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

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)

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

Fluconazole Pharmacokinetics and Safety in Premature Infants

Invasive candidiasis (IC) in the premature infant population is a common infection that results in substantial morbidity and mortality. For these patients, fluconazole is among the first line therapies to treat and prevent IC, and yet few prospective studies investigating its pharmacokinetics (PK) and safety have been performed in this vulnerable population. We review five phase I studies examining the PK of fluconazole in premature infants, which demonstrate markedly differing kinetics compared to adults. Based on these data, a treatment dose of 12 mg/kg/day, with the potential need of a loading dose of 25 mg/kg to achieve rapid steady state concentrations, achieves surrogate pharmacodynamic targets. Additionally, fluconazole appears to be safe to use in this population, with only minimal reversible hepatobiliary effects

Pharmacokinetics of Moxifloxacin in an Infant With Mycoplasma hominis Meningitis

Treatment of Mycoplasma hominis meningitis in infants is limited by a lack of consensus regarding therapy and limited pharmacokinetic data for agents to which M. hominis is susceptible. We report the successful treatment of a premature infant with M. hominis meningitis with doxycycline and moxifloxacin and provide a pharmacokinetic profile of moxifloxacin

External Evaluation of a Gentamicin Infant Population Pharmacokinetic Model Using Data from a National Electronic Health Record Database

Gentamicin is a common antibiotic used in neonates and infants. A recently published population pharmacokinetic (PK) model was developed using data from multiple studies, and the objective of our analyses is to evaluate the feasibility of using a national electronic health record (EHR) database to further externally evaluate this model. Our results suggest that with proper data capture procedures, EHR data can serve as a potential data source for external evaluation of PK models

Urinary tract infection concordance with positive blood and cerebrospinal fluid cultures in the neonatal intensive care unit

Urinary tract infections (UTI) are common in the neonatal intensive care unit (NICU). Blood, urine, and cerebrospinal fluid (CSF) cultures are frequently obtained to evaluate for infection. We sought to determine the concordance between positive urine cultures and blood or CSF cultures

Predictors of Positive Cerebrospinal Fluid Cultures in Infants With Bacteremia

BACKGROUND: Meningitis causes substantial morbidity and mortality in hospitalized infants. There is no consensus on the ability of blood cultures to predict results from cerebrospinal fluid (CSF) cultures in hospitalized infants. METHODS: We used the Pediatrix Medical Group database of infants discharged from 333 neonatal intensive care units between 1997 and 2011. We identified all infants with a positive blood culture and a CSF culture obtained within 3 days. We evaluated the odds of a concordant blood-CSF culture pair, controlling for severity of illness, organism type, gestational age, day of blood culture and blood-CSF culture pairing, exposure to CSF-penetrating antibiotics and the presence of a ventriculo-peritoneal shunt. RESULTS: We identified 8839 infants with 9408 blood-CSF culture pairs. Serratia marcescens (24/227, 11%) and Streptococcus pneumoniae (7/64, 11%) had the highest proportion of concordant blood-CSF culture pairs. The presence of a ventriculo-peritoneal shunt, as well as timing of the CSF culture on the same day as the blood culture, were associated with increased odds of blood-CSF culture pair concordance-odds ratio = 3.87 (95% confidence interval; 2.59-5.78) and 6.11 (2.81-13.24), respectively. CONCLUSION: The frequency of blood-CSF culture pair concordance is related to organism type and to the timing of the CSF culture in relation to the blood culture

Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

ABSTRACT Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution ( V ). The final model included the effect of serum creatinine (SCR) level on CL and the effect of ECMO on V as follows: CL (in liters per hour) = 0.019 × weight × (SCR/0.4) −0.29 × exp(η CL ) and V (in liters) = 0.93 × weight × 1.4 ECMO × exp(η V ). The fluconazole V was increased in children supported by ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12 mg/kg of body weight) and treatment (35 mg/kg) paired with standard maintenance doses to achieve exposures similar to those of children not on ECMO

Anaerobic Antimicrobial Therapy After Necrotizing Enterocolitis in VLBW Infants

To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants