Journal of Antimicrobial Chemotherapy最新文献

Background: Heteroresistance (HR) in Pseudomonas aeruginosa causes misclassification as 'susceptible (S)' on routine antibiotic susceptibility techniques, potentially contributing to subsequent treatment failure. This study aimed to explore clinically relevant risk factors for HR compared with S (S-HR), and resistant (R) compared with HR (HR-R) phenotypes. Additionally, we explored whether integrating medical history and laboratory data can enable rapid and accurate identification of HR and R phenotypes in this pathogen.

Methods: This retrospective study included 420 P. aeruginosa strains collected from 2011 to 2024 in China. The strains were categorized into three groups according to their sensitivity to meropenem: non-heteroresistant susceptible, heteroresistant and non-heteroresistant resistant. Logistic regression, random forest and XGBoost models were constructed using variables identified through LASSO (least absolute shrinkage and selection operator) regression. The models' performance was evaluated via 10-fold cross-validation comparing area under the receiver operating characteristic curve (AUROC), sensitivity and specificity.

Results: Multivariate analyses identified central venous catheters as an independent risk factor for S-HR, and malignant solid tumours, pulmonary infections, mechanical ventilation and carbapenem use for HR-R. A discriminating diagnostic model, combining clinical and laboratory data, showed an AUROC of 0.919 for HR-R and 0.856 for S-HR. The calibration plots indicated good alignment between the estimated and observed probabilities.

Conclusions: This study presents a validated two-stage risk assessment model to discriminate the two phases of meropenem heteroresistance in P. aeruginosa. By identifying novel stage-specific risk factors and delivering a practical tool compatible with clinical workflows, this model facilitates the early identification and targeted intervention of HR, offering novel insights into the mechanistic dissection of HR.

Background: Carbapenem antibiotics are critical therapies for multidrug-resistant infections, but their comparative haematologic safety profiles remain poorly characterized. We systematically evaluated haematologic adverse events associated with meropenem, ertapenem, imipenem and doripenem using pharmacovigilance data.

Methods: We analyzed the FDA Adverse Event Reporting System (FAERS) database from January 2013 to July 2025. Disproportionality analysis was performed using reporting odds ratios (RORs) with 95% confidence intervals for haematologic adverse events.

Results: Sixteen distinct haematologic adverse events were identified. Meropenem demonstrated the most extensive toxicity profile with significant signals for 15 adverse events, including severe conditions: thrombocytosis (ROR = 24.941), eosinophilia (ROR = 24.663), bone marrow failure (ROR = 13.113), agranulocytosis (ROR = 11.57) and pancytopenia (ROR = 11.131). Imipenem demonstrated signals for nine events, notably thrombocytopenia and eosinophilia. Ertapenem demonstrated nine events: leucopenia (ROR = 3.843) and neutropenia (ROR = 2.469). No reports were identified for doripenem.

Conclusions: Significant differences exist in haematologic safety profiles among carbapenems. Meropenem shows the broadest spectrum of severe toxicity, while other carbapenems demonstrate fewer reports. demonstrates fewer reported haematologic safety signals and not a most favourable haematologic safety profile. These differential safety profiles should inform further studies on carbapenem selection, including patients with baseline haematologic disorders.

Background: Antibiotic resistance and tolerance pose dual challenges to clinical antibiotic therapy, with tolerance potentially accelerating resistance evolution. LYSC98, a candidate drug that has just received clinical approval in China, has been reported to have bactericidal activity against antibiotic-resistant Staphylococcus aureus. However, its mechanism and activity against antibiotic-resistant bacteria in tolerant state remains unexplored.

Objectives: To evaluate the antibacterial activity of LYSC98 against antibiotic-resistant bacteria in different metabolite states, and to elucidate its mechanism of action.

Materials and methods: MIC values of antimicrobial agents were determined using broth microdilution. Time-kill assays were used to evaluate the bactericidal effect. SEM and TEM were conducted to visualize the morphological changes. Membrane permeability was determined by propidium iodide.

Results: LYSC98 showed potent antibacterial activity against Gram-positive pathogens, with MICs ranging from 0.06 to 2 mg/L. It demonstrated a rapid bactericidal effect against antibiotic-resistant pathogens, irrespective of their growth phase or tolerant state, and conferred an extended post-antibiotic effect. Significantly, LYSC98 displayed a low potential for resistance development. It targeted both bacterial cell wall and membrane, with in vitro membrane assays indicating selective damage to these structures and no observed harm to mammalian cells.

Conclusions: LYSC98's rapid bactericidal activity, selective disruption of bacteria without harming mammalian cells and low propensity for resistance development make it a novel promising candidate for combating chronic, clinically recalcitrant infections.

Objectives: The COVID-19 pandemic impacted healthcare use, with mixed reports regarding impacts on antimicrobial resistance. The aim was to identify changes in healthcare utilisation and antibiotic prescribing related to the COVID-19 pandemic and quantify subsequent impacts on antibiotic resistance in clinical Escherichia coli isolates in Scotland.

Methods: Data involving ∼490 000 people from January 2018 to March 2022 were analysed. Joinpoint regression analyses identified trend changes in healthcare encounters, and antibiotic use in community and hospital settings. Using these joinpoints as an 'intervention' timepoint, interrupted time series analysis quantified associated changes in proportions of E. coli blood and urine culture isolates that were antibiotic resistant and multidrug resistant (MDR).

Results: January 2020 was identified as the intervention point. From 26% resistant (not MDR) and 35% MDR among urine E. coli isolates immediately pre-intervention, there were changes in level of +2.5% (95%CI -0.4% to 5.4%) and trend of +0.3% (95%CI 0.1% to 0.5%) per month for resistant (not MDR), and level change of +0.4% (95%CI -2.0% to 2.8%) but trend change of -0.3% (95%CI -0.5% to -0.1%) per month for MDR. By 9 month post-intervention, compared with predicted levels without intervention, resistant (not MDR) proportions increased while MDR proportions decreased. Similar changes occurred among blood culture isolates, but with less certainty around estimates.

Conclusion: Small but significant reductions in MDR E. coli resulted from COVID-19-related changes in healthcare and antibiotic use. The findings are critical for antimicrobial stewardship and infection control interventions and evaluation.

Objectives: Age-related pathophysiological changes may impact the pharmacokinetics and pharmacodynamics (PK/PD) of ß-lactam antibiotics, potentially resulting in suboptimal concentrations in older adults. This study evaluated PK/PD target attainment with current intravenous amoxicillin-clavulanate and piperacillin-tazobactam dosing regimens in older adults, identified risk factors for target non-attainment, and assessed the prevalence of toxic concentrations.

Methods: This was a prospective, observational PK study in geriatric inpatients (≥75 years) who were treated intravenously with amoxicillin-clavulanate (1 g/0.2 g q6h as a 30-minute infusion) or piperacillin-tazobactam (4 g/0.5 g q6h as a 3-hour infusion). Trough blood samples were collected in steady-state conditions. Target attainment was evaluated against a 100%fT > MIC target. Risk factors for target non-attainment were identified by multivariable logistic regression analysis. Toxicity thresholds were defined as total Cmin concentrations of 80 mg/L for amoxicillin and 157.2 mg/L for piperacillin.

Results: Seventy-four patients (median age (IQR): 87 years (83-90)) were included. The PK/PD target was achieved in 15 of 35 and 33 of 39 patients for amoxicillin-clavulanate and piperacillin-tazobactam, respectively. Multivariable logistic regression analysis revealed an effect of comorbidity burden, assessed by the Cumulative Illness Rating Scale-Geriatric (CIRS-G), and estimated glomerular filtration rate that explained 23.8% of target non-attainment (P < 0.05). Receiver operator characteristic curves identified an eGFR of 67 mL/min/1.73m2 as a threshold associated with an increased risk of target non-attainment. Toxicity thresholds were never exceeded in this study.

Conclusions: Health status and renal function, rather than chronological age, play a significant role in target non-attainment among older adults. Further research is required to delineate predictors for interpatient variability in PK and develop evidence-based dosing strategies.

Trial registration: Registration in ClinicalTrials.govTrial registration number: NCT04436991Registration date: 16/06/2020.

Objectives: To investigate the species distribution and antifungal susceptibility profiles of clinical mould isolates from China to olorofim, manogepix, amphotericin B, triazoles and echinocandins.

Methods: Isolates were collected from patients at 10 tertiary hospitals across China between 2019 and 2024. Species identification was performed by sequence analysis. Antifungal susceptibility testing was performed according to the CLSI reference methods. The cyp51A, cyp51B and hmg1 genes from triazole-resistant isolates were amplified to identify mutations associated with resistance.

Results: Aspergillus spp. (92.02%) remained the most prevalent pathogens, followed by Fusarium spp. (4.18%) and Mucorales (1.90%). The proportion of non-A. fumigatus isolates showed an increasing trend. The majority of Aspergillus spp. were susceptible/WT to triazoles (97.52%), with posaconazole showing the highest potency. Among the triazole-resistant Aspergillus isolates, two harboured cyp51A mutations (TR46/Y121F/T289A, G441S) and one carried an hmg1 mutation (V827L). Notably, the novel antifungals olorofim and manogepix were highly potent against most tested moulds, including triazole-resistant Aspergillus isolates. For Fusarium spp., manogepix showed low MECs, whereas olorofim and triazoles showed higher and more species-specific MICs. Both novel agents showed high MIC/MECs against Mucorales isolates, and triazole MIC distributions varied markedly between species.

Conclusions: A. fumigatus sensu stricto remained the predominant pathogen while non-A. fumigatus moulds became increasingly prevalent. Triazole resistance among clinical Aspergillus isolates was uncommon but was associated with cross-resistance and target gene mutations. Novel antifungals olorofim and manogepix demonstrated potent in vitro activity against a broad range of clinical moulds, including triazole-resistant Aspergillus isolates.

Background: Antimicrobial resistance among Enterobacter cloacae complex and Klebsiella aerogenes is a growing clinical challenge, often driven by AmpC β-lactamase hyperproduction. This phenotype limits therapeutic options to cefepime or carbapenems.

Objectives: To assess the in vitro activity of conventional β-lactams, such as cefepime, piperacillin/tazobactam or carbapenems, and new-generation agents, including ceftazidime/avibactam, cefepime/taniborbactam, imipenem/relebactam, meropenem/vaborbactam, and cefiderocol, against AmpC-hyperproducing E. cloacae complex and K. aerogenes.

Methods: A total of 314 clinical isolates (200 E. cloacae complex and 114 K. aerogenes) recovered between March and December 2024, from eight Spanish centres were tested by broth microdilution (EUCAST). AmpC hyperproduction was confirmed phenotypically and carbapenemase was screened phenotypically/molecularly. WGS was performed for (i) 84 E. cloacae complex isolates, and (ii) six isolates with reduced susceptibility to at least one novel agent.

Results: High resistance rates were observed for piperacillin/tazobactam (up to 82.4%) and cefepime (up to 20.5%), whereas carbapenems showed variable activity. New-generation agents exhibited excellent activity, with susceptibility rates ≥99% in both species. Resistance to at least one new agent was found in only six isolates. In the WGS-analysed E. cloacae complex subset, Enterobacter hormaechei predominated (75%) with high STs and blaACT allele diversity. In the six reduced-susceptibility isolates, no carbapenemase or explanatory acquired β-lactamase was found.

Conclusions: Our findings underscore the need to take this phenotype into account in clinical practice and confirm the limited activity of conventional β-lactams against AmpC-hyperproducing E. cloacae complex and K. aerogenes, and support the use of newer agents as effective alternatives.