High Probability Of Target Attainment Research Articles

Development and application of neonatal physiology-based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment.

Antimicrobial resistance increasingly complicates neonatal sepsis in a global context. Fosfomycin and amikacin are two agents being tested in an ongoing multicenter neonatal sepsis trial. Although neonatal pharmacokinetics (PKs) have been described for these drugs, the physiological variability within neonatal populations makes population PKs in this group uncertain. Physiologically-based pharmacokinetic (PBPK) models were developed in Simcyp for fosfomycin and amikacin sequentially for adult, pediatric, and neonatal populations, with visual and quantitative validation compared to observed data at each stage. Simulations were performed using the final validated neonatal models to determine drug exposures for each drug across a demographic range, with probability of target attainment (PTA) assessments. Successfully validated neonatal PBPK models were developed for both fosfomycin and amikacin. PTA analysis demonstrated high probability of target attainment for amikacin 15 mg/kg i.v. q24h and fosfomycin 100 mg/kg (in neonates aged 0-7 days) or 150 mg/kg (in neonates aged 7-28 days) i.v. q12h for Enterobacterales with fosfomycin and amikacin minimum inhibitory concentrations at the adult breakpoints. Repeat analysis in premature populations demonstrated the same result. PTA analysis for a proposed combination fosfomycin-amikacin target was also performed. The simulated regimens, tested in a neonatal sepsis trial, are likely to be adequate for neonates across different postnatal ages and gestational age. This work demonstrates a template for determining target attainment for antimicrobials (alone or in combination) in special populations without sufficient available PK data to otherwise assess with traditional pharmacometric methods.

Relebactam restores susceptibility of resistant Pseudomonas aeruginosa and Enterobacterales and enhances imipenem activity against chromosomal AmpC-producing species: analysis of global SMART 2018–2020

BackgroundCarbapenem-resistant bacteria are an increasing problem in clinical practice; thus, it is important to identify β-lactamase inhibitors (e.g., relebactam) that can restore carbapenem susceptibility. We report analyses of relebactam enhancement of imipenem activity against both imipenem-nonsusceptible (NS) and imipenem-susceptible (S) Pseudomonas aeruginosa and Enterobacterales. Gram-negative bacterial isolates were collected for the ongoing Study for Monitoring Antimicrobial Resistance Trends global surveillance program. Clinical and Laboratory Standards Institute–defined broth microdilution minimum inhibitory concentrations (MIC) were used to determine the imipenem and imipenem/relebactam antibacterial susceptibilities of P. aeruginosa and Enterobacterales isolates.ResultsBetween 2018 and 2020, 36.2% of P. aeruginosa (N = 23,073) and 8.2% of Enterobacterales (N = 91,769) isolates were imipenem-NS. Relebactam restored imipenem susceptibility in 64.1% and 49.4% of imipenem-NS P. aeruginosa and Enterobacterales isolates, respectively. Restoration of susceptibility was largely observed among K. pneumoniae carbapenemase-producing Enterobacterales and carbapenemase-negative P. aeruginosa. Relebactam also caused a lowering of imipenem MIC among imipenem-S P. aeruginosa and Enterobacterales isolates from chromosomal Ambler class C β-lactamase (AmpC)–producing species. For both imipenem-NS and imipenem-S P. aeruginosa isolates, relebactam reduced the imipenem MIC mode from 16 μg/mL to 1 μg/mL and from 2 μg/mL to 0.5 μg/mL, respectively, compared with imipenem alone.ConclusionsRelebactam restored imipenem susceptibility among nonsusceptible isolates of P. aeruginosa and Enterobacterales and enhanced imipenem susceptibility among susceptible isolates of P. aeruginosa and isolates from Enterobacterales species that can produce chromosomal AmpC. The reduced imipenem modal MIC values with relebactam may result in a higher probability of target attainment in patients.

Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India.

Linezolid is an oxazolidinone used to treat multidrug-resistant tuberculosis (MDR-TB), including in the recently-endorsed shorter 6-month treatment regimens. Due to its narrow therapeutic index, linezolid is often either dose-adjusted or discontinued due to intolerance or toxicity during treatment, and the optimal balance between linezolid efficacy and toxicity remains unclear. India carries a significant burden of MDR-TB cases in the world, but limited information on the pharmacokinetics of linezolid and minimum inhibitory concentration (MIC) distribution is available from Indian MDR-TB patients. We enrolled participants from a tertiary care centre in Mumbai, India, treated for MDR-TB and receiving linezolid daily doses of 600 or 300mg. Pharmacokinetic visits were scheduled between 1 and 15 months after treatment initiation to undergo intensive or sparse blood sampling. Linezolid concentration versus time data were analysed using non-linear mixed-effects modelling, with simulations to evaluate doses for different scenarios. We enrolled 183 participants (121 females), with a median age of 26 years (interquartile range [IQR] 21-35), weight 55.0kg (IQR 45.6-65.8), and fat-free mass 38.7kg (IQR 32.7-46.0). Linezolid pharmacokinetics was best described by a one-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption. The typical clearance value was 3.81L/h. Simulations predicted that treatment with 300mg daily achieves a high probability of target attainment (PTA) when linezolid MIC was ≤0.25mg/L (61.5% of participant samples tested), while 600mg daily would be required if MIC were 0.5mg/L (29% of samples). While linezolid 300mg daily is predicted to achieve effective targets for the majority of adults with MDR-TB, it failed to achieve the therapeutic target for 21% participants. A dose of 600mg had a PTA >90% for all susceptible samples, but with a higher likelihood of exceeding toxicity thresholds (31% vs 9.6%). These data suggest potential benefit to individualized dosing taking host and microbial characteristics into account to improve the likelihood of treatment efficacy while minimizing risk of toxicity from linezolid for the treatment of MDR-TB. Further prospective evaluation in different clinical settings is urgently needed to inform safety and efficacy of these lower doses.

611. Meropenem Dosage Optimization in Critically Ill Patients Based on a Population Pharmacokinetic Approach.

Abstract Background Meropenem (MRP) is commonly used to treat serious infections and displays wide variability in plasma concentrations after administration of the same dose in critically ill patients due to factors that affect MRP volume of distribution (V) and clearance (CL) (e.g. edema, sepsis, kidney failure). These alterations could lead to not achieve the pharmacokinetic/pharmacodinamic (PK/PD) target with the consequent failure of antibacterial therapy. The aim of this study was to describe MRP pharmacokinetic parameters in critically ill patients in order to establish safe and effective initial dosing regimens adapted to patients characteristics. Methods This prospective observational study enrolled 78 critically ill patients receiving MRP based on the clinical, biochemical and microbiological findings. Blood sampling occurred at pre-dose, 1, 3 and 6h post-dose. MRP plasma concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic modelling and Monte Carlo simulations were executed with NONMEM. Several regimen dosages of MRP under different scenarios were simulated in order to achieve high probability of target attainment (PTA > 90%) for PK/PD targets of %t > CMI 50% and 100%. Results In critically-ill Mexican patients, MRP PK were best described by a one compartment model. The final population model was: CL (L/h) = 11.9 ∗ (CLCr/102.23) and V (L) = 25.2. Final model was internally validated proving that it was stable and showed an adequate estimation of variability. Precision and bias fit were assessed through external validation comparing the predictive performance of the base and final models. Different initial dosage regimens were found for CLCr values in which the clinician can choose between a lower dose, a longer dosage interval or a shorter infusion time. However, for patients with augmented renal clearance or PK/PD target 100%t > MIC it was observed that no regimen complied PTA > 90%, suggesting a continuous infusion would be more appropriate. Conclusion This study demonstrates the wide variability in MRP pharmacokinetics and enhances the need to include therapeutic drug monitoring as part of stewardships interventions in critically ill patients to maximize bacteriological and clinical responses. Disclosures All Authors: No reported disclosures.

624. Probability of Target Attainment of Ceftolozane/Tazobactam Among Adult Patients with Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia Secondary to Pseudomonas aeruginosa in Latin America

Abstract Background Pseudomonas aeruginosa (Pa) is a common cause of nosocomial pneumonia; resistance among traditionally used empiric agents is observed frequently. To improve patient outcomes, a heightened focus has been placed on evaluating the adequacy of recommended dosing regimens, particularly of beta-lactams. The Phase 3 study ASPECT-NP demonstrated the efficacy and safety of 3 g of ceftolozane/tazobactam (C/T) infused every 8 h for 8 to 14 days for treatment of adults with Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia (HAP/VAP). We assessed the Probability of Target Attainment (PTA) of the C/T 3g dosage regimen in patients with HAP/VAP due to Pa, with an additional focus on carbapenem-resistant Pa, from Latin America. Methods Non duplicate Pa isolates from a respiratory source were collected as part of the SMART surveillance program from 36 sites in 10 Latin American countries during 2017-2020. MICs were determined by broth microdilution and interpreted by CLSI criteria. C and T concentration-time profiles were simulated in plasma and ELF following administration of the approved 3g (2g/1g) C/T dose (or equivalent dose adjusted based on renal function) administered by 1-hour infusion every 8 hours. PTA in plasma and ELF was calculated using the PK/PD target of 30% fT > MIC for C. T does not contribute to the antipseudomonal activity of C and therefore was not considered. Results A total of 2,757 P. aeruginosa were collected, of which 1208 (43.8%) were carbapenem nonsusceptible. C/T susceptiblity was 87.7% against all Pa and 73.4% among carbapenem nonsusceptible strains. At C/T doses of 2g/1g (CrCL > 50mL/min); 1g/0.5g (30mL/min≤ CrCL≤ 50mL/min), and 500mg/250mg (15mL/min≤ CrCL≤29mL/min), steady-state ceftolozane plasma and ELF PTA was 100% and > 99%, respectively, for isolates with an MIC at the Pa susceptiblity breakpoint of 4 µg/mL. Ceftolozane plasma and ELF PTA remained above 90% up to an MIC of 16 µg/mL and 8 µg/mL, respectively. Conclusion The regulatory approved pneumonia dosage regimen of C/T 3g (administered over 1 hour) every 8 hours (or equivalent dose adjusted based on renal function) resulted in high plasma and ELF PTAs sufficient to cover the vast majority of circulating P. aeruginosa present in Latin America, including carbapenem resistant strains. Disclosures Aline Okuma, PharmD, MSD Brazil: Employee Thales Polis, MD, MSD Brazil: Employee Jacqueline Pavia, MD, MSD COLOMBIA: EMPLOYEE Gustavo Mizuno, PharmD, MSD Brazil: Employee Jacqueline Ferrari, MD, MSD Brazil: Employee Charles A. DeRyke, PharmD, Merck & Co., Inc. Merck Research Laboratories: Stocks/Bonds.

Superiority of ceftazidime off-label high-dose regimen in PK/PD target attainment during treatment of extensively drug-resistant Pseudomonas aeruginosa infections in cancer patients.

The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. In patients treated with off-label high-dose ceftazidime (3 g every 6h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.

Population Pharmacokinetic Modeling for Ceftazidime-Avibactam Renal Dose Adjustments in Pediatric Patients 3 months and Older.

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination developed to treat serious Gram-negative bacterial infections; approved indications include complicated urinary tract infection, complicated intra-abdominal infection, and hospital-acquired pneumonia including ventilator-associated pneumonia in patients ≥ 3 months old. Because of the predominantly renal clearance of ceftazidime and avibactam, dose adjustments (reductions) are required for patients with estimated creatinine clearance (CrCL) ≤ 50 mL/min. We describe the application of combined adult and pediatric population pharmacokinetic models in developing ceftazidime-avibactam dose recommendations for pediatric patients ≥ 2 to < 18 years old with body surface area-normalized CrCL ≤ 50 mL/min/1.73 m2 , including moderate, severe, or very severe renal impairment, or end-stage renal disease requiring hemodialysis, and for patients ≥ 3 months to < 2 years old with mild, moderate, or severe renal impairment. Models included allometric scaling for all subjects and simulations (1,000 subjects per age group, renal function group, and indication) were performed nonparametrically using post hoc random effects. Doses were selected based on simulated pediatric patients achieving steady-state exposures similar to adults and high probability of target attainment (using a simultaneous joint target for both ceftazidime and avibactam). Because there were few children with renal impairment in the ceftazidime-avibactam clinical trials, selected pediatric doses were guided by extrapolation and matching of adult exposures associated with efficacy and within established safety margins. The recommended doses for pediatric patients with estimated CrCL ≤ 50 mL/min/1.73 m2 use equivalent adjustments in dose quantity and/or administration interval (vs. the corresponding age group with normal renal function) as those for adults.

Improving the efficacy for meropenem therapy requires a high probability of target attainment in critically ill infants and children.

Probability of target attainment is the key factor influencing the outcome of meropenem therapy. The objective of the present study was to evaluate the relationship between the time in which the plasma free concentration of meropenem exceeds the minimum inhibitory concentration of pathogens (fT >MIC) during therapy and the clinical outcome of treatment to optimize meropenem therapy. Critically ill children with infections who had received intravenous meropenem monotherapy were included. The relationship between fT >MIC of meropenem and effectiveness and safety were explored. Data from 53 children (mean age ± standard deviation, 26 months ± 38) were available for final analysis. Children with fT >MIC ≥ 5.6 h (n = 14) had a more significant improvement in antibacterial efficacy in terms of decrease in fever (p = 0.02), white blood cell count (p = 0.014), and C-reactive protein (p = 0.02) compared with children with fT >MIC < 5.6 h (n = 39) after meropenem therapy completed. No drug-related adverse events were shown to have a causal association with meropenem therapy. Our study shows the clinical benefits of sufficient target attainment of meropenem therapy. Meeting a suitable pharmacodynamic target attainment of meropenem is required to ensure better antibacterial efficacy in critically ill infants and children. Clinical Trial Registration: clinicaltrials.gov, Identifier NCT03643497.

Ertapenem Concentrations in Obese Patients Undergoing Surgery.

Background: Antimicrobial prophylaxis is a cornerstone to preventing surgical site infections (SSIs). Ertapenem, a carbapenem antibiotic, is commonly used for surgical prophylaxis for many different procedures, including patients undergoing colorectal and other gastrointestinal surgeries. Obesity complicates surgical intervention and increases the risk for SSIs. This study aims to describe the pharmacokinetics of ertapenem for surgical prophylaxis using a population pharmacokinetic model. Patients and Methods: Ten patients were recruited and given a single dose of ertapenem 1 g intravenous over 30 minutes. Plasma samples were obtained at multiple time points over 24 hours and assayed via validated high-performance liquid chromatography (HPLC). Pharmacokinetic analyses were conducted using a population pharmacokinetic analysis to generate pharmacokinetic parameters used in the subsequent 5,000 patient Monte Carlo simulation. The probability of target attainment (PTA) for free drug concentrations remaining above the minimum inhibitory concentration (MIC) for ≥40% was used. Results: The mean maximum plasma concentration and area under the concentration time curve (AUC0-∞) was 40.7 ± 16.5 and 148.8 ± 28.0, respectively, with a half-life of the terminal portion to be 4.3 ± 0.8 hours. Monte Carlo simulations observed PTAs above 90% for MICs ≤0.25 and ≤0.125 mcg/mL in surgeries up to three and four hours, respectively. Sufficiently high PTAs were not attainable for MICs of ≥0.5 mcg/mL. Conclusions: Ertapenem given as 1 g single dose may be an appropriate candidate for surgical prophylaxis in obese patients undergoing surgeries of four hours or less.

1080. Relebactam Increases Imipenem Activity Against Imipenem-Nonsusceptible and -Susceptible Pseudomonas aeruginosa and Enterobacterales: Assessment of Isolates from RESTORE-IMI 2

BackgroundRelebactam (REL) inhibits class A and C β-lactamases (BLs) and is approved in the US in the combination imipenem/cilastatin/REL (IMI/REL) for hospital acquired bacterial pneumonia (HABP) and ventilator associated bacterial pneumonia (VABP), and also in patients with limited treatment options for complicated urinary tract infections and complicated intraabdominal infections. The objective of this study was to evaluate the potentiation of imipenem (IMI) by REL in baseline respiratory isolates from the recently completed Phase 3 RESTORE-IMI 2 study that demonstrated efficacy and safety of IMI/REL in the treatment of patients with HABP/VABP.MethodsBaseline lower respiratory tract (LRT) isolates were evaluated for IMI MICs in the presence and absence of REL using broth microdilution and CLSI interpretive criteria. All Pseudomonas aeruginosa and Enterobacterales for which IMI/REL is either indicated or the MIC90 is less than or equal to the susceptibility breakpoint were evaluated.ResultsSummary statistics and the MIC distribution for P. aeruginosa are shown in the figure. For P. aeruginosa, REL reduces the IMI mode MIC of IMI-nonsusceptible (IMI-NS) (MIC >2) isolates ≥8-fold (from 16-32 to 2 µg/mL) and that of IMI-susceptible (IMI-S) (MIC ≤2) isolates ≥2-fold (from 1 to ≤0.5 µg/mL). Among Enterobacterales, the IMI mode MIC of IMI-NS (MIC >1) isolates was reduced ≥4-fold (from 2 to ≤0.5 µg/mL). REL enhanced the activity of IMI among IMI-S isolates (MIC ≤1), most notably observed in Enterobacterales species that produce a chromosomal AmpC, increasing the proportion with MIC ≤0.5 µg/mL from 76% to 98%.MIC Distribution and Summary Statistics of RESTORE IMI-2 Isolates ConclusionAmong baseline LRT isolates from RESTORE-IMI 2 the potentiation of IMI by REL results in the restoration of susceptibility among IMI-NS P. aeruginosa and Enterobacterales and enhanced IMI activity among IMI-S isolates. This enhanced activity among IMI-S Enterobacterales is most notable among species with reported chromosomal expression of AmpC. This lowering of IMI MICs upon addition of REL contributes to the high probability of target attainment (≥90%) observed following administration of IMI/REL 1.25g every 6 hours, further supporting the IMI/REL efficacy data observed in RESTORE-IMI 2.Disclosures David W. Hilbert, PhD, Merck (Employee) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Maria C. Losada, BA, Merck (Employee) Pamela Moise, PharmD, Merck (Employee) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck (Employee) Katherine Young, MS, Merck (Employee)

Pharmacokinetics and Safety of Single-Dose Amphotericin B Colloidal Dispersion in Healthy Chinese Subjects and Population Pharmacokinetic/Pharmacodynamic Analysis to Inform Clinical Efficacy in Invasive Infections Caused by Candida albicans

Amphotericin B colloidal dispersion (ABCD) is a less toxic formulation of amphotericin B for the treatment of invasive fungal infections. The pharmacokinetic (PK) profile and safety of a generic ABCD were investigated after a single dose (0.5 to 1.5 mg/kg) administered as an intravenous infusion in 30 healthy Chinese subjects. PK data from healthy Chinese male subjects were applied for developing a population PK model to predict the PK profiles of standard doses (3 or 4 mg/kg) in patients. A 5000-time Monte Carlo simulation of AUC0-24/MIC target was implemented to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) under standard doses. The PK profiles of intravenous administration of ABCD were best described by a 3-compartmental model with a time-varying clearance and a dose-dependent volume of distribution in the peripheral compartment. PK/pharmacodynamic (PK/PD) analysis revealed that 3 or 4 mg/kg ABCD once a day resulted in favorable CRF (>98%) with 2-log reduction of Candida albicans. A high PTA (>90%) was achieved at MIC ≤2 mg/L for the dosing regimen of ABCD 3 mg/kg and 4 mg/kg for MIC ≤4 mg/L. PK/PD analysis indicated that a favorable efficacy of ABCD could be reached at a dose of 3 or 4 mg/kg once daily for 14 to 28 days to treat invasive fungal infections caused by C albicans. ClinicalTrials.gov identifier: NCT03577509.

Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial

BackgroundThe randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function.MethodsBaseline renal function was categorized as normal renal function (creatinine clearance 80–130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit.ResultsA > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [− 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; − 2.6 [− 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; − 2.1 [− 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [− 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [− 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [− 8.7 to 19.0]).ConclusionsC/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC.Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

Caspofungin pharmacokinetics and probability of target attainment in ICU patients in China

Effective antifungal therapy is important to reduce mortality in patients with invasive fungal infections (IFIs). Numerous factors affect pharmacokinetic/pharmacodynamic (PK/PD) parameters in critically-ill patients. To guide individualised administration in critically-ill patients, it is of great significance to determine the population pharmacokinetics of caspofungin. A prospective study in 42 ICU patients with IFIs was conducted in China. A population pharmacokinetic model of caspofungin was established using a non-linear mixed-effects model, which was utilised to investigate the effects of demographic indices, liver function and kidney function on pharmacokinetics. Additionally, appropriate dosages of caspofungin under various scenarios were determined based on MICs and probability of target attainment (PTA) at specific dosages. In critically-ill Chinese patients, clearance (CL), volume of distribution (V) and area under the curve at steady-state (AUCss) of caspofungin were 0.32 L/h, 6.77 L and 135.47 mg•h/L, respectively. Blood albumin and total bilirubin levels were factors affecting CL, while body weight was the only factor affecting V among Chinese people with relatively low weight compared with other populations. A maintenance dose of 50 mg caspofungin achieved a high PTA for treating IFIs caused by Candida albicans (MIC ≤ 0.06 mg/L) and Candida glabrata (MIC ≤ 0.125 mg/L). The maintenance dose of caspofungin should be adjusted to 70-200 mg for IFIs caused by C. albicans (MIC, 0.06-0.125 mg/L). For IFIs caused by Candida parapsilosis, an MIC > 0.03 mg/L is associated with a very low PTA, but higher doses of caspofungin or alternative antifungals need to be further studied. The population pharmacokinetic model established here described well the PK/PD characteristics of caspofungin in critically-ill Chinese patients. These results could guide the formulation of individualised caspofungin dosing regimens for critically-ill patients.

Comparative Pharmacodynamics of Echinocandins against Aspergillus fumigatus Using an In Vitro Pharmacokinetic/Pharmacodynamic Model That Correlates with Clinical Response to Caspofungin Therapy: Is There a Place for Dose Optimization?

Echinocandins have been used as primary therapy of invasive aspergillosis (IA), with suboptimal results at standard dosing. Here, we explored the efficacy of dose escalation in a validated in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. Six echinocandin wild-type (WT) and three non-WT A. fumigatus isolates were tested in an in vitro PK/PD model simulating anidulafungin, caspofungin, and micafungin exposures with a free drug maximum concentration (fCmax) of 0.01 to 16 mg/liter and a half-life (t1/2) of 8 to 22 h. The relationship between the area under the dosing interval time-free drug concentration curve (fAUC0-24)/minimum effective concentration (MEC) and % aberrant mycelium formation was analyzed. PK/PD indices associated with 50 to 99.99% maximal activity (EI50 to EI99.99) were correlated with the clinical outcome of a 50-mg/day standard dose of caspofungin. The probability of target attainment (PTA) was calculated for different dosing regimens of each echinocandin via Monte Carlo analysis. A sigmoidal PK/PD relationship was found for WT isolates with EI99 values of 766, 8.8, and 115 fAUC0-24/CLSI MEC for anidulafungin, caspofungin, and micafungin, respectively. No aberrant mycelia were observed for non-WT isolates, irrespective of their MEC and drug exposure. The EI99, EI99.9, and EI99.99 values corresponded to 2-, 3-, and 4-log10 formation of aberrant mycelia and correlated with survival, favorable, and complete response rates to caspofungin primary therapy in patients with IA. A very low PTA (<13%) was found for the standard doses of all echinocandins, whereas a PTA of ≥90% was found with 100 and 150 mg/day of caspofungin and 1,400 mg/day micafungin against WT isolates. For anidulafungin, the PTA for 1,500 mg/day was 10%. Among the three echinocandins, only caspofungin at 2 or 3 times the licensed dosing was associated with a high PTA. Caspofungin dose escalation might deserve clinical validation.

Comparing probability of target attainment against Staphylococcus aureus for ceftaroline fosamil, vancomycin, daptomycin, linezolid, and ceftriaxone in complicated skin and soft tissue infection using pharmacokinetic/pharmacodynamic models

For recently licensed antibiotics, such as the cephalosporin ceftaroline fosamil, probability of target attainment (PTA) curves, showing the percentage of patients reaching a predefined pharmacokinetic (PK)/pharmacodynamic (PD) target at different bacterial minimum inhibitory concentrations (MICs), have been used to support and justify dose recommendations across patient populations. However, information on PTA for older antibiotics is limited. A retrospective analysis was conducted to construct PTA curves for 4 antibiotics against Staphylococcus aureus in patients with complicated skin and soft tissue infections (cSSTIs). PK models for vancomycin, linezolid, daptomycin, and ceftriaxone were selected from the literature based on large numbers of subjects with covariates representative of patients in Europe and/or the United States. An existing model was available for ceftaroline fosamil. Standard and high-dosage regimens were used to compare the PTA of each antibiotic at MIC values 0.03 to 64 mg/L for a simulated set of patients with cSSTI caused by S. aureus. These were compared to proportions of S. aureus isolates at each MIC from global surveillance data. Ceftaroline achieved PTAs >99.9% for bacteriostatic and bactericidal targets at the MIC90 (1 mg/L), whereas the comparators failed to achieve PTAs >90%, at bacteriostatic or bactericidal targets, even when clinical doses were increased beyond those recommended. PTA analysis can be used to compare different drugs with the same simulated patient dataset, subject to availability of an appropriate PK model and robust exposure targets. This analysis shows that some antibiotics commonly used to treat cSSTIs may fail to reach high PTAs relative to contemporary MIC90 estimates.

Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice

ObjectivesNovel therapeutics are urgently required for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) causing critical infections with high mortality. Here we assessed the therapeutic potential of the clinical-stage drug candidate EBL-1003 (crystalline free base of apramycin) in the treatment of CRAB lung infections. MethodsThe genotypic and phenotypic susceptibility of CRAB clinical isolates to aminoglycosides and colistin was assessed by database mining and broth microdilution. The therapeutic potential was assessed by target attainment simulations on the basis of time–kill kinetics, a murine lung infection model, comparative pharmacokinetic analysis in plasma, epithelial lining fluid (ELF) and lung tissue, and pharmacokinetic/pharmacodynamic (PKPD) modelling. ResultsResistance gene annotations of 5451 CRAB genomes deposited in the National Database of Antibiotic Resistant Organisms (NDARO) suggested >99.9% of genotypic susceptibility to apramycin. Low susceptibility to standard-of-care aminoglycosides and high susceptibility to EBL-1003 were confirmed by antimicrobial susceptibility testing of 100 A. baumannii isolates. Time–kill experiments and a mouse lung infection model with the extremely drug-resistant CRAB strain AR Bank #0282 resulted in rapid 4-log CFU reduction both in vitro and in vivo. A single dose of 125 mg/kg EBL-1003 in CRAB-infected mice resulted in an AUC of 339 h × μg/mL in plasma and 299 h × μg/mL in ELF, suggesting a lung penetration of 88%. PKPD simulations suggested a previously predicted dose of 30 mg/kg in patients (creatinine clearance (CLCr) = 80 mL/min) to result in >99% probability of –2 log target attainment for MICs up to 16 μg/mL. ConclusionsThis study provides proof of concept for the efficacy of EBL-1003 in the treatment of CRAB lung infections. Broad in vitro coverage, rapid killing, potent in vivo efficacy, and a high probability of target attainment render EBL-1003 a strong therapeutic candidate for a priority pathogen for which treatment options are very limited.

Pharmacokinetics and Monte Carlo Dosing Simulations of Imipenem in Critically Ill Patients with Life-Threatening Severe Infections During Support with Extracorporeal Membrane Oxygenation.

BackgroundExtracorporeal membrane oxygenation (ECMO), a cardiopulmonary bypass device, has been found to increase the profound pathophysiological changes associated with life-threatening severe infections in patients with multiple comorbidities, which results in alterations of pharmacokinetic patterns for antibiotics.ObjectivesThe aims of this study were (1) to determine the pharmacokinetics of imipenem and (2) to assess the probability of target attainment (PTA) for imipenem in critically ill patients with life-threatening severe infections during support with ECMO.MethodsThe pharmacokinetic studies were carried out following administration of 0.5 g of imipenem every 6 h on the 4th dose of drug administration in 10 patients and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentrations remained above minimum inhibitory concentration (T > MIC) and 80% T > MIC.ResultsThe median values of volume of distribution and total clearance (CL) of imipenem in these patients were 13.98 L and 9.78 L/h, respectively. A high PTA (≥ 90%) for a target of 80% with a MIC of 4 μg/mL in patients with CLCR 60–120 mL/min and flow rate of ECMO circuit 3–5.5 L/min was observed when imipenem was administered by a 4-h infusion of 1 g every 6 h.ConclusionsA high dosage regimen such as 1 g every 6 h of imipenem may be required to achieve pharmacodynamic targets against less susceptible pathogens in this patient population.ClinicalTrial.gov IdentifierNCT03776305, date of registration: 11 December 2018.Electronic supplementary materialThe online version of this article (10.1007/s13318-020-00643-3) contains supplementary material, which is available to authorized users.

Population pharmacokinetics of standard-dose meropenem in critically ill patients on continuous renal replacement therapy: a prospective observational trial

BackgroundThe primary objective of this study was to develop a population pharmacokinetic model of meropenem, based on the population of critically ill adult patients undergoing CRRT. The secondary one was to examine the relationship between patient characteristics (covariates) and individual PK parameters. Finally, we aimed to perform Monte Carlo simulations to assess the probability of target attainment (PTA) of %T > MIC considering the uncertainty of PK parameters.Materials and methodsThe study population included 19 adult critically ill patients on CRRT, receiving 1 g of meropenem in 1-h infusions every 8 h. Blood samples were collected prior to (time zero) and 15, 30, 45, 60, 75, 90, 120, 180, 240 and 480 min after the start of meropenem administration. Population nonlinear mixed-effects modeling was conducted using NONMEM software, Fortran, and Wings for NONMEM.ResultsA two-compartment model was used to describe the available data. Typical values of the central and peripheral volume of distribution, and the CRRT and inter-compartmental clearance for a theoretical patient with 24.6 g/l albumin concertation were V1 = 27.9 l, V2 = 33.7 l, ClCRRT = 15.1 l/h, and Q = 21.1 l/h. A significant covariate relationship between V1 and albumin concentration was observed in the data that was described by a power relationship with − 2.87 exponent. Subsequently performed Monte Carlo simulations of the model allowed us to assess the impact of albumin concentration on PTA. The 40%T > 2 mg/l target was reached in more than 90% of subjects after 1-h infusion of 1000 mg q8h and steady-state conditions. The more stringent 100%T > 2 mg/l target requires higher doses and/or longer infusion durations that depend on the albumin concentration.ConclusionsThe population PK model was successfully developed to describe the time course of meropenem concentrations. The hypoalbuminemia was found to be associated with higher PTA in the CRRT patients after multiple short-term infusions.

1547. Modeling Pharmacokinetics and Pharmacodynamics of Meropenem Utilizing a Novel Infusion Method of Bolus to Prolonged Infusion

BackgroundDose optimization of antibiotics has been shown to increase the likelihood of achieving pharmacodynamic efficacy targets and improve clinical outcomes. For carbapenems, achieving greater than 40% time above minimum inhibitory concentration (T>MIC) has been shown to be correlated with clinical efficacy. Increasing bacterial resistance and rising MICs makes it more difficult for clinicians to rely on traditional dosing strategies to meet pharmacodynamic goals. Further optimization methods beyond extended infusion may be necessary to achieve certain pharmacodynamics goals.MethodsWe performed a Monte Carlo simulation investigating a novel method of meropenem administration, bolus to prolonged infusion (BPI). Multiple meropenem dosing regimens utilizing BPI were evaluated over 5000 patients utilizing pharmacokinetic profiles from 30 total patients. Patients were studied in 3 separate groups: <120 kg, ≥120 kg/non-critically ill and ≥120 kg/critically-ill. Bolus doses varied from 250–1000 mg and were paired with infusion doses varying from 500–1500 mg. Bolus plus infusion time totaled 3 hours and each dose was modeled with an 8-hour interval for both first dose and at steady state; BPI dosing was utilized for each dose. The primary outcome was probability of target attainment (PTA) of 40% time above minimum inhibitory concentration (T>MIC). Secondary outcomes included PTA 54% T>MIC and PTA 100% T>MIC.ResultsAll doses studied achieved > 90% PTA of 40% T>MIC for MICs of ≤8 μg/mL at both first dose and steady state in the <120 kg and ≥120 kg/non-critically ill patient groups. In the ≥120 kg/critically ill patient group, all doses achieved > 90% PTA of 40% T>MIC for MICs of ≤4 μg/mL.ConclusionBPI achieves high probability of target attainment at nonresistant MICs for Pseudomonas aeruginosa and enteric Gram-negative organisms across the 3 patient groups studied.Disclosures All authors: No reported disclosures.

Population pharmacokinetics and Monte Carlo simulations of sulbactam to optimize dosage regimens in patients with ventilator-associated pneumonia caused by Acinetobacter baumannii

BackgroundVentilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) Acinetobacter baumannii remains one of the leading causes of the high mortality rate in critically ill patients. Sulbactam has been considered as an alternative concomitant medication with other effective antimicrobial agents for the treatment of these MDR microorganisms. The aims of this study were (i) to characterize the population pharmacokinetics (PK) and (ii) to assess the efficacy of various dosage regimens of sulbactam in terms of probability of target attainment (PTA). MethodsThe PK studies were carried out following administration of 2 g of sulbactam every 12 h on the 7th dose of drug administration in 16 patients with VAP, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% and 60% the exposure time during which the total plasma drug concentration remained above the MIC (T>MIC). ResultsThe volume of distribution and total clearance of sulbactam were 22.17 ± 1.60 L and 6.76 ± 2.37 L/h, respectively. For pathogens with a MIC of 8 μg/mL, the high PTAs of achieving (≥90%) 60% T>MIC in patients with serum albumin 1.7–2.4 g/dL and CLCR 90–120 mL/min following administration of sulbactam as a 4-h infusion of 1 g every 6 h, 2 g every 12 h, and 2 g every 8 h were 98.65%, 78.07% and 98.23%, respectively. For pathogens with a MIC of 16 μg/mL, the high PTAs of achieving (≥90%) 60% T>MIC in patients with serum albumin 1.7–2.4 g/dL and CLCR 90–120 mL/min following administration of sulbactam as a 4-h infusion of 2 g every 6 h, and 3 g every 8 h were 98.83% and 95.59%, respectively. ConclusionThese findings indicate that high dosage combination regimens are required for the treatment of life-threatening infections in critically ill patients with VAP.