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.

Population Pharmacokinetics and AUC-Guided Dosing of Tobramycin in the Treatment of Infections Caused by Glucose-Nonfermenting Gram-Negative Bacteria.

PURPOSE: Tobramycin (TOB) exhibits variable pharmacokinetic properties due to the clinical condition of patients. This study aimed to investigate the AUC-guided dosing of TOB based on population pharmacokinetic analysis in the treatment of infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. METHODS: This retrospective study was conducted between January 2010 and December 2020 after obtaining approval from our institutional review board. For 53 patients who received therapeutic drug monitoring of TOB, a population pharmacokinetic model was developed with covariates of estimated glomerular filtration rate using serum creatinine (eGFRcre) on clearance (CL) and weight on both CL and Vd in exponential error modeling (CL = 2.84 × [weight/70] × eGFRcre0.568, interindividual variability [IIV] = 31.1%; Vd = 26.3 × [weight/70], IIV = 20.2%; residual variability = 28.8%). FINDINGS: The final regression model for predicting 30-day mortality was developed with risk factors of AUC during a 24-hour period after the first dose to MIC ratio (odds ratio [OR] = 0.996; 95% CI, 0.968-1.003) and serum albumin (OR = 0.137; 95% CI, 0.022-0.632). The final regression model for predicting acute kidney injury was developed with the risk factors of C-reactive protein (OR = 1.136; 95% CI, 1.040-1.266) and AUC during a 72-hour period after the first dose (OR = 1.004; 95% CI, 1.000-1.001). A dose of 8 or 15 mg/kg was beneficial for achievement of AUC during a 24-hour period after the first dose/MIC >80 and trough concentration <1 µg/mL in patients with preserved kidney function and TOB CL >4.47 L/h/70 kg in the events of MIC of 1 or 2 µg/mL, respectively. We propose that the first dose of 15, 11, 10, 8, and 7 mg/kg for eGFRcre >90, 60 to 89, 45 to 59, 30 to 44, and 15 to 29 mL/min/1.73 m2 be followed by therapeutic drug monitoring at peak and 24 hours after the first dose. IMPLICATIONS: This study suggests that TOB use encourages the replacement of trough- and peak-targeted dosing with AUC-guided dosing.

Lowered Risk of Nephrotoxicity through Intervention against the Combined Use of Vancomycin and Tazobactam/Piperacillin: A Retrospective Cohort Study.

The combined use of vancomycin (VCM) and tazobactam/piperacillin (TAZ/PIPC) is a major risk factor for nephrotoxicity. We sought to evaluate interventions against the combined use of VCM and TAZ/PIPC. This retrospective cohort study involved patients who considered the combined use of VCM and TAZ/PIPC as a treatment. Patients that had either or both antimicrobials replaced were assigned to the intervention group, whereas those who were continued on combination therapy were assigned to the comparison group. The primary endpoint was the incidence of acute kidney injury (AKI). The survival rate of patients on day 30 was evaluated as the secondary endpoint. The comparison and intervention groups were composed of 65 and 68 patients, respectively, and the incidence rates of AKI were 44.6% and 17.6%, respectively. Cox proportional hazard analysis identified the intervention as the only independent factor against AKI development, with a hazard ratio of 0.282 (95% confidence interval [CI], 0.141 to 0.565). For the incidence of AKI of grade greater than 1, the hazard ratio was 0.114 (95% CI, 0.025 to 0.497). The survival rates on day 30 in the comparison and intervention groups were 92.3% and 91.2%, respectively, with a relative risk of 0.988 (95% CI, 0.892 to 1.094). The trough VCM concentration was not associated with the incidence of AKI in patients receiving the combination therapy. This study demonstrated that intervention against the combined use of VCM and TAZ/PIPC can lower the risk of nephrotoxicity. IMPORTANCE The combined use of vancomycin (VCM) and tazobactam/piperacillin (TAZ/PIPC) is a major risk factor for nephrotoxicity. We retrospectively evaluated interventions against the combined use of VCM and TAZ/PIPC. Patients for whom either or both antimicrobials were replaced were assigned to the intervention group (65 patients), whereas those who were continued on combination therapy were assigned to the comparison group (68 patients). The primary endpoint was the incidence of acute kidney injury (AKI). The incidence rates of AKI in the intervention and comparison groups were 44.6% and 17.6%, respectively. Cox proportional hazard analysis identified intervention as the only independent factor against AKI development, with a hazard ratio of 0.282 (95% confidence interval [CI], 0.141 to 0.565). In conclusion, this study demonstrated that intervention against the combined use of VCM and TAZ/PIPC can lower the risk of nephrotoxicity.

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.

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.

Continuous high-dose infusion of doripenem in a pneumonia patient infected by carbapenem-resistant Pseudomonas aeruginosa: a case report.

BACKGROUND: Despite the high mortality of patients with sepsis and carbapenem-resistant bacteria infection, appropriate antimicrobial therapies are yet to be established. Here, we have reported the case of a patient with pneumonia that subsequently developed by carbapenem-resistant Pseudomonas aeruginosa infection and was treated with a continuous high-dose infusion of doripenem. CASE PRESENTATION: We started a continuous intravenous infusion of doripenem 3 g/day although the 59-year-old woman (body weight, 45 kg) had developed septic acute kidney injury, followed by continuous renal replacement therapy (the effluent flow rate was 650 mL/h). The minimum inhibitory concentration (MIC) of doripenem was 8 mg/L. The concentration of unbound doripenem in the serum was measured by using high-performance liquid chromatography. Twenty hours after the initial dose, the patient's serum level of doripenem was 47.8 µg/mL; the level decreased to 33.6 µg/mL at 111 h after initial dosing. The unbound doripenem concentration in the serum was maintained four times above the MIC throughout the treatment. After the completion of 11 days of dosing, the patient was discharged from the intensive care unit. During the treatment period, the MIC remained at 8 mg/L. CONCLUSIONS: A continuous high-dose infusion of doripenem is a potentially efficient strategy for the treatment of antimicrobial-resistant bacteria. Moreover, therapeutic drug monitoring may be useful for patients displaying variable pharmacokinetics, because the MIC is generally high in resistant bacteria.

Raltegravir blocks the infectivity of red-fluorescent-protein (mCherry)-labeled HIV-1JR-FL in the setting of post-exposure prophylaxis in NOD/SCID/Jak3-/- mice transplanted with human PBMCs.

Employing NOD/SCID/Jak3-/- mice transplanted with human PBMCs (hNOJ mice) and replication-competent, red-fluorescent-protein (mCherry; mC)-labeled HIV-1JR-FL (HIVmC), we examined whether early antiretroviral treatment blocked the establishment of HIV-1 infection. The use of hNOJ mice and HIVmC enabled us to visually locate infection foci and to examine the early dynamics of HIVmC infection without using a large amount of antiretroviral unlike in non-human primate models. Although when raltegravir (RAL) administration was begun 1 day after intraperitoneal (ip) inoculation of HIVmC, no plasma p24 or plasma HIV-1-RNA (pRNA) were detected in 10 of 12 hNOJ (hNOJmCRAL+) mice as assessed on the last day of the 14-day continuous twice-daily RAL administration, all 10 untreated hNOJmC (hNOJmCRAL-) mice became positive for p24 and pRNA and had significantly swollen lymph nodes in peritoneal cavity and abundant p24+/mC+/CD3+/CD4+ T cells and p24+/mC+/CD68+ monocytes/macrophages were identified in their omenta and mesenteric lymphoid tissues/lymph nodes upon necropsy of the mice on day 14. In 12 hNOJmCRAL+ mice, no significantly swollen lymph nodes were seen compared to hNOJmCRAL- mice; however, in the omentum of the 2 hNOJmCRAL+ mice that were positive for pRNA and in site RNA, mC+/p24+/CD3+/CD83+ cells were identified, suggesting that viral breakthrough occurred later in the observation period. The present data suggest that the use of hNOJ mouse model and HIVmC may shed light on the study of early-phase dynamics of HIV-1 infection and cellular events in post-exposure/pre-exposure prophylaxis.

Role of P-glycoprotein in the efflux of raltegravir from human intestinal cells and CD4+ T-cells as an interaction target for anti-HIV agents.

Cellular efflux and uptake transports of several anti-HIV agents are mediated by plasma membrane-localized solute transporters. However, transporters involved in raltegravir disposition have not been fully characterized. Here, we performed in vitro studies to identify transporters mediating transcellular transport of raltegravir. Transepithelial raltegravir transport was examined using porcine kidney epithelial cell line (LLC-PK1) and LLC-PK1 cells stably transfected with P-glycoprotein (also known as Multiple drug resistance 1) (L-MDR1). Transepithelial transport of raltegravir in Caco-2 cell monolayers, and intracellular accumulation of raltegravir in the MT-2 and MT-4 (CD4+ T-) cells were measured in the presence or absence of anti-HIV agents. The uptake of raltegravir was investigated in HEK-293 cells expressing each of several solute carrier family transporters. The apical-to-basal raltegravir transport was significantly decreased in L-MDR1 as compared to that in LLC-PK1 monolayers. In HEK-293 cells expressing breast cancer resistance protein (BCRP), raltegravir accumulation was lower than that in the mock-transfected cells. In Caco-2 cells, protease inhibitors including nelfinavir, ritonavir and lopinavir enhanced the apical-to-basal transport of raltegravir. By contrast, reverse transcriptase inhibitors such as zidovudine, efavirenz, and nevirapine, had no effect on raltegravir transport. The cellular accumulation of raltegravir in MT-2 cells, which express P-glycoprotein, was significantly increased in the presence of protease inhibitors. By contrast, protease inhibitors only marginally increased the accumulation of raltegravir in MT-4 cells, in which P-glycoprotein is not expressed. The present findings suggest that raltegravir is a substrate of both P-glycoprotein and BCRP. Protease inhibitors increase the absorptive transport of raltegravir in Caco-2 cells, and the cellular accumulation in T-cells, at least in part, by P-glycoprotein-mediated interaction.