Antimicrobial Agents and Chemotherapy最新文献

Invasive pulmonary aspergillosis (IPA), mainly caused by A. fumigatus, remains a life-threatening fungal infection, with rising reports of infections caused by resistant species such as Aspergillus lentulus and Aspergillus calidoustus. EL219 (formerly known as SF001) is a novel, next-generation polyene with enhanced ergosterol selectivity and reduced nephrotoxicity. We evaluated the efficacy of EL219 compared to liposomal amphotericin B (LAMB) in vitro using the Clinical Laboratory and Standards Institute M38 methodology and in immunosuppressed murine models of IPA caused by A. fumigatus, A. lentulus, and A. calidoustus. Immunosuppressed ICR mice were infected via inhalation (A. fumigatus) or via intratracheal instillation (A. lentulus and A. calidoustus), then treated intravenously once daily with placebo, EL219 (0.3, 1.5, 7.5, and 30 mg/kg), or LAMB (5 mg/kg) starting 16 h post-infection. Treatment lasted 4 days (A. fumigatus and A. lentulus) or 7 days (A. calidoustus). Survival through Day 21 and lung fungal burden at Day 4 were assessed. EL219 showed enhanced in vitro activity against A. lentulus and A. calidoustus compared to LAMB. EL219 significantly improved survival in a dose-dependent manner, with 30 mg/kg outperforming LAMB. EL219 also resulted in >5-log fungal burden reductions in A. fumigatus-infected lungs. EL219 demonstrated broad-spectrum efficacy, improved survival, and reduced lung fungal burden, supporting its potential as a novel therapy for IPA.

We evaluated the activity of aztreonam-avibactam and comparators tested against 490 MBL-producing Enterobacterales isolates collected in 27 countries during 2019-2022. The most common MBL was NDM-1, which was detected among 307 isolates. The genes encoding NDM-5 and VIM-1 were detected among 68 and 53 isolates, respectively. Other 14 MBL-encoding genes or combinations were detected among 62 isolates. Mexico, Turkey, and Greece had the highest number of isolates (60, 59, and 57, respectively). All isolates were susceptible to aztreonam-avibactam (MIC_50/90, 0.12/0.5 mg/L) when applying the EUCAST or FDA recently approved breakpoints (≤4 mg/L susceptible). Cefiderocol inhibited 66.7%/90.8% of the isolates when using EUCAST/FDA breakpoints. Cefepime-taniborbactam was active against 36.7%/55.5% of the isolates using the cefepime breakpoint for comparison purposes. Tigecycline and colistin inhibited 94.1% and 76.6% of the isolates (FDA and EUCAST breakpoints, respectively). The analysis of resistance mechanisms and genetic background of the MBL-producing isolates demonstrated genetic diversity among main species and presence of multiple resistance mechanisms including other β-lactamases, porin changes, and disruptions of efflux pump repressors. Aztreonam-avibactam was active despite the presence of these additional resistance mechanisms, but cefiderocol and cefepime-taniborbactam displayed variable activity. PBP3 YRIN and YRIK insertions were observed among 30 MBL-producing E. coli isolates. Aztreonam-avibactam MIC values ranged from 0.03 to 4 mg/L for these isolates, including an isolate carrying bla_NDM-7, bla_CMY-42, and porin changes. MBL-producing organisms are still considered an unmet medical need. Aztreonam-avibactam was active against this large collection of MBL-producing isolates that had elevated MIC values for many comparator agents.

Antimicrobial resistance driven by multidrug-resistant (MDR) Gram-negative pathogens poses a major global threat, contributing to substantial morbidity and mortality. Novel β-lactam/β-lactamase inhibitor combinations, particularly meropenem-vaborbactam (M/V) and ceftazidime-avibactam (C/A), have expanded therapeutic options; however, their comparative efficacy and safety remain uncertain. This meta-analysis compared M/V and C/A in adult patients with MDR Gram-negative infections. MEDLINE, Embase, and Cochrane Central were searched for studies evaluating M/V versus C/A in hospitalized adults. Outcomes included all-cause mortality, clinical cure, and microbiological recurrence; safety was assessed qualitatively. Data were synthesized using Review Manager, with trial sequential analysis (TSA) applied to minimize random error. Five retrospective cohort studies (three full articles and two conference abstracts) comprising 3,280 patients were included, of whom 577 received M/V and 2,703 received C/A. Populations predominantly consisted of older adults aged 57-70 years, with respiratory tract infections being most common. Pooled analyses demonstrated no statistically significant differences between M/V compared to C/A in all-cause mortality (Odds ratio [OR] 0.87; 95% CI 0.69-1.11; P = 0.26; I² = 16%), clinical cure (OR 1.41; 95% CI 0.66-3.03; P = 0.37; I² = 55%), and microbiological recurrence (OR 0.67; 95% CI 0.32-1.40; P = 0.29; I² = 0%). Qualitative synthesis indicated comparable tolerability. TSA for mortality demonstrated insufficient evidence for definitive conclusions. M/V showed no statistically significant difference over C/A; therefore, selection should be guided judiciously based on clinical context. Further studies are needed to define the optimal role of each agent within antimicrobial stewardship frameworks.

Pneumococcal conjugate vaccines (PCVs) have significantly reduced disease burden caused by Streptococcus pneumoniae, a leading cause of childhood morbidity and mortality globally. The rise of non-vaccine serotypes is a frequent phenomenon after the use of these PCVs. This study is a national surveillance that includes all pneumococcal isolates causing invasive pneumococcal disease (IPD) (4,455 isolates) in the pediatric population to analyze the changes of strains with reduced susceptibility (IPD-RS) to different antibiotics (1,458 to penicillin/1,304 to erythromycin) and the impact of PCVs and COVID-19 pandemic on antibiotic resistance. Six periods are differentiated according to this decline: pre-PCV13, early PCV13, middle PCV13, late PCV13, COVID-19, and reopening. Between 2009 and 2023, overall IPD cases in Spain decreased by over 60% in children aged 1-4 years and by approximately 50% in infants under 1 year of age. Nevertheless, an increase in IPD-RS caused by non-PCV13 serotypes was observed, with serotype 24F being the most prevalent, which is not included in the currently licensed PCVs. The introduction of PCV13 showed a substantial impact on reducing IPD in children. The COVID-19 pandemic led to a temporary decline in the burden of disease caused by resistant strains in 2020 due to non-pharmacological measures followed by a subsequent recovery.

The combined use of phages and antibiotics offers an alternative avenue against multidrug-resistant bacteria. We have previously described the synergistic antibacterial effect of the phage pB23 and meropenem combination against carbapenem-resistant Acinetobacter baumannii (CRAB). The study uncovers the underlying molecular mechanism of phage resistance in CRAB mediated by a novel stop-gain mutation in the gene gtr9. Through phenotypic characterization of pleiotropy, including reduction of capsular polysaccharide production and biofilm formation caused by the mutation in gtr9, we revealed an evolutionary trade-off mechanism whereby phage-resistant CRAB exhibits reduced carbapenem resistance. The zebrafish infection model demonstrated that these phage-resistant mutants were attenuated in virulence in vivo. Throughout continuous passage experiments in vitro, gtr9 mutants displayed the stability of decreased growth rate, phage resistance, and virulence reduction. The combination therapy between phage pB23 and meropenem in different matrices exhibited consistent synergistic antibacterial activity in vitro, demonstrating its potential therapeutic in vivo. Collectively, our study reveals a trade-off mechanism underlying phage-antibiotic synergy, thereby providing a novel insight into bacterial resistance evolution and demonstrating the therapeutic potential of this approach against CRAB infections.

The increasing prevalence of Mycoplasma genitalium (MG) strains harboring macrolide and quinolone resistance-associated mutations (MRMs and QRMs, respectively) is a growing global concern. However, data on resistance patterns and genetic diversity in Japan remain limited. This study investigated MRMs and QRMs, genetic diversity using mgpB and MG309 typing, and their association with treatment outcome in MG strains collected in Tokyo, Japan, between 2023 and 2025. Between 2023 and 2025, 188 clinical samples from 162 MG-positive patients were analyzed. Resistance mutations in 23S rRNA, parC, and gyrA were sequenced, and molecular typing was performed. Treatment outcomes were assessed using test-of-cure results. MRMs in 23S rRNA and QRMs in parC S83I and gyrA were identified in 94.4%, 65.5%, and 22.5% of samples, respectively. Dual-class resistance (MRMs + QRMs) was found in 89.4% of strains. Phylogenetic analysis based on mgpB and MG309 typing revealed the emergence of dual-class drug-resistant clonal complexes, particularly those harboring mgpB alleles 79, 140, 161, and 184. Dual-QRMs were significantly associated with quinolone treatment failure (52.4% vs 23.5%, P = 0.016). Dual-class drug-resistant MG strains, including emerging clonal complexes, are spreading in Tokyo, Japan. These findings emphasize the need for continued molecular surveillance and prudent antimicrobial use to preserve treatment efficacy.

While caspofungin is increasingly used to treat invasive fungal infections in pediatric intensive care unit (PICU) patients, its pharmacokinetic profile in this population remains poorly understood, and current dosing regimens are not firmly supported by scientific evidence. This study aimed to characterize the population pharmacokinetics of caspofungin in critically ill children and to identify dosing strategies for optimal exposure. The prospective clinical study was conducted among pediatrics in PICU. Population pharmacokinetic analysis and Monte Carlo simulations were performed. A total of 138 plasma samples collected from 29 pediatric patients (0.33-16 years) were included in the final analysis. The two-compartment model with allometric scaling on body surface area (BSA, exponential 1 for volume of distribution and 0.66 for clearance) accurately described time courses of caspofungin. Extracorporeal membrane oxygenation (ECMO) significantly increased the central volume of distribution (effect coefficient 18.2). There was no significant difference in area under the concentration curve (AUC) between patients with and without ECMO support. Simulations demonstrated that tAUC_ss,24h/MIC-based PTA results showed no significant differences between ECMO and non-ECMO groups and supported the current dosing regimen. A fixed maintenance dose (MD) is appropriate for patients with BSA ≥ 1.4 m², while the standard BSA-based MD remains preferable for those with BSA <1.4 m². Our study confirmed the recommended caspofungin dosing regimen in Chinese critically ill PICU patients. Although the number of patients receiving ECMO in this study was limited, future studies with a larger ECMO population are warranted to further validate these findings.This study is registered with ClinicalTrials.gov as NCT04961593.

The role of TetA variants in mediating tigecycline and eravacycline resistance in Klebsiella pneumoniae remains a critical area of investigation. However, there has been a lack of systematic characterization of the epidemiology, resistance phenotypes, and fitness costs of TetA variants. Here, we identified 28 TetA variants in K. pneumoniae from the National Center for Biotechnology Information database from 824 isolates, categorizing them into three phylogenetically distinct clades. Among these, four variants were shown to mediate eravacycline resistance, with concurrent but variable effects on tigecycline susceptibility. Notably, these resistance-conferring variants exhibited limited dissemination across clinical and environmental strains. Analyses revealed that their expression imposes a significant fitness cost, markedly reducing bacterial tolerance to the clinical disinfectant H₂O₂ and an environmental heavy metal cadmium-a trait critical for survival under ecological stress. This trade-off likely explains the limited prevalence of these variants despite their resistance phenotypes. Our findings highlight the evolutionary constraints affecting the spread of TetA-mediated antibiotic resistance and underscore the need for One Health-driven surveillance to monitor variants with potential risk in human, animal, and environmental reservoirs. This work provides novel insights into the interplay between resistance determinants and bacterial adaptability, offering a framework for predicting resistance dynamics in K. pneumoniae within the context of interconnected ecological and clinical ecosystems.

The development of new regimens to treat tuberculosis (TB), the disease caused by Mycobacterium tuberculosis, is critical to improving patient outcomes and decreasing global infectious disease mortality. Early evaluation of candidate regimens in non-clinical models of TB, such as the relapsing mouse model (RMM), remains an important step in prioritizing the most efficacious regimens for further clinical evaluation. Although RMM studies may be informative, they are also animal-, labor-, and time-intensive to complete and represent a significant investment in time and resources during non-clinical development. Given the strong pipeline of regimens in development, identification of "leaner" RMM studies may have a significant impact on resource utilization, and hence we compared alternative study designs to identify study attributes that can be modified to improve resource use, particularly animal use. By simulating relapse outcomes from "virtual" studies (i.e., groups of mice treated for selected durations with control and hypothetical anti-TB regimens) followed by model-based analysis of the simulated data, we were able to compare the "true" (input) values with model estimates of time to 95% cure probability (T₉₅) and assess bias and precision of competing designs. Using this approach, we demonstrated that 28% fewer mice could be used in RMM studies while maintaining low bias and a precision for T₉₅ estimation within ±1-2 weeks for most regimens. Therefore, it is expected that RMM studies based upon the alternative designs evaluated herein may be employed to promote improved animal stewardship while generating informative data for decision-making.

Neonatal doses for the off-patent antibiotics fosfomycin and flomoxef, which offer coverage against many extended-spectrum beta-lactamase (ESBL)-producing organisms, are based on limited data. We performed a pharmacokinetic (PK) and safety study of fosfomycin and flomoxef to confirm proposed neonatal dosing before further investigation in a trial (NeoSep1, ISRCTN48721236). Neonates with suspected sepsis, weighing more than 1,000 g, were sequentially enrolled into three antibiotic treatment cohorts: fosfomycin and amikacin (Cohort 1), flomoxef and amikacin (Cohort 2), and flomoxef and fosfomycin (Cohort 3), and followed for 28 days. Plasma samples were taken for PK assessment, with population PK modeling and simulations performed. Sixty-two neonates (48/62 [77%] preterm; 48/62 [77%] ≤7 days postnatal age [PNA]) received at least one dose of study antibiotics. Fosfomycin and flomoxef plasma concentrations were best described by a two-compartment and a one-compartment model, respectively, with postmenstrual age and PNA significantly influencing clearance. The probability of target attainment for fosfomycin was 100% for minimum inhibitory concentrations (MICs) of up to 8 mg/L, and for flomoxef, it was 100% for MICs of up to 0.5 mg/L. Adverse events (AEs) were common in this critically ill cohort. Thirteen (21%) neonates developed 19 trial antibiotic-related AEs (17 with grade ≤2, and 2 of grade 3), none of which required modification or discontinuation of allocated treatment. Seven neonates (11.6%) died. In this predominately preterm population, fosfomycin and flomoxef were safe, with drug exposures similar to published studies supporting the proposed doses for the larger, randomized NeoSep1 trial.This study is registered with ISRCTN48721236.