Association of the clinical efficacy of vancomycin with the novel pharmacokinetic parameter area under the trough level (AUTL) in elderly patients with hospital-acquired pneumonia.

The pharmacokinetic-pharmacodynamic parameter that best predicts the efficacy of vancomycin is the ratio of the area under the concentration versus time curve (AUC) to the minimum inhibitory concentration (MIC). A 24-h AUC (AUC24 )/MIC ratio ≥ 400 was recommended in an American consensus review, but vancomycin treatment occasionally fails despite maintenance of AUC24 /MIC ≥ 400. We evaluated the association between clinical efficacy of vancomycin and two novel pharmacokinetic parameters, the 'area under the trough level' (AUTL) and the 'area above the trough level' (AATL), in hospitalized elderly patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. The subjects were hospitalized elderly patients who were administered vancomycin for treatment of MRSA pneumonia between 2006 and 2012 at Sasebo Chuo Hospital (Nagasaki, Japan). Pharmacokinetic parameters of vancomycin were estimated for each patient by Bayesian analysis using population pharmacokinetic parameters for Japanese patients. Based on the patient-specific parameters thus obtained, AUC24 values were calculated as the vancomycin dosage divided by vancomycin clearance. AUTL was calculated as the trough serum concentration multiplied by 24 h, whereas AATL was calculated by subtracting AUTL from AUC24 . Logistic regression analysis demonstrated that efficacy of vancomycin was more strongly associated with AUTL than AUC24 . The optimal cut-off value of AUTL was 331 μg∙h/mL, which means that the optimal cut-off value of the trough serum concentration was 13·8 μg/mL. Efficacy of vancomycin was associated with AUTL, a novel pharmacokinetic parameter. Determining the target AUTL or trough concentration may enhance the efficacy of vancomycin therapy in elderly patients with MRSA pneumonia. Given that nephrotoxicity may increase with a Ctrough in excess of 15 μg/mL, this level should ideally not be exceeded.

Fukumori S ，Tsuji Y ，Mizoguchi A ，Kasai H ，Ishibashi T ，Iwamura N ，To H ... -  《-》

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 ... -  《-》

Area under the concentration-time curve to minimum inhibitory concentration ratio as a predictor of vancomycin treatment outcome in methicillin-resistant Staphylococcus aureus bacteraemia.

There have been few clinical studies on the association between the 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. Patients with MRSA bacteraemia between July 2009 and January 2012 were analysed retrospectively. All adult patients treated with vancomycin for ≥72 h without dialysis were included. The MIC was determined by Etest and broth microdilution (BMD). Initial steady-state AUC24 was estimated using a Bayesian model, and the AUC24/MIC cut-off value for differentiating treatment success and failure was calculated by classification and regression tree (CART) analysis. In total, 76 patients were enrolled; vancomycin treatment failure occurred in 20 patients (26.3%). Catheter-related infection was the most frequent (35.5%), followed by surgical site infection (26.3%), whilst 25 (32.9%) had complicated infections. In univariate analysis, decreased MRSA vancomycin susceptibility (MIC≥1.5 mg/L) and vancomycin trough levels (15-20 mg/L) were not associated with treatment outcomes. In the CART analysis, low initial vancomycin AUC24/MIC (<430 by Etest; <398.5 by BMD) was associated with a higher treatment failure rate (50.0% vs. 25.0%, P=0.039 by Etest; 45.0% vs. 23.2%; P=0.065 by BMD). In multivariate analysis, low initial vancomycin AUC24/MIC was a significant risk factor for treatment failure [adjusted odds ratio (aOR)=4.39, 95% confidence interval (CI), 1.26-15.35 by Etest; aOR=3.73, 95% CI 1.10-12.61 by BMD]. In MRSA bacteraemia, a low initial vancomycin AUC24/MIC is an independent risk factor for vancomycin treatment failure.

Jung Y ，Song KH ，Cho Je ，Kim HS ，Kim NH ，Kim TS ，Choe PG ，Chung JY ，Park WB ，Bang JH ，Kim ES ，Park KU ，Park SW ，Kim HB ，Kim NJ ，Oh MD ... -  《-》

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 ... -  《-》

A stewardship program's retrospective evaluation of vancomycin AUC24/MIC and time to microbiological clearance in patients with methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis.

Gawronski KM ，Goff DA ，Brown J ，Khadem TM ，Bauer KA ... -  《-》