Current Issue : October-December Volume : 2025 Issue Number : 4 Articles : 5 Articles
Ampicillin plus ceftriaxone (AC) is a first-line treatment for Enterococcus faecalis infective endocarditis (IE). Its administration in outpatient parenteral antibiotic treatment (OPAT) programs is challenging. The design of a ceftriaxone regimen suitable for OPAT requires deep knowledge of ceftriaxone pharmacokinetics (PK). Objective: We aim to explore ceftriaxone PK in elderly patients and propose dose regimens adapted to OPAT to maintain synergistic concentrations (Cs) with ampicillin against E. faecalis. Methods: We conducted a prospective observational pharmacokinetic study on patients (>55 years old) affected by E. faecalis IE. Ceftriaxone free concentration was measured at three time-points: before the administration (Cmin) and two and four hours after ceftriaxone administration (C2 and C4). Both structural and covariate population pharmacokinetic models were built. Monte Carlo simulations of six ceftriaxone dosages were performed and the probability of target attainment (PTA) of an optimal Cs range was analyzed. The pharmacokinetic/pharmacodynamic index (PK/PD) to predict efficacy was defined as maintaining free ceftriaxone concentrations superior to the Cs at 50–100% of the dosing interval (fT ≥ Cs ≥ 50–100% of the dosing interval). Ceftriaxone dosing regimens were considered optimal if at least 90% of the simulated population was able to achieve the defined PK/PD targets. Results: Twenty-four episodes from 16 patients were included. Mean free ceftriaxone concentration pre-dose, +2 h, and +4 h were Cmin = 7.8 ± 6.5 mg/L, C2 = 34 ± 26.5 mg/L, and C4 = 22.7 ± 19.7 mg/L, respectively. A two-compartment model with first-order absorption and elimination best described the data. Ceftriaxone one-hour infusions only achieved the minimum PK/PD target when the 2 g/12 h regimen was tested. On the other hand, ceftriaxone continuous infusion maintained a Cs above the PK/PD target for 100% of the dosing interval using ceftriaxone 4–6 g regimens. Conclusions: Our findings suggest that the optimal ceftriaxone exposure may be achieved using high-dose continuous infusions to ensure an ampicillin-killing effect when treating E. faecalis IE....
The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin, as well as the placental transfer of enrofloxacin and ciprofloxacin, have not been studied. The aims of this study were (1) to evaluate the pharmacokinetics of enrofloxacin and ciprofloxacin by intravenous and intramuscular administration of 7.5 mg/kg in pregnant goats; (2) to determine the placental transfer of enrofloxacin and ciprofloxacin; (3) to conduct a PK/PD analysis to calculate the PK/PD cutoff of different dose regimens; and (4) to evaluate the tentative epidemiological cutoff values for coagulase-negative staphylococci wild-type isolates from goats. Plasmatic concentrations of enrofloxacin and ciprofloxacin in pregnant goats were well described by the parent–metabolite model. Simultaneous modeling of enrofloxacin and ciprofloxacin in each individual allowed for a PK/PD analysis that considered both drugs with antimicrobial activity. Our results show that both enrofloxacin and ciprofloxacin crossed the placenta in goats: fetal/maternal concentration ratio were 0.58 ± 0.05 and 0.03 ± 0.01 for enrofloxacin and ciprofloxacin. MIC values of coagulasenegative staphylococci isolates (n = 90) were obtained, and tentative epidemiological cutoffs were calculated at 0.25 and 0.5 mg/L for enrofloxacin and ciprofloxacin. According to PK/PDco values, an intravenous dose regimen of 10 mg/kg/day was considered the most appropriate, but based on the PK/PDco, culture, and AST data, an effective dosing regimen with the lowest possible dose could be selected to minimize the potential risk of fetal exposure to enrofloxacin....
Background/Objectives: Extracorporeal membrane oxygenation (ECMO) is increasingly used in critically ill patients, but may significantly alter the pharmacokinetics (PK) of antifungals. Data on plasma concentrations of Isavuconazole (IsaPlasm) in ECMO patients are limited. Our objective is to evaluate Isavuconazole exposure and variability in critically ill COVID-19 patients receiving ECMO. Methods: We conducted a pharmacokinetic analysis of Isavuconazole in critically ill patients receiving Veno-Venous ECMO for respiratory support. Plasma concentrations were measured using therapeutic drug monitoring (TDM) at multiple time points, including sampling before and after the membrane oxygenator. PK parameters—Area Under Curve (AUC0–24), Minimum Plasma Concentration (Cmin), Elimination Half-Life (T1/2), volume of distribution (Vd), and clearance (CL)—were estimated and compared with published data in non-ECMO populations. Results: Five patients were included. The median AUC0–24 was 227.3 μg·h/mL (IQR 182.4–311.35), higher than reported in non-ECMO patients. The median Vd was 761 L (727–832), suggesting extensive peripheral distribution and potential drug sequestration in the ECMO circuit. CL was increased (1.6 L/h, IQR 1.5–3.4). Two patients with recently replaced ECMO circuits exhibited significant drug loss across the membrane. Obesity and hypoalbuminemia were identified as factors associated with altered drug exposure. Conclusions: Isavuconazole pharmacokinetics show marked variability in critically ill ECMO patients. Increased AUC and Vd, along with reduced clearance, highlight the need for individualized dosing....
Background: Mithramycin (MTM) is a polyketide anti-cancer natural product previously identified as an EWS-FLI1 inhibitor. This oncogenic transcription factor is a canonical target for drug development in Ewing sarcoma. However, poor pharmacokinetics have been identified as a critical liability of MTM, preventing its further development. Through semisynthetic chemical modifications, we identified mithramycin SA-Trp (MTMSA-Trp) as being a pharmacologically superior congener. To explore their pharmacokinetic (PK) differences, this study examined the plasma PKs and plasma protein binding (PPB) of MTM and MTMSA-Trp in mice, rats, and monkeys. Methods: Protein binding was investigated by rapid equilibrium dialysis in plasma from mice, rats, monkeys, and humans. The pharmacokinetics were investigated at milligram- and microgram-level doses in mice and rats. The pharmacokinetics in monkeys were investigated using the cassette dosing approach at two microgram-level doses. The MTMSA-Trp pharmacokinetic linearity was evaluated in mice at 0.3, 1, 3, and 10 mg/kg doses. All samples were analyzed using LC-MS/MS. Results: Plasma protein binding was higher for MTMSA-Trp (1–4% unbound) than for MTM (10–30% unbound) across species, except in athymic nude mice (1–4% unbound and <1% for mithramycin and MTMSA-Trp, respectively). In mice and rats, MTMSA-Trp had significantly lower clearance than MTM at both milligram and microgram doses; however, the difference in plasma exposure was more pronounced at milligram doses. Consistent with the rodent PK results, cassette microdosing in monkeys showed that the clearance of MTMSA-Trp was lower than that of MTM, but the differences were less pronounced. In the dose proportionality study, MTMSA-Trp showed linear pharmacokinetics at 1, 3, and 10 mg/kg doses. Conclusions: MTMSA-Trp has significantly lower clearance than MTM in rodent models. This is a significant improvement compared to the parent drug, MTM, and warrants further evaluation of PKs in non-rodent models to enable the prediction of MTMSA-Trp PK in humans....
Background/Objectives: The increasing prevalence of urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL)-producing organisms poses a significant clinical challenge worldwide due to limited oral treatment options. Tebipenem (TBPM), an oral carbapenem antibiotic, is currently approved only for pediatric use in Japan, with no adult indication established. International studies have shown promising results for ESBL-producing infections, but optimal dosing regimens for Japanese adults with varying renal function have not been established. This study aimed to determine the optimal TBPM dosing regimens for ESBL-producing Enterobacterales UTIs in Japanese patients stratified by renal function, providing evidence for potential adult approval applications in Japan. Methods: Monte Carlo simulations (MCSs) were performed using pharmacokinetic parameters derived from clinical trials in Japanese subjects. Various dosing regimens were evaluated across different creatinine clearance (CCR) ranges and minimum inhibitory concentrations (MICs). The pharmacokinetic/pharmacodynamic target was set at fAUC0–24/MIC·1/tau ≥ 34.58, with a ≥90% probability of target attainment (PTA) considered optimal. Results: For patients with severe renal impairment (CCR < 30 mL/min), 150 mg q12 h achieved a >90% PTA against ESBL-producing organisms with an MIC of 0.03 mg/L. For moderate-to-severe renal impairment (30 ≤ CCR < 50 mL/min) and moderate renal impairment (50 ≤ CCR < 80 mL/min), 300 mg q8 h maintained a >90% PTA. For normal renal function (CCR ≥ 80 mL/min), 600 mg q8 h was required to achieve the target PTA. Conclusions: This first Japanese PK/PD analysis of TBPM in ESBL-producing UTIs provides evidence-based dosing recommendations across various renal function levels. TBPM, with appropriate renal-adjusted dosing, may offer an effective oral treatment option for patients who have traditionally required hospitalization for parenteral therapy....
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