Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial.

BACKGROUND: Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. METHODS: NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was -10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996). FINDINGS: Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference -7% [95% CI -15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). INTERPRETATION: In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. FUNDING: EU Seventh Framework Programme for research, technological development and demonstration.

Plasma and CSF pharmacokinetics of meropenem in neonates and young infants: results from the NeoMero studies.

Background: Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking. Objectives: To determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS). Methods: Data were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed. Results: A one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome. Conclusions: Simulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.

Pharmacokinetics of Penicillin G in Preterm and Term Neonates.

Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but have been poorly described for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We describe the PK of penicillin G in neonates with a gestational age (GA) of ≥32 weeks and a postnatal age of <72 h. Penicillin G was administered intravenously at a dose of 25,000 or 50,000 IU/kg of body weight every 12 h (q12h). At steady state, PK blood samples were collected prior to and at 5 min, 1 h, 3 h, 8 h, and 12 h after injection. Noncompartmental PK analysis was performed with WinNonlin software. With those data in combination with data from neonates with a GA of ≤28 weeks, we developed a population PK model using NONMEM software and performed probability of target attainment (PTA) simulations. In total, 16 neonates with a GA of ≥32 weeks were included in noncompartmental analysis. The median volume of distribution (V) was 0.50 liters/kg (interquartile range, 0.42 to 0.57 liters/kg), the median clearance (CL) was 0.21 liters/h (interquartile range, 0.16 to 0.29 liters/kg), and the median half-life was 3.6 h (interquartile range, 3.2 to 4.3 h). In the population PK analysis that included 35 neonates, a two-compartment model best described the data. The final parameter estimates were 10.3 liters/70 kg and 29.8 liters/70 kg for V of the central and peripheral compartments, respectively, and 13.2 liters/h/70 kg for CL. Considering the fraction of unbound penicillin G to be 40%, the PTA of an unbound drug concentration that exceeds the MIC for 40% of the dosing interval was >90% for MICs of ≤2 mg/liter with doses of 25,000 IU/kg q12h. In neonates, regardless of GA, the PK parameters of penicillin G were similar. The dose of 25,000 IU/kg q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 h of life. (This study was registered with the EU Clinical Trials Register under EudraCT number 2012-002836-97.).

DosOpt: A Tool for Personalized Bayesian Dose Adjustment of Vancomycin in Neonates.

BACKGROUND: Our main aim has been to design a framework to improve vancomycin dosing in neonates. This required the development and verification of a computerized dose adjustment application, DosOpt, to guide the selection. METHODS: Model fitting in DosOpt uses Bayesian methods for deriving individual pharmacokinetic (PK) estimates from population priors and patient therapeutic drug monitoring measurements. These are used to simulate concentration-time curves and target-constrained dose optimization. DosOpt was verified by assessing bias and precision through several error metrics and normalized prediction distribution errors on samples simulated from the Anderson et al PK model. The performance of DosOpt was also evaluated using retrospective clinical data. Achieved probabilities of target concentration attainment were benchmarked against corresponding attainments in our clinical retrospective data set. RESULTS: Simulations showed no systemic forecast biases. Normalized prediction distribution error values of the base model were distributed by standardized Gaussian (P = 0.1), showing good model suitability. A retrospective test data set included 149 treatment episodes with 1-10 vancomycin concentration measurements per patient (median 2). Individual concentrations in PK estimation improved probability of target attainment and decreased the variance of the estimation. Including 3 individual concentrations in the kinetics estimation increased the probability of Ctrough attainment within 10-15 mg/L from 16% obtained with no individual data (95% confidence interval, 11%-24%) to 43% (21%-47%). CONCLUSIONS: DosOpt uses individual concentration data to estimate kinetics and find optimal doses that increase the probability of achieving desired trough concentrations. Its performance started to exceed target levels attained in retrospective clinical data sets with the inclusion of a single individual input concentration. This tool is freely available at http://www.biit.cs.ut.ee/DosOpt.

Pharmacokinetics of doripenem during high volume hemodiafiltration in patients with septic shock.

Pharmacokinetics (PK) of doripenem was determined during high volume hemodiafiltration (HVHDF) in patients with septic shock. A single 500 mg dose of doripenem was administered as a 1 hour infusion during HVHDF to 9 patients. Arterial blood samples were collected before and at 30 or 60 minute intervals over 8 hours (12 samples) after study drug administration. Doripenem concentrations were determined by ultrahigh performance liquid chromatography-tandem mass spectrometry. Population PK analysis and Monte Carlo simulation of 1,000 subjects were performed. The median convective volume of HVHDF was 10.3 L/h and urine output during the sampling period was 70 mL. The population mean total doripenem clearance on HVHDF was 6.82 L/h, volume of distribution of central compartment 10.8 L, and of peripheral compartment 12.1 L. Doses of 500 mg every 8 hours resulted in 88.5% probability of attaining the target of 50% time over MIC for bacteria with MIC = 2 µg/mL at 48 hours, when doubling of MIC during that time was assumed. Significant elimination of doripenem occurs during HVHDF. Doses of 500 mg every 8 hours are necessary for treatment of infections caused by susceptible bacteria during extended HVHDF.

Comparison of two alternative study designs in assessment of medicines utilisation in neonates.

BACKGROUND: Estimates of prevalence are known to be affected by the design of cross-sectional studies. A pan-European study provided an opportunity to compare the effect of two cross-sectional study designs on estimates of medicines use. METHODS: A Service evaluation survey (SES) and a web-based point-prevalence study (PPS) were conducted as part of a European study of neonatal exposure to excipients. Neonatal units from all European Union countries plus Iceland, Norway, Switzerland and Serbia were invited to participate. All medicines prescribed to neonates were recorded during three-day and one-day study periods in the SES and PPS, respectively. In the PPS individual demographic and prescription data were also collected.To compare the probabilities that a particular medicine would be reported by each study multilevel mixed effects logistic regression models with crossed random effects were applied. The relationship between medicines exposure at the unit and individual levels in the PPS data was assessed using polynomial regression with square root transformation. RESULTS: Of 31 invited countries 20 and 21 with 115 and 89 units joined the SES and PPS, respectively. Out of 5,572,859 live births in invited countries in 2010 a higher proportion was covered by units participating in the SES compared to the PPS (11% vs 6%, respectively; OR 1.89; 95% CI 1.87-1.89). A greater number of active pharmaceutical ingredients (API), manufacturers and trade names were registered in the SES compared to the PPS. High correlation between the two studies in frequency of use for each specified API was seen (R2 = 0.86). The average probability of a department to use a given API was greater in the SES compared to the PPS (OR 2.36; 95% CI 2.05-2.73) with higher frequency of use and longer average duration of prescription further increasing the difference. The polynomial regression model described the correlation between APIs exposure on unit and individual level well (R2 = 0.93). CONCLUSION: The simple data structure and longer study period of the SES resulted in improved recruitment and higher likelihood of capture for a given API. The frequency of use at the unit level appears a good surrogate of individual exposure rates.