Published papers

© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature. 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%.

Background: In this study, we investigated the risk factors for daptomycin-associated creatine phosphokinase (CPK) elevation and established a risk score for CPK elevation. Methods: Patients who received daptomycin at our hospital were classified into the non-elevated or elevated CPK group based on their peak CPK levels during daptomycin therapy. Univariable and multivariable analyses were performed, and a risk score and prediction model for the incidence probability of CPK elevation were calculated based on logistic regression analysis. Results: The non-elevated and elevated CPK groups included 181 and 17 patients, respectively. Logistic regression analysis revealed that concomitant statin use (odds ratio [OR], 4.45 [95% confidence interval {CI}, 1.40-14.47]; risk score 4), concomitant antihistamine use (OR, 5.66 [95% CI, 1.58-20.75]; risk score 4), and trough concentration (Cmin) between 20 and <30 μg/mL (OR, 14.48 [95% CI, 2.90-87.13]; risk score 5) and ≥30.0 μg/mL (OR, 24.64 [95% CI, 3.21-204.53]; risk score 5) were risk factors for daptomycin-associated CPK elevation. The predicted incidence probabilities of CPK elevation were <10% (low risk), 10%-<25% (moderate risk), and ≥25% (high risk) with total risk scores of ≤4, 5-6, and ≥8, respectively. The risk prediction model exhibited a good fit (area under the receiver operating characteristic curve, 0.85 [95% CI,. 74-.95]). Conclusions: These results suggested that concomitant use of statins with antihistamines and Cmin ≥20 μg/mL were risk factors for daptomycin-associated CPK elevation. Our prediction model might aid in reducing the incidence of daptomycin-associated CPK elevation.

Methaemoglobin (metHb) possesses inherent characteristics that facilitate reversible binding to hydrogen sulphide. Exogenous hydrogen sulphide supplementation imparts beneficial bioactive effects, including antioxidant and anti-inflammatory; hence, we hypothesized that the metHb-hydrogen sulphide complex could act as a hydrogen sulphide donor for medication. In this study, we prepared a hydrosulphide-metHb-albumin (H2S-metHb-albumin) cluster and examined its applicability as a hydrogen sulphide donor in the mice model of hepatic ischemia-reperfusion injury. Structural analysis revealed that the H2S-metHb-albumin cluster exhibited a nanostructure wherein one metHb was wrapped by an average of three albumins, and hydrogen sulphide was bound to the haem. Additionally, the H2S-metHb-albumin cluster exhibited low-pH responsiveness, leading to sustained release of hydrogen sulphide. Owing to these structural and pharmaceutical characteristics, the severity of hepatic ischemia-reperfusion injury was alleviated via antioxidant and anti-inflammatory effects of the H2S-metHb-albumin cluster treatment. The protective effects were more potent in the H2S-metHb-albumin cluster compared to that in a conventional hydrogen sulphide donor (sodium hydrogen sulphide). No abnormal signs of toxic and biological responses were observed after the H2S-metHb-albumin cluster administration, confirming high biological compatibility. These results successfully establish the proof of concept that the H2S-metHb-albumin cluster is a promising hydrogen sulphide donor. To the best of our knowledge, this is the first report demonstrating the remarkable potential of metHb as a biomaterial for hydrogen sulphide donors.

Purpose: The clinical value of pharmacist-led multidisciplinary support for candidemia is poorly established. This study examines whether shifting from an antimicrobial stewardship team (AST) to a pharmacist-led infectious disease support team (IDST) model improves bundle adherence and clinical outcomes among patients with candidemia. Methods: This retrospective cohort study at Yamanashi Prefectural Central Hospital included hospitalized patients with at least one positive blood culture set for Candida spp. from April 2018 to September 2025. Patients who died within 48 h of candidemia confirmation or had unknown 28-day survival status were excluded. The primary outcome was adherence to an 8-item candidemia treatment bundle; secondary outcomes were 28-day mortality and microbiological eradication rates. Clinical outcomes and risk factors were analyzed using Kaplan–Meier and Cox proportional hazards models. Results: This study included 89 patients with a median age of 74 years. Candida albicans emerged as the predominant pathogen. In total, 61.8% of participants achieved bundle adherence of at least 75%. The IDST group demonstrated significantly higher adherence to multiple bundle components and a higher overall achievement rate compared with the non-IDST group. Additionally, the IDST group exhibited lower 28-day mortality (29.2% vs. 56.1%, P = 0.019) and higher microbiological eradication rates (87.5% vs. 61.0%, P = 0.006). Multivariable Cox analysis revealed that IDST intervention was independently associated with reduced 28-day mortality (hazard ratio: 0.452; 95% confidence interval: 0.220–0.926, P = 0.030). Conclusion: IDST intervention is associated with improved adherence to the candidemia bundle, lower 28-day mortality, and higher microbiological eradication rates.

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: – Renal function may be overestimated in patients with hepatic dysfunction because of reduced creatinine production; however, its impact on the vancomycin dosing regimen is unclear. In this study, the characteristics of steady-state vancomycin area under the concentration–time curve (AUCss) estimation and optimal strategies for its clinical management were determined. Methods: – This multicenter, retrospective, observational study included adult patients who received vancomycin between January 2018 and December 2023; trough concentrations were measured. Patients with albumin levels of <2 g/dL with hepatic dysfunction were defined as having cirrhosis, hepatic failure, or other hepatic dysfunctions. A deviation of ≥30% in the AUCss ratio, calculated as the Bayesian-estimated AUC using trough concentrations divided by the AUC derived from population pharmacokinetic parameters, was considered attributable to hepatic dysfunction. Multivariate analysis was conducted to calculate the adjusted odds ratio (aOR) and 95% confidence interval (CI) for factors associated with an AUCss deviation of ≥30%. Results: – In total, 157 patients (63 with and 94 without hepatic dysfunction) were included in the study. Multivariate analysis identified hepatic dysfunction (aOR, 2.257; 95% CI, 1.104–4.618) and creatinine clearance (aOR, 1.016; 95% CI, 1.006–1.027) as factors associated with an AUCss deviation of ≥30%. Patients with hepatic dysfunction had higher AUCss and steady-state trough ratios (P <0.001 and P = 0.017, respectively). Conclusions: – Early therapeutic drug monitoring may be beneficial in patients with hepatic dysfunction because deviations of ≥30% between population-based and Bayesian AUC estimates have been observed in this population.

© 2020 Objectives: This systematic review and meta-analysis was designed to determine the optimal trough concentration of voriconazole for children with invasive fungal infections (IFIs). Methods: We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and Japana Centra Revuo Medicina) for clinical studies describing the voriconazole trough concentration. We used stepwise cut-off values of 1.0–2.0 mg/L for efficacy and 3.0–6.0 mg/L for safety. The efficacy outcomes were treatment success and all-cause mortality, and the safety outcomes were hepatotoxicity, neurotoxicity and all-cause adverse events. Results: Nine studies involving 211 patients were included in the analysis. The probability of treatment success against IFIs was significantly increased at cut-off values of ≥1.0 mg/L (odds ratio [OR] = 2.65, 95% confidence interval [CI] = 1.20–5.87). Our analysis did not find any relationship between the trough concentration and survival. Concerning safety, the occurrence of any outcomes did not significantly differ according to the voriconazole trough concentrations at any cut-off value. However, in a subgroup analysis of Asian study locations, a significantly higher risk of hepatotoxicity was demonstrated at voriconazole trough cut-off values ≥ 3.0 mg/L (OR = 8.40, 95% CI = 1.36–51.92). Although a significant correlation between the voriconazole concentration and hepatotoxicity was evident in regression curve analysis, (y = 0.1198e0.2298x), no correlation was demonstrated for neurotoxicity (y = 0.3913e−0.008x). Conclusion: Our findings suggest that the optimal trough concentration for increasing clinical success and minimizing hepatotoxicity during voriconazole therapy in children with IFIs, particularly for Asian populations, is 1.0–3.0 mg/L.

© 2020 Elsevier B.V. Recently, immune checkpoint inhibitors, including anti-programmed cell death protein 1 (PD-1) antibodies, have dramatically changed treatment strategies for several cancers. In pharmacokinetic/pharmacodynamic studies, experiments using a variety of animal species are assumed. We have identified optimal multiple reaction monitoring transitions for signature candidate peptides of nivolumab in human, mouse, and rat plasma and developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify nivolumab (an anti-PD-1 antibody) using trastuzumab as the internal standard. Calibration curves were linear in the range of 1–200 µg/mL. The intra- and inter-day precision and accuracy in human plasma fulfilled Food and Drug Administration guideline criteria for bioanalytical validation. There was no need to change the measurement method in mouse plasma. On the other hand, in rat plasma, an interference peak was observed at a retention time similar to that of the surrogate peptide ASGITFSNSGMHWVR (550.75 > 661.50) employed in human and mouse plasma. Therefore, we confirmed that ASQSVSSYLAWYQQKPGQAPR (785.0 > 940.2) can be used as an alternate nivolumab surrogate peptide in rat plasma at the same concentration range as used in human and mouse plasma. Using our method, the concentration range and a gradual increase in trough value were confirmed in clinical samples from two antibody-treated patients, including one with gastric cancer and one with non-small-cell lung cancer. The time course and blood concentration transition also were evaluated in nivolumab administration experiments in mouse and rat. The present study showed that the selection of the optimal peptide is essential for accurate LC-MS/MS measurement of nivolumab concentration in human, mouse, and rat plasma. The method developed here is expected to be of use in non-clinical and clinical pharmacokinetic studies.

Background: Metronidazole (MNZ) can be administered for various infections. The impact of comorbidities/concomitant drugs on MNZ-induced central nervous system (CNS) disorders remains unclear. Research design and methods: We assessed the risk of metronidazole-related CNS disorders using the Japan Adverse Drug Event Report (JADER, May 2023) and the US Food and Drug Administration Adverse Event Reporting System (FAERS, Q1 2023), excluding comorbidities/concomitant drugs. Clonazepam and diazepam were evaluated as potential prophylactics based on the efficacy of benzodiazepines for MNZ-related CNS disorders. Reporting odds ratios (ROR) and 95% confidence intervals (CI) were calculated. Additionally, sensitivity analysis by sex and age was conducted. Results: The ROR (95% CI) of CNS disorders associated with MNZ in JADER and FAERS were 3.16 (2.69–3.72) and 1.69 (1.64–1.73), respectively. MNZ was significantly related to CNS disorders after excluding comorbidities (brain/spinal cord or liver abscesses) and concomitant drugs (glucocorticoids, antiepileptic, antiparkinson, and schizophrenia drugs). In sensitivity analysis, MNZ was significantly related to CNS disorders, despite sex and age. The ROR in the concomitant with clonazepam (CZP) was 0.70 (0.53–0.92) in FAERS. Conclusion: MNZ may be associated with CNS disorders, even if comorbidities/concomitant drugs that are potential risk factors for CNS disorders are excluded. Additionally, CZP may suppress CNS disorders.

The global incidence and prevalence of pulmonary disease caused by the Mycobacterium avium complex (MAC), mainly comprising M. avium and Mycobacterium intracellulare, is increasing. However, treating MAC pulmonary disease is challenging in cases of clarithromycin (CLR)-resistant MAC or where the patients experience adverse effects or drug interactions with the few available antibiotics. Therefore, developing novel and highly effective antibiotics against MAC is crucial. Although the efficacy of dual β-lactams against Mycobacterium abscessus has been receiving attention, the efficacy of dual β-lactams against MAC remains unclear. Here, we used MAC type strains and clinical isolates to determine whether dual β-lactams were effective against MAC and which combinations synergistically inhibited bacterial growth using a broth microdilution checkerboard assay with 6 oral and 22 intravenous antibiotics. The combination effect and antibacterial activity differed between M. avium and M. intracellulare. Five combinations of oral β-lactams and 78 combinations of intravenous β-lactams showed a synergistic effect against the M. avium type strain. Among the M. avium clinical isolates, faropenem combined with cefuroxime showed the highest synergistic effect, and amoxicillin combined with tebipenem showed the lowest minimum inhibitory concentration. There was no significant difference in the combination effects between the CLR-susceptible and CLR-resistant M. avium clinical isolates in these pairs. In conclusion, regardless of CLR susceptibility, the oral β-lactam combinations were effective against M. avium. Thus, when treating MAC pulmonary disease, it is crucial to determine whether M. avium or M. intracellulare is the cause. IMPORTANCE Mycobacterium avium complex causes chronic respiratory infections, but treatment is often limited by drug resistance, intolerance, or interactions. As new therapeutic strategies are urgently needed, we focused on β-lactam antibiotics, which are widely used and well tolerated. Although dual β-lactams are effective against Mycobacterium abscessus, their utility against Mycobacterium avium complex has remained largely unexplored. Our in vitro study revealed that several β-lactam combinations are effective against Mycobacterium avium, regardless of drug resistance, indicating potential for clinical use. In contrast, Mycobacterium intracellulare showed lower susceptibility to β-lactams. Given this difference in drug susceptibility, we emphasize the clinical need to distinguish Mycobacterium avium and Mycobacterium intracellulare to optimize treatment of Mycobacterium avium complex pulmonary disease.

d-Amino acid oxidase (DAO) inhibitors are novel candidate therapeutic agents for neurodegenerative diseases. In this study, a novel inhibition assay using WST-8 as a detection reagent was developed and its effectiveness for evaluating redox-based enzyme kinetics was tested. Furthermore, using this assay, we also investigated the inhibitory activities of uremic toxins and endogenous amino acid metabolites. Briefly, a mixture of DAO, WST-8, and d-amino acids was allowed to react in phosphate buffer and DAO activity was detected as an increase in absorbance when both d-serine and DAO were present. However, as reducing compounds could potentially cause false-positive results, we confirmed that the detection of DAO activity in this system was mediated by the redox reaction of WST-8. Critically, we verified that this assay could be used to evaluate the inhibitory activity of known DAO inhibitors, including uremic toxins which showed weak DAO inhibition. This study establishes an alternative assay system that can be utilized for assessing DAO-inhibitory activity and other enzymatic reactions mediated by redox reactions.

Background Nacubactam (OP0595) is a newly developed diazabicyclooctane β-lactamase inhibitor used in combination with cefepime or aztreonam. We assessed the efficacy and safety of cefepime–nacubactam and aztreonam–nacubactam versus imipenem–cilastatin in complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis. Methods The Integral-1 global, phase 3, multicentre, randomised, double-blind study recruited adults (aged ≥18 years) with cUTI or acute uncomplicated pyelonephritis at 79 sites in Bulgaria, China, Czech Republic, Estonia, Georgia, Japan, Latvia, Lithuania, and Slovakia. Patients were randomly assigned (2:1:1) to receive intravenous cefepime (2 g) plus nacubactam (1 g), aztreonam (2 g) plus nacubactam (1 g), or imipenem (1 g) plus cilastatin (1 g) every 8 h for 5–14 days. Randomisation was stratified by diagnosis and geographical region. The primary endpoint was the proportion of patients achieving composite clinical and microbiological success at test of cure in the microbiological modified intention-to-treat population—all patients who were randomly assigned, received any amount of the study drug, and had a baseline qualifying pathogen that was susceptible to imipenem and meropenem. The prespecified non-inferiority margin was more than 15 percentage points difference; the superiority margin was more than zero percentage points difference, for the lower bound of the two-sided 95% CI for imipenem–cilastatin. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , NCT05887908 . Findings Between May 22, 2023, and Nov 26, 2024, 614 patients were randomly assigned and 431 were included in the primary efficacy analysis (cefepime–nacubactam [n=214], aztreonam–nacubactam [n=112], or imipenem–cilastatin [n=105]); 228 patients (53%) were male and 203 (47%) were female. The primary endpoint was achieved by 176 (82%) of 214, 81 (72%) of 112, and 64 (61%) of 105 patients in the cefepime–nacubactam, aztreonam–nacubactam, and imipenem–cilastatin groups, respectively. The percentage difference in the success rate versus imipenem–cilastatin was 21·3% (95% CI 10·9 to 32·0) for cefepime–nacubactam (non-inferior and superior), and 11·4% (−1·2 to 23·7) for aztreonam–nacubactam (non-inferior). Treatment-emergent adverse events were reported in 100 (33%) of 306, 45 (30%) of 152, and 65 (43%) of 150 patients in the cefepime–nacubactam, aztreonam–nacubactam, and imipenem–cilastatin groups, respectively. No treatment-related deaths occurred. Interpretation Cefepime–nacubactam and aztreonam–nacubactam are potential treatment options for Gram-negative cUTI and acute uncomplicated pyelonephritis, including infections caused by antimicrobial-resistant strains. Funding Meiji Seika Pharma and Japan Agency for Medical Research and Development.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia carries high mortality. At Yamanashi Prefectural Central Hospital, antimicrobial stewardship has focused on appropriate drug use. In 2022, a pharmacist-coordinated Infectious Disease Support Team (IDST) was established to optimize management, including diagnostics, dosing, and treatment duration. We evaluated the effects of IDST participation on the adherence to a predefined Staphylococcus aureus bacteraemia treatment bundle and mortality. Methods: We conducted a single-centre retrospective cohort study of adults with MRSA bacteraemia diagnosed between April 2020 and June 2025. Patients were categorized into IDST intervention or non-intervention groups. Bundle adherence (≥ 75% defined as ≥ 9/12 items) and 28- and 90-day mortality were analysed using Kaplan–Meier analysis with log-rank tests and Cox proportional-hazards models; two-sided P < 0.05 was considered significant. Results: Eighty-five patients were included in the present study. Overall, bundle adherence ≥75% occurred in 57.6%; adherence was higher with IDST than without (79.5% vs 39.1%); 28-day mortality occurred in 26 (30.6%) and 90-day mortality in 42 (49.4%), respectively. Survival analysis showed lower 28-day (log-rank P=0.031) and 90-day mortality (P=0.017) with IDST. In multi-variable models, IDST remained independently protective at 28 days (hazard ratio [HR] 0.328, 95% CI: 0.136–0.792; P=0.013) and 90 days (HR 0.427, 95% CI: 0.215–0.846; P=0.015). Conclusions: Pharmacist-coordinated IDST co-management significantly improved adherence to evidence-based care and was associated with reduced short- and intermediate-term mortality in patients with MRSA bacteraemia. This model may be applicable to hospitals with limited continuous on-site availability of infectious disease physicians, provided that specialist oversight remains accessible.

© 2020 The Authors Objectives: The long-term stability of antimicrobials dissolved in infusion solution is necessary to establish and spread the outpatient parenteral antimicrobial therapy (OPAT). In this study, we evaluated the stability of antimicrobial agents dissolved in infusion solutions. Methods: The antimicrobial agents were dissolved in infusion solutions and kept at 25 °C and 31.1 °C for 24 h or 4 °C for 10 days in a polypropylene tube or an elastomeric infusion pump. The stability was measured by high-performance liquid chromatography. Results and conclusion: The residual ratio of cefazolin (CEZ), cefmetazole (CMZ), piperacillin (PIPC), and tazobactam (TAZ) at 31.1 °C for 24 h was as follows: 95.7 ± 3.0%, 94.8 ± 0.9%, 102.6 ± 1.8%, and 103.9 ± 3.6% in saline, respectively; 94.7 ± 3.0%, 94.3 ± 1.5%, 106.1 ± 3.0%, and 107.3 ± 2.4% in 5% dextrose solution, respectively. The residual ratio of these antimicrobials at 4 °C for 10 days was maintained above 90% in both saline and 5% dextrose solution. The residual ratio of all the above antimicrobials in an elastomeric infusion pump at 31.1 °C for 24 h was equivalent to that in the polypropylene tube. On the other hand, doripenem and meropenem were not stable in any infusion solution at 31.1 °C. CEZ, CMZ, and PIPC/TAZ dissolved in saline or 5% dextrose solution can be used in OPAT with continuous infusion pumps.

Background: First-generation cephalosporins have good activity against gram-positive bacteria and are extensively used in horses. There are few reports of pharmacokinetics and pharmacodynamics (PK/PD) analysis of cephalosporins in horses. Objective: To optimise the dosages of the two first-generation cephalosporins cephalothin (CET) and cefazolin (CEZ) in horses using PK/PD concepts. Study design: Experimental study with single administration. Methods: Drug plasma concentrations following a single intravenous (i.v.) administration of 22 mg/kg bodyweight (bwt) CET in 12 horses and of 10 mg/kg bwt CEZ in six horses were measured using LC-MS/MS. Data were modelled using a nonlinear mixed effect modelling followed by Monte Carlo simulations. Minimum inhibitory concentrations (MICs) against Streptococcus zooepidemicus and Staphylococcus aureus isolated from horses were determined by the microbroth dilution method. Results: The percentages of CET and CEZ binding to serum proteins were 19.9% ± 8.4% and 15.2% ± 8.5% respectively. For both CET and CEZ, the MIC against S. zooepidemicus was 0.12 mg/L and against S. aureus was 0.5 mg/L. For CET, to achieve a probability of target attainment (PTA) of 90% for a PK/PD target of a free serum plasma concentration exceeding the MIC for 40% of the dosing interval, an empirical CET dosage regimen of 22 mg/kg bwt q8h and 22 mg/kg bwt q4h i.v. administration were required for S. zooepidemicus and S. aureus respectively. For CEZ, the corresponding dosage regimens were 10 mg/kg bwt q12h and 10 mg/kg bwt q8h. Main limitations: Small sample size only in healthy horses. Conclusions: For CET, more frequent administration than that currently recommended (22 mg/kg bwt q6–12h) is required to empirically control S. aureus infection in horses. For CEZ, less frequent administration compared to the dosage regimen currently proposed (10–22 mg/kg bwt q6h) could control S. zooepidemicus and S. aureus infections in horses. 90 90

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.

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.

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.

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.