Journal of Antimicrobial Chemotherapy最新文献

Background: Periprosthetic joint infections pose clinical and socioeconomic challenges. Gram-negative pathogens are associated with poorer outcomes compared with Gram-positive organisms. Rising antimicrobial resistance limits treatment options. The new combination of cefepime/enmetazobactam offers a promising carbapenem-sparing therapy.

Objectives: To investigate the distribution and the time above the minimum inhibitory concentration for cefepime and the time above the threshold concentration for enmetazobactam during the first and third dosing intervals in tissues relevant to periprosthetic joint infection, following either intermittent short-term infusion or continuous infusion in a preclinical, randomized porcine model.

Materials and methods: Sixteen pigs were randomized to receive cefepime/enmetazobactam either as a short-term infusion (2 g/0.5 g over 2 h) or continuous infusion (initial dosage of 1 g/0.25 g administered over 15 min followed by 2 g/0.5 g over 7 h and 45 min) in three dosing intervals of 8 h. Microdialysis was used to dynamically sample interstitial fluid concentrations of cefepime and enmetazobactam from cancellous bone, subcutaneous tissue and synovial fluid. Plasma samples were collected as reference. The following dosing interval targets were applied: for cefepime, 60% T > MIC of 8 mg/L and for enmetazobactam, 45% of T > Ct of 2 mg/L.

Results: All pigs reached the predetermined targets in all investigated compartments following both administration forms. For all targets, compartments, dosing intervals and administration forms, the mean T > MIC for cefepime was ≥92% and mean T > Ct for enmetazobactam was ≥99%.

Conclusion: Cefepime/enmetazobactam demonstrated robust tissue distribution, reaching the applied pharmacokinetic/pharmacodynamic targets in all investigated tissue compartments, regardless of the mode of administration. From a pharmacokinetic view, cefepime/enmetazobactam may prove useful in future Gram-negative periprosthetic joint infection settings.

Background: Voriconazole is widely used for invasive fungal infections in critically ill patients, but its pharmacokinetics may be significantly altered by extracorporeal membrane oxygenation (ECMO). Data on the impact of different ECMO modes are limited.

Methods: We performed a retrospective observational study including all patients admitted to the ICU from January 2018 to May 2025 who were treated with voriconazole for suspected fungal infections. Voriconazole trough concentrations (Cmin) were compared between ECMO and non-ECMO patients. Multivariate linear regression was used to identify clinical predictors of Cmin, and subgroup analyses were performed by ECMO mode and other relevant covariates.

Results: A total of 166 patients (492 samples) were included, including 33 ECMO patients (111 samples) and 133 non-ECMO patients (381 samples). There was no significant difference in voriconazole trough concentrations between the ECMO and non-ECMO groups. When stratified by mode, VAV-ECMO was associated with significantly lower concentrations than non-ECMO (P = 0.004), whereas VV- and VA-ECMO were comparable to non-ECMO. In multivariate linear regression, increasing age and coadministration with amiodarone were associated with higher voriconazole Cmin, whereas lower albumin levels and concomitant CRRT were associated with reduced concentrations.

Conclusions: ECMO support did not significantly reduce voriconazole Cmin compared with the non-ECMO group. However, VAV-ECMO is associated with reduced voriconazole exposure, suggesting a configuration-specific rather than uniform ECMO effect. Routine therapeutic drug monitoring remains essential.

Objectives: To evaluate the in vitro activity of cefepime in association with a β-lactamase inhibitor (enmetazobactam) or β-lactam enhancer (BLE), zidebactam, against carbapenem-resistant Acinetobacter baumannii (CRAB) strains susceptible or resistant to sulbactam/durlobactam.

Material and methods: Twenty-one CRAB clinical isolates were characterized by WGS and AST to cefepime/enmetazobactam, cefepime/zidebactam and comparators was determined.

Results: Resistome analysis revealed that all CRAB carried blaOXA-23 carbapenemase genes, while blaADC-25 and blaOXA-66 β-lactamase genes were observed exclusively in sulbactam/durlobactam-resistant strains. Analysis of penicillin-binding protein genes demonstrated the presence of specific mutations within PBP3 (N392T) previously associated to the resistance to sulbactam/durlobactam. Phenotypic analysis revealed that cefepime/enmetazobactam did not exert antibacterial activity against CRAB, while cefepime/zidebactam displayed potent bactericidal activity against both sulbactam/durlobactam-susceptible and -resistant strains.

Conclusions: These results demonstrate that cefepime/zidebactam exhibited potent in vitro antibacterial activity against CRAB producing OXA carbapenemase and support its clinical use against both sulbactam/durlobactam-susceptible or -resistant isolates.

Background and objective: With the redefinition of the EUCAST 'I' susceptibility category, from 'intermediate' to 'susceptible, increased exposure', the focus is now to use higher doses to treat infections of this category. These higher dosages in adults provided by EUCAST are fixed, yet it is uncertain whether a similar increase should apply to paediatric doses. We aimed to compare antibiotic exposure in adults and children, using pragmatic physiologically based pharmacokinetic (PBPK) modelling and simulation to evaluate the need for dose increases in children for the 'I' susceptibility category micro-organisms.

Methods: For amoxicillin, ceftazidime, cefuroxime and ciprofloxacin, we used existing PBPK models and verified them with published adult and paediatric pharmacokinetic data. Then, the adult EUCAST category 'I' doses and a wide paediatric dosage range was simulated. We compared AUC values as a surrogate for antibiotic exposure. In addition, simulations were performed to assess the PTA of the adult and paediatric doses for specific drug-micro-organism combinations.

Results: Model verification proved successful for all antibiotics. Simulations showed that antibiotic plasma exposure increases with decreasing age using current paediatric doses. Simulating doses for neonates and infants resulted in substantially higher AUCs compared with adults receiving the EUCAST 'I' dose. Simulations showed that PTA is highly variable with age and can be poor in case of less susceptible micro-organisms.

Conclusions: In contrast to adults, there is no need to increase the currently recommended paediatric dosages for the tested antibiotics. At the same time, further simulations showed that the PTA varies by drug-micro-organism combination and age, providing a potential opportunity to tailor doses to individual patients.

The therapeutic landscape of acute leukaemia (AL) has evolved profoundly with the introduction of targeted and differentiation agents, altering the epidemiology of invasive fungal disease (IFD). While antifungal prophylaxis with triazoles remains standard for patients receiving intensive chemotherapy, this paradigm may no longer apply to those treated with novel regimens. Targeted agents such as tyrosine kinase inhibitors, blinatumomab, inotuzumab ozogamycin, ivosidenib, gilteritinib, and venetoclax are associated with higher remission rates, shorter or absent neutropenia, and minimal mucosal injury-key determinants of IFD risk. As a result, the incidence of IFD appears markedly lower in such populations. Redefining antifungal prophylactic strategies must account for this therapeutic heterogeneity to avoid overexposure to antifungal drugs and misdirected research priorities. Updated, risk-adapted strategies-integrating treatment intensity, myelotoxicity, and drug interactions-are essential to define which AL patients truly benefit from primary antifungal prophylaxis in the modern era.

Background: Antimicrobial resistance threatens oral treatment options for acute uncomplicated urinary tract infection (uUTI). Gepotidacin (Blujepa) is a novel oral triazaacenaphthylene antibiotic evaluated in Phase 3 trials versus nitrofurantoin.

Objectives: To pool Phase 3 randomized evidence comparing gepotidacin and nitrofurantoin for efficacy and safety in female uUTI.

Methods: PRISMA-compliant systematic review and random-effects meta-analysis of Phase 3 randomized controlled trials. Two investigators independently screened records (using Rayyan), extracted data and assessed risk of bias with RoB 2; certainty was rated with GRADE. Outcomes were pooled as risk ratios (RR) or mean differences with 95% confidence intervals (CI) using RevMan 5.4.

Results: Three trials (EAGLE-2, EAGLE-3 and EAGLE-J) including 3510 participants (gepotidacin n = 1853; nitrofurantoin n = 1657) were included. Gepotidacin increased composite therapeutic success versus nitrofurantoin (RR 1.20; 95% CI 1.10-1.31; I2 = 0%; P < 0.001) and improved microbiological eradication (RR 1.14; 95% CI 1.07-1.21; I2 = 2%; P < 0.001). Gastrointestinal adverse events were more frequent with gepotidacin (diarrhoea RR 5.51; 95% CI 4.08-7.45; nausea RR 2.49; 95% CI 1.56-3.97). Serious adverse events were rare and similar between groups. Certainty of evidence per outcome is presented in Table S2 (available as Supplementary data at JAC Online).

Conclusions: Gepotidacin provides superior composite and microbiological outcomes relative to nitrofurantoin for female uUTI but is associated with increased mild-to-moderate gastrointestinal toxicity. Long-term tolerability and resistance surveillance are recommended.

Objectives: Zintrodiazine (ZY-19489) is a novel triaminopyrimidine-class antimalarial with potent activity against Plasmodium falciparum, including resistant strains. To support paediatric development and meet regulatory requirements, we conducted a comprehensive juvenile toxicity study of Zintrodiazine in rats, focusing on growth, neurodevelopment and toxicokinetics.

Methods: Wistar rats were administered vehicle and 30, 45 or 60 mg/kg/day Zintrodiazine orally from postnatal day (PND) 10-45, followed by a 4-week recovery (PND 46-73). Endpoints included clinical observations, neurobehavioural assays (open field, acoustic startle/pre-pulse inhibition and Morris water maze), sexual maturation, bone growth, clinical pathology, organ weights and histopathology. Toxicokinetic profiling at PND 21 and 45 assessed age- and sex-related exposure differences.

Results: No treatment-related mortality, clinical signs or developmental impairment were observed. Body weight, food intake, sexual maturation and femur length were unaffected. Neurobehavioural performance remained normal across all assays. Transient, non-dose-dependent changes in liver and renal biomarkers observed at terminal phase resolved at the end of recovery. Minimal, reversible vacuolation consistent with phospholipidosis was observed in the liver, lymphoid, pulmonary and adrenal tissues at ≥30 mg/kg/day, without inflammation or necrosis. Systemic exposure was dose-proportional; females exhibited higher parent compound and metabolite (ZY-20486) levels, while metabolite exposure declined with age, consistent with maturational biotransformation. The no-observed-adverse-effect level was 60 mg/kg/day (Cmax ≤1572 ng/mL; AUClast ≤35 592 h·ng/mL).

Conclusions: Zintrodiazine demonstrated a favourable juvenile safety profile, with no adverse effects on growth, neurodevelopment or sexual maturation at clinically relevant exposures. These findings provide critical regulatory data supporting progression into paediatric clinical trials and highlight Zintrodiazine's potential as a safe and effective antimalarial for children.

Klebsiella pneumoniae (KP) is a Gram-negative, opportunistic pathogen known for causing hospital/community-acquired infections, with carbapenem-resistant Klebsiella pneumoniae (CRKP) being a major global health threat due to its resistance to last-resort antibiotics. Tigecycline is one of the most commonly used and accessible agents for CRKP treatment. However, the rapid spread of resistance genes via mobile genetic elements has led to an increase in bacterial resistance, thereby undermining the clinical efficacy. Additionally, controversy remains regarding the MIC breakpoint of tigecycline for KP, with either overestimation or underestimation of resistance rates, which complicates evaluation and selection of appropriate treatment regimens for clinicians. This review aims to elucidate the mechanisms of tigecycline resistance in KP strains, including the newly discovered mutants or resistance mechanisms mediated by efflux pumps and two-component regulatory systems. Subsequently, a global epidemiology of CRKP isolates with different tigecycline MIC values is conducted, finding that the resistance rates in Asia are higher than that in Europe and America. Furthermore, the latest clinical progresses of tigecycline in terms of dosage, combination regimen and adverse events are analysed.

Background: The ototoxic potential of aminoglycosides has limited their use. Although their effects on adult hearing have been extensively studied, there is limited research on their potential effects on newborns following intrauterine exposure. However, aminoglycosides are commonly used to treat urinary tract infections during pregnancy.

Objectives and methods: Evaluate the incidence of sensorineural hearing loss (SNHL) in neonates who were exposed to aminoglycosides in utero. A cohort of children born between 2018 and 2024 at a single urban hospital was analysed; all underwent universal hearing screening and, if necessary, a complete diagnostic audiological evaluation. Hearing test results of newborns whose mothers were exposed to aminoglycosides in utero were compared with those of unexposed newborns.

Results: A total of 39 237 newborns were included in the study. Of these, 85 were exposed in utero to aminoglycosides: gentamicin (13, 34 and 33 in first, second and third trimesters, respectively) or amikacin (3 and 4 in second and third trimesters, respectively), for a mean of three doses. Exposed children had significantly higher rates of other risk factors for hearing loss, including prolonged ICU stay, low birth weight and a family history of hearing loss. However, no exposed newborns developed SNHL, compared to 100 unexposed newborns.

Discussion: Among 85 children exposed to aminoglycosides in utero, mostly to gentamicin, no cases of congenital SNHL were observed, despite the higher prevalence of other risk factors. Although limited by a relatively small number of aminoglycoside exposures, these findings suggest that short courses of aminoglycosides during pregnancy are not likely to be associated with increased risk of congenital SNHL.