Optimization of Linezolid Dosing Regimens for Treatment of Vancomycin-Resistant Enterococci Infection

Wichai Santimaleeworagun,Changpradub Dhitiwat,Jatapat Hemapanpairoa,Sudaluck Thunyaharn 대한감염학회 2021 Infection and Chemotherapy Vol.53 No.3

Background: Linezolid, an oxazolidinone antibiotic, is recommended for vancomycinresistant enterococci (VRE). However, 100% free-drug concentration above the minimum inhibitory concentration (fT>MIC) and an area under the curve of free drug to MIC ratio (fAUC24/MIC) >100 were associated with favorable clinical outcome with less emerging resistance. A plasma trough concentration (Ctrough) of linezolid ≥9 µg/mL was also related to hematologic toxicity. Thus, linezolid dose optimization is needed for VRE treatment. The study aimed to determine the in vitro linezolid activity against clinical VRE isolates and linezolid dosing regimens in critically ill patients who met the target pharmacokinetics/ pharmacodynamics (PK/PD) for VRE treatment. Materials and Methods: Enterococcal isolates from enterococcal-infected patients were obtained between 2014 and 2018 at Phramongkutklao Hospital. We used Monte Carlo simulation to calculate the probability of target attainment, and the cumulative fraction of response (CFR) of the free area under the curve to MIC ratio (fAUIC24) was used to calculate the fAUC24/MIC 80 - 100 and fT/MIC >85 - 100% of the interval time of administration for clinical response and microbiological eradication as well as the Ctrough ≥9 µg/mL for the probability of hematologic toxicity. Results: For linezolid MIC determination, the MIC median (MIC50), MIC for 90% growth (MIC90), and range for linezolid were 1.5 µg/mL, 2 µg/mL, and 0.72 - 2 µg/mL, respectively. A dosing regimen of 1,200 mg either once daily or as a divided dose every 12 h gave target attainments of fAUC24/MICs >80 and >100, which exceeded 90% for MICs ≤1 and ≤1 µg/mL, respectively, with a rate of hematologic toxicity <15%. If the expected fT>MICs were >85% and 100%, a 1,200-mg divided dose every 12 h could cover VRE isolates having linezolid MICs ≤1 µg/mL and ≤0.75 µg/mL. Even 600 mg every 8 h and 1,200 mg as a continuous infusion gave a higher target attainment of fAUC24/MIC and a fT>MIC and the target CFR, but those regimens gave Ctrough ≥9 µg/mL rates of 40.7% and 99.6%. Conclusion: The current dosing of 1,200 mg/day might be optimal treatment for infection by VRE isolates with documented MICs ≤1 µg/mL. For treatment of VRE with a MIC of 2 µg/mL or to achieve the target CFR, the use of linezolid with other antibiotic combinations might help achieve the PK/PD target, provide better clinical outcome, and prevent resistance.

Optimizing the Dosing Regimens of Tigecycline against Vancomycin-Resistant Enterococci in the Treatment of Intra-abdominal and Skin and Soft Tissue Infections

Wichai Santimaleeworagun,Jatapat Hemapanpairoa,Dhitiwat Changpradub,Sudaluck Thunyaharn 대한감염학회 2020 Infection and Chemotherapy Vol.52 No.3

Tigecycline was previously considered to have activity against vancomycin-resistant Enterococcus (VRE) isolates, but the optimal dose was not clarified. Thus, this study assessed the in vitro activity of tigecycline against clinical VRE isolates to determine its optimal regimens for complicated intra-abdominal (cIAIs) and complicated skin/soft tissue infections (cSSTIs). We used Monte Carlo simulation to calculate the probability of target attainment (PTA) and the cumulative fraction of response for the ratio of the free area under the curve to the minimum inhibitory concentration (MIC) (fAUIC24), which were 17.9 and 6.9 for treating cSSTIs and cIAIs, respectively. All clinical isolates were Enterococcus faecium. Only a maintenance dose of 200 mg/day tigecycline gave the target attainment of fAUIC24 >17.9, and PTA exceeded 90% for MIC ≤0.38 µg/mL. Meanwhile, this dose gave the target attainment of fAUIC24 >6.9, and PTA exceeded 90% for MIC ≤1 µg/mL. All simulated tigecycline dosing regimens met the fAUIC24 targets more than 90% of the cumulative fraction of response. Despite its apparent efficacy, a daily tigecycline dose of 200 mg is recommended for VRE isolates with MICs of ≤0.38 µg/mL and ≤1 µg/mL for treating cSSTIs and cIAIs, respectively.

Fosfomycin Dosing Regimens based on Monte Carlo Simulation for Treated Carbapenem-Resistant Enterobacteriaceae Infection

Kanchanasurakit Sukrit,Santimaleeworagun Wichai,Charles E. McPherson, III,Piriyachananusorn Napacha,Boonsong Benjawan,Katwilat Papanin,Saokaew Surasak 대한감염학회 2020 Infection and Chemotherapy Vol.52 No.4

Background: Infections by Carbapenem-Resistant Enterobacteriaceae (CRE) remain a leading cause of death in critically ill patients. Fosfomycin has been regarded as an alternative therapy for treatment of infections caused by CRE organisms. The purpose of this study is to evaluate clinical outcomes amongst patients with CRE infection who are receiving a fosfomycin dosing regimen using a Monte Carlo simulation and fosfomycin minimum inhibitory concentration (MIC). Materials and Methods: Fosfomycin MIC was defined by the E-test method. We used Fosfomycin pharmacokinetic parameters from a previously published study. The percent of the time period in which the drug concentration exceeded the MIC, or %T>MIC, used in this study were determined to be 70% of T>MIC and 100% of T>MIC, respectively. All dosing regimens were estimated for the probability of target attainment using a Monte Carlo simulation. Results: In this study, we found the MIC's of fosfomycin against CRE isolates ranged from 8 mg/L to 96 mg/L. The total daily dose of fosfomycin ranged from 16 - 24 g and was administered utilizing various fosfomycin dosing regimens to achieve the pharmacokinetic/ pharmacodynamic (PK/PD) target in pathogens with a MIC of 32 mg/L for 70%T>MIC and a MIC of 12 mg/L for 100%T>MIC, respectively. For the twelve patients who received the recommended fosfomycin dosing regimen, eleven achieved bacterial eradication for a microbiological cure rate of 91%; and of those patients achieving eradication, two died despite having negative cultures for CRE; the one remaining patient had bacterial persistence. The most commonly observed adverse drug reactions were hypernatremia (3 cases) and hypokalemia (3 cases) and acute kidney injury (3 cases). Conclusion: Our findings suggest fosfomycin has tended to good efficacy when using dosing regimens that achieve the PK/PD target. Nonetheless, further validation of these regimens in larger populations is needed.

Colistin plus Sulbactam or Fosfomycin against Carbapenem-Resistant Acinetobacter baumannii: Improved Efficacy or Decreased Risk of Nephrotoxicity?

Saelim Weerayuth,Changpradub Dhitiwat,Sudaluck Thunyaharn,Juntanawiwat Piraporn,Nulsopapon Parnrada,Santimaleeworagun Wichai 대한감염학회 2021 Infection and Chemotherapy Vol.53 No.1

Background: Acinetobacter baumannii has been recognized as a cause of nosocomial infection. To date, polymyxins, the last-resort therapeutic agents for carbapenem-resistant A. baumannii (CRAB). Thus, the small number of effective antibiotic options against CRAB represents a challenge to human health. This study examined the appropriate dosage regimens of colistin alone or in combination with sulbactam or fosfomycin using Monte Carlo simulation with the aims of improving efficacy and reducing the risk of nephrotoxicity. Materials and Methods: Clinical CRAB isolates were obtained from patients admitted to Phramongkutklao Hospital in 2014 and 2015. The minimum inhibitory concentration (MIC) of colistin for each CRAB isolate was determined using the broth dilution method, whereas those of sulbactam and fosfomycin were determined using the agar dilution method. Each drug regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). Nephrotoxicity based on RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria was indicated by colistin trough concentration exceeding ≥3.3 µg/mL. Results: A total of 50 CRAB isolates were included. The MIC50 and MIC90 were 64 and 128 µg/mL, respectively, for sulbactam, 256 and 2,048 µg/mL, respectively, for fosfomycin, and 1 and 4 µg/mL, respectively, for colistin. In patients with creatinine clearance of 91 – 130 m/min, the dosing regimens of 180 mg every 12 h and 150 mg every 8 h achieved ≥ 90% of target of the area under the free drug plasma concentration–time curve from 0 to 24 hr (fAUC24)/MIC ≥25 against isolates MICs of ≤0.25 and ≤0.5 µg/mL, respectively, and their rates of colistin trough concentration more than ≥3.3 µg/mL were 35 and 54%, respectively. Colistin combined with sulbactam or fosfomycin decreased the colistin MIC of CRAB isolates from 1 – 16 µg/mL to 0.0625 – 1 and 0.0625 – 2 µg/mL, respectively. Based on CFR ≥ 90%, no colistin monotherapy regimens in patients with creatinine clearance of 91 – 130 mL/min were effective against all of the studied CRAB isolates. For improving efficacy and reducing the risk of nephrotoxicity, colistin 150 mg given every 12 h together with sulbactam (≥6 g/day) or fosfomycin (≥18 g/day) was effective in patients with creatinine clearance of 91 – 130 mL/min. Additionally, both colistin combination regimens were effective against five colistin-resistant A. baumannii isolates. Conclusion: Colistin monotherapy at the maximum recommended dose might not cover some CRAB isolates. Colistin combination therapy appears appropriate for achieving the pharmacokinetic/pharmacodynamic targets of CRAB treatment.

Vancomycin Area under the Curve and Pharmacokinetic Parameters during the First 24 Hours of Treatment in Critically Ill Patients using Bayesian Forecasting

Pongchaidecha Manat,Changpradub Dhitiwat,Bannalung Kanjana,Seejuntra Kajeewan,Thongmee Sutthanuch,Unnual Aminta,Santimaleeworagun Wichai 대한감염학회 2020 Infection and Chemotherapy Vol.52 No.4

Background: Currently, the achievement of the target area under the curve (AUC)/ minimum inhibitory concentration ratio during the first 24 - 48 h of treatment is associated with reduced 30-day mortality and greater microbiological eradication in patients with methicillin-resistant Staphylococcus aureus bacteremia. This study aimed to determine the AUC and pharmacokinetic parameters on the first day of vancomycin administration based on the Bayesian theorem to optimize the dosing regimen in critically ill patients. Materials and Methods: This retrospective study included participants meeting the following criteria: 1) ≥18 years old; 2) receipt of at least one dose of vancomycin; 3) measurement of 2 vancomycin serum concentrations during the first 24 h of treatment; and 4) an intensive care unit admission, mechanical ventilator use, or an Acute Physiology and Chronic Health Evaluation II score >15 points. The AUC on day 1 of treatment and the estimated vancomycin pharmacokinetic parameters were measured using PrecisePK software based on the Bayesian theorem. Results: We obtained 132 vancomycin concentrations from 66 patients. The vancomycin pharmacokinetic parameters were as follows: AUC0-24, 571.09 (± standard deviation [SD] 188.62) mg/L·h; clearance (CL), 2.97 (± SD 1.81) L/h; volume of distribution (Vd), 50.60 (± SD 13.91) L; elimination rate constant, 0.062 (± SD 0.039) h−1; and half-life, 18.19 (± SD 15.96) h. Focusing on the vancomycin loading dose, AUC0-24 400 - 600 was achieved in 41.7, 46.1, 44.4, and 26.3% of patients with loading doses of <20, 20 – 24.9, 25 – 30, and >30 mg/kg, respectively. Whereas AUC0-24 ≥521 was achieved in 50, 50, 77.8, and 84.2% of patients with loading doses of <20, 20 – 24.9, 25 – 30, and >30 mg/kg, respectively. The CL of vancomycin was correlated with creatinine CL, whereas the Vd of vancomycin was significantly correlated with age and body weight. Conclusion: This study revealed that the higher Vd and CL values on the first day of vancomycin therapy were found in critically ill patients. Additionally, a higher vancomycin loading dose (25 – 30 mg/kg) might be required to achieve target of AUC0-24 during early phase of administration for critically ill patients.