Purpose The incidence of infections with vancomycin-resistant enterococci (VRE) is increasing, with associated high mortality rates and limited therapeutic choices. We investigated the clinical characteristics and treatment outcomes of VRE infection and also determined the in vitro effect of monotherapy and combined antimicrobials against clinical VRE isolates. Patients and methods Clinical data and bacterial isolates obtained from patients with VRE infections between January 2014 and April 2018 at Phramongkutklao Hospital were reviewed. The clinical outcomes included in-hospital mortality, 30-day mortality, and microbiological eradication. Clonal relationships were assessed by random amplified polymorphic DNA analysis. In vitro activity of linezolid, tigecycline, fosfomycin, gentamicin, chloramphenicol, and ampicillin were determined by minimum inhibitory concentration (MIC) values. Tests of synergy of fosfomycin- or gentamicin-based combinations by the checkerboard method were reported with the fractional inhibitory concentration index or MIC reduction, respectively. Results Among 26 cases of VRE infection, nosocomial and gastrointestinal infections were the most common. There were various treatment regimens, but linezolid-containing regimens were generally used. In-hospital and 30-day mortality were 73.1% and 57.7%, respectively. Higher mortality was significantly associated with illness severity. The VRE isolates tested were universally susceptible to linezolid and tigecycline. A synergistic or additive effect was observed for fosfomycin combined with linezolid (100%) and with tigecycline (83.3%). Fourfold or greater MIC reduction was observed for linezolid or fosfomycin plus gentamicin at concentrations 1 (58.3%, 62.5%), 2 (83.3%, 62.5%), and 4 μg/mL (91.6%, 62.5%). Conclusion In-hospital mortality among patients with VRE infection was high. Linezolid remains a treatment of choice. However, combination therapy such as linezolid plus fosfomycin and linezolid plus gentamicin should be considered in cases of serious infection.

The prevalence of enterococcal infection, especially E. faecium, is increasing, and the issue of the impact of vancomycin resistance on clinical outcomes is controversial. This study aimed to investigate the clinical outcomes of infection caused by E. faecium and determine the risk factors associated with mortality. This retrospective study was performed at the Phramongkutklao Hospital during the period from 2014 to 2018. One hundred and forty-five patients with E. faecium infections were enrolled. The 30-day and 90-day mortality rates of patients infected with vancomycin resistant (VR)-E. faecium vs. vancomycin susceptible (VS)-E. faecium were 57.7% vs. 38.7% and 69.2% vs. 47.1%, respectively. The median length of hospitalization was significantly longer in patients with VR-E. faecium infection. In logistic regression analysis, VR-E. faecium, Sequential Organ Failure Assessment (SOFA) scores, and bone and joint infections were significant risk factors associated with both 30-day and 90-day mortality. Moreover, Cox proportional hazards model showed that VR-E. faecium infection (HR 1.91; 95%CI 1.09–3.37), SOFA scores of 6–9 points (HR 2.69; 95%CI 1.15–6.29), SOFA scores ≥ 10 points (HR 3.71; 95%CI 1.70–8.13), and bone and joint infections (HR 0.08; 95%CI 0.01–0.62) were significant risk factors for mortality. In conclusion, the present study confirmed the impact of VR-E. faecium infection on mortality and hospitalization duration. Thus, the appropriate antibiotic regimen for VR-E. faecium infection, especially for severely ill patients, is an effective strategy for improving treatment outcomes.

Background Linezolid, an oxazolidinone antibiotic, is recommended for vancomycin-resistant enterococci (VRE). However, 100% free-drug concentration above the minimum inhibitory concentration ( f T>MIC) and an area under the curve of free drug to MIC ratio ( f AUC24/MIC) >100 were associated with favorable clinical outcome with less emerging resistance. A plasma trough concentration (C trough ) 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 ( f AUIC 24 ) was used to calculate the f AUC24/MIC 80 - 100 and f T/MIC >85 - 100% of the interval time of administration for clinical response and microbiological eradication as well as the C trough ≥9 µg/mL for the probability of hematologic toxicity. Results For linezolid MIC determination, the MIC median (MIC 50 ), MIC for 90% growth (MIC 90 ), 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 f AUC24/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 f T>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 f AUC24/MIC and a f T>MIC and the target CFR, but those regimens gave C trough ≥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.

Daptomycin, a lipopeptide antibiotic, is one of the therapeutic options used for the treatment of vancomycin-resistant enterococci (VRE). Recently, the Clinical and Laboratory Standards Institute (CLSI) M100 30th edition has removed the susceptibility (S) breakpoint for Enterococcus faecium and replaced it with a susceptible dose-dependent (SDD) breakpoint of ≤4 μg/mL, with a suggested dosage of 8–12 mg/kg/day. Herein, we aimed to determine the minimum inhibitory concentration (MIC) values of daptomycin against clinical VRE isolates and to study the appropriate daptomycin dosing regimens among critically ill patients based on the new susceptibility CLSI breakpoint. The MIC determination of daptomycin was performed using E-test strips among clinical VRE strains isolated from patients at the Phramongkutklao Hospital. We used Monte Carlo simulation to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the ratio of the free area under the curve to MIC (fAUC0–24/MIC) > 27.4 and fAUC0–24/MIC > 20 for survival and microbiological response, respectively, at the first day and steady state. Further, we determined that the simulated daptomycin dosing regimen met the minimum concentration (Cmin) requirements for safety of being below 24.3 mg/L. All of the 48 VRE isolates were E. faecium strains, and the percentiles at the 50th and 90th MIC of daptomycin were 1 and 1.5 μg/mL, respectively. At MIC ≤ 2 μg/mL, a daptomycin dosage of 12 mg/kg/day achieved the PTA target of survival and microbiological response at the first 24 h time point and steady state. For a MIC of 4 μg/mL, none of the dosage regimens achieved the PTA target. For CFR, a dosage of 8–12 mg/kg/day could achieve the 90% CFR target at the first day and steady state. All dosing regimens had a low probability of Cmin being greater than 24.3 mg/L. In conclusion, the MIC of VRE against daptomycin is quite low, and loading and maintenance doses with 8 mg/kg/day were determined to be optimal and safe.