Daptomycin Dosage Optimization in Renal Impairment Using Model-Informed Precision Dosing.

Daptomycin's efficacy and toxicity are closely related to its exposure, which can vary widely among individuals. The patient, a 59-year-old male with an estimated glomerular filtration rate (eGFR) of 12 mL/min/1.73 m² and a weight of 64 kg, was treated with 850 mg of daptomycin every other day for infective endocarditis caused by methicillin-resistant Staphylococcus aureus (MRSA). For patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m², the dosing recommendations are not explicitly defined in the endocarditis guidelines. Subsequently, the pharmacology department was contacted to adjust the dosage. A population pharmacokinetic model developed by Dvorchik et al. was used for Bayesian estimation of the patient's pharmacokinetic parameters. The 24-hour area under the curve (AUC24) of daptomycin was calculated at steady state using peak and trough plasma samples. The minimum inhibitory concentration (MIC) of the MRSA strain was 0.25 mg/L. An AUC24/MIC ratio below 666 is associated with higher mortality risk, while an AUC24 above 939 h·mg/L correlates with increased risk of muscular toxicity. Initial AUC24 estimation was 1091 h·mg/L. Following a dosage reduction to 700 mg every other day, the AUC24 increased to 1600 h·mg/L. Further reduction to 500 mg every other day brought the AUC24 down to 750 h mg/L, with two subsequent measurements showing consistent AUC24 values of 500 h·mg/L, which is within the target range. Daptomycin ended 6 weeks after the initial negative blood culture, with no adverse effects or recurrence of MRSA infection. This case underscores the need for therapeutic drug monitoring and a multidisciplinary approach to adjust daptomycin doses in patients with renal impairment.

Sayadi H ，Fromage Y ，Labriffe M ，Danthu C ，Monchaud C ，Woillard JB ... -  《-》

Therapeutic Drug Monitoring of Vancomycin in Adult Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia or Pneumonia.

Vancomycin remains widely used for methicillin-resistant Staphylococcus aureus (MRSA) infections; however, treatment failure rates up to 50% have been reported. At the authors' institution, monitoring of trough concentration is the standard of care for therapeutic drug monitoring of vancomycin. New guidelines support use of the ratio of 24-hour area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) as the pharmacodynamic index most likely to predict outcomes in patients with MRSA-associated infections. To determine the discordance rate between trough levels and AUC24/MIC values and how treatment failure and nephrotoxicity outcomes compare between those achieving and not achieving their pharmacodynamic targets. This retrospective cohort study involved patients with MRSA bacteremia or pneumonia admitted to the study hospital between March 1, 2014, and December 31, 2018, and treated with vancomycin. Data for trough concentrations were collected, and minimum concentrations (C min) were extrapolated. The AUC24/MIC values were determined using validated population pharmacokinetic models. The C min and AUC24/MIC values were characterized as below, within, or above pharmacodynamic targets (15-20 mg/L and 400-600, respectively). Discordance was defined as any instance where a patient's paired C min and AUC24/MIC values fell in different ranges (i.e., below, within, or above) relative to the target ranges. Predictors of treatment failure and nephrotoxicity were determined using logistic regression. A total of 128 patients were included in the analyses. Of these, 73 (57%) received an initial vancomycin dose less than 15 mg/kg. The discordance rate between C min and AUC24/MIC values was 21% (27/128). Rates of treatment failure and nephrotoxicity were 34% (43/128) and 18% (23/128), respectively. No clinical variables were found to predict discordance. Logistic regression identified initiation of vancomycin after a positive culture result (odds ratio [OR] 4.41, 95% confidence interval [CI] 1.36-14.3) and achievement of target AUC24/MIC after 4 days (OR 3.48, 95% CI 1.39-8.70) as modifiable predictors of treatment failure. The relationship between vancomycin monitoring and outcome is likely confounded by inadequate empiric or initial dosing. Before any modification of practice with respect to vancomycin monitoring, empiric vancomycin dosing should be optimized.

Marko R ，Hajjar J ，Nzeribe V ，Pittman M ，Deslandes V ，Sant N ，Cowan J ，Kyermentang K ，Ramsay T ，Zelenitsky S ，Kanji S ... -  《-》

Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model.

Firsov AA ，Smirnova MV ，Lubenko IY ，Vostrov SN ，Portnoy YA ，Zinner SH ... -  《JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY》

Implementation of a two-point pharmacokinetic AUC-based vancomycin therapeutic drug monitoring approach in patients with methicillin-resistant Staphylococcus aureus bacteraemia.

Limited evidence exists evaluating pharmacokinetic thresholds for vancomycin efficacy and nephrotoxicity using non-Bayesian methods. The objective of this study was to evaluate the 24-h steady-state vancomycin area under the concentration-time curve (AUC24) thresholds for efficacy and nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus bacteraemia (MRSA-B) after implementing two-point pharmacokinetic therapeutic drug monitoring. A single-centre, retrospective cohort study was performed including adult patients admitted between 1 June 2016 and 1 January 2018 with MRSA-B treated with vancomycin for ≥72 h. The AUC24 was calculated using peak and trough vancomycin serum concentrations. Clinical success was defined as defervescence and blood culture sterilisation by Day 7. Nephrotoxicity was defined as an increase in serum creatinine of >0.5 mg/dL (or ≥50%) from baseline. Classification and regression tree (CART) analyses were performed to identify AUC24 thresholds for efficacy and nephrotoxicity. Forty-six patients were included in the study. Clinical success and nephrotoxicity were observed in 81.8% and 13.0%, respectively. The CART-derived vancomycin AUC24 thresholds for clinical success and nephrotoxicity were ≥297 mg·h/L and ≥710 mg·h/L, respectively. Patients with an AUC24 ≥297 mg·h/L had a >2.7-fold increase in clinical success compared with those who did not (89.5% vs. 33.3%, respectively; P = 0.01), and patients with an AUC24 ≥710 mg·h/L had a >7-fold increase in nephrotoxicity compared with those with an AUC24 <710 mg·h/L (66.7% vs. 9.3%, respectively; P = 0.04). This study supports current recommendations to target vancomycin AUC24 values of 400-600 mg·h/L when calculated using two-point pharmacokinetics, although a wider range may exist.

Mogle BT ，Steele JM ，Seabury RW ，Dang UJ ，Kufel WD ... -  《-》

Impact of area under the concentration-time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteraemia.

There have been few clinical studies on the association between the vancomycin 24-h area under the concentration-time curve (AUC24) to minimum inhibitory concentration (MIC) ratio and vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus (MRSA) infections. To examine this association and to establish a suitable cut-off value for AUC24/MIC, a multicentre prospective observational study was conducted in patients with MRSA bacteraemia. Data were collected on all patients aged ≥18 years with MRSA bacteraemia treated with vancomycin for ≥72 h without dialysis. The MIC was determined by broth microdilution (BMD) and Etest. Treatment failure was defined as (i) 30-day mortality, (ii) persistent bacteraemia (≥7 days) and (iii) recurrence (≤30 days after completion of therapy). AUC24 was estimated by a Bayesian approach based on individual vancomycin concentrations. The AUC24/MIC cut-off value for differentiating treatment success and failure was calculated by Classification and Regression Tree (CART) analysis. In total, 117 patients were enrolled, among which vancomycin treatment failure occurred in 38 (32.5%). In univariate analysis, high vancomycin MIC and low trough levels were unrelated to treatment outcomes. In the CART analysis, low vancomycin AUC24/MIC [<392.7 (BMD) and <397.2 (Etest)] was associated with treatment failure. In multivariate analysis, low AUC24/MIC was a risk factor for treatment failure [adjusted odds ratio (aOR)=3.50, 95% confidence interval (CI) 1.39-8.82 by BMD; aOR=5.61, 95% CI 2.07-15.24 by Etest]. AUC24/MIC is associated with vancomycin treatment outcomes in MRSA bacteraemia, and seeking individualised AUC24/MIC ratios above target (>400) may improve treatment outcomes.

Song KH ，Kim HB ，Kim HS ，Lee MJ ，Jung Y ，Kim G ，Hwang JH ，Kim NH ，Kim M ，Kim CJ ，Choe PG ，Chung JY ，Park WB ，Kim ES ，Park KU ，Kim NJ ，Kim EC ，Oh MD ... -  《-》