Optimization of Intermittent Vancomycin Dosage Regimens for Thai Critically Ill Population Infected by MRSA in the Era of the “MIC Creep” Phenomenon

Background: the shifting of minimum inhibitory concentration (MIC) of methicillin-resistant Staphylocuccus aureus (MRSA) strains to the higher value has emerged to worsen clinical outcome to the patients particularly critically ill population.  The aim of this study was to identify the most appropriate dosage regimen of vancomycin to treat infection caused by MRSA with higher MIC in critically ill Thai population. Methods: 10,000 replications of intermittent vancomycin dosage regimens were performed using Monte Carlo simulation. Pharmacokinetic parameters were derived from a population pharmacokinetic study conducted specifically in Thai population. The probability of target attainment (PTA) and cumulative fraction of response (CFR) of each dosage regimen were calculated. Risk of nephrotoxicity was also calculated and used as a consideration in determining the most appropriate dosage regimen of vancomycin. Results: in order to achieve desired PTA > 80% vancomycin at higher dosing regimens were needed including 3g/day and 4 g/day for MIC 1.5mg/L and 2.0 mg/L, respectively. Highest CFR of 94.40% and 93.57% were from vancomycin 1 g every 6 h and 2 g every 12h. Standard dose of vancomycin and total dose of vancomycin 3 g/day provided approximately 51% and 73% CFR. Risk of nephrotoxicity afforded by giving 1.5g every 12h and 2g every 12h of vancomycin were 26.59% and 31.20%, respectively. Conclusion: the result from this study recommended intermittent dosage regimen 1.5g every 12h and 2g every 12h should be implemented as definite antibiotic treatment when considered infection caused by MRSA with MIC 1.5 and 2.0 mg/L, respectively

Population Pharmacokinetics of Vancomycin in Thai Patients

Population pharmacokinetics of vancomycin in Thai adult patients was determined by non-linear mixed-effects approach using 319 vancomycin serum concentrations from 212 patients. The data were best fitted by a two-compartment model and it was used to examine the effect of patient characteristics on the vancomycin pharmacokinetics. In the final model, there was a linear relationship between vancomycin clearance, CL (L/h), and creatinine clearance calculated by Cockcroft-Gault equation, CLCr (mL/min): CL  =0.044  ×  CLCr. Meanwhile, volume of central compartment, V1 (L), was linearly related with the age (years old): V1 = 0.542  × Age. Intercompartment clearance (Q) and volume of peripheral compartment (V2) was 6.95 L/h and 44.2 L, respectively. The interindividual variability for CL, V1, Q, and V2 was 35.78, 20.93, 39.50, and 57.27%, respectively. Whereas, the intraindividual variability was 4.51 mg/L. Final model then was applied to predict serum vancomycin concentrations on validation group. Predictive performance revealed a bias of −1.43 mg/L (95% CI: −5.82–2.99) and a precision of 12.2 mg/L (95% CI: −1.60–26.16). In conclusion, population pharmacokinetic of vancomycin in Thai adult patients was developed. The model could be used to create vancomycin dosage regimen in the type of patient similar with the present study

Effect of Localized Corrosion of Steel on Chloride-Induced Concrete Cover Cracking in Reinforced Concrete Structures

Abstract: Concrete cover cracking due to reinforcement corrosion is widely accepted as a limit-state indicator in defining the end of functional service life for existing reinforced concrete (RC) structures undergoing corrosion. Many of the currently available durability prediction models are incapable of providing realistic estimates of remaining service lives of RC structures beyond the corrosion initiation point. Therefore, the need to incorporate the length of the corrosion propagation stage in a comprehensive durability prediction approach has recently received much research attention. Previous research focus however was mostly limited to the case of uniformly corroding reinforcement with only few studies addressing the commonly encountered case of localized rebar corrosion. It was empirically shown in a previous study that localized corrosion can have a mitigating effect on time to concrete cover cracking due to the larger required depth of rebar corrosion penetration (Critical penetration or Xcrit). The present research was focused on developing a model for predicting Xcrit for various degrees of corrosion localization including new cases of highly localized corrosion. Accelerated corrosion testing of controlled anodic regions along axial rebars in sound concrete cylinders suggested that localized corrosion can increase Xcrit by up to about a factor of 10. The effect of corrosion localization on the orientation of corrosion-induced surface cracks was also addressed. Testing of freely corroding pre-cracked RC pipe specimens in a chloride-containing environment indicated that steel corrosion can be localized at intersection regions with the pre-existing cracks and uniformly distributed around the reinforcing steel perimeter. Numerical modeling was undertaken to substantiate the experimentally observed trends on a theoretical basis for various degrees of corrosion localization. A mechanical model was developed to improve understanding of the underlying mechanism responsible for corrosion-induced stresses. A thick-walled multiple-cylinder approach was employed to simulate crack initiation and propagation to account for the residual strength property of concrete after cracking by applying the principles of applied elasticity. For a given concrete cover depth, the amount of Xcrit was shown by modeling to be largely determined by the length of corroding region and the capacity of the induced cracks to accommodate produced rusts. The properties of both concrete-rebar interface and corrosion products were also found to have a significant impact on Xcrit. Based on the model and experimental trends and comparisons with literature data, an improved relationship for the estimation of Xcrit was proposed. An electrochemical model was also formulated to address the possible role of corrosion aggravation due to macrocell coupling in counteracting the mitigating effect of increased Xcrit on time to concrete cover cracking. Findings confirmed that corrosion localization can reasonably be considered a mitigating factor for extending the corrosion propagation stage, and provided more precise quantification to that effect

The Pharmacodynamics Optimization of Intermittent Vancomycin Dosage Regimens in Methicillin-Resistant Staphylococcus aureus Infections with MIC of 1.5 and 2.0 mg/L in Thai Population

Background There are increasing number of articles questioning the efficacy of vancomycin to treat methicillin-resistant Staphylococcus aureus (MRSA) with MIC 1.5mg/L and 2.0mg/L. However, vancomycin is still used as the cornerstone treatment of MRSA infection particularly in most of developing countries with limited alternative MRSA coverage antibiotics. Owing to the interest whether vancomycin still enable to be used as the cornerstone treatment for MIC 1.5mg/L and 2mg/L, present study was conducted to analyze the achievement of vancomycin desired PK-PD indices in MRSA-infected Thai population. Methods Monte Carlo simulation by using 10,000 replications was performed for several vancomycin intermittent dosage regimens ranging from 1g every 6, 8, 12h, 1.5g and 2 g every 12h. Vancomycin concentrations were estimated from population PK study conducted in 212 Thai population. The probability of target attainment (PTA) of each intermittent dosage regimen was calculated from the number of simulated patients who achieved AUC24/MIC ≥400 for MIC 1.5mg/L and 2.0mg/L divided by total number of replication. Results Dosage regimen 1g every 12h couldn’t afford desired PTA for MRSA with MIC 1.5mg/L and 2.0mg/L. Considering the MRSA with MIC 1.5mg/L, dosage regimen 1g every 8h and 1.5g every 12h could afford PTA >80%. However, if particular conditions required PTA >90%, dosage regimen 1g every 6 hours or 2g every 12h should be recommended as the most appropriate dosage regimen. While, for MRSA with MIC 2.0mg/L, only dosage regimens 4g/day, either given as 1g every 6h or 2g every 12h, could afford PTA >80%. No any dosage regimens could afford PTA >90% for MRSA with MIC 2.0mg/L. All PTA achievement represented the PTA at steady state condition. Conclusions Intermittent dosage regimen at least 3g/day and 4g/day were needed to afford desired PTA achievement for MRSA with MIC 1.5mg/L and 2.0mg/L, respectively. Finding of present study could be used as a guidance in determining the best intermittent dosage regimen in documented vancomycin treatment. Further study was needed to determine the most appropriate intermittent dosage regimen that could achieve the desired PTA for the 1st 24h

Vancomycin continuous infusion dose optimization for the treatment of “MIC Creep” methicillin-resistant Staphylococcus aureus infections in critically-ill Thai patients

Background: Giving vancomycin to a patient with rapidly changing physiologic conditions that will affect its pharmacokinetics (PKs), such as critically-ill patient, is challenging. Moreover, the shifting phenomenon of vancomycin’s MIC of MRSA strain to the higher value, also known as “MIC Creep”, will escalate the difficulty to determine the optimum dose of vancomyin. Owing to the vancomycin’s desired pharmacokinetic-pharmacodynamic (PK-PD) indices affording good clinical outcome for the treated patients, i.e AUC0-24/MIC ≥400mg.hr/L, extending the infusion was expected to ensure the achievement of this intended PK-PD indices. The objective of the present study was to determine the most appropriate continuous infusion vancomycin dosage regimen to treat “MIC Creep” MRSA infections in critically-ill Thai patients. Methods: Monte Carlo simulation by using 10,000 replications was performed for several vancomycin continuous dosage regimens with or without loading dose (LD). For dosage regimens without LD, the simulated vancomycin dose was ranging from 2g, 3g, and 4g every 24h. Loading dose ranging from 1-5g were simulated to the continuous infusion 2g as a maintenance dose (MD). While, LD ranging from 1g-4g and 1g-3g were simulated to the MD 3g and 4g, consecutively. Vancomycin concentrations were estimated from population PK study conducted in 212 Thai patients. The probability of target attainments (PTAs) of each dosage regimen were calculated from the number of simulated patients who achieved AUC24/MIC ≥400 for MIC 1.5mg/L and 2.0mg/L divided by total number of replication. Results: If PTA at least 80% was allowed as the threshold, continuous dosage regimen of 4g every 24h without LD, MD 3g with LD 2g-4g, and MD 4g with LD 2g-3g could afford the desired PTA for MRSA with MIC 1.5mg/L. No any continuous dosage regimen without LD and only dosage regimen given as MD 4g with LD 3g could afford PTA >80% for MRSA with MIC 2mg/L. However, if particular conditions required PTA >90%, only continuous dosage regimen of 4g every 24h without LD, MD 3g with LD 3g-4g, and MD 4g with LD 2g-3g could afford the desired PTA for MRSA with MIC 1.5mg/L. No any continuous dosage regimen with or without LD could afford PTA >90% for MRSA with MIC 2mg/L. All PTA achievement represented the PTA at steady state condition. Conclusions: Continuous dosage regimen of 4g/day without LD or at least 3g/day with LD 2g were needed to afford particular intended PTA achievement for MRSA with MIC 1.5mg/L. Continuous dosage regimen was not effectively used to treat MRSA with MIC 2mg/L. Finding of the present study could be used as a guidance in determining the best continuous dosage regimen in documented vancomycin treatment. Further study was needed to identify the risk of nephrotoxicity afforded by each dosage regimen. Acknowledgement: Author was supported by Siam Pharmaceutical to present the finding at ECCMID 2016

Population Pharmacokinetics of Vancomycin in Thai Patients

Population pharmacokinetics of vancomycin in Thai adult patients was determined by non-linear mixed-effects approach using 319 vancomycin serum concentrations from 212 patients. The data were best fitted by a two-compartment model and it was used to examine the effect of patient characteristics on the vancomycin pharmacokinetics. In the final model, there was a linear relationship between vancomycin clearance, CL (L/h), and creatinine clearance calculated by Cockcroft-Gault equation, CL Cr (mL/min): CL = 0.044 × CL Cr . Meanwhile, volume of central compartment, V 1 (L), was linearly related with the age (years old): V 1 = 0.542 × Age. Intercompartment clearance (Q) and volume of peripheral compartment (V 2 ) was 6.95 L/h and 44.2 L, respectively. The interindividual variability for CL, V 1 , Q, and V 2 was 35.78, 20.93, 39.50, and 57.27%, respectively. Whereas, the intraindividual variability was 4.51 mg/L. Final model then was applied to predict serum vancomycin concentrations on validation group. Predictive performance revealed a bias of −1.43 mg/L (95% CI : −5.82-2.99) and a precision of 12.2 mg/L (95% CI: −1. 60-26.16). In conclusion, population pharmacokinetic of vancomycin in Thai adult patients was developed. The model could be used to create vancomycin dosage regimen in the type of patient similar with the present study

Implementation of a nutrition program reduced post-discharge growth restriction in Thai very low birth weight preterm infants

© 2016 by the authors; licensee MDPI, Basel, Switzerland. Very low birth weight (VLBW) preterm infants are vulnerable to growth restriction after discharge due to cumulative protein and energy deficits during their hospital stay and early post-discharge period. The current study evaluated the effectiveness of the preterm infant, post-discharge nutrition (PIN) program to reduce post-discharge growth restriction in Thai VLBW preterm infants. A prospective, non-randomized interventional cohort study was undertaken to assess the growth of 22 VLBW preterm infants who received the PIN program and compared them with 22 VLBW preterm infants who received conventional nutrition services. Infant’s growth was recorded monthly until the infants reached six months’ corrected age (6-moCA). Intervention infants had significantly greater body weights (p = 0.013) and head circumferences (p = 0.009). Also, a greater proportion of the intervention group recovered their weight to the standard weight at 4-moCA (p = 0.027) and at 6-moCA (p = 0.007) and their head circumference to the standard head circumference at 6-moCA (p = 0.004) compared to their historical comparison counterparts. Enlistment in the PIN program thus resulted in significantly reduced post-discharge growth restriction in VLBW preterm infants. Further research on longer term effects of the program on infant’s growth and development is warranted