Pharmacokinetics of an Elevated Dosage of Micafungin in Premature Neonates

Smith, P. Brian; Walsh, Thomas J.; Hope, William; Arrieta, Antonio; Takada, Akitsugu; Kovanda, Laura; Kearns, Gregory L.; Kaufman, David; Sawamoto, Taiji; Buell, Donald N.; Benjamin, Daniel K.

doi:10.1097/inf.0b013e3181910e2d

Cited by 134 publications

(88 citation statements)

References 20 publications

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“…Neither M1 nor M2 has inherent antifungal activity, and the antifungal activity of M5 is 1/125 that of the parent compound (19). In addition, there do not appear to be any issues in terms of toxicity or other adverse effects when micafungin is administered at high doses (e.g., 15 mg/kg) (7,16). The most interesting observation is that there is an association between M5 exposure and younger age, i.e., M5 exposure is higher in younger patients.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Micafungin and Its Metabolites M1 and M5 in Children and Adolescents

Hope

Kaibara

Roy

et al. 2015

Antimicrob Agents Chemother

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The aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment of Candida infections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and <17 years were obtained from four phase I and two phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve at 24 hours (AUC 24 ) of micafungin within the 10th to 90th percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 g · h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg of body weight/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC 24 target range for invasive candidiasis. Cutoffs of 40 or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for the prevention of invasive candidiasis, the treatment of invasive candidiasis, and the treatment of esophageal candidiasis, respectively, in children aged 4 months to <17 years. Micafungin is an echinocandin antifungal agent with activity against medically important fungal pathogens such as Candida spp. and Aspergillus spp. (1). It is licensed worldwide for the treatment of adults with invasive candidiasis, the prevention of invasive Candida infections, and the treatment of esophageal candidiasis. A dosage of 100 mg/day is used in adults weighing Ͼ40 kg with candidemia and/or invasive candidiasis. There is no additional benefit in using a higher dosage of 150 mg/day in these patients (2). A dosage of 50 mg/day is used for the prevention of invasive Candida infections in neutropenic patients, while a dosage of 150 mg/day is used for the treatment of esophageal candidiasis.The U.S. Food and Drug Administration (FDA) has approved the use of micafungin for pediatric patients Ͼ4 months of age for the same indications as adults (3). Micafungin is licensed by the European Medicines Agency (EMA) for the treatment of children (including neonates) and adolescents Ͻ16 years of age with invasive candidiasis and as prophylaxis in patients Ͻ16 years of age who are undergoing hematopoietic stem cell transplant or who are expected to have neutropenia (1).The safety and pharmacokinetics (PK) of micafungin in neonates, children, and adolescents have been determined in a number of clinical studies (4, 5). These studies enrolled patients across different age groups and have led to th...

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Micafungin and Its Metabolites M1 and M5 in Children and Adolescents

Hope

Kaibara

Roy

et al. 2015

Antimicrob Agents Chemother

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“…[82][83][84][85] Two of the most commonly used echinocandins, caspofungin and micafungin, have comparative susceptibility and safety profiles. There are ongoing pharmacokinetic trials of anidulafungin in neonates.…”

Section: Management Of Candidiasismentioning

confidence: 99%

Recent Developments and Current Issues in the Epidemiology, Diagnosis, and Management of Bacterial and Fungal Neonatal Sepsis

2013

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The definition of neonatal sepsis is complicated by the frequent presence of noninfectious conditions that resemble those of sepsis, especially in very low-birth-weight (VLBW) preterm infants and by the absence of optimal diagnostic tests. Although growth of an organism from a sterile site is the "gold standard" for definitive diagnosis, it is not always possible to isolate a causative pathogen. Invasive infections can occur in seemingly asymptomatic neonates. Therefore, assessment of history and risk factors in combination with diagnostic tests are used to identify neonates who are more likely to be infected.The definitions of early onset sepsis (EOS) and late onset sepsis (LOS) are subject to subspecialist variation. Many investigators, including those who participate in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Network and the Vermont Oxford Network, define EOS by the onset of signs/symptoms and an associated positive culture at or before 72 hours of life. LOS is characterized by the onset of symptoms consistent with sepsis at greater than 72 hours of life. These classifications of EOS and LOS reflect the differing etiologies and proposed pathophysiology of pathogens commonly associated with the timing of Keywords ► neonatal sepsis ► invasive candidiasis ► epidemiology ► management AbstractIdentifying neonates with sepsis is complicated by variability in clinical presentation. The incidence of early onset sepsis (EOS) resulting from invasive group B streptococcal (GBS) infections has been notably reduced by the widespread delivery of intrapartum antibiotic prophylaxis. Rates of EOS attributable to non-GBS etiologies have remained constant, and ampicillin-resistant Escherichia coli has become more prevalent. Lateonset sepsis (LOS) attributable to gram-positive organisms including coagulase-negative Staphylococci and Staphylococcus aureus is associated with increased morbidity and mortality among premature infants. Invasive candidiasis is an emerging cause of LOS, especially among infants who receive broad-spectrum antimicrobial agents. Prophylactic fluconazole administration to very low-birth-weight (VLBW) neonates during the first 6 weeks of life prevents invasive candidiasis in neonatal intensive care units (NICU) with high rates of fungal infections. Targeted fluconazole prophylaxis may be beneficial in VLBW neonates who receive care in NICUs with lower rates of invasive fungal infections. Assessment of immune function, neutrophil markers, acute phase reactants, and utilization of sepsis screening scores may contribute to the management of sepsis. Maternal decolonization, antimicrobial stewardship, early enteral feeding, and optimal infection control practices are potential practical strategies for reducing the burden of neonatal sepsis.

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“…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.…”

Section: Treatment Of Invasive Fungal Infectionsmentioning

confidence: 99%

“…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).…”

Section: Treatment Of Invasive Fungal Infectionsmentioning

confidence: 99%

Challenging issues in neonatal candidiasis

Kaufman

2010

Current Medical Research and Opinion

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In an era of quality improvement and 'getting to zero (infections and/or related mortality),' neonatal candidiasis is ripe for evidence-based initiatives. Knowledge of each institution's invasive Candida infection (ICI) incidence and infection-related mortality is critical to evaluate disease burden and effective interventions. Evidenced-based interventions include: antifungal prophylaxis, starting with appropriate dosing, and prompt removal of central venous catheters (CVC). There is A-I evidence supporting antifungal prophylaxis with fluconazole, and it should be considered in every neonatal intensive care unit (NICU). The literature supports targeting infants51000 g and/or 27 weeks, because this group has high infection-related mortality and neurodevelopmental impairment in 57% of survivors. Antifungal prophylaxis has been shown to nearly eliminate infection-related mortality. Interventions start with prenatal initiatives, with women being treated for vaginal candidiasis, especially with preterm labor or complications. Targeting modifiable risk factors, including restriction policies for use of third-and fourth-generation cephalosporins, carbapenems, H2-antagonists, proton pump inhibitors, and postnatal steroids; guidelines for CVC care and removal; and feeding practices, with promotion of early feedings and breast milk, may also reduce risk. A few studies have emerged on empiric antifungal therapy with sepsis evaluations for preterm infants 51500 g and other high-risk patients that have shown favorable effects of eliminating mortality, but these have not been compared to appropriate antifungal therapy and central line removal. Further study of empiric therapy, prospective treatment studies with higher targeted dosing of amphotericin B preparations, fluconazole, and new antifungals with prompt CVC removal may contribute to a 100% survival rate for those infants41000 g and 28 weeks not receiving antifungal prophylaxis. Evaluation of ICI incidence and mortality by gestational age and birth week should be followed in each NICU, to evaluate infection control and prevention.

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Pharmacokinetics of an Elevated Dosage of Micafungin in Premature Neonates

Cited by 134 publications

References 20 publications

Population Pharmacokinetics of Micafungin and Its Metabolites M1 and M5 in Children and Adolescents

Population Pharmacokinetics of Micafungin and Its Metabolites M1 and M5 in Children and Adolescents

Recent Developments and Current Issues in the Epidemiology, Diagnosis, and Management of Bacterial and Fungal Neonatal Sepsis

Challenging issues in neonatal candidiasis

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