Pharmacokinetics of oral fluconazole in premature infants

Wenzl, Tobias G.; Schefels, J.; Hörnchen, H; Skopnik, H.

doi:10.1007/s004310050906

Cited by 51 publications

(35 citation statements)

References 5 publications

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“…A loading dose would be necessary to reach the desired steady-state concentration rapidly. Our data suggest that the lower fluconazole dosages frequently used in the neonatal population result in underexposure and may partially explain the prolonged periods of candidemia (5) and episodes of breakthrough candidemia (23).…”

Section: Discussionmentioning

confidence: 84%

“…It is minimally metabolized, is eliminated as active drug in the urine, and effectively penetrates tissues and cerebrospinal fluid. Although it is frequently used in the neonatal population, remarkably little fluconazole PK data have been published for neonates, with studies being limited to a small number of preterm 24-to 29-weekgestation neonates (9,21,23). Existing data are thus insufficient for the development of a generalized dosing guidance.…”

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confidence: 99%

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Population Pharmacokinetics of Fluconazole in Young Infants

Wade

Kaufman

et al. 2008

Antimicrob Agents Chemother

160

143

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Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23-to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (

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Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 99%

Population Pharmacokinetics of Fluconazole in Young Infants

Wade

Kaufman

et al. 2008

Antimicrob Agents Chemother

160

143

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“…Furthermore, we set out to minimize the invasiveness of the prophylaxis while nonetheless allowing (by the oral route) its completion in neonates who no longer required an intravenous access, thus avoiding discontinuances before 30 and 45 days in NE-VLBW and ELBW neonates, respectively. Several clinical 24 and pharmacokinetic studies have demonstrated the equal bioavailability of intravenous and oral fluconazole, [34][35][36]40 and in such neonates, continuing the prophylaxis is advisable because the risk factors for SFI do not disappear when the intravenous access is removed.…”

Section: Discussionmentioning

confidence: 99%

“…This schedule was based on experiences and published pharmacokinetic data from preterm neonates. 24,[33][34][35][36] Routine surveillance (serum alanine aminotransferase and aspartate aminotransferase concentrations checked twice) was performed to record the presence of drug-related adverse effects or toxicity. Neonates were also screened for interactions between fluconazole and other concomitantly prescribed drugs and for any clinical manifestation that might be related to the use of fluconazole.…”

Section: Prophylaxis With Fluconazole In Group B Neonatesmentioning

confidence: 99%

Prophylactic Fluconazole Is Effective in Preventing Fungal Colonization and Fungal Systemic Infections in Preterm Neonates: A Single-Center, 6-Year, Retrospective Cohort Study

Manzoni

Arisio²,

Mostert³

et al. 2006

Pediatrics

140

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OBJECTIVE. Despite the promising preliminary results observed in extremely low birth weight (ELBW) populations, the use of fluconazole to prevent fungal colonization and infection in preterm neonates in the NICU is still an open question and not yet recommended as a standard of care. We have reviewed our 6-year series to assess the effectiveness and safety of this form of prophylaxis.METHODS. This retrospective study consisted of 465 neonates who weighed Ͻ1500 g at birth and were admitted to our NICU in the period 1998 -2003. Those who were born between 1998 and 2000 and did not receive fluconazole prophylaxis (group A, n ϭ 240) were compared with those who were born between 2001 and 2003 and treated with fluconazole until the 30th day of life (45th for neonates Ͻ1000 g at birth; group B, n ϭ 225). Weekly surveillance cultures were obtained from all patients. Incidence of fungal colonization, incidence of systemic fungal infection (SFI), rate of progression from colonization to infection, and mortality rates attributable to fungi were calculated for both groups and separately for neonates who were Ͻ1000 g (ELBW) and were 1001 to 1500 g (NE-VLBW) at birth.RESULTS. Overall fungal colonization was significantly lower in group B (24.0%) than in group A (43.8%; relative risk [RR]: 0.406; 95% confidence interval [CI]: 0.273-0.605). The same was true of neonates with colonization in multiple sites (2.6% vs 5.8%) and of those with colonization from high-risk sites (5.8% vs 19.2%). SFI incidence was significantly lower in group B (10 of 225 cases; 4.4%) than in group A (40 of 240 cases; 16.7%; RR: 0.233; 95% CI: 0.113-0.447). Reduction of both colonization and SFI in group B was greater in the ELBW neonates and also significant in the NE-VLBW neonates. Rate of progression from colonization to infection was significantly lower in group B (0.17 vs 0.38; RR: 0.369; 95% CI: 0.159 -0.815). Crude mortality rate attributable to Candida species www.pediatrics.org/cgi

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“…Previous PK studies in infants suggested increasing fluconazole clearance (CL) over the first postnatal weeks (10)(11)(12)(13). However, the PK of fluconazole in infants of Ͻ750 g birth weight have not been extensively evaluated, and it is this population that has the highest risk for invasive candidiasis where prophylaxis has the most potential for benefit (14).…”

mentioning

confidence: 99%

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

Momper

Capparelli

Wade

et al. 2016

Antimicrob Agents Chemother

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Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.

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Pharmacokinetics of oral fluconazole in premature infants

Abstract: Oral fluconazole seems to be a safe and effective treatment for Candida albicans septicaemia even in premature infants.

Cited by 51 publications

References 5 publications

Population Pharmacokinetics of Fluconazole in Young Infants

Population Pharmacokinetics of Fluconazole in Young Infants

Prophylactic Fluconazole Is Effective in Preventing Fungal Colonization and Fungal Systemic Infections in Preterm Neonates: A Single-Center, 6-Year, Retrospective Cohort Study

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

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