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Introduction: Vancomycin requires a population pharmacokinetic (popPK) model to estimate the area under the concentration-time curve (AUC), and an AUC-guided dosing strategy is necessary. This study aimed to develop a popPK model for vancomycin using a real-world database pooled from a nationwide web application (PAT)., Methods: In this retrospective study, the PAT database between December 14, 2022 and April 6, 2023 was used to develop a popPK model. The model was validated and compared with six existing models based on the predictive performance of datasets from another PAT database and the Kumamoto University Hospital. The developed model determined the dosing strategy for achieving the target AUC., Results: The modeling populations consisted of 7146 (13,372 concentrations from the PAT database), 3805 (7540 concentrations from the PAT database), and 783 (1775 concentrations from Kumamoto University Hospital) individuals. A two-compartment popPK model was developed that incorporated creatinine clearance as a covariate for clearance and body weight for central and peripheral volumes of distribution. The validation demonstrated that the popPK model exhibited the smallest mean absolute prediction error of 5.07, outperforming others (ranging from 5.10 to 5.83). The dosing strategies suggested a first dose of 30 mg/kg and maintenance doses adjusted for kidney function and age., Conclusions: This study demonstrated the updating of PAT through the validation and development of a popPK model using a vast amount of data collected from anonymous PAT users., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Objectives: Compared with vancomycin trough concentration (C min )-guided dosing, area under the concentration-time curve (AUC)-guided dosing is associated with decreased acute kidney injury (AKI). However, whether C min -guided or AUC-guided dosing should be used in patients other than those with serious MRSA infections remains uncertain. The purposes of this multicentre study were to identify risk factors for early- and late-phase vancomycin-induced AKI and to identify candidates for AUC-guided dosing, rather than C min -guided dosing, who require a more accurate dose titration to reduce the AKI risk., Methods: A multivariate logistic regression analysis was applied to identify risk factors for AKI. Additionally, the cut‑off day for AKI onset, cut-off C min for AKI, safe C min for reduced AKI risk and probability of AKI were calculated., Results: In total, 8.4% (159/1882) of patients developed AKI. AKI occurred within the first 7 days of therapy (early phase) in the vast majority of patients. Significant risk factors for AKI during the early phase were identified as C min > 20 mg/L, ICU stay, concurrent diuretic or piperacillin/tazobactam use, and pre-existing renal dysfunction. A temporarily elevated C min (>15-20 mg/L) was not associated with a greater risk of AKI. In patients with risk factors, the cut-off C min for AKI and the estimated safe C min for reduced AKI risk were 18.8-21.0 mg/L and <11.7-13.5 mg/L, respectively., Conclusion: Patients with known AKI risk factors require a low target C min . The presence of several risk factors for AKI may indicate a need for more accurate dose titration using AUC-guided dosing., Competing Interests: Competing interests YT received grant support from Shionogi & Co., Ltd. and payment for lectures from Astellas Pharma Inc. and MSD Japan; KM received grant support from Meiji Seika Pharma Co., Ltd. All other authors declare no competing interests., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: Therapeutic drug monitoring guided by the area under the concentration-time curve (AUC-guided TDM) is recommended for vancomycin. However, validated efficient software remains elusive to popularize AUC-guided TDM in Japan. The aim of this study was to validate a newly developed web application, PAT, for AUC estimation., Methods: PAT was developed on the R ver. 3.6.2 platform for use with mobile phones and personal computers. AUC estimated by PAT (AUC PAT ) was evaluated against the reference AUC (AUC REF ) calculated with the log-linear trapezoidal rule using eight measured concentrations, or against AUC (AUC BM-P ) calculated using an evaluated available software with clinical data., Results: Investigating the best sampling points with limited sampling, PAT produced the least bias using two concentrations at 1 h and 11 h after the end of infusion (slope 1.18, intercept -15.57, median AUC PAT /AUC REF 0.93 [range 0.81-1.24]), where only one estimation (6%) was out of the predetermined acceptable range of 0.8-1.2. Employment of only a trough concentration was more biased (AUC PAT /AUC REF range 0.73-1.30 for 11 h, AUC PAT /AUC REF range 0.62-1.40 for 23 h). In comparison with the evaluated software, AUC PAT was not biased against the AUC BM-P (slope 1.04, intercept -15.80, median AUC PAT /AUC BM-P 1.00 [range 0.86-1.10])., Conclusions: The new application using two concentrations was appropriately validated and might be efficient in popularizing the AUC-guided TDM of vancomycin.

Background: This systematic review and meta-analysis explored the relationship between vancomycin (VCM) monitoring strategies and VCM effectiveness and safety., Methods: We conducted our analysis using the MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials electronic databases searched on August 9, 2020. We calculated odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia with VCM trough concentrations ≥15 μg/mL had significantly lower treatment failure rates (OR 0.63, 95% CI 0.47-0.85). The incidence of acute kidney injury (AKI) increased with increased trough concentrations and was significantly higher for trough concentrations ≥20 μg/mL compared to those at 15-20 μg/mL (OR 2.39, 95% CI 1.78-3.20). Analysis of the target area under the curve/minimum inhibitory concentration ratios (AUC/MIC) showed significantly lower treatment failure rates for high AUC/MIC (cut-off 400 ± 15%) (OR 0.28, 95% CI 0.18-0.45). The safety analysis revealed that high AUC value (cut-off 600 ± 15%) significantly increased the risk of AKI (OR 2.10, 95% CI 1.13-3.89). Our meta-analysis of differences in monitoring strategies included four studies. The incidence of AKI tended to be lower in AUC-guided monitoring than in trough-guided monitoring (OR 0.54, 95% CI 0.28-1.01); however, it was not significant in the analysis of mortality., Conclusions: We identified VCM trough concentrations and AUC values that correlated with effectiveness and safety. Furthermore, compared to trough-guided monitoring, AUC-guided monitoring showed potential for decreasing nephrotoxicity.

What Is Known and Objective: Vancomycin therapeutic guidelines suggest a loading dose of 25-30 mg/kg for seriously ill patients. However, high-quality data to guide the use of loading doses are lacking. We aimed to evaluate whether a loading dose (a) achieved a target trough concentration at steady state and (b) improved early clinical response., Methods: Patients with an estimated glomerular filtration rate ≥ 90 mL/min/1.73 m 2 were included. A loading dose of 25 mg/kg vancomycin followed by 15 mg/kg twice daily was compared with traditional dosing. A C min sample was obtained before the fifth dose. An early clinical response 48-72 hours after the start of therapy and clinical success at end of therapy (EOT) was evaluated in patients with methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Staphylococci or Enterococcus faecium., Results: There was no significant difference in C min between the regimen with and without a loading dose (median: 10.4 and 10.2 µg/mL, P = .54). Proportions of patients achieving 10-20 and 15-20 µg/mL were 56.9% and 5.6%, respectively, in patients with a loading dose. Although there was no significant difference in success rate at EOT between groups, a loading dose was associated with increased early clinical response for all infections (adjusted odds ratio [OR]: 4.588, 95% confidence interval [CI]: 1.373-15.330) and MRSA infections (OR: 12.065, 95% CI: 1.821-79.959). Study limitations included no C min measurements within 24 hours and the inclusion of less critically ill patients., What Is New and Conclusion: A loading dose of 25 mg/kg followed by 15 mg/kg twice daily did not achieve the optimal Cmin at steady state in patients with normal renal function. However, more early clinical responses were obtained with a loading dose compared with traditional dosing, possibly because of a prompt albeit temporary achievement of a more effective concentration., (© 2020 John Wiley & Sons Ltd.)

The aim of this study was to investigate the timing of therapeutic drug monitoring (TDM) in patients with impaired renal function treated with once-daily administration of vancomycin (VCM). Once-daily administration was selected for patients whose creatinine clearance (Ccr) was <80 ml/min. TDM was conducted on day 3 or on day 4. Adult patients whose VCM dosage was not altered according to initial C min and for whom subsequent follow-up TDM was performed within 1 week were entered into the study. Patients whose renal function deteriorated at follow-up TDM were excluded. One hundred sixty-five patients were eligible for analysis. Among patients with once-daily dosing, relative increases of C min at follow-up TDM compared with initial TDM were 34.5 ± 39.2 % in TDM on day 3 and 16.6 ± 20.6 % in TDM on day 4 (P = 0.016). In contrast, there was no significant difference in the relative increase of C min between TDM on days 3 and 4 (26.1 ± 39.6 vs. 18.4 ± 25.6 %, P = 0.551) in the twice-daily regimen. On multivariate analysis, TDM on day 3 alone (odds ratio, 4.93; 95 % confidence interval, 1.71-14.2) was selected as an independent risk factor associated with a relative increase of C min by >30 % in the once-daily regimen. Steady-state VCM serum concentration was not achieved on day 3 in the once-daily regimen in patients with impaired renal function, and TDM on day 3 caused underestimation of C min.

Recent studies demonstrated that mortality associated with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia was high when vancomycin was used to treat infections with strains that had a high vancomycin minimum inhibitory concentration (MIC). This study compared several characteristics of vancomycin MIC 2 μg/ml strains isolated from bacteremia with those isolated from infections other than bacteremia. A total of 128 episodes of MRSA bacteremia between 2005 and 2008 were followed-up, and compared with 631 MRSA infections other than bacteremia. The isolation of strains with a 2 μg/ml MIC accounted for 32.0% of isolates from MRSA bacteremia, whereas strains with a 2 μg/ml MIC comprised 9.0% of MRSA isolated from other sites (p < 0.001). The incidence of pneumonia as the source of infection was significantly higher in patients with bacteremia from strains with a 2 μg/ml MIC than in those with ≤1 μg/ml MIC. Prior vancomycin use did not correlate with the isolation of 2 μg/ml strains. The efficacy of glycopeptides as 1st line therapy in patients infected with 2 μg/ml strains was significantly lower than that for patients infected with ≤1 μg/ml strains (30.0 vs. 78.8%, p < 0.001) in bacteremia. In the analysis of infections other than bacteremia, efficacy did not reveal a significant difference according to MIC (69.0 vs. 79.6%, p = 0.109). In bacteremia, mortality was 65.8% in patients with 2 μg/ml strains and 19.5% in patients with ≤1 μg/ml strains (p < 0.001), whereas there was no significant difference in mortality from infections other than bacteremia (10.7 vs. 7.8%, p = 0.617). In multivariate analysis, bacteremia with 2 μg/ml strains, intensive care unit (ICU) stay, and liver cirrhosis were independent risk factors for death in patients with bacteremia, and initial appropriate therapy lowered the risk. Several characteristics such as a higher incidence than at other infection sites, a high incidence of pneumonia as a source of infection, a low success rate of vancomycin therapy, and poor prognosis were confirmed in 2 μg/ml MIC MRSA isolated from bacteremia; however, a low success rate of vancomycin and poor prognosis were not apparent in 2 μg/ml MIC MRSA strains isolated from infections other than bacteremia.

Background: To promote model-informed precision dosing (MIPD) for vancomycin (VCM), we developed statements for therapeutic drug monitoring (TDM). Methods: Ten clinical questions were selected. The committee conducted a systematic review and meta-analysis as well as clinical studies to establish recommendations for area under the concentration-time curve (AUC)-guided dosing. Results: AUC-guided dosing tended to more strongly decrease the risk of acute kidney injury (AKI) than trough-guided dosing, and a lower risk of treatment failure was demonstrated for higher AUC/minimum inhibitory concentration (MIC) ratios (cut-off of 400). Higher AUCs (cut-off of 600 μg·h/mL) significantly increased the risk of AKI. Although Bayesian estimation with two-point measurement was recommended, the trough concentration alone may be used in patients with mild infections in whom VCM was administered with q12h. To increase the concentration on days 1–2, the routine use of a loading dose is required. TDM on day 2 before steady state is reached should be considered to optimize the dose in patients with serious infections and a high risk of AKI. Conclusions: These VCM TDM guidelines provide recommendations based on MIPD to increase treatment response while preventing adverse effects. [ABSTRACT FROM AUTHOR]

Area under the concentration–time curve (AUC)-guided vancomycin treatment is associated with decreased nephrotoxicity. It is preferable to obtain two samples to estimate the AUC. This study examined the usefulness of AUC estimation via trough concentration (Cmin)-only sampling of 260 adults infected with methicillin-resistant Staphylococcus aureus (MRSA) who received vancomycin. The exact Cmin sampling time was used for Bayesian estimation. A significantly higher early treatment response was observed in patients with a day 2 AUC ≥ 400 µg·h/mL than those with <400 µg·h/mL, and a significantly higher early nephrotoxicity rate was observed in patients with a day 2 AUC ≥ 600 µg·h/mL than those with <600 µg·h/mL. These AUC cutoff values constituted independent factors for each outcome. In sub-analysis, the discrimination ability for early clinical outcomes using these AUC cutoffs was confirmed only in patients with q12 vancomycin administration. A significant difference in early treatment response using the 400 µg·h/mL cutoff was obtained only in patients with low-risk infections. The usefulness of the vancomycin AUC target to decrease nephrotoxicity while assuring clinical efficacy was even confirmed with a single Cmin measurement. However, assessment with two samples might be required in patients with q24 administration or high/moderate-risk MRSA infections. [ABSTRACT FROM AUTHOR]

A correction to the article "Preferable timing of therapeutic drug monitoring in patients with impaired renal function treated with once-daily administration of vancomycin," by Yoshiko Takahashi and colleagues that was published online in April 10, 2013 issue is presented.

We carried out a systematic review and meta-analysis exploring the relationship between vancomycin (VCM) trough concentrations and its effectiveness and nephrotoxicity in pediatric patients. We conducted our analysis using MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials as electronic databases (June 29, 2019). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We identified 16 studies that were eligible for the meta-analysis. A total of 351 and 3,266 patients were included in the analysis for effectiveness and nephrotoxicity, respectively. Pediatric MRSA infection patients with VCM trough concentrations ≥ 10 μg/mL had significantly lower treatment failure rates (OR 0.54, 95% CI 0.30–0.96). The incidence of nephrotoxicity was significantly higher in trough concentrations ≥ 15 μg/mL than when they were < 15 μg/mL (OR 3.02, 95% CI 2.08–4.38). We identified the optimal VCM trough concentrations associated with effectiveness and nephrotoxicity in pediatric patients with MRSA infection. Further prospective studies are needed to find optimal dosing and monitoring strategy on VCM in pediatric population. [ABSTRACT FROM AUTHOR]