Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model

Combinations of two and more drugs with different target sites are being used as a new treatment regimen for resistant clones of bacteria. Though, achieving the right combination of the drugs for optimal dosage regimen is challenging. In our study, we studied the antimicrobial effect of aditoprim, a novel dihydrofolate reductase inhibitor, and its synergistic effect with sulfamethoxazole. Synergy testing was performed by checkerboard micro dilution method and validation of different checkerboard ratios by static and dynamic time-kill analysis and in vitro pharmacokinetic/pharmacodynamics (PK/PD) model, and semi mechanistic PK/PD modeling was used to calculate and validate the synergistic effect of drug combination. Both checkerboard and static time-kill assays demonstrated the greater synergistic effect [fractional inhibitory concentration index (FICI) = 0.37] of the aditoprim [minimum inhibitory concentration (MIC) = 0.25 µg/ml]-sulfamethoxazole (MIC=>64 µg/ml) combination against all T. Pyogenes isolates. In the in vitro PK/PD model, the dosage proportion of sulfamethoxazole 4 mg/ml twice a day in combination with steady-state aditoprim 1 mg/ml efficiently repressed the growth of bacteria in 24 h with the ratio of 2-log10 decrease, related to the early inoculum against three T. Pyogenes isolates. The semi mechanistic PK/PD model projected that a combination of a high dose of aditoprim (2 mg/ml) with sulfamethoxazole (2 mg/day) was necessary to attain the killing of bacteria below the detection limit (limit of detection (LOD); i.e., 1 log10 CFU/ml) at 24 h with an MIC sulfamethoxazole (SMZ) of 64 µg/ml. However, it is anticipated that a combination of high dose of aditoprim with sulfamethoxazole is critical to attain the suppressed bacterial growth to < LOD. This study represents essential PK/PD modeling for optimization of combination of aditoprim and sulfamethoxazole to suppress growth of T. Pyogenens.

Pharmacometric approach to assist dosage regimen design in neonates undergoing therapeutic hypothermia

Background Therapeutic hypothermia (TH) is the treatment of choice for neonates diagnosed with perinatal asphyxia (PA). Dosing recommendations of various therapeutic agents including antimicrobials were not specifically available for the neonates undergoing TH. Methods A systematic search methodology was used to identify pharmacokinetic (PK) studies of antimicrobials during TH. Antimicrobials with multiple PK studies were identified to create a generalizable PK model. Pharmacometric simulations were performed using the PUMAS software platform to reproduce the results of published studies. A suitable model that could reproduce the results of all other published studies was identified. With the help of a generalizable model, an optimal dosage regimen was designed considering the important covariates of the identified model. Results With the systematic search, only gentamicin had multiple PK reports during TH. A generalizable model was identified and the model predictions could match the reported/observed concentrations of publications. Birth weight and serum creatinine were the significant covariates influencing the PK of gentamicin in neonates. A dosage nomogram was designed using pharmacometric simulations to maintain gentamicin concentrations below 10 μg/mL at peak and below 2 μg/mL at trough. Conclusions A generalizable PK model for gentamicin during TH in neonates was identified. Using the model, a dosing nomogram for gentamicin was designed. Impact Dosing guidelines for antimicrobials during TH in neonates is lacking. This is the first study to identify the generalizable model for gentamicin during TH in neonates. Nomogram, proposed in the study, will aid the clinicians to individualize gentamicin dosing regimen for neonates considering the birth weight and serum creatinine.

Determination of Susceptibility Breakpoint for Cefquinome against Streptococcus suis in Pigs

Streptococcus suis (S. suis), a zoonotic pathogen, causes severe diseases in both pigs and human beings. Cefquinome can display excellent antibacterial activity against gram-negative and gram-positive bacteria. The aim of this study was to derive an optimal dosage of cefquinome against S. suis with a pharmacokinetic/pharmacodynamic (PK/PD) integration model in the target infection site and to investigate the cutoffs monitoring the changes of resistance. The minimum inhibitory concentration (MIC) distribution of cefquinome against 342 S. suis strains was determined. MIC50 and MIC90 were 0.06 and 0.25 μg/mL, respectively. The wild-type cutoff was calculated as 1 μg/mL. A two-compartmental model was applied to calculate the main pharmacokinetic parameters after 2 mg/kg cefquinome administered intramuscularly. An optimized dosage regimen of 3.08 mg/kg for 2-log10 CFU reduction was proposed by ex vivo PK/PD model of infected swine. The pharmacokinetic-pharmacodynamic cutoff was calculated as 0.06 μg/mL based on PK/PD targets. Based on the clinical effectiveness study of pathogenic MIC isolates, the clinical cutoff was calculated as 0.5 μg/mL. A clinical breakpoint was proposed as 1 μg/mL. In conclusion, the results offer a reference for determining susceptibility breakpoint of cefquinome against S. suis and avoiding resistance emergence by following the optimal dosage regimen.

Optimization of Dosage Regimen of Meropenem in Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation: A Prospective Cohort Study

BackgroundPatients receiving venoarterial extracorporeal membrane oxygenation (VA ECMO) therapy often require antibiotics to prevent and treat infections. Our objective was to determine an optimal dosage regimen of meropenem in patients receiving VA ECMO by developing a population pharmacokinetic model.MethodsThis was a prospective cohort study. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF). The population pharmacokinetic model was developed using nonlinear mixed-effects modelling. A Monte Carlo simulation was used (n=10,000) to assess the probability of target attainment.ResultsThirteen adult patients on ECMO receiving meropenem were included. Meropenem pharmacokinetics was best fitted by a two-compartment model. Covariate analysis indicated that continuous renal replacement therapy (CRRT) was negatively correlated with clearance (CL). The final pharmacokinetic model was: CL (L/h) = 3.79 × 0.44CRRT; where use of CRRT = 1, no CRRT = 0, central volume of distribution (L) = 2.4, peripheral volume of distribution (L) = 8.56, and intercompartmental clearance (L/h) = 21.3. According to the simulation results, 1–2 g q8h intravenous administration over 20 min was sufficient in patients without CRRT for both susceptible (minimum inhibitory concentration (MIC) = 2 mg/L) and resistant (MIC = 8 mg/L) pathogens, regardless of ECMO use (40% fT>MIC target). However, if more aggressive treatment is needed (100% fT>MIC target), dose increment or extended infusion is recommended.ConclusionsWe established a population pharmacokinetic model for meropenem in patients receiving VA ECMO and suggested an optimal dosage regimen. These results should improve treatment success and survival in VA ECMO patients. Clinicaltrials.gov registration # NCT02581280

Exposure–Response Analysis for Selection of Optimal Dosage Regimen of Anifrolumab in Patients With Systemic Lupus Erythematosus

Objectives The randomized, double-blind, phase 2 b MUSE study evaluated the efficacy and safety of the type I interferon receptor antibody anifrolumab (300 mg or 1000 mg every 4 weeks) compared with placebo for 52 weeks in patients with chronic, moderate to severe SLE. Characterizing the exposure–response relationship of anifrolumab in MUSE will enable selection of its optimal dosage regimen in two phase 3 studies in patients with SLE. Methods The exposure–response relationship, pharmacokinetics (PK), and SLE Responder Index (SRI[4]) efficacy data were analysed using a population approach. A dropout hazard function was also incorporated into the SRI(4) model to describe the voluntary patient withdrawals during the 1-year treatment period. Results The population PK model found that type I IFN test–high patients, and patients with a higher body weight, had significantly greater clearance of anifrolumab. Stochastic clinical simulations demonstrated that doses <300 mg would lead to a greater-than-proportional reduction in drug exposure owing to type I interferon alpha receptor–mediated drug clearance (antigen-sink effect, more rapid drug clearance at lower concentrations) and suboptimal SRI(4) responses with wider confidence intervals. Conclusions Based on PK, efficacy, and safety considerations, anifrolumab 300 mg every 4 weeks was recommended as the optimal dosage for pivotal phase 3 studies in patients with SLE.

Population pharmacokinetic analysis and dose regimen optimization in Japanese infants with an extremely low birth weight

Vancomycin is a synthetic antibiotic effective against gram-positive pathogens. Although the clinical applicability of vancomycin for infants has been increasing, the pharmacokinetic data of vancomycin in extremely low-birth-weight infants are limited. The aim of this study was to construct a population pharmacokinetics model for vancomycin in extremely low-birth-weight infants and establish an optimal dosage regimen. We enrolled children aged less than 1 yr with a birth weight of less than 1000 g and body weight at vancomycin prescription of less than 1500 g. Pharmacokinetic data from 19 patients were analyzed and a population pharmacokinetics model was developed using nonlinear mixed-effects modeling software. Goodness-of-fit plots, a nonparametric bootstrap analysis, and a prediction-corrected visual predictive check were employed to evaluate the final model. The dosage regimen was optimized based on the final model. The pharmacokinetic data fit a one-compartment model with first-order elimination, and body weight and estimated serum creatinine level were used as significant covariates. In a simulation using the final model, the optimal dosage regimen, especially when the serum creatinine level (>0.6 mg/dL) was high, was 5.0–7.5 mg/kg twice a day every 12 h; this was required to reduce the dosage compared with that in previous studies. The recommended doses based on the current target time-course concentration curves may not be appropriate for extremely low-birth-weight infants.

Comparison of Amikacin Pharmacokinetics in Neonates Following Implementation of a New Dosage Protocol

OBJECTIVES The primary aim was to compare attainment of goal serum amikacin concentrations using two dosage regimens in patients admitted to a neonatal intensive care unit. Secondary objectives included comparison of percentages of supratherapeutic trough concentrations, and subtherapeutic and supratherapeutic peak concentrations. METHODS This was an Institutional Review Board–approved, retrospective study of neonates receiving amikacin during January–December 2013 (group 1) and January–December 2014 (group 2). Group 1 received amikacin dosage consistent with published recommendations, whereas group 2 was dosed using a modified protocol that was based on postmenstrual and postnatal age. Goal serum amikacin peak concentration was defined as 20 to 35 mg/L; hence, subtherapeutic and supratherapeutic peak concentrations were defined as <20 mg/L and >35 mg/L, respectively. Supratherapeutic trough concentrations were >8 mg/L. Between-group analysis was performed using Wilcoxon-Mann-Whitney test, Student t-test or χ2, or Fisher exact analysis as appropriate with a p value <0.05. RESULTS A total of 278 neonates were included (group 1: n = 144; group 2: n = 134). Most patients were male (60%) and were admitted for prematurity or respiratory distress (77%). The median gestational age in group 1 was 34.4 weeks (range, 30.0–37.9 weeks) versus group 2 at 36.9 weeks (range, 31.4–38.9 weeks), whereas the postnatal age was similar between both groups at 4 days. There was a significant increase in attaining goal peak amikacin concentrations between groups 1 and 2, 34% versus 84%, p < 0.001, and decrease in supratherapeutic peak concentrations, 65% versus 12%, p < 0.001. There was no significant difference in subtherapeutic peak or supratherapeutic trough concentrations. CONCLUSIONS A modified neonatal amikacin dosage protocol resulted in increased peak amikacin serum concentration compared with published dosage recommendations. Future research should focus on determination of the optimal dosage regimen in neonates.