Determining the Pharmacokinetics and Pharmacodynamics of Antibiotics in Premature Infants

In the United States, approximately 13% of the annual birth cohort is born preterm (<37 weeks gestational age). These infants are at high risk of systemic infections, and most are treated with antimicrobial agents. In spite of their common use, antimicrobials lack pharmacokinetic (PK) data in preterm infants. Extrapolation of dosing information from older children and adults to preterm infants often results in therapeutic failures or unwanted toxicities. Therefore, PK studies in this population are needed. Unique challenges posed by preterm infants, however, limit the ability to evaluate drug disposition in this population. Novel, minimal-risk methods can provide the platform to overcome these challenges and optimize antimicrobial dosing. In this proposal, several of these methods were employed to deliver antimicrobial dosing recommendations specifically designed for preterm infants. Two commonly used antimicrobials, piperacillin and metronidazole, were used to evaluate the utility of these methods. A multiplex liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of ampicillin, piperacillin, tazobactam, meropenem, acyclovir, and metronidazole in ultra-low (<50 uL) human plasma was developed and validated. This method was used to analyze drug concentration data from sparse, scavenged, and dried blood spot PK samples collected from preterm infants <32 weeks gestational age at birth. The scavenged concentration data were analyzed by population PK methodologies and used to derive PK parameters and identify covariates (serum creatinine and postmenstrual age) that explain inter-individual variability in piperacillin and metronidazole clearance. When compared to historical data from small studies using traditional PK sampling, piperacillin concentrations were 2-10-fold lower in the scavenged sampling approach, which prevented the determination of optimal dosing recommendations for piperacillin. In contrast, scavenged sampling proved successful for metronidazole and allowed for the development of a simplified, postmenstrual age-based dosing regimen. Piperacillin and tazobactam dried blood spot sampling proved successful as a proof-of-concept application. Dried blood spot piperacillin and tazobactam concentrations can be used as surrogate for plasma measurements. Novel, minimal-risk methods are powerful tools to evaluate the pharmacokinetics/pharmacodynamics of antimicrobials in preterm infants. The success of these methods is drug-dependent, and they should be systematically studied prior to universal implementation

An opportunistic study evaluating pharmacokinetics of sildenafil for the treatment of pulmonary hypertension in infants

To assess sildenafil and N-desmethyl sildenafil (DMS) exposure in infants receiving sildenafil for the treatment of pulmonary hypertension (PH)

Bacterial Meningitis in Infants

Neonatal bacterial meningitis is an uncommon but devastating infection. Although the incidence and mortality have declined over the last several decades, morbidity among survivors remains high. The types and distribution of causative pathogens are related to birth gestational age, postnatal age, and geographic region. Confirming the diagnosis of meningitis can be difficult. Clinical signs are often subtle, and the lumbar puncture is frequently deferred in clinically unstable infants. When obtained, confirmatory testing with cerebrospinal fluid (CSF) culture is often compromised by antepartum or postnatal antibiotic exposure. While blood cultures and CSF parameters may be helpful in cases where the diagnosis is uncertain, bacterial meningitis occurs in infants without bacteremia and with normal CSF parameters. Newer tests such as the polymerase chain reaction are promising but require further study. Prompt treatment with appropriate antibiotics is essential to optimize outcomes. Successful efforts to prevent meningitis in infants have included the use of intrapartum antibiotic prophylaxis against Group B Streptococcus (GBS). Clinical trials investigating the use of a GBS vaccine for the prevention of neonatal GBS disease are ongoing

Evidence-based guidelines for pediatric clinical trials: focus on StaR Child Health

Clinical trials in children are challenging and filled with important ethical considerations that differ from adults. Given difficulties associated with pediatric clinical trials, off-label prescribing is a common practice in pediatrics, which can lead to adverse safety events and efficacy failures. To overcome these consequences, in the past 15 years, legislation in the USA and Europe has provided incentives to industry and increased government funding to conduct pediatric trials. Pediatric trial networks have also been formed to decrease the knowledge gap. However, challenges to performing pediatric trials and lack of standardization and guidelines regarding studies in children still exist. Standards for Research (StaR) in Child Health, begun in 2009, aims to improve the design, conduct and reporting of pediatric trials. This organization uses a consensus guideline approach involving academic, government and industry stakeholders to identify and disseminate best practices for pediatric trials. Six out of 11 planned standards are currently published

Pharmacokinetics and safety of recently approved drugs used to treat methicillin-resistant Staphylococcus aureus infections in infants, children and adults

Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant cause of morbidity in hospitalized infants. Over the past 15 years, several drugs have been approved for the treatment of S. aureus infections in adults (linezolid, quinupristin/dalfopristin, daptomycin, telavancin, tigecycline, and ceftaroline). The use of there majority of these drugs has extended into the treatment of MRSA infections in infants, frequently with minimal safety or dosing information. Only linezolid is approved for use in infants, and pharmacokinetic data in infants are limited to linezolid and daptomycin. Pediatric trials are underway for ceftaroline, telavancin, and daptomycin; however, none of these studies includes infants. Here, we review current pharmacokinetic, safety, and efficacy data of these drugs with a specific focus in infants

Pharmacologic studies in vulnerable populations: Using the pediatric experience

Historically, few data exist to guide dosing in children and pregnant women. Multiple barriers to inclusion of these vulnerable populations in clinical trials have led to this paucity of data. However, federal legislation targeted at pediatric therapeutics, innovative clinical trial design, use of quantitative clinical pharmacology methods, and pediatric thought leadership and collaboration have successfully overcome many existing barriers. This success has resulted in improved knowledge on pharmacokinetics, safety, and efficacy of therapeutics in children. To date, research in pregnant women has not been characterized by similar success. Wide gaps in knowledge remain despite the common use of therapeutics in pregnancy. Given the similar barriers to drug research and development in pediatric and pregnant populations, the route toward success in children may serve as a model for the advancement of drug development and appropriate drug administration in pregnant women

Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures

Abstract Aims Sildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects. Methods A population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance. Results The analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9) −1.33 L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus &lt;10 mmHg (median area under the curve=533 versus 792 µg*h/L). Discussion Elevated hepatic pressure delays clearance of the sildenafil metabolite – des-methyl-sildenafil – and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation

Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK)

The Role of Human Cytochrome P450 Enzymes in the Formation of 2-Hydroxymetronidazole: CYP2A6 is the High Affinity (Low Km) Catalyst

Despite metronidazole’s widespread clinical use since the 1960s, the specific enzymes involved in its biotransformation have not been previously identified. Hence, in vitro studies were conducted to identify and characterize the cytochrome P450 enzymes involved in the formation of the major metabolite, 2-hydroxymetronidazole. Formation of 2-hydroxymetronidazole in human liver microsomes was consistent with biphasic, Michaelis-Menten kinetics. Although several cDNA-expressed P450 enzymes catalyzed 2-hydroxymetronidazole formation at a supratherapeutic concentration of metronidazole (2000 μM), at a “therapeutic concentration” of 100 μM only CYPs 2A6, 3A4, 3A5, and 3A7 catalyzed metronidazole 2-hydroxylation at rates substantially greater than control vector, and CYP2A6 catalyzed 2-hydroxymetronidazole formation at rates 6-fold higher than the next most active enzyme. Kinetic studies with these recombinant enzymes revealed that CYP2A6 has a Km = 289 μM which is comparable to the Km for the high-affinity (low-Km) enzyme in human liver microsomes, whereas the Km values for the CYP3A enzymes corresponded with the low-affinity (high-Km) component. The sample-to-sample variation in 2-hydroxymetronidazole formation correlated significantly with CYP2A6 activity (r ≥ 0.970, P 99%). Chemical and antibody inhibitors of other P450 enzymes had little or no effect on metronidazole 2-hydroxylation. These results suggest that CYP2A6 is the primary catalyst responsible for the 2-hydroxylation of metronidazole, a reaction that may function as a marker of CYP2A6 activity both in vitro and in vivo

Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants

Abstract Background The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood. Objectives The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants. Methods We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model. Results We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration–time curve over 24 hours (AUC 24,SS ) and maximum concentration of sildenafil (C max,SS,SIL ) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC 24,SS ; 1.19 (0.78, 1.82) for C max,SS,SIL . Conclusions We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil’s safety profile in infants is warranted