Journal of Antimicrobial Chemotherapy最新文献

Objectives: Gepotidacin is a novel triazaacenaphthylene topoisomerase inhibitor that has demonstrated non-inferiority to 500 mg of intramuscular ceftriaxone plus 1 g of oral azithromycin for the treatment of uncomplicated urogenital gonorrhoea. We evaluated gepotidacin in vitro activity against a panel of ceftriaxone-resistant Neisseria gonorrhoeae isolates that were referred to the UK Health Security Agency between 2015 and 2023.

Methods: Gepotidacin and comparator antimicrobials were tested against 23 ceftriaxone-resistant (MIC ≥0.25 mg/L) N. gonorrhoeae isolates by agar dilution. Genomic sequences were examined for known resistance determinants and sequence types.

Results: Gepotidacin inhibited the majority (96%) of isolates at ≤2 mg/L, with MIC range, MIC50 and MIC90 values of 0.25-4, 0.5 and 2 mg/L, respectively. All 23 isolates had amino-acid modifications associated with ciprofloxacin resistance, including the rare GyrA A92P alteration in 10 isolates, none of which are believed to effect gepotidacin binding. All isolates had mutations causing the overexpression of the MtrCDE efflux pump and 10 isolates had mutations causing the overexpression of the NorM efflux pump. Nine different MLSTs were subdivided into 16 and 14 NG-MAST and NG-STAR types, respectively. MLST ST8123 was the most prevalent MLST and the gepotidacin MIC range against this sequence type was similar to the overall distribution.

Conclusion: Overall, gepotidacin was active in vitro against this challenging panel of ceftriaxone-resistant gonococcal clinical isolates. Gepotidacin activity does not seem to be affected in this ceftriaxone-resistant set of strains. A structural analysis suggests that the rare GyrA A92P alteration identified in this study does not affect gepotidacin binding.

Objectives: There are few data on the penetration of daptomycin into the cerebrospinal fluid (CSF) of patients with bacterial meningitis. This ancillary study of the AddaMap trial aimed to assess the CSF penetration of intravenous daptomycin in 13 patients with pneumococcal meningitis.

Patients and methods: Daptomycin was administered at 10 mg/kg/day to 13 patients with pneumococcal meningitis admitted to the Dijon University Hospital. Blood and CSF samples were collected on days 3 and 8. The population pharmacokinetics of daptomycin in plasma and CSF were studied using a two-compartment model.

Results: A large inter-individual variability in plasma areas under the curve (median, 25-75-percentile), 7843 h.mg/L (6606-9264), plasma peak, 107.5 mg/L (81.4-126.3) and trough 14 mg/L (7.6-19.3) concentrations and elimination half-lives, 8.8 hours (7.9-10.8), was observed. In CSF, the maximum concentration was 0.88 mg/L (0.57-2.82), and the elimination half-life was 23.8 hours (18.7-39.3). The AUC CSF/plasma ratio was 2.20% (1.7-2.3). Daptomycin CSF penetration was significantly correlated with CSF levels of proteins and lactate. CSF concentrations, 0.67 mg/L (0.39-0.86), were above the MIC90 of pneumococci resistant to beta-lactam. Simulations showed that a loading dose could reduce the time required to reach a biologically active concentration in CSF.

Conclusion: We conclude that daptomycin administered at a dose of 10 mg/kg/day achieves CSF concentrations that may exert non-lytic anti-pneumococcal effects and demonstrate significant activity against highly resistant pneumococcal strains. These findings suggest that daptomycin could be considered as a valuable adjunctive therapy in the treatment of pneumococcal meningitis.

Background: Resistance-associated mutations (RAMs) to second-generation integrase strand-transfer inhibitors (INSTIs) have been increasingly observed among people with HIV (PWH) who experienced virological failure on dolutegravir-based ART. However, data on dolutegravir resistance in the Asia-Pacific region remain limited, and data on RAMs during virological failure while receiving bictegravir-based ART are even more scarce.

Methods: In this multicentre, retrospective study in Taiwan, PWH with treatment failure on second-generation INSTI-based ART and successful amplification of the integrase gene were included. Data collected included HIV-1 subtypes, plasma viral loads (PVLs), CD4 counts and clinical characteristics. RAMs were identified using the 2025 IAS-USA mutation list and interpreted using the Stanford HIVdb algorithm.

Results: From 2016 to 2022, 73 and 127 PWH experienced treatment failure on bictegravir- and dolutegravir-based ART, respectively, and had successful genotypic resistance testing. Median PVL at failure was 4.7 log10 copies/mL, and median CD4 count was 225 cells/mm3, with no significant between-group differences. RAMs to second-generation INSTIs were detected in 5.5% (4/73) of bictegravir- and 4.8% (6/127) of dolutegravir-treated individuals (P = 0.33). Common RAMs included Q148H/K/R (3.5%), G140A/C/R/S (3.0%) and R263K (1.5%), with comparable distributions between the two groups. Among eight PWH retained in care, four achieved viral suppression after switching to salvage ART, and four with continuation of INSTI-based ART.

Conclusions: Although RAMs to second-generation INSTIs may be detected during treatment failure, the overall prevalence remains low for both dolutegravir- and bictegravir-based ART. Viral resuppression can be achieved through salvage therapy or continued use of second-generation INSTI-based regimens.

Background: Tigecycline is increasingly used off-label for hospital-acquired pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB). While the standard-dose regimen (100 mg loading dose followed by 50 mg q12h) yields suboptimal outcomes, a high-dose regimen (200 mg loading dose followed by 100 mg q12h) has been proposed to improve efficacy, but its clinical benefits remain controversial. This study aimed to compare microbiological responses of standard- and high-dose tigecycline regimens under simulated lung exposure.

Methods: Two clinical CRAB isolates (CRAB21824 and CRAB21849) were characterized by tigecycline susceptibility testing and carbapenemase phenotypic/genotypic analysis. A hollow-fibre infection model (HFIM) along with semi-mechanistic PK/PD modelling was employed to simulate tigecycline pharmacokinetics in epithelial lining fluid of pneumonia patients and assess the antibacterial activity and resistance development under both dosing regimens. Tigecycline resistance mechanisms were investigated using whole-genome resequencing and molecular docking.

Results: Tigecycline MICs were 1 and 0.25 mg/L for CRAB21824 and CRAB21849, respectively. Both strains carried blaOXA-66 and blaOXA-23, encoding Class D carbapenemase, but lacked Class A and B carbapenemases. HFIM-driven semi-mechanistic PK/PD modelling revealed strain- and dose-dependent antibacterial activity of tigecycline. The high-dose regimen exhibited prolonged antimicrobial effects compared to standard dosing. However, it ultimately led to bacterial regrowth for CRAB21849, despite achieving the pharmacodynamic target of AUC0-24h/MIC >4.5. A missense mutation in adeB (c.218T > G, p.Val73Gly) enhancing tigecycline efflux was identified as the resistance mechanism.

Conclusion: While high-dose tigecycline enhanced antibacterial efficacy, its failure to prevent efflux-mediated resistance in specific strains highlights the inherent limitations of dose escalation for CRAB pneumonia treatment.

Background: Klebsiella pneumoniae poses a critical global health threat due to its increasing resistance to polymyxin, the last-line antibiotic. Outer membrane remodelling, mediated by various two-component systems (TCS), is primarily involved in the development of polymyxin resistance (PolR). This study conducted an in-depth analysis of mutations within TCS-associated genes that contribute to PolR in K. pneumoniae.

Methods: A systematic literature search was conducted in PubMed, Google Scholar, ScienceDirect and Scopus to identify studies reporting TCS-mediated PolR in K. pneumoniae. Data on gene mutations, mutation sites and geographical distribution were extracted. In silico analyses using PROVEAN and DynaMut2 were performed to predict the structural consequences and functional impact of the mutations.

Results: Our study revealed that disruptions in the MgrB protein, primarily through IS elements and amino acid substitutions, are the major drivers of PolR. Additionally, notable mutations were observed in the PhoPQ, PmrAB and CrrAB TCSs among the PolR strains, which may potentially impact the function of these modules. Moreover, several such mutations were found to be located in specific hotspot regions in the protein structure and have a distinct geographical distribution.

Conclusions: This study provides a comprehensive overview of TCS-mediated PolR mechanisms in K. pneumoniae, highlighting the diversity and functional impact of mutations in key regulatory genes. The prevalence of IS elements, particularly in mgrB, and point mutations in mgrB, phoPQ, pmrAB and crrAB underscores the complex evolutionary pathways leading to PolR. Understanding these mechanisms is crucial for developing effective strategies to combat the spread of PolR  K. pneumoniae.

Objectives: To assess the adherence of Ghanaian healthcare laboratories to AST standards and to assess discrepancies between breakpoint-defining dosages and recommended doses in Ghanaian National Standard Treatment Guidelines (NSTGs).

Methods: Nineteen laboratories were issued electronic questionnaires regarding AST methods and guidance. NSTG doses and breakpoint-defining dosages were compared to determine the applicability of AST standards.

Results: Eleven of the 19 laboratories responded. Traditional biochemical species identification was the most common method among surveyed laboratories, with disc diffusion being the main AST method. All laboratories reported using CLSI standards. Major quality assurance issues identified regarding AST testing included the use of outdated standards, failure to consistently determine inoculum density, irregular use of quality control strains, and agent limitations on antibiotic disc panels. Discrepancies in definitions for multidrug resistance and the testing of such isolates were also identified.When comparing recommended NSTG doses to breakpoint-defining dosages, the EUCAST standard had a higher number of doses available for review (30/30, 100% versus 14/30, 47%) and a higher percentage of full agreement (19/30, 63% versus 6/30, 20%) compared with CLSI. Discrepancies between breakpoint-defining and recommended dosages were found for meropenem, ceftriaxone, and amoxicillin-clavulanic acid oral/iv, leading to potential underdosing.

Conclusions: This study highlights the need for rigorous adherence to AST standards and outlines considerations for the adoption of AST standards in a low-middle-income country.

Background: Antimicrobial stewardship (AMS) programmes are led by multi-professional teams and are central to optimizing antimicrobial use and minimizing inappropriate use. Although frameworks exist that describe the knowledge and skills relating to antimicrobial resistance (AMR) and AMS for generalist healthcare professionals, there is a need to provide a framework for AMS specialists working in the NHS that supports the development of flexible capabilities rather than granular competencies.

Objectives: To develop a multi-professional capability framework to recognize and develop the specialist knowledge and skills of AMS staff across all sectors of healthcare, including adult and paediatric services, at all levels of post-foundation specialist practice.

Methods: A modified Delphi approach was adopted. Initial capability statements were derived from a literature review. An expert panel of UK-based AMS professionals participated in two Delphi survey rounds to assess the importance of each capability statement and map level of delivery against level of practice. Descriptors of practice and professional development resources were identified through follow-up workshops and consultation.

Results: From 922 source statements, 45 capability statements were agreed and structured into four domains: AMS Professional Practice, Leadership and Management, Education, and Research and Quality Improvement. Consensus was reached across all statements following two Delphi rounds. Descriptors of practice and development resources were identified to support benchmarking and professional development across all levels of specialist practice.

Conclusions: This multi-professional capability framework defines AMS specialist practice relevant to all NHS sectors, supporting professional development, career progression, and strategic workforce planning across all professional groups.

Objectives: Optimal antimicrobial exposure in epithelial lining fluid (ELF) is critical for meropenem efficacy in pneumonia, yet ELF pharmacokinetic data remain scarce, particularly in children. To address this, we aimed to develop a model capable of predicting meropenem concentrations in both plasma and ELF for evaluating pharmacodynamic target attainment under clinical dosing strategies.

Methods: A physiologically based pharmacokinetic (PBPK) model was developed to simulate unbound meropenem concentrations in plasma and ELF. An empirical penetration coefficient (ρ) was incorporated to link lung intracellular concentrations to ELF concentrations, modelled as a function of clinical and inflammatory covariates. Following validation, the percentage of time over a dosing interval that the free drug concentration remains above the MIC(%ƒT > MIC), of meropenem plasma and ELF were related to in-hospital mortality. Monte Carlo simulations were conducted to assess the PTA for 40%ƒT >  MIC under varying regimens, MIC ranges (0.25-16 mg/L) and penetration scenarios.

Results: The PBPK model accurately predicted meropenem exposures in both plasma and ELF. ELF penetration was significantly influenced by physiological and pathological factors. ELF %ƒT >  MIC showed higher interindividual variability compared with that of plasma and was more strongly correlated with survival in both adult (P = 0.073) and paediatric patients (P = 0.013). Although prolonging the infusion improved ELF target attainment for susceptible pathogens (MIC ≤4 mg/L) with adequate penetration, it failed against high-MIC strains or with poor lung penetration.

Conclusions: These findings underscore the importance of targeting infection-site pharmacokinetics over plasma exposure for better therapeutic efficacy in pneumonia. The model can be used to optimize dosing strategies.

Background: Considerable inter-individual variability in the pharmacokinetics of long-acting injectable (LAI) rilpivirine and cabotegravir has been reported. Here, we sought to evaluate intra- and inter-individual variability of rilpivirine and cabotegravir plasma trough concentrations and to assess the influence of demographic factors and body composition on drug exposure in people with HIV (PWH) receiving LAI therapy.

Methods: This retrospective observational study included PWH treated with LAI rilpivirine and cabotegravir for ≥16 months, with at least three consecutive plasma trough concentration assessments. Body composition was estimated by bioelectrical impedance analysis. Associations between drug levels and clinical variables were analysed using univariate and multivariate regression analysis.

Results: Forty-eight PWH were included (mean age 47 ± 15 years, 17% females). Rilpivirine and cabotegravir showed moderate intra-individual variability in trough concentrations (28-30%), with <1% of samples below the therapeutic threshold. Cabotegravir trough concentrations were significantly higher in women than in men (3285 ± 921 versus 2096 ± 775 ng/mL; P < 0001) and in participants aged >65 years compared with younger individuals (2826 ± 455 ng/mL versus 2119 ± 1006 ng/mL; P = 0044); in addition, cabotegravir levels inversely correlated with skeletal muscle mass (r = -0.45; P = 0.008) and bone mass (r = -0.47; P = 0006). On the contrary, rilpivirine concentrations showed no significant associations with demographic or body composition variables. Multivariate analysis confirmed age, sex and muscle mass as independent predictors of cabotegravir exposure.

Conclusions: Sex, age and muscle mass significantly influence cabotegravir-but not rilpivirine-trough concentrations in PWH receiving LAI therapy. Therapeutic drug monitoring combined with body composition assessment may help to optimize dosing interval adjustment.