scholarly journals Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Jeffrey P. Hammel ◽  
Elizabeth A. Lakota ◽  
M. Courtney Safir ◽  
Brian D. VanScoy ◽  
...  
Keyword(s):  
Compartment Model ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Total Drug ◽  
Target Attainment ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time

ABSTRACT ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PK­PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

scholarly journals Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
J. C. Bader ◽  
E. A. Lakota ◽  
G. E. Dale ◽  
H. S. Sader ◽  
J. H. Rex ◽  
...  
Keyword(s):  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Total Drug ◽  
Target Attainment ◽  
Dose Selection ◽  
Content Type ◽  
Drug Concentrations ◽  
Pathogen Prevalence ◽  
Hospital Acquired

ABSTRACT Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa. A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%T>MIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %T>MIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 μg/ml, respectively (MIC90 values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/VABP.

scholarly journals 1392. Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses to Support Inhaled ME1100 Dose Selection

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S427-S428
Author(s):  
Sujata M Bhavnani ◽  
Jeffrey P Hammel ◽  
Elizabeth A Lakota ◽  
Brian D VanScoy ◽  
Yu Nagira ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Phase 1 ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Total Drug ◽  
Target Attainment ◽  
Research Support ◽  
Dose Selection

Abstract Background ME1100 (arbekacin inhalational solution) is an inhaled aminoglycoside being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). PK-PD target attainment analyses were undertaken to evaluate ME1100 regimens for patients with HABP/VABP arising from Klebsiella pneumoniae (KP), Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA), including those with renal impairment. Methods Data used included a population pharmacokinetic (PPK) model developed using Phase 1 and post-marketing PK data, nonclinical PK-PD targets from one compartment in vitro and/or in vivo infection models, and MIC data. Using parameter estimates from the PPK model (four-compartment model with first-order elimination), total-drug epithelial lining fluid concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr; mL/minute/1.73 m2) and by CLcr group. Twice daily (BID) ME1100 regimens ranging from 300 to 900 mg were assessed in simulated patients with CLcr >80 to ≤120 mL/minute/1.73 m2. Percent probabilities of PK-PD target attainment by MIC were determined based on total-drug ELF AUC:MIC ratio targets associated with 1- and 2-log10 CFU reductions from baseline for KP, PA and SA using Day 1 AUC. Regimens in simulated patients with renal impairment that best matched the BID regimen in the normal CLcr group with high percent probabilities of PK-PD target attainment and a low percent probability of Cmin > 2 mg/L were identified. Results ME1100 600 mg BID in simulated patients with CLcr >80 to ≤120 mL/minute/1.73 m2, with 600 mg once daily, 450 mg BID and 600 mg BID in simulated patients with CLcr of 0 to ≤30, >30 to ≤50 and >50 to ≤80 mL/minute/1.73 m2, respectively, achieved high percent probabilities of PK-PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at relevant MIC values for KP, PA and SA, and relatively lower Cmin values. In simulated patients with varying CLcr who received these regimens, high percent probabilities of PK-PD target attainment were achieved for KP, PA and SA at the upper margins of the MIC distributions (Figures 1–3). Conclusion The data provide support for ME1100 dose selection for patients with HABP/VAPB. Disclosures S. M. Bhavnani, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. J. P. Hammel, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. E. A. Lakota, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. B. D. VanScoy, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. Y. Nagira, Meiji Seika Pharma Co. Ltd.: Employee, Salary. C. M. Rubino, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. N. Sato, Meiji Seika Pharma Co. Ltd.: Employee, Salary. T. Koresawa, Meiji Seika Pharma Co. Ltd.: Employee, Salary. K. Kondo, Meiji Seika Pharma Co. Ltd.: Employee, Salary. P. G. Ambrose, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support.

scholarly journals Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline against Haemophilus influenzae Using a One-Compartment In Vitro Infection Model

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Brian D. VanScoy ◽  
Elizabeth A. Lakota ◽  
Haley Conde ◽  
Jennifer McCauley ◽  
Lawrence Friedrich ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Antimicrobial Agents ◽  
Nonlinear Least Squares ◽  
Infection Model ◽  
Least Squares Regression ◽  
Total Drug ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time

ABSTRACT Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination (r2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.

scholarly journals Comparative Efficacies of Tedizolid Phosphate, Vancomycin, and Daptomycin in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis

2015 ◽  
Vol 59 (6) ◽  
pp. 3252-3256 ◽  
Author(s):  
Liana C. Chan ◽  
Li Basuino ◽  
Etyene C. Dip ◽  
Henry F. Chambers
Keyword(s):  
Staphylococcus Aureus ◽  
Rabbit Model ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Dose Ranging

ABSTRACTTedizolid, the active component of the prodrug tedizolid phosphate, is a novel oxazolidinone that is approximately 4 times more active by weight than linezolid againstStaphylococcus aureusin vitro. Thein vivoefficacy of tedizolid phosphate (15 mg/kg body weight intravenous [i.v.] twice a day [b.i.d.]) was compared to those of vancomycin (30 mg/kg i.v. b.i.d.) and daptomycin (18 mg/kg i.v. once a day [q.d.]) in a rabbit model of aortic valve endocarditis (AVE) caused by methicillin-resistantS. aureusstrain COL (infection inoculum of 107CFU). Median vegetation titers of daptomycin-treated rabbits were significantly lower than those of rabbits treated with tedizolid phosphate (15 mg/kg b.i.d.) (P= 0.016), whereas titers for vancomycin-treated compared to tedizolid-treated rabbits were not different (P= 0.984). The numbers of organisms in spleen and kidney tissues were similar for all treatment groups. A dose-ranging experiment was performed with tedizolid phosphate (2, 4, and 8 mg/kg b.i.d.) compared to vancomycin (30 mg/kg b.i.d.), using a higher infecting inoculum (108CFU) to determine the lowest efficacious dose of tedizolid phosphate. Tedizolid phosphate (2 mg/kg) (equivalent to 60% of the area under the concentration-time curve from 0 to 24 h (AUC0–24) for the human 200-mg dose approved by the U.S. Food and Drug Administration) was not efficacious. Tedizolid phosphate at 4 mg/kg (equivalent to 75% of the AUC0–24for the human 400-mg dose) and 8 mg/kg produced lower vegetation titers than the control, but neither was as efficacious as vancomycin.

scholarly journals Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Jian Zhou ◽  
Kimberly R. Ledesma ◽  
Kai-Tai Chang ◽  
Henrietta Abodakpi ◽  
Song Gao ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Dose Linearity ◽  
Unit Reduction ◽  
The Relationship

ABSTRACT Multidrug-resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using five A. baumannii isolates with a broad range of susceptibility (MIC ranged from 0.25 mg/liter to 16 mg/liter). The pharmacokinetics of minocycline (single dose of 25 mg/kg of body weight, 50 mg/kg, 100 mg/kg, and a humanized regimen, given intraperitoneally) in serum and epithelial lining fluid (ELF) were characterized. Dose linearity was observed for doses up to 50 mg/kg and pulmonary penetration ratios (area under the concentration-time curve in ELF from 0 to 24 h [AUCELF,0–24]/area under the concentration time curve in serum from 0 to 24 h [AUCserum,0–24]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against different A. baumannii isolates were calculated. The maximum efficacy at 24 h was approximately 1.5-log-unit reduction of pulmonary bacterial burdens from baseline. The AUC/MIC ratio was the PK-PD index most closely correlating to the bacterial burden (r 2 = 0.81). The required AUCELF,0–24/MIC for maintaining stasis and achieving 1-log-unit reduction were 140 and 410, respectively. These findings could guide the treatment of infections caused by A. baumannii using minocycline in the future. Additional studies to examine resistance development during therapy are warranted.

scholarly journals Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Elizabeth A. Lakota ◽  
Justin C. Bader ◽  
Voon Ong ◽  
Ken Bartizal ◽  
Lynn Miesel ◽  
...  
Keyword(s):  
Time Course ◽  
Fungicidal Activity ◽  
Control Group ◽  
Time Curve ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Treatment Control Group ◽  
Pharmacological Basis

ABSTRACT CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (∼133 h in humans, ∼70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no-treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC0–168) was administered as a single dose, a >2 log10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens.

scholarly journals 2562. Re-Appraisal of Aminoglycoside (AG) Susceptibility Testing Breakpoints Based on the Application of Pharmacokinetics–Pharmacodynamics (PK-PD) and Contemporary Microbiology Surveillance Data

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S71-S71 ◽  
Author(s):  
Sujata M Bhavnani ◽  
Nikolas J Onufrak ◽  
Jeffrey P Hammel ◽  
David R Andes ◽  
John S Bradley ◽  
...  
Keyword(s):  
Susceptibility Testing ◽  
Surveillance Data ◽  
Simulated Patients ◽  
High Dose ◽  
Target Attainment ◽  
In Vitro Susceptibility ◽  
Population Pk ◽  
Dosing Regimens

Abstract Background Resistance to AGs and numerous other classes continues to emerge. To ensure that susceptibility is accurately characterized and that clinicians have reliable data to select effective agents, appropriate in vitro susceptibility testing interpretive criteria (susceptible breakpoints [BKPTs]) are crucial to ensure optimal patient care. Recently, USCAST, the USA voice to EUCAST/EMA, evaluated the BKPTs for the 3 most commonly used AGs, gentamicin, tobramycin, and amikacin [Bhavnani et al., IDWeek 2016; P-1977]. As a result of consultation from interested parties, which included evaluating AG dosing regimens provided in the US-FDA product package inserts and simulated patients with varying creatinine clearance, these BKPTS were reassessed. Methods Data sources considered included longitudinal US reference MIC distributions using in vitro surveillance data collected over 18 years, QC performance (MIC, disk diffusion), population pharmacokinetics (PK), and in vivo PK-PD models. Using population PK models, PK-PD targets for efficacy and Monte Carlo simulation, percent probabilities of PK-PD target attainment by MIC after administration of traditional and extended interval AG dosing regimens were evaluated among simulated patients. Epidemiological cut-off and PK-PD BKPTs were considered when recommending BKPTs for AG–pathogen pairs. Results An example of PK-PD target attainment analysis output is provided in Figure 1 and a subset of recommended AG BKPTs for 3 pathogens is shown in Table 1. Updated USCAST BKPTs, which were based on the application of population PK and PK-PD models, simulation techniques, and contemporary MIC distribution statistics, are generally lower than those of EUCAST/EMA, USA-FDA, and CLSI. Adequate PK-PD target attainment was not achieved for some AG-pathogen pairs, even when high-dose AG dosing regimens and PK-PD targets for stasis were evaluated (e.g., gentamicin vs. P. aeruginosa; amikacin vs. S. aureus). Conclusion These revised AG BKPT recommendations, which will be made freely available to EUCAST, USA-FDA, and CLSI, will be finalized after considering comments from additional interested stakeholders. This process will be followed in an effort to bring harmonization to global BKPTs for AGs. Disclosures All authors: No reported disclosures.

scholarly journals Physiologically Relevant In Vitro-In Vivo Correlation (IVIVC) Approach for Sildenafil with Site-Dependent Dissolution

Pharmaceutics ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 251 ◽  
Author(s):  
Tae Hwan Kim ◽  
Soyoung Shin ◽  
Seok Won Jeong ◽  
Jong Bong Lee ◽  
Beom Soo Shin
Keyword(s):  
Dissolution Kinetics ◽  
Immediate Release ◽  
Relative Bioavailability ◽  
Wet Granulation ◽  
Population Pharmacokinetic ◽  
Beagle Dogs ◽  
Concentration Time ◽  
In Vivo Dissolution

This study aimed to establish a physiologically relevant in vitro-in vivo correlation (IVIVC) model reflecting site-dependent dissolution kinetics for sildenafil based on population-pharmacokinetic (POP-PK) modeling. An immediate release (IR, 20 mg) and three sustained release (SR, 60 mg) sildenafil tablets were prepared by wet granulation method. In vitro dissolutions were determined by the paddle method at pH 1.2, 4.5, and 6.8 media. The in vivo pharmacokinetics were assessed after oral administration of the prepared IR and SR formulations to Beagle dogs (n = 12). The dissolution of sildenafil from SR formulations was incomplete at pH 6.8, which was not observed at pH 1.2 and pH 4.5. The relative bioavailability was reduced with the decrease of the dissolution rate. Moreover, secondary peaks were observed in the plasma concentration-time curves, which may result from site-dependent dissolution. Thus, a POP-PK model was developed to reflect the site-dependent dissolution by separately describing the dissolution and absorption processes, which allowed for estimation of the in vivo dissolution of sildenafil. Finally, an IVIVC was established and validated by correlating the in vitro and in vivo dissolution rates. The present approach may be applied to establish IVIVC for various drugs with complex dissolution kinetics for the development of new formulations.

scholarly journals Development of a Population Pharmacokinetic Model for Parecoxib and Its Active Metabolite Valdecoxib after Parenteral Parecoxib Administration in Children

2012 ◽  
Vol 116 (5) ◽  
pp. 1124-1133 ◽  
Author(s):  
Bruce Hullett ◽  
Sam Salman ◽  
Sean J. O'Halloran ◽  
Deborah Peirce ◽  
Kylie Davies ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Pharmacokinetic Model ◽  
Inhibitory Concentration ◽  
Prediction Interval ◽  
Cyclooxygenase 2 ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Concentration Time

Background Parecoxib is a cyclooxygenase-2 selective inhibitor used in management of postoperative pain in adults. This study aimed to provide pediatric pharmacokinetic information for parecoxib and its active metabolite valdecoxib. Methods Thirty-eight children undergoing surgery received parecoxib (1 mg/kg IV to a maximum of 40 mg) at induction of anesthesia, and plasma samples were collected for drug measurement. Population pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Area under the valdecoxib concentration-time curve and time above cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib were simulated. Results A three-compartment model best represented parecoxib disposition, whereas one compartment was adequate for valdecoxib. Age was linearly correlated with parecoxib clearance (5.0% increase/yr). There was a sigmoid relationship between age and both valdecoxib clearance and distribution volume. Time to 50% maturation was 87 weeks postmenstrual age for both. In simulations using allometric-based doses the 90% prediction interval of valdecoxib concentration-time curve in children 2-12.7 yr included the mean for adults given 40 mg parecoxib IV. Simulated free valdecoxib plasma concentration remained above the in vitro 50% inhibitory concentrations for more than 12 h. In children younger than 2 yr, a dose reduction is likely required due to ongoing metabolic maturation. Conclusions The final pharmacokinetic model gave a robust representation of parecoxib and valdecoxib disposition. Area under the valdecoxib concentration-time curve was similar to that in adults (40 mg), and simulated free valdecoxib concentration was above the cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib for at least 12 h.

scholarly journals Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

2018 ◽  
Vol 62 (4) ◽  
pp. e01647-17 ◽  
Author(s):  
Sheng-Hsuan Tseng ◽  
Chuan Poh Lim ◽  
Qi Chen ◽  
Cheng Cai Tang ◽  
Sing Teang Kong ◽  
...  
Keyword(s):  
Steady State ◽  
Trough Concentration ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

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