A simulation study on model-informed precision dosing of amikacin for achieving target area under the concentration-time curve.

AIMS: Amikacin requires therapeutic drug monitoring for optimum efficacy; however, the optimal model-informed precision dosing strategy for the area under the concentration-time curve (AUC) of amikacin is uncertain. This simulation study aimed to determine the efficient blood sampling points using the Bayesian forecasting approach for early achievement of the target AUC range for amikacin in critically ill patients. METHODS: We generated a virtual population of 3000 individuals using 2 validated population pharmacokinetic models identified using a systematic literature search. AUC for each blood sampling point was evaluated using the probability of achieving a ratio of estimated/reference AUC at steady state in the 0.8-1.2 range. RESULTS: On day 1, the 1-point samplings for population pharmacokinetic models showed a priori probabilities of 26.3 and 45.6%, which increased to 47.3 and 94.4% at 23 and 15 h, respectively. Using 2-point sampling at the peak (3 and 4 h) and trough (24 h) on day 1, these probabilities further increased to 72.3 and 99.5%, respectively. These probabilities were comparable on days 2 and 3, regardless of 3 and 6 sampling points or estimated glomerular filtration rate. These results indicated the higher predictive accuracy of 2-point sampling than 1-point sampling on day 1 for amikacin AUC estimation. Moreover, 2-point sampling was a more reasonable approach than rich sampling. CONCLUSIONS: This study contributes to the development of an efficient model-informed precision dosing strategy for early targeting of amikacin AUC in critically ill patients.

Optimizing Cefiderocol Dosing Through Population Pharmacokinetic/Pharmacodynamic Simulation: An Assessment of Drug Cost Reductions.

BACKGROUND: Cefiderocol is a siderophore cephalosporin antibiotic with bactericidal activity against carbapenem-resistant Enterobacterales. However, an efficient dosing strategy is yet to be developed. This study aimed to evaluate efficient lower-dose regimens and estimate potential drug cost reductions. METHODS: This simulation study used a virtual population of 10,000 resampled individuals based on a reported population pharmacokinetic model. The target index for maximal bactericidal activity was the time for the unbound cefiderocol concentration to be above the minimum inhibitory concentration (TAM_unbound) of 100%, which was determined using a minimum inhibitory concentration distribution or specific value. RESULTS: The probability of achieving 100% TAM_unbound with the standard, low- (reduced by 1 g or one dose), and extended low- (reduced by 2 g or 2 doses) dose regimens was nearly 100%. The lowest probability of achieving 100% TAM_unbound with the extended low-dose regimen at a creatinine clearance range of 90-120 mL/min was 86.4%. The probability of achieving TAM_unbound of 100% was more than 90% for MIC of ≤0.5 mcg/mL with the extended low-dosing regimen. Furthermore, using an efficient dosing regimen reduced the medical costs over a 10-day treatment period for 10 patients, from $122,826.50 to $62,665.69 $ and ¥12,598,187 $ to ¥5,451,173 in the United States and Japan, respectively. CONCLUSIONSS: A lower dosing regimen for cefiderocol could result in substantial reductions in drug costs while still achieving 100% TAM_unbound.

Population Pharmacokinetic Modeling of Unbound Meropenem in Patients Undergoing Continuous Renal Replacement Therapy: An Observational Cohort Study.

BACKGROUND: The most effective dosing strategy of meropenem for patients undergoing continuous renal replacement therapy (CRRT) remains uncertain. This study aimed to analyze the population pharmacokinetics (popPKs) of unbound meropenem and establish an appropriate dosing approach. METHODS: This prospective study involved 19 patients for the development of a popPK model and an additional 10 for its validation. Ethical approval was obtained. RESULTS: The clearance of unbound meropenem was influenced by the sequential organ failure assessment (SOFA) score [=2.22 × (SOFA score/12)^1.88] and the effluent flow rate from the CRRT device, with an interindividual variability of 44.5%. The volume of distribution was affected by the simplified acute physiology score II [=23.1 × (simplified acute physiology score II/52)^1.54]. Monte Carlo simulations suggested meropenem doses ranging from 1.0 to 3.0 g/d using continuous infusion to achieve a target time above the 4 times of minimum inhibitory concentration of the unbound form (%fT>4×MIC) of 100% for definitive therapy. For empirical therapy, a dose of 1.0 g/d using continuous infusion was recommended to target %fT>MIC of 100%. CONCLUSIONS: This study developed a popPK model for unbound meropenem in patients undergoing CRRT and formulated dosing guidelines. CLINICAL TRIAL REGISTRATION: UMIN000024321.

Dose Individualization of Cefepime for Febrile Neutropenia in Patients With Lymphoma or Multiple Myeloma: Implications for Therapeutic Drug Monitoring.

BACKGROUND: Optimal cefepime dosing is a challenge because of its dose-dependent neurotoxicity. This study aimed to determine individualized cefepime dosing for febrile neutropenia in patients with lymphoma or multiple myeloma. METHODS: This prospective study enrolled 16 patients receiving cefepime at a dose of 2 g every 12 hours. Unbound concentrations were determined at 0.5 hours, 7.2 hours [at the 60% time point of the 12 hours administration interval (C7.2h)], and 11 hours (trough concentration) after the first infusion (rate: 2 g/h). The primary and secondary end points were the predictive performance of the area under the unbound concentration-time curve (AUC unbound ) and the effect of unbound cefepime pharmacokinetic parameters on clinical response, respectively. RESULTS: The mean (SD) AUC unbound was 689.7 (226.6) mcg h/mL, which correlated with C7.2h (R 2 = 0.90), and the Bayesian posterior AUC unbound using only the trough concentration (R 2 = 0.66). Although higher exposure was more likely to show a better clinical response, each parameter did not indicate a statistical significance between positive and negative clinical responses ( P = 0.0907 for creatinine clearance (Ccr), 0.2523 for C7.2h, 0.4079 for trough concentration, and 0.1142 for AUC unbound ). Cutoff values were calculated as 80.2 mL/min for Ccr (sensitivity: 0.889, specificity: 0.714), 18.6 mcg/mL for C7.2h (sensitivity: 0.571, specificity: 1.000), and 9.2 mcg/mL for trough concentration (sensitivity: 0.571, specificity: 1.000). When aiming for a time above 100% the minimum inhibitory concentration, both continuous infusion of 4 g/d and intermittent infusion of 2 g every 8 hours achieved a probability of approximately 100% at a minimum inhibitory concentration of 8 mcg/mL. CONCLUSIONS: Therapeutic drug monitoring by sampling at C7.2h or trough can facilitate rapid dose optimization. Continuous infusion of 4 g/d was recommended. Intermittent dosing of 2 g every 8 hours was alternatively suggested for patients with a Ccr of 60-90 mL/min.

Optimal Teicoplanin Trough Concentration With Therapeutic Drug Monitoring in Children: A Systematic Review and Meta-analysis.

BACKGROUND: Teicoplanin is used to treat serious Gram-positive bacterial infections. However, the optimal trough concentrations for pediatric patients remain unclear owing to the lack of monitoring guidelines. This study aimed to determine the optimal teicoplanin trough concentration for treating Gram-positive bacterial infections in children. METHODS: A systematic review was conducted using 4 databases. Stepwise cutoffs within the range of 10-30 mcg/mL were used for efficacy and safety. Studies were included if they reported treatment success rates and/or all-cause mortality, nephrotoxicity, hepatotoxicity, and thrombocytopenia according to the trough concentration. RESULTS: The meta-analysis included 12 studies involving 830 pediatric patients. Teicoplanin cutoff values of 10, 15, 20, and 30 mcg/mL were reported in 9, 8, 9, and 2 studies, respectively. Trough concentrations <10 mcg/mL significantly reduced the treatment success rate, with an odds ratio of 0.07 and a 95% confidence interval ranging from 0.01 to 0.40. The overall treatment success rate was 50.0% versus 95.7% observed at concentrations ≥10 mcg/mL. However, no significant difference was observed at the 15-, 20-, and 30-mcg/mL cutoffs, when compared with lower concentrations. Trough concentrations <20 mcg/mL were associated with a decreased risk of nephrotoxicity (odds ratio = 0.21; 95% confidence interval, 0.08-0.55). However, hepatotoxicity and thrombocytopenia showed no significant associations with trough concentration ranges between 10 and 30 mcg/mL. CONCLUSIONS: Although further prospective studies are required for validation, the authors' findings suggest that 10- to 20-mcg/mL teicoplanin is the optimal trough concentration for enhanced clinical success and reduced toxicity in pediatric patients.

A cohort study of the risk factors and the target AUC to avoid vancomycin-associated acute kidney injury in pediatric patients.

OBJECTIVES: In recent years, Vancomycin (VCM) dosing design using area under the concentration-time curve (AUC) has been recommended as a measure of efficacy and safety, but there are fewer reports on pediatric patients than on adults. In this study, we evaluated the threshold of AUC for AKI occurrence in pediatric patients and investigated the factors that contribute to the occurrence of AKI. METHODS: Pediatric patients aged 1-15 years on VCM treatment who underwent TDM at Kagoshima University Hospital from April 2016 to March 2022 were included in the computation of AUC using pediatric population pharmacokinetic parameters. RESULTS: The ROC curve showed that the AUC threshold for the risk of developing AKI was 583.0 µg・h/mL, and the AUC-ROC curve was 0.873 (sensitivity 0.930, specificity 0.750). Univariate analysis showed that factors associated with AKI incidence were the duration of VCM administration, ICU admission, and AUCSS. Concomitant medications identified as risk factors for AKI incidence were tazobactam/piperacillin, liposomal amphotericin B, calcineurin inhibitors, contrast agents, and H2-receptor blockers. The multivariate analysis showed that AUC ≧ 583.0 µg・h/mL (odds ratio 20.14, 95% CI 3.52-115.22, p < 0.001) and H2-receptor blockers (odds ratio 8.70, 95% confidence interval = 1.38-54.87, p = 0.02) were independent factors for AKI incidence. CONCLUSIONS: We showed that in pediatric patients receiving VCM, the risk of AKI increases as AUC increases. The findings imply that concurrent use of VCM and H2-receptor blockers may increase the risk of AKI.

Validation and development of population pharmacokinetic model of vancomycin using a real-world database from a nationwide free web application.

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.

Model-Informed Precision Dosing of Vancomycin in Adult Patients Undergoing Hemodialysis.

Model-informed precision dosing (MIPD) maximizes the probability of successful dosing in patients undergoing hemodialysis. In these patients, area under the concentration-time curve (AUC)-guided dosing is recommended for vancomycin. However, this model is yet to be developed. The purpose of this study was to address this issue. The overall mass transfer-area coefficient (KoA) was used for the estimation of vancomycin hemodialysis clearance. A population pharmacokinetic (popPK) model was developed, resulting in a fixed-effect parameter for nonhemodialysis clearance of 0.316 liters/h. This popPK model was externally evaluated, with a resulting mean absolute error of 13.4% and mean prediction error of -0.17%. KoA-predicted hemodialysis clearance was prospectively evaluated for vancomycin (n = 10) and meropenem (n = 10), with a correlation equation being obtained (slope of 1.099, intercept of 1.642; r = 0.927, P < 0.001). An experimental evaluation using an in vitro hemodialysis circuit validated the developed model of KoA-predicted hemodialysis clearance using vancomycin, meropenem, vitamin B6, and inulin in 12 hemodialysis settings. This popPK model indicated a maximum a priori dosing for vancomycin-a loading dose of 30 mg/kg, which achieves the target AUC for 24 h after first dose with a probability of 93.0%, ensured by a predialysis concentration of >15 µg/mL. Maintenance doses of 12 mg/kg after every hemodialysis session could achieve the required exposure, with a probability of 80.6%. In conclusion, this study demonstrated that KoA-predicted hemodialysis clearance may lead to an upgrade from conventional dosing to MIPD for vancomycin in patients undergoing hemodialysis.

Optimal timing for therapeutic drug monitoring of voriconazole to prevent adverse effects in Japanese patients.

BACKGROUND: The optimal timing for therapeutic drug monitoring (TDM) of voriconazole in Asians, who have higher rates of poor metabolisers than non-Asians, is unclear. This can cause unexpectedly high concentrations and delays in reaching steady-state levels. OBJECTIVES: To determine the appropriate timing of TDM in Japanese patients receiving voriconazole. PATIENTS/METHODS: Trough levels (Cmin ) were measured on days 3-5 (recommended timing, RT) and days 6-14 (delayed timing, DT) after starting voriconazole in patients receiving an appropriate dosage. Considering bioavailability, Cmin was only compared in patients receiving oral voriconazole. RESULTS: A total of 289 and 186 patients were included in the safety and pharmacokinetic analyses, respectively. There was a significant difference in Cmin measured no later than and after day 5 (3.59 ± 2.12 [RT] vs. 4.77 ± 3.88 µg/mL [DT], p = .023), whereas no significant difference was observed on cutoff day 6 (3.91 ± 2.60 vs. 4.40 ± 3.94 µg/mL, p = .465), suggesting that Cmin close to the steady-state was achieved after day 5. DT causes a delay in achieving the therapeutic range. The hepatotoxicity rates were 21.5% and 36.8% in the RT and DT groups, respectively (p = .004); DT was an independent risk factor for hepatotoxicity. CONCLUSION: Although steady-state concentrations may not be achieved by day 5, early dose optimisation using RT can prevent hepatotoxicity in Japanese patients. TDM should be performed on days 3-5 to ensure safety. However, subsequent TDM may be necessary due to a possible further increase in Cmin .

Performance of Area under the Concentration-Time Curve Estimations of Vancomycin with Limited Sampling by a Newly Developed Web Application.

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 (AUCPAT) was evaluated against the reference AUC (AUCREF) calculated with the log-linear trapezoidal rule using eight measured concentrations, or against AUC (AUCBM-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 AUCPAT/AUCREF 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 (AUCPAT/AUCREF range 0.73-1.30 for 11 h, AUCPAT/AUCREF range 0.62-1.40 for 23 h). In comparison with the evaluated software, AUCPAT was not biased against the AUCBM-P (slope 1.04, intercept -15.80, median AUCPAT/AUCBM-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.

The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing.

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.

Evaluation of once-daily dosing and target concentrations in therapeutic drug monitoring for arbekacin: A meta-analysis.

INTRODUCTION: Arbekacin is the first aminoglycoside antibacterial agent approved for treating methicillin-resistant Staphylococcus aureus infection in Japan. Although therapeutic drug monitoring (TDM) is recommended during arbekacin treatment, little evidence for the target exposure and once-daily dosing has been reported. This study aimed to clarify the target peak/trough concentrations and the effectiveness of once-daily dosing of arbekacin against nephrotoxicity or treatment failure via meta-analysis. METHODS: A literature search was performed using MEDLINE, Cochrane Library, and Ichushi-Web. RESULTS: Nine observational cohort studies met the inclusion criteria. A peak arbekacin concentration of ≥15-16 µg/mL did not exhibit a statistically significant lower risk of treatment failure (risk ratio [RR] = 0.61, 95% confidence interval [CI] = 0.30-1.24). A trough arbekacin concentration of <2 µg/mL resulted in a significantly lower risk of nephrotoxicity (RR = 0.30, 95% CI = 0.15-0.61). Once-daily dosing significantly reduced the risk of treatment failure (RR = 0.61, 95% CI = 0.39-0.97) but not nephrotoxicity (RR = 0.54, 95% CI = 0.16-1.75). CONCLUSIONS: Once-daily dosing can improve the therapeutic efficacy of arbekacin, and a trough arbekacin concentration of <2 µg/mL can reduce the risk of nephrotoxicity. A peak arbekacin concentration of ≥15-16 µg/mL did not exhibit the significant lower risk of treatment failure. Additional clinical trials are required to confirm these findings.

The optimal trough-guided monitoring of vancomycin in children: Systematic review and meta-analyses.

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.

Development of Vancomycin Dose Individualization Strategy by Bayesian Prediction in Patients Receiving Continuous Renal Replacement Therapy.

PURPOSE: Vancomycin (VCM) concentration is often out of therapeutic range (10-20 µg/ml) in patients receiving continuous renal replacement therapy (CRRT). The purposes of this study were to develop a practical VCM population pharmacokinetic (PPK) model and to evaluate the potential of Bayesian prediction-based therapeutic drug monitoring (Bayes-TDM) in VCM dose individualization for patients receiving CRRT. METHODS: We developed a VCM PPK model using 80 therapeutic concentrations in 17 patients receiving CRRT. Bayes-TDM with the VCM PPK model was evaluated in 23 patients after PPK modeling. RESULTS: We identified the covariates reduced urine output (RUO, <0.5 ml/kg/h) and effluent flow rate of CRRT for the VCM PPK model. The mean VCM non CRRT clearance (CLnonCRRT) was 2.12 l/h. RUO lowered CLnonCRRT to 0.34 l/h. The volume of distribution was 91.3 l/70 kg. The target concentration attainment rate by Bayes-TDM was higher (87.0%) than that by the PPK modeling period (53.8%, P = 0.046). The variance of the second measured concentrations by the Bayes-TDM was lower (11.5, standard deviation: 3.4 µg/ml) than that by the PPK modeling period (50.5, standard deviation: 7.1 µg/ml, P = 0.003). CONCLUSIONS: Bayes-TDM could be a useful tool for VCM dose individualization in patients receiving CRRT.

Augmented teicoplanin clearance through probable adsorption onto a polymethyl methacrylate (PMMA) hemofilter during continuous venovenous hemodiafiltration.

Teicoplanin, a glycopeptide antibiotic against Gram-positive bacteria, is used during continuous venovenous hemodiafiltration (CVVHDF), though adsorption onto a hemofilter has been observed in an in-vitro study. We report a case of extensive augmentation of teicoplanin clearance by a polymethyl methacrylate (PMMA) hemofilter. A 74-year-old man (body weight 53 kg) was performed CVVHDF with the PMMA hemofilter. The effluent flow rate maintained at 600-650 mL/h. The measured teicoplanin clearance was 31.0 mL/min, and the clearance was reduced to 11.1 mL/min over the next 6.5 hours. In conclusion, we should closely monitor teicoplanin dosing during CVVHDF using a PMMA membrane hemofilter.

Clinical evaluation of cefotiam in the treatment of bacteremia caused by Escherichia coli, Klebsiella species, and Proteus mirabilis: A retrospective study.

Bacteremia is often caused by gram-negative bacteria (represented by EKP; Escherichia coli, Klebsiella species, and Proteus mirabilis), and the excessive use of cefazolin, as the first-line antimicrobial in its treatment, has been a source of concern in the emergence of resistant strains. As an antimicrobial, cefotiam may be an alternative to cefazolin; however, little evidence is available for its use in the treatment of bacteremia. The purpose of this non-inferiority study was to retrospectively compare the therapeutic efficacy of cefotiam with some antimicrobials of narrow spectrum (cefazolin, cefmetazole, and flomoxef) in the treatment of EKP-induced bacteremia. The number of patients recruited was 32 in the cefotiam group and 29 in the control group. In the primary endpoint, the survival rate on day 28 for the cefotiam group and the control group was 93.5% and 89.3%, respectively (relative risk at day 28, 1.048; 95% confidence interval, 0.894-1.227). In the secondary end point, treatment success rate in the two groups was 71.9% and 69.0%, respectively (relative risk, 1.042; 95% confidence interval, 0.752-1.445). Intensive care unit admission, low body weight, hypoalbuminemia, and infections unassociated with the urinary tract were identified to be the risk factors responsible for treatment failure. We demonstrated cefotiam may be non-inferior to other antimicrobials of similar spectrum, in terms of survival rate, in EKP-induced bacteremia.

A case of recovery from aphasia following dose reduction of cefepime by bayesian prediction-based therapeutic drug monitoring.

Cefepime is known to exert bactericidal activity against Pseudomonas aeruginosa. Cefepime-induced neurotoxicity, most likely caused by increased exposure, has recently become a major concern in clinical practice; therefore, appropriate dose reduction of cefepime should be applied with respect to patients with low cefepime clearance (mostly eliminated by the kidneys). Here, we report a case in which Bayesian prediction-based therapeutic drug monitoring (Bayes-TDM) was effectively used to reduce the dose of cefepime in a patient with pneumonia to prevent neurotoxic complications. A woman (age: 59 years, body weight: 32.5 kg, serum creatinine concentration: 1.02 mg/dL) developed pneumonia caused by P. aeruginosa while receiving treatment for scleroderma and systemic lupus erythematosus. She started treatment with a dosing regimen of 1.0 g of cefepime every 8 h (day X). On day X+5, aphasia developed, and the serum cefepime concentration was 71.3 mg/L at trough. This concentration was twice or thrice higher than the reported safe concentration of cefepime (22 or 35 mg/L at trough). Therefore, we reduced the dose of cefepime to 0.5 g every 12 h using Bayes-TDM from day X+7. As a result, the severity of aphasia decreased by day X+10, and this dose was successfully continued up to day X+13 without further adjustment. In conclusion, individualizing doses by Bayes-TDM may be useful in preventing adverse effects associated with cefepime treatment.

Development and evaluation of a vancomycin dosing nomogram to achieve the target area under the concentration-time curve. A retrospective study.

Although the superiority of vancomycin dosing based on area under the concentration-time curve (AUC0-24) over that based on trough concentration has been reported, a dosing strategy to achieve the target AUC0-24 has yet to be developed. The objective of this study was to develop a convenient useable nomogram for vancomycin dosing to obtain the target AUC0-24 (400 µg h/mL). The nomogram was pharmacokinetically developed in a retrospective manner. The number of enrolled patients and concentrations was 166 and 309 for development of the nomogram, 99 and 181 for evaluation of the nomogram, respectively. The nomogram was developed as doses per personal body weight corresponding to each range of estimated glomerular filtration rate (eGFR), which was identified to be the covariate for vancomycin clearance by non-linear mixed effect modeling. The nomogram described the surrogate trough concentration for the target AUC0-24 was calculatedly different for each eGFR range (9.3-15.0 µg/mL). The rate of attainment of therapeutic range using surrogate trough concentration to obtain the target AUC0-24 was 63.8% in the evaluation period. We have developed and evaluated the first convenient useable nomogram of vancomycin dosing to obtain the target AUC0-24.

Observational study to determine the optimal dose of daptomycin based on pharmacokinetic/pharmacodynamic analysis.

High doses of daptomycin (DAP) (>6 mg/kg/day) have been preliminarily recommended in recent practical guidelines for methicillin-resistant Staphylococcus aureus infection, to achieve better clinical effects. While such doses can elevate the plasma trough concentration (Cmin) of DAP, there is an associated risk of creatine phosphokinase (CPK) elevation warranting further investigation. In the current study relationships between DAP Cmin and CPK elevation were investigated, and optimal DAP doses were determined. Plasma DAP concentrations were measured in 20 patients. Logistic regression analysis was performed to assess relationships between DAP Cmin and CPK elevation, then a population pharmacokinetic model of DAP was developed. To determine an optimal DAP dose a Monte Carlo simulation (MCS) was performed to minimize the risk of CPK elevation and maximize the probability of successful treatment. In logistic regression analysis DAP Cmin was significantly associated with CPK elevation (odds ratio 1.21, p = 0.048). With respect to dose-dependent increases in the probability of CPK elevation and exposure to DAP, MCS estimated an optimal DAP dose of 4-6 mg/kg/day, corresponding to a minimum inhibitory concentration (MIC) of ≤0.5 µg/mL. For an MIC of 1 µg/mL, MCS estimated an optimal DAP dose of 10 mg/kg/day. However, the probability of CPK elevation associated with high doses of DAP was higher than that associated with the approved doses. In cases where high doses of DAP are administered, close CPK monitoring is required and therapeutic drug monitoring of DAP may be desirable.

Therapeutic drug monitoring based on early measurements of serum teicoplanin levels in Japanese patients.

BACKGROUND: The serum level of teicoplanin (TEIC) is immediately elevated following administration of the recommended dose. In this study, the predictability of the serum trough for TEIC was investigated at day 2 or 3 (C(2-3)), and the authors performed a simulation based on the Bayesian method using C(2-3) in Japanese patients. METHODS: Patients whose the serum trough level was measured within 48 hours (C(2-3)) and at steady state (Css) were eligible for the study. C(2-3) was compared with the predicted level based on the population mean method, and Css was compared with the predicted Css based on both the Bayesian method using C(2-3) and the population mean method. Bias and prediction accuracy were evaluated by the mean prediction error and the mean absolute prediction error (MAE), respectively. RESULTS: The observed and predicted C(2-3) values were 13.2 ± 4.2 µg/mL and 10.4 ± 2.1 µg/mL, respectively. The observed Css was 17.1 ± 3.7 µg/mL, and the predicted Css values based on the Bayesian method and the population mean method were 16.8 ± 2.4 µg/mL and 15.3 ± 2.1 µg/mL, respectively. The mean prediction error and MAE for Css based on the population mean method were -1.87 µg/mL (not significant) and 3.45 µg/mL, respectively, and those based on the Bayesian method were -0.35 µg/mL (not significant) and 2.27 µg/mL, respectively. The change in MAE was 1.18 µg/mL (P < 0.05). CONCLUSIONS: A simulation based on the Bayesian method using C(2-3) of TEIC is acceptable in clinical settings.