Journal of Antimicrobial Chemotherapy最新文献

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.

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.

Background: Gender shapes health behaviours, access, and outcomes, thereby influencing antibiotic use. Intersecting socio-economic factors, such as education, labour force participation, and political representation, further mediate gender differences in the risk of antimicrobial resistance (AMR). However, evidence linking gender inequalities to antibiotic consumption remains limited.

Methods: This study is an observational, country-level analysis using IQVIA MIDAS® data on yearly antibiotic consumption (defined daily doses/DDDs) from 70 countries (2000-22). We used four gender equality indicators: proportion of females with secondary or higher education, female-to-male labour force participation (FMLFP) ratio, proportion of women in parliament, and share of female population. Using country and year fixed-effects regression models, the study estimated within-country associations between these indicators and overall antibiotic consumption, as well as by antibiotic class, controlling for income, education, healthcare access, and health spending, and demographics. Sensitivity was assessed through an alternative model specification, stratified analyses by income groups and by time periods.

Results: Antibiotic consumption varied widely across countries with an average of 19.13 DDDs per day per 1000 population. Our main findings are that higher female education (P < 0.05) and FMLFP ratio (P < 0.01) were significantly associated with lower antibiotic consumption, while a higher share of females in the population was significantly associated with slightly higher consumption (P < 0.01). Women's parliamentary representation showed no significant association. These associations remained directionally consistent across alternative model specifications and income groups.

Conclusions: Gender inequalities influence antibiotic consumption patterns. The study underscores the need for a community-based approach in tackling AMR, specifically, investments in gender-responsive AMR strategies.

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.

Background and objectives: An allometric miltefosine regimen dosed based on fat-free mass (FFM) is effective and safe in treating children with visceral leishmaniasis (VL). However, its complexity hinders successful implementation in endemic areas. We aimed to develop a simplified dosing based on weight bands (WBs) that achieves equivalent miltefosine exposure in a paediatric VL population using a simulation-based approach.

Methods: Utilizing demographic data from 9379 Eastern African paediatric VL patients, WHO-CDC growth curves were adjusted to create a realistic virtual paediatric VL population. The virtual children were given either an allometric FFM-based, a WB-based or a 2.5 mg/kg dosing of miltefosine per day. To compare the regimens, two pharmacokinetic metrics were derived from the simulated patient population receiving the allometric FFM-based regimen: the 5th percentile of the time above the concentration associated with 90% in vitro intracellular parasite killing for efficacy and the 95th percentile of the AUC for safety. The performance of the dosing regimens was evaluated for both 14- and 28-day regimens.

Results: A virtual population was constructed that closely resembled real-world paediatric Eastern African VL patients' height- and weight-for-age distributions. Target attainment rates for the two pharmacokinetic metrics tested differed by less than 1.5% between the final WB- and FFM-based dosing regimens. The final doses in mg were 20 for children under 6 kg, 30 for 6.0-9.9 kg, 50 for 10.0-14.9 kg, 60 for 15.0-19.9 kg, 70 for 20.0-24.9 kg and 80 for 25.0-29.9 kg, for both 14- and 28-day regimens.

Conclusions: Our simplified WB-based dosing strategy offers a practical alternative for allometric miltefosine dosing in children, yielding satisfactory exposure levels.

Background: Hypoalbuminaemia in patients with MSSA bacteraemia is associated with a delayed time to blood culture sterilization and increased mortality. Although this phenomenon has been postulated to be due to suboptimal antimicrobial exposure, the albumin thresholds that predispose patients to worse outcomes remain unclear.

Methods: This was a multicentre, retrospective study of adult patients with MSSA-positive blood cultures for at least 48 h despite treatment with in vitro active antimicrobials. To determine the precise cut-off for defining hypoalbuminaemia, we applied a bootstrap resampling approach in combination with Cox proportional hazards models. A range of candidate albumin thresholds was evaluated to identify the optimal value that maximized the partial log-likelihood of the Cox model, with time from target therapy to negative blood cultures as the outcome.

Results: Among the 461 patients screened, 285 patients met the inclusion criteria; 34% (97/285) were people who inject drugs and 45% (130/285) had definite endocarditis. The median (IQR) albumin level was 2.4 (2-2.9) g/dL. The albumin threshold that corresponded to the highest mean bootstrapped log-likelihood was ≤3.0 g/dL. After propensity score weighting, patients with an albumin level of ≤3.0 g/dL had a significantly slower time to blood culture sterilization compared with patients with albumin levels >3 g/dL (HR = 0.6; 95% CI: 0.44-0.81; P < 0.01).

Conclusions: In the largest study to evaluate the impact of hypoalbuminaemia on the outcomes of patients with MSSA bacteraemia, we identified a cut-off value of albumin ≤3 g/dL to be associated with an increased risk for a delayed blood culture sterilization.

Background: Salmonella enterica serovar Typhi results in >160 000 deaths annually. In endemic regions, infections disproportionately affect infants and children. Current diagnostics rely on culture-based approaches that lack sensitivity and require infrastructure and skills that are not always possible in developing regions.

Objectives: We developed a suite of rapid, sensitive and specific molecular diagnostic tools to detect S. Typhi, and markers of extensive antimicrobial resistance (AMR), with the capacity to be used in low- and middle-income countries (LMIC).

Methods: Singleplex and multiplex PCR assays, recombinase polymerase amplification with lateral flow detection (RPA-LF) assays and loop-mediated isothermal amplification (LAMP) assays were developed, targeting markers consistent with Salmonella Typhi and makers of extensive AMR (blaCTX-M-15 and qnrS1). Assays were tested across four banks of samples (n = 115 total) to assess sensitivity, specificity and limit of detection.

Results: Singleplex and multiplex PCR assays demonstrated excellent sensitivity (100%) and specificity (96%-100%) for detection of XDR S. Typhi and extensive AMR, particularly the H58 clade deletion and STY4669 genes of S. Typhi. Similarly, sensitivity and specificity were also observed for RPA-LF assays (100% sensitivity, 96%-100% specificity) and LAMP assays (100% sensitivity, 87.5%-100% specificity) for all targets.

Conclusions: These tools are timely, providing a range of options for targeted detection of XDR S. Typhi in the laboratory or nearer to the point of care. These assays have the potential to improve resistance-guided therapy for S. Typhi, which is important given the increasing prevalence of XDR S. Typhi in endemic regions of Pakistan, and increasing case reports globally.