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Population pharmacokinetics and safety of continuous oxacillin in preterm and term neonates and infants
Adam Lee1, Catherine Liu2, M Tuan Tran3
1Department of Infectious Diseases, Children's Hospital of Orange County, Orange, California, USA.
Abstract:
Staphylococcus aureus increasingly causes late-onset neonatal sepsis with mortality ≤25%. Oxacillin treats methicillin-susceptible Staphylococcus aureus (MSSA). No previous studies inform dosing. Time above MIC of unbound oxacillin (fT>MIC) 100% of dosing interval is a desired pharmacodynamic (PD) target in immunocompromised/septic patients. Our objective was to characterize oxacillin pharmacokinetics (PK) and PD in young infants. We conducted a prospective PK/PD study in infants ≤90 days. We divided four cohorts per gestational (GA <32/≥32 weeks) and postnatal age (PNA <14/≥14 days). Patients received 25 mg/kg loading doses followed by continuous infusions of 120 (<32 weeks/<14 days) or 160 mg/kg/day. Population PK parameters were estimated using NONMEM. Dosing regimens were evaluated using Monte Carlo simulations to estimate the probability of PD target attainment. Outcomes were collected. We enrolled 22 infants, median (IQR) GA 38 weeks (30-39) and PNA 32 days (12-46). PNA and weight were covariates for oxacillin clearance. Unbound steady-state oxacillin concentrations remained >MIC 0.5 throughout the dosing interval for >90% of modeled patients for all age groups on 160 mg/kg/day continuous infusions. Infants with PNA ≤28 days met PD targets at MIC 1; <90% of all modeled patients on continuous infusion met PD targets at MIC 2. Modeled infants receiving 200 mg/kg/day oxacillin divided q4h/q6h failed to meet PD targets up to MIC 2. All patients survived to discharge. A few serious adverse events were noted. 160 mg/kg/day continuous oxacillin was well tolerated and achieved PD targets for MIC ≤0.5 across all age groups. Modeled intermittent dosing ≤200 mg/kg/day divided q4h/q6h, 8 times the Food and Drug Administration-labeled dose of 25 mg/kg daily, failed to achieve PD targets. The FDA-recommended oxacillin dose is inadequate and may help explain high mortality.
Insights
Oxacillin dosing for neonatal sepsis needs improvement. A continuous infusion of 160 mg/kg/day achieved therapeutic targets in infants, unlike standard intermittent dosing, suggesting current FDA recommendations are insufficient.
Area of Science:
- Neonatal pharmacology
- Infectious disease pharmacodynamics
- Pediatric pharmacokinetics
Background:
- Neonatal sepsis caused by *Staphylococcus aureus* has high mortality.
- Optimal oxacillin dosing for neonatal methicillin-susceptible *Staphylococcus aureus* (MSSA) infections is not established.
- Pharmacodynamic targets, such as 100% time above the minimum inhibitory concentration (MIC), are crucial for effective treatment in vulnerable populations.
Purpose of the Study:
- To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of oxacillin in neonates and young infants.
- To evaluate the probability of achieving target PK/PD endpoints with different oxacillin dosing regimens.
- To assess the adequacy of current Food and Drug Administration (FDA)-recommended oxacillin dosing for neonatal sepsis.
Main Methods:
- A prospective PK/PD study enrolled 22 infants aged ≤90 days, stratified by gestational and postnatal age.
- Oxacillin dosing involved a loading dose followed by continuous infusions (120 or 160 mg/kg/day) or simulated intermittent dosing.
- Population PK modeling (NONMEM) and Monte Carlo simulations were used to estimate PK parameters and probability of target attainment (PTA).
Main Results:
- Postnatal age and weight were significant covariates for oxacillin clearance.
- A continuous infusion of 160 mg/kg/day achieved unbound oxacillin concentrations >MIC 0.5 for >90% of modeled patients across all age groups.
- Intermittent oxacillin dosing regimens, even at doses significantly higher than FDA-labeled recommendations, failed to consistently achieve target PK/PD endpoints, particularly at higher MICs (≥2).
Conclusions:
- Continuous infusion oxacillin at 160 mg/kg/day is well-tolerated and achieves desired PK/PD targets for MSSA infections in infants with MIC ≤0.5.
- Current FDA-recommended oxacillin dosing for neonates is likely inadequate, potentially contributing to treatment failures and mortality.
- Optimized dosing strategies, such as continuous infusions, are necessary to improve outcomes for neonatal sepsis caused by MSSA.
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