Published papers

Aim: Evidence supporting area under the concentration–time curve (AUC)–guided vancomycin dosing in overweight and obese patients remains limited. This multicentre retrospective study aimed to identify pragmatic loading dose (LD) and maintenance dose (MD) ranges associated with target AUC attainment in this population. Methods: Patients aged ≥15 years with a body mass index (BMI) ≥ 25 kg/m2 who received vancomycin for ≥3 days and had ≥2 trough concentration measurements were included from four Japanese hospitals (2012–2025). AUC0–24 and steady-state AUC24 (AUCss) were estimated using Bayesian software. Multivariate logistic regression analyses identified factors associated with achieving target AUCs (AUC0–24: 400–500 μg·h/mL; AUCss: 400–600 μg·h/mL). Results: Among 209 patients (median BMI 27.2 kg/m2), LD was independently associated with attainment of target AUC0–24 (OR 1.08, 95% CI 1.02–1.15). An LD of approximately 20 mg/kg was associated with early target exposure. For maintenance therapy, estimated glomerular filtration rate (eGFR) and MD were independently associated with AUCss attainment (OR 0.979, 95% CI 0.964–0.995, p = 0.008; OR 1.050, 95% CI 1.010–1.090, p = 0.018, respectively). Pragmatic interim MD ranges were approximately 9.2, 16.2 and 26.3 mg/kg/day for patients with eGFR<30, 30–60 and >60 mL/min/1.73 m2, respectively. Conclusion: In this multicentre real-world cohort of overweight/obese adults, an LD around 20 mg/kg (ceiling 2 g) was associated with early AUC0–24 target attainment. MD and renal function were independent predictors of AUCss, informing interim renal-stratified MD ranges until TDM results become available. Early TDM remains essential given significant inter-individual variability.

Antimicrobial efficacy in pneumonia is strongly influenced by site-specific drug exposure; however, pharmacokinetic/pharmacodynamic (PK/PD) indices based on plasma concentrations may not adequately reflect drug exposure at the pulmonary infection site. This study evaluated how differences in pulmonary distribution influence the magnitude and interpretation of PK/PD targets by comparing three fluoroquinolones with distinct epithelial lining fluid (ELF) penetration profiles. Using a murine Streptococcus pneumoniae lung infection model, levofloxacin (LVFX), garenoxacin (GRNX), and lascufloxacin (LSFX) were evaluated under identical experimental conditions. Minimum-inhibitory concentrations (MICs) were determined by broth microdilution. Pharmacokinetics were assessed in plasma and ELF, and pharmacodynamics were quantified as changes in pulmonary bacterial burden. PK/PD relationships and exposure targets were estimated based on plasma- and ELF-derived indices. The MICs of LVFX, GRNX, and LSFX were 0.512, 0.032, and 0.032 mg/L, respectively. In plasma-based PK/PD analyses, GRNX and LSFX exhibited bactericidal effects at lower fAUC/MIC values than LVFX. In contrast, ELF-based analyses revealed greater interdrug differences in PK/PD targets attributable to differences in ELF penetration. Notably, LSFX showed substantial divergence between plasma- and ELF-based PK/PD targets, indicating a strong influence of site-specific exposure on antibacterial efficacy. When ELF-based PK/PD targets were translated to predicted human plasma exposure, the resulting values were generally consistent with reported clinical PK/PD benchmarks. Site-specific PK/PD analysis incorporating pulmonary drug distribution is important for interpreting antimicrobial efficacy in pneumonia. For agents with high ELF penetration, ELF-based PK/PD targets may provide a more relevant framework for understanding antibacterial effects and optimizing dosing strategies.

Objective: Two-point sampling (peak and trough concentrations) is considered the most accurate method for estimating the area under the concentration–time curve (AUC) of vancomycin (VCM). However, one-point sampling (trough concentration alone) can reduce the burden of therapeutic drug monitoring (TDM). Although the agreement between one-point and two-point AUC estimates during follow-up TDM has been evaluated using the Oda model, its applicability to the Yasuhara model remains unclear. Therefore, this study evaluated this agreement using the Yasuhara model. Methods: This multicenter, retrospective, observational study included patients from nine institutions who received VCM between September 2020 and December 2023 and underwent two-point sampling during both initial and follow-up TDM. The AUC values were estimated using the Yasuhara model. Factors associated with an AUC discrepancy of ≥10% were evaluated using univariate and multivariable analyses. In addition, patients with AUC discrepancies were descriptively characterized. Results: Among 256 patients, the one-point and two-point AUC estimates were strongly correlated (r = 0.982, p < 0.001), and eight patients (3.1%) exhibited an AUC discrepancy. Age ≤60 years (p = 0.050) and BMI ≥25 kg/m2 (p = 0.049) were associated with an AUC discrepancy in the univariate analysis but not in multivariable analysis. Patients with an AUC discrepancy commonly had hypoalbuminemia, heart failure, or ICU admission. Conclusions: During follow-up TDM using the Yasuhara model, one-point AUC estimates differed by <10% from two-point sampling in 96.9% of patients. When an appropriate regimen is established based on initial TDM, one-point sampling may provide AUC estimates in agreement with two-point sampling.

Background: Enterococcus faecalis infective endocarditis (EFIE) remains a formidable infection requiring prolonged antimicrobial therapy. Although β-lactam/aminoglycoside (BL + AG) combination therapy has long been regarded as the standard treatment, AG-associated toxicities pose a major clinical dilemma. Recently, dual β-lactam therapy with ampicillin/ceftriaxone (A + C) has become an established treatment option. This systematic review and meta-analysis aimed to compare the efficacy and safety of A + C versus BL + AG therapy in patients with EFIE. Methods: A literature search was conducted using PubMed, the Cochrane Library, Web of Science, and ClinicalTrials.gov. Clinical studies comparing A + C versus BL + AG for EFIE were included. Primary outcomes were mortality and relapse rates. Secondary outcomes included overall adverse events, renal adverse events, ototoxicity/vestibular toxicity, skin rash, Clostridioides difficile diarrhea, and regimen changes or discontinuation. Pooled ORs and 95% CIs were estimated utilizing random-effects models. Results: Six studies involving 619 patients with EFIE were included. Cumulative mortality (OR 1.10, 95% CI: 0.73–1.65) and relapse rates (OR 1.08, 95% CI: 0.39–3.01) did not differ significantly between A + C and BL + AG. However, A + C was associated with significantly lower incidences of total adverse events (OR 0.20, 95% CI: 0.08–0.53), renal adverse events (OR 0.34, 95% CI: 0.19–0.58), ototoxicity/vestibular toxicity (OR 0.07, 95% CI: 0.01–0.37), and antibiotic regimen change (OR 0.20, 95% CI: 0.10–0.39) or discontinuation (OR 0.17, 95% CI: 0.05–0.56). Conclusion: A + C therapy was associated with a more favorable safety profile than BL + AG therapy, with no significant differences in efficacy, mortality, or relapse in patients with EFIE. These findings support the use of A + C as an important therapeutic option for patients at increased risk of AG-associated toxicity.

In addition to the 23-valent pneumococcal polysaccharide vaccine (PPSV23), the 13-valent and 15-valent pneumococcal conjugate vaccines (PCV13 and PCV15, respectively) are currently utilized as optional vaccines for adults. Although PCV15 provides broader serotype coverage than PCV13, comparative evidence regarding their immunogenicity, safety, and optimal clinical application remains limited. This systematic review and meta-analysis evaluated the immunogenicity and safety of PCV13 and PCV15, both as monotherapy and in combination with PPSV23. We conducted a comprehensive systematic search of PubMed, the Cochrane Library, Web of Science, and ClinicalTrials.gov for randomized controlled trials (RCTs) published through September 15, 2023. Eligible studies included those comparing PCV13 and PCV15, as well as their respective sequential schedules with PPSV23, in adults. Outcomes included opsonophagocytic activity geometric mean titer ratios (OPA GMTRs), immunoglobulin G geometric mean concentration ratios (IgG GMCRs), and adverse event incidence. Risk ratios and 95% confidence intervals were calculated using the inverse variance–weighted method and DerSimonian–Laird random-effects model. Six RCTs (n = 6460) comparing PCV13 and PCV15 monotherapy demonstrated significantly higher OPA GMTRs and IgG GMCRs for the six shared serotypes in the PCV15 group. Injection-site pain and myalgia were more common with PCV15, whereas other adverse events showed no differences. Three RCTs (n = 2279) comparing PPSV23/PCV13 with PPSV23/PCV15 demonstrated higher immune responses for several serotypes in the PPSV23/PCV15 group, with comparable safety profiles. Overall, PCV15 provides broader serotype coverage and elicits robust immunogenicity while maintaining a safety profile comparable to that of PCV13, whether administered as monotherapy or in sequential vaccination with PPSV23.

Practical Antimicrobial Therapeutic Drug Monitoring (PAT) for vancomycin using Bayesian estimation is recommended for calculating the area under the concentration–time curve (AUC). In 2025, PAT was updated from version 3 to version 4, but differences in AUC estimations between these versions have not been examined. This study aimed to compare AUC estimations from both versions in the same patients.We conducted a multicenter, retrospective, observational study involving adult patients who received vancomycin treatment between September 2020 and December 2023, who underwent two-point sampling for initial TDM. AUC was calculated using both versions in three phases: 0–24 h (AUC0–24), 24–48 h (AUC24–48), and at steady state (AUCss).The sample included 894 cases. AUC values from versions 3 and 4 showed a high correlation (r = 0.947–0.964), but phase-related differences emerged. Version 4 yielded significantly lower AUC0–24 and AUC24–48 values (median: 420.7 μg h/mL vs 373.5 μg h/mL, p < 0.001; 398.9 μg h/mL vs 379.8 μg h/mL, p < 0.001), while AUCss was significantly higher in version 4 (448.4 μg h/mL vs 498.2 μg h/mL, p < 0.001).Since differences in population pharmacokinetic models can affect estimation results, clinicians should be aware that AUC estimations may vary depending on the PAT version used, and the results should be interpreted with caution.

The 23-valent pneumococcal polysaccharide (PPSV23) and 13-valent pneumococcal conjugate (PCV13) vaccines are available for the prevention of infections caused by Streptococcus pneumoniae. This systematic review and meta-analysis evaluated the immunogenicity and safety of PPSV23 and PCV13 co-vaccination (PCV13/PPSV23) compared with PPSV23 monotherapy in adult populations. PubMed, Cochrane Library, Web of Science, and ClinicalTrials.gov were systematically searched for randomized controlled trials (RCTs) comparing PCV13/PPSV23 co-vaccination with PPSV23 monotherapy published until September 15, 2023. Immunogenicity was assessed using the geometric mean titer ratio (GMTR) of opsonophagocytic activity (OPA), which reflects bactericidal activity against each serotype. The safety outcomes included local and systemic adverse events. The risk ratios and 95% confidence intervals were calculated using the inverse variance-weighted method. The meta-analysis included 4 RCTs involving 2739 participants. The OPA GMTRs for 11 of the 13 evaluated serotypes were significantly higher in the PCV13/PPSV23 group than those in the PPSV23 group. The safety analysis showed no statistically significant differences in the incidence of adverse events between the 2 groups across all assessed outcomes. PCV13/PPSV23 showed significantly higher immunogenicity against the pneumococcal serotypes and maintained a safety profile comparable to that of PPSV23. These results support the potential utility of PCV13/PPSV23 as an effective strategy for preventing pneumococcal diseases in older adults.

Objectives To clarify the relationship between acute kidney injury (AKI) and vancomycin use in patients with renal impairment and to establish a risk score for AKI. Methods In this retrospective, multicentre, observational cohort study, trough and peak blood samples were collected from patients who initiated vancomycin therapy. The cumulative incidence of AKI within 14 days was compared among three groups classified according to renal function (estimated glomerular filtration rate ≥ 60, 30-59 and <30 mL/min/1.73 m2). The risk score and predicted probability of AKI incidence were calculated. AKI was defined in accordance with the Kidney Disease Improving Global Outcomes criteria. Results The incidence of AKI was 11.7% (99/847). No statistically significant difference was detected in the cumulative incidence of AKI among the three groups (P = 0.103). Cox proportional hazard analysis showed that the use of tazobactam/piperacillin [HR: 3.3, 95% CI (2.18-4.99), 2 points], vasopressors/inotropes [HR: 3.0, 95% CI (2.02-4.51), 2 points] and area under the concentration-time curve (AUC) on Day 2 [500-600 µg·h/mL: HR, 2.4, 95% CI (1.50-3.89), 1 point; >600 µg·h/mL: HR, 4.4, 95% CI (2.62-7.37), 3 points] were significantly related to the development of AKI. The predicted probabilities of AKI incidence were <5% (low-risk), 5% to <20% (moderate-risk), 20% to <40% (high-risk) and 40% to 67% (very high-risk), with total points of 0, 1-2, 3-4 and ≥5, respectively. Conclusions A risk prediction model was developed for AKI based on AUC exposure and concomitant medications, and no difference in AKI risk was observed across renal function categories.

Introduction: Nacubactam is a novel β-lactamase inhibitor with intrinsic antibacterial activity that shows therapeutic potential against carbapenemase-producing Enterobacterales when administered with β-lactam antibiotics. Pharmacokinetics/pharmacodynamics (PK/PD) analyses based on drug concentrations at the site of infection are recommended to better evaluate antibiotic efficacy. A new PD index, the instantaneous minimum inhibitory concentration (MICi), which dynamically reflects the changing susceptibility of β-lactams during co-administration with β-lactamase inhibitors, has recently been proposed. This study aimed to assess the efficacy of cefepime combined with nacubactam in a murine model of pneumonia using MICi-based PK/PD analysis in the lung epithelial lining fluid (ELF). Methods: In vitro pharmacodynamic testing using the checkerboard method was conducted with two β-lactamase-producing Klebsiella pneumoniae strains. In vivo PK and PD studies were performed in neutropenic mice using both β-lactamase-producing and non-producing strains. Drug concentrations in plasma and ELF were measured, and MICi-based PK/PD analysis was conducted. Results: In vitro, the MIC of cefepime decreased in a concentration-dependent manner with increasing nacubactam. In the murine model of pneumonia, cefepime monotherapy resulted in bacterial changes of 0.12–4.30 log10 CFU/lung, while the combination therapy reduced bacterial counts by −5.93 to −0.234 log10 CFU/lung. The percentage of time that free cefepime concentrations exceeded MICi (T > MICi) was highly correlated with bacterial reduction. The target T > MICi for maximal effect was estimated to be 29.3 %. Conclusions: These findings support the utility of MICi-based PK/PD analysis for optimizing combination antibiotic therapy in pneumonia.

Background: Nacubactam (NAC), a new diazabicyclooctane β-lactamase inhibitor, is being developed for use together with aztreonam (AZT) and cefepime (CFPM). However, the effective clinical dosages of AZT/NAC and CFPM/NAC have not yet been established. We have previously shown that free time above instantaneous MIC (fT > MICi) is a valuable pharmacokinetic (PK)/pharmacodynamic parameter for β-lactam (BL)/NAC in a mouse thigh infection model. Objectives: This study simulated the fT > MICi (%) for AZT/NAC and CFPM/NAC against carbapenemase-producing Enterobacterales (CPE) with different MIC in humans to estimate the clinical efficacy at practically achievable combination doses of AZT/NAC and CFPM/NAC. Methods: Using previously reported PK parameters of each drug in humans and chequerboard MIC data, we calculated the fT > MICi (%) for AZT/NAC and CFPM/NAC in 10 000 simulated patients to predict the percentages of target attainment of bacteriostatic and bactericidal efficacies at various combined doses. Results: The results predicted that both BL/NAC combinations could achieve 100% 2 log10-kill against CPE strains at the lowest combination dose (0.5 g/0.5 g q8h). Additionally, in MIC studies examining BLs/NAC at a 1:1 ratio, the dosage regimen for strains with MICcomb ≤ 1 mg/L was expected to offer 100% bactericidal efficacy (2 log10-kill) at 0.5 g/0.5 g q8h or higher doses. For strains with 1 mg/L < MICcomb ≤ 16 mg/L, BLs/NAC at a 2 g/2 g q8h was predicted to produce bactericidal efficacy (1 log10-kill). At MICcomb = 32 mg/L, some bacteriostatic effect was expected at high BL doses. Conclusions: AZT/NAC and CFPM/NAC are bactericidal against CPE at practically achievable dosages.

Purpose: Cefditoren, the active form of cefditoren pivoxil, is an oral cephalosporin antimicrobial drug. Although cefditoren exhibits high antimicrobial activity against Streptococcus pneumoniae, its pharmacokinetics/pharmacodynamics (PK/PD) characteristics remain unknown. This study aimed to determine its PK/PD parameter with target values for cefditoren against S. pneumoniae in S. pneumoniae lung-infected mice and to simulate MIC range of S. pneumoniae that can be expected to be treated at approved cefditoren doses in human using population pharmacokinetic (PPK) data from patients. Methods: Susceptibility testing and time-kill assays against S. pneumoniae ATCC® 49619 were performed for in vitro PD evaluation. Based on the results of a PK study in healthy mice and PD studies in S. pneumoniae lung-infected mice, optimal PK/PD parameters were determined using the correlation curve between the PK/PD parameters and lung bacterial count changes. The target value was calculated to achieve a 2 log10 reduction in the lung bacterial counts. Results: In vitro PD evaluation showed that cefditoren had a potent antimicrobial effect against S. pneumoniae in a time-dependent manner at concentrations above the MIC. In PK/PD analyses, both fAUC24/MIC and fCmax/MIC were well correlated with bactericidal efficacy, achieving 2 log10-kill with fAUC24/MIC ≥ 63 and fCmax/MIC ≥ 16. Conclusions: Cefditoren pivoxil has good therapeutic efficacy against acute pneumonia caused by S. pneumoniae with a MIC ≤ 0.031–0.063 mg/L at approved doses in adults and children.

Purpose: Cefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC. Methods: The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice. Results: The minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0 µg/mL, respectively. Time–kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4–64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively. Conclusion: CMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve “fT>MIC” ≥ 69.6% for the treatment of ESBL-EC infections.

Background: Population pharmacokinetic (PPK) models of vancomycin (VCM) commonly use creatinine clearance (CLcr) as a covariate for clearance (CL). However, relying on CLcr in patients of advanced age may lead to inaccuracies in estimating VCM clearance. Therefore, this study aimed to develop and validate a new PPK model specifically for patients aged 75 years and older. Methods: PPK analysis was performed based on the blood concentrations of VCM (n = 159 patients). The predictive performance of the developed model was compared with that of previous models using mean absolute error (MAE) and mean squared error (MSE) for another dataset. Results: The PPK analysis optimized a two-compartment model using CLcr and the Alb levels as covariates at the central compartment of VCM clearance. The final model was as follows: CL (L/h) = 1.96 × (CLcr/3.09) 0.63 × (Serum albumin (Alb) /2.3) 0.22 × exponential (0.11). Clearance between the central and peripheral compartments (L/h) = 4.86. Central compartment volume of distribution (L) = 31.78. Peripheral compartment volume of distribution (L) = 53.64. The validation study revealed that compared with those of previous models (ranging from 0.67 to 0.79 L/h and from 0.81 to 1.11 (L/h)2, respectively), the final model demonstrated the smallest MAE of 0.60 L/h and MSE of 0.65 (L/h)2 for patients of advanced age with serum creatinine levels of < 0.6 mg/dL. Conclusion: The PPK model of VCM for patients of advanced age was optimized by adding the Alb levels and CLcr as covariates for CL. The predictive accuracy of the PPK model for patients with an SCr of < 0.6 mg/dL tended to be higher than those of previous models based just on CLcr. Thus, dosage is suggested to be adjusted based on CLcr and Alb levels for patients with an SCr of < 0.6 mg/dL.

Background: Nacubactam, a new β-lactamase inhibitor with antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. However, determining pharmacokinetics/pharmacodynamics (PK/PD) parameters in β-lactam/β-lactamase inhibitor combinations remains challenging. We aimed to establish a practical PK/PD analysis method for aztreonam/nacubactam that incorporates instantaneous MIC (MICi). Methods: Based on chequerboard MIC measurements, MICi of aztreonam against carbapenemase-producing Klebsiella pneumoniae in the presence of nacubactam was simulated. Results: The mean change in the bacterial count of thigh-infected mice in an in vivo PD study was plotted based on %fT>MICi and analysed using the inhibitory effect sigmoid Imax model. fT>MICi calculated from the PK experiments showed a high correlation with the in vivo bactericidal effect, suggesting that fT>MICi is the optimal PK/PD parameter for aztreonam/nacubactam. The target values of fT>MICi achieving growth inhibition, 1 log10 kill and 2 log10 kill, were 22, 38% and 75%, respectively. Conclusions: The PK/PD analysis method proposed in this study is promising for determining practical PK/PD parameters in combination therapy. In addition, this is the first report of aztreonam/nacubactam showing a potent in vivo therapeutic effect against NDM-producing K. pneumoniae.

Purpose: Vancomycin-resistant enterococci (VRE) have recently become a major cause of nosocomial infections and a global public health concern. Tedizolid exhibits powerful antibacterial activity against VRE in vitro, but its pharmacokinetic/pharmacodynamic (PK/PD) parameters remain unclear. Therefore, we aimed to determine the PK/PD indices of tedizolid action on VRE and the mechanisms underlying the PK/PD indices differences of tedizolid against VRE and methicillin-resistant Staphylococcus aureus (MRSA). Methods: Optimal PK/PD target values of tedizolid were determined in vitro, based on time-kill curves and post-antibiotic effects (PAEs), and in vivo, using mouse models of thigh infection with VRE and MRSA strains. Results: The tedizolid bactericidal activity on VRE and MRSA was time-dependent. Correlations were closest between fAUC24/MIC and the tedizolid PK/PD index against MRSA and VRE. To achieve 1 log10 kill tedizolid fAUC24/MIC in neutropenic mouse models of thigh infection with VRE and MRSA should be 14.2 and 138.5, respectively. The PAEs of tedizolid against VRE and MRSA were 2.39 and 0.99 h, respectively. Conclusion: Tedizolid showed bactericidal effects against VRE even in neutropenic mice unlike MRSA, which could be attributed to its longer PAE against VRE. Hence, we hypothesize that tedizolid treatment against VRE infections is promising for achieving therapeutic success in clinical.

Purpose: Nacubactam (NAC) is a novel diazabicyclooctane β-lactamase inhibitor used in combination with cefepime (CFPM). In this study, we aimed to determine the target pharmacokinetics (PK) and pharmacodynamics (PD) values of CFPM/NAC in mice infected with β-lactamase-producing Enterobacterales, such as the carbapenemase-producing Enterobacterales. Methods: Three strains of β-lactamase-producing Enterobacterales, Klebsiella pneumoniae MSC 21444, Escherichia coli MSC 20662, and K. pneumoniae ATCC BAA-1898, were used for checkerboard assays and fractionation studies and dose-range studies. A PK study was performed in neutropenic mice. Additionally, PK/PD analysis was performed based on the instantaneous minimum inhibitory concentration (MICi) concept. Results: Checkerboard measurements revealed that higher NAC concentrations decreased the CFPM MIC in a concentration-dependent manner. In all tested strains, fT > MICi calculated from the PK experiments showed a high correlation with the mean change in the bacterial count of thigh-infected mice in the in vivo PD study, suggesting that fT > MICi is an optimal PK/PD parameter for monitoring the CFPM/NAC combination. The target fT > MICi values for CFPM/NAC to achieve a bacteriostatic effect, 1-log10-kill, and 2-log10-kill values were 30, 49, and 94%, respectively. Conclusions: Our results indicate that fT > MICi is a PK/PD parameter is suitable for monitoring the CFPM/NAC combination. The minimum target value for achieving a static effect against β-lactamase-producing Enterobacterales is 30%.

Purpose: Although flomoxef (FMOX) has attracted substantial attention as an antibiotic against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-producing E. coli), the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of FMOX against ESBL-producing E. coli is unclear. The aim of this study was to determine the PK/PD index of FMOX against ESBL-producing E. coli. Methods: In vitro time-kill curve studies and in vivo PK/PD experiments were carried out. Results: Time–kill curves exhibited a unique bactericidal activity: time-dependent activity at low concentrations and concentration-dependent activity at high concentrations. In neutropenic murine thigh infection experiments, the antibacterial activity of FMOX correlated with the time that the free drug concentration remaining above the minimum inhibitory concentration (MIC) (fT>MIC) and the ratio of the area under the free drug concentration–time curve for a 24 h period to the MIC (fAUC24/MIC). However, the burden of ESBL producing E. coli significantly reduced when the time intervals for administration were shorter among three dosage regimens with same magnitude of fAUC24/MIC, indicating that fT>MIC is significant PK/PD index. The target value of fT>MIC for 1 log10 kill reduction was 35.1%. Conclusions: fT>MIC is the most significant PK/PD index of FMOX against ESBL-producing E. coli and its target value is ≥ 40%.

During therapeutic drug monitoring (TDM) for vancomycin (VCM), the area under the concentration-time curve (AUC) is important for balancing efficacy versus toxicity. In a previous study, we developed a decision tree (DT) model to achieve the target AUC during TDM over the follow-up period (AUCfollow-up). This study aimed to validate the DT model for achieving the target AUCfollow-up. Patients who received VCM for at least 72 h and had an initial TDM within four doses between January 2023 and December 2023 were analyzed. The AUC of the initial TDM was calculated over 2-point (peak/trough) concentrations via Bayesian estimation. The target AUCfollow-up was defined as 400–600 μg h/mL. Among 188 patients (median age [interquartile range], 66 [56, 79] years; 50 % female), the target AUCfollow-up was achieved in 70 % (132/188). When the predicted AUC was 400–600 μg h/mL, 84 % (102/121) achieved the target AUCfollow-up. In a 12 h dosing interval subgroup, 86 % (88/102) achieved the target AUCfollow-up. Conversely, when the predicted AUC was <400 or >600 μg h/mL, the proportion who achieved the target AUCfollow-up dropped to 44 % (30/67). Only 30 % (3/10) of those with creatinine clearance rates of >130 mL/min/1.73 m2 achieved the target. The area under the receiver operating characteristics curve was 0.74, and the R2 value was 0.15. Our findings confirmed the external validity of the DT model and supported its use for optimizing VCM dosing. Overall, the DT model offers a reliable framework for achieving target AUC values during follow-up for TDM, aiding safe and effective treatment.