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 (fAUIC 24 ) 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.

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) (fAUIC 24 ), 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 fAUIC 24>17.9, and PTA exceeded 90% for MIC ≤0.38 µg/mL. Meanwhile, this dose gave the target attainment of fAUIC 24>6.9, and PTA exceeded 90% for MIC ≤1 µg/mL. All simulated tigecycline dosing regimens met the fAUIC 24 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.

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 (fAUIC 24 ) 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.

Background: In Thailand, active antibiotics against Gram-negative bacteria are limited. The re-emergence of intravenous (IV) fosfomycin is an alternative. IV fosfomycin has broadspectrum activity, relative safety, and availability. The limitations of the clinical use of IV fosfomycin include the lack of susceptibility reports and unclear dosing. Therefore, this study was designed to examine the prescription pattern of IV fosfomycin in Chonburi Hospital, a provincial hospital in Thailand. Materials and Methods: A retrospective descriptive study involving in-patients aged ≥18 years who received IV fosfomycin between February 2019 and January 2020. Data were collected from the electronic patient records. Results: Of 265 patients, 254 (95.8%) and 11 (4.2%) received IV fosfomycin for treatment and prophylaxis, respectively. IV fosfomycin was prescribed for empirical and definitive treatment. All 166 organisms were Gram-negative bacteria (GNB), including Enterobacterales (47.0%), Acinetobacter baumannii (44.0%), and Pseudomonas aeruginosa (9.0%). Moreover, 141 (87.6%) isolates were carbapenem-resistant GNB (CR-GNB). The most commonly used IV fosfomycin regimen contained colistin or aminoglycosides. Furthermore, 35.3% of the combination regimens contained one active antibiotic. The appropriate dosage of IV fosfomycin for treating urinary tract infection was 71.8%. The 14-day all-cause mortality rate in CR-GNB was 45.0%. Conclusion IV fosfomycin is reserved for secondary use in treating nosocomial infection with resistant GNB. It is used synergistically with other antibiotics. At least one active antibiotic and the optimal fosfomycin dosage should be considered. An antimicrobial stewardship program should be implemented for the optimal use of fosfomycin.