulafungin in infants Michael Cohen-Wolkowieza, Brian Smitha,⁎, Lauren Pipera, Cassie Morana, Ping Liub, Angela Kashubac, Edmund Capparellid, Thomas Walshe, William Hopef, Daniel K. Benjamin Jr.a a Duke University, Durham, United States b Pfizer, Inc., New London, United States c University of North Carolina, Chapel Hill, United States d University of California at San Diego, San Diego, United States e National Cancer Institute, Bethesda, United States f University of Manchester, Manchester, United States
Background: Disseminated candidiasis and hematogenous Candida meningoencephalitis (HCME) cause substantial morbidity and mortality in premature infants. The echinocandins are attractive products for this population given their safety profiles. Experimental models of HCME suggest that high echinocandin weight-based dosages are required for successful therapy. The PK of anidulafungin in infants remains uncharacterized. The objective of this open-label study was to determine the safety and PK of multiple dose intravenous anidulafungin in infants <24 months of age at risk of invasive fungal infections. Design and population: Subjects received a 3 mg/kg loading dose followed by a maintenance dose of 1.5 mg/kg every 24 h for 3–5 consecutive days. A total of 4–5 plasma samples were obtained from each subject at steady state (doses 3–5). Material and methods: PK parameters were generated using NCA analysis in WinNonlin v5.
S97
Results: Data from 34 steady state anidulafungin concentrations in 7 infants are presented (Table). No drug related adverse events were seen during therapy. One death occurred upon discontinuation of extracorporeal membrane oxygenation per standard of care.
Subject
Clearance (L/kg/h)
AUCss (µg h/mL)
Cmax (µg/mL)
Estimated gestational age (wks)
Postnatal days
1 2 3 4 5 6 7 Mean SD
0.049 0.016 0.016 0.015 0.018 0.013 0.027 0.022 0.013
30.5 94.1 92.3 101.8 82.0 113.6 54.6 81.3 28.9
2.2 5.4 4.1 5.8 4.7 7.2 3.6 4.7 1.7
36 38 35 37 37 39 24 35.1 5.1
24 28 50 68 104 169 197 91.4 68.5
AUC: area under the curve; Cmax: maximum concentration.
Conclusions: Anidulafungin 1.5 mg/kg/day (loading dose 3 mg/kg) was well tolerated in these infants. The total exposure (AUCss) at this dosage was within 20% of that observed in older children given the same weight-based dosage and adults receiving 100 mg/day. Optimal dosing for Candida meningoencephalitis remains to be determined. doi:10.1016/j.earlhumdev.2009.08.039
Antifungal therapy for candidemia: Outcomes Cassie Morana, Daniel K. Benjaminb, Brian Smitha,⁎, Michael Cohen-Wolkowieza, Clark Reesec, Daniel K. Benjamin Jr.a a Duke University, Durham, United States b Clemson University, Clemson, United States c Pediatrix–Obstetrix Center for Research and Education, Sunrise, United States
Background: Candidiasis is a leading cause of morbidity and mortality in neonates. Although several antifungal agents are used in this population, safety and efficacy data are limited. We sought to determine the mortality, length of hospital stay, and time to infection clearance for neonates treated with different antifungal regimens. Design and population: This was a retrospective cohort study of neonates <120 days of age admitted to 248 neonatal intensive care units managed by the Pediatrix Medical Group in the United States between 1996 and 2007. Material and methods: We collected data for 1277 neonates who had a blood, urine, or cerebrospinal fluid culture positive for Candida and were treated with an antifungal agent. We compared outcomes for each antifungal agent. Results: The mean gestational age and birth weight were 27 weeks and 1108 g. Overall mortality was 19%; time to discharge 62 days; and duration of infection 5 days. Controlling for gestational age, birth weight, race, sex, and maternal age, there was no difference in mortality, time to discharge, or time to clear infection in patients treated with fluconazole alone versus those treated with amphotericin B deoxycholate or liposomal amphotericin alone. There was no difference in outcome for patients who received antifungal prophylaxis, compared to those that did not receive prophylaxis. Conclusions: Outcomes were not dependent upon the antifungal agent or the use of prophylaxis.
doi:10.1016/j.earlhumdev.2009.08.040