Journal of Antimicrobial Chemotherapy最新文献

Biofilm-associated infections represent a major therapeutic challenge due to reduced antimicrobial susceptibility and the limited predictive value of conventional pharmacokinetic/pharmacodynamic (PK/PD) indices with clinical outcome. A wide spectrum of experimental models has been developed to study biofilms, ranging from simple in vitro assays to ex vivo tissue-derived systems and in vivo infection models. Each category provides distinct advantages: in vitro platforms enable high-throughput compound screening and measurement of biofilm-specific indices such as MBIC and MBEC; ex vivo models preserve host tissue architecture and allow investigation of topical therapies and therapeutic windows; and in vivo systems are indispensable for analysing host-pathogen interactions and systemic PK/PD relationships. No single model is sufficient to replicate clinical biofilm complexity, but combined use and progressive standardization can improve translational value. This review provides a structured overview of available models, their PK/PD readouts and their strengths and limitations, aiming to guide model selection in preclinical biofilm research and antimicrobial development.

Objectives: To describe meropenem population pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation (ECMO) with or without renal replacement therapy (RRT), and to identify dosing regimens likely to achieve safe and effective exposures.

Methods: Serial blood samples were collected over a single dosing interval during ECMO. Total plasma concentrations were measured by a validated assay. Population pharmacokinetic modelling and Monte Carlo dosing simulations were performed using Monolix. Dosing regimens were assessed against efficacy targets (Cmin ≥2 or ≥8 mg/L) and a toxicity threshold (Cmin >45 mg/L).

Results: A total of 150 plasma concentration-time points were obtained from 18 patients. Meropenem pharmacokinetics were best described by a two-compartment model with first-order elimination. ECMO flow rate significantly influenced the volume of distribution of the central compartment, while estimated creatinine clearance and concomitant RRT significantly influenced drug clearance. Using the primary efficacy target of 2 mg/L, a meropenem dose of 1 g every 8 h as continuous infusion was the most appropriate regimen for patients with a creatinine clearance of 60-130 mL/min receiving ECMO at a flow rate of 4-6 L/min. In patients receiving RRT, this regimen demonstrated less than 4% probability of reaching toxic concentrations and 100% probability of achieving the efficacy target across all simulated scenarios. The regimen remained robust against the higher efficacy target of 8 mg/L in most scenarios.

Conclusions: A meropenem dose of 1 g every 8 h as continuous infusion is safe and efficacious in most critically ill patients receiving ECMO with or without concomitant RRT.

Background and objectives: Integrase strand transfer inhibitors (INSTIs) and NNRTIs are widely used in the treatment of HIV, but the real-world adverse events (AEs) profiles of these drugs remain inadequately characterized. We prioritized AEs reported with INSTIs and NNRTIs using data from the FDA Adverse Event Reporting System (FAERS).

Methods: Using FAERS data (from FDA approval to June 2024) for 10 drugs (cabotegravir, dolutegravir, raltegravir, elvitegravir, bictegravir, nevirapine, efavirenz, rilpivirine, doravirine and etravirine), we assessed AE clinical priority using a multi-criteria score. The score evaluated four criteria: clinical relevance, reporting proportion, case fatality rate and signal stability. We calculated reporting odds ratios (RORs) with 95% CIs; signals required the lower limit of 95% CIs of the ROR, ROR025 > 1 after Bonferroni correction across [N] tested AEs per drug. Events related to medication errors or HIV-related conditions were excluded. A case-by-case assessment was conducted to evaluate the confounding factors from co-medications and indications.

Results: We found 4487/6362 (70.5%) were low priority (0-2 points) and 1849/6362 (29.1%) were moderate (3-5 points), 2, 8, 6 and 15 marginally high-priority (≥4.5 points) adverse pregnancy outcomes were identified with dolutegravir, raltegravir, nevirapine, efavirenz, respectively; 26 AEs were high clinical priorities (>5 points). After case-by-case assessment, five noteworthy AEs remained. These included efavirenz-related haemolytic anaemia, etravirine-related hepatic failure, dolutegravir-related foetal death, raltegravir-related drug reaction with eosinophilia and systemic symptoms, and raltegravir-related hepatic failure.

Conclusions: This study provides a systematic framework for evaluating post-marketing AEs of INSTIs and NNRTIs using a semi-quantitative scoring system. Our findings identified five high-priority AEs that require clinical validation and further investigation.

Objectives: To assess the prevalence of transmitted drug resistance mutations (TDRMs) and the impact of pre-existing resistance mutations, including minority variants, on virological response in ART-naïve individuals initiating dolutegravir-based triple therapy using next-generation sequencing (GRT-NGS).

Methods: A multicentre, retrospective cohort study was conducted including ART-naïve individuals who started a dolutegravir-3DR between 2015 and 2019. Baseline GRT-NGS Illumina®, covering RT, PR and IN genes identified primary (P-DRM) and secondary/polymorphic (S/p-DRM) mutations in high-abundance drug resistance variants (HA-DRVs; ≥20%) and low-abundance drug resistance variants (LA-DRVs; 1%-19%). Virological failure (VF) was defined as two consecutive HIV-1 RNA ≥ 50 copies/mL. Virological response was assessed at Weeks 48 and 96.

Results: Of 326 participants, 86% were male and 72% were MSM; 78% received DTG/ABC/3TC and 22% TDF/FTC + DTG. At least one TDRM was detected in 24% and any DRM in 48% of subjects. Virological suppression was achieved in 76% by intention-to-treat (ITT), 97% on-treatment (OT) and 56% (ITT), 94% (ITT) at Weeks 48 and 96, respectively. VF occurred in 11 subjects (3.4%), mostly within 48 weeks, all with low-level viraemia (<1000 copies/mL; 8 < 200 copies/mL) and no emergent of new DRM in HA-DRVs with phenotypic impact. Among those with pre-existing DRM, including 36 P-HA-DRVs, 79 S/p-HA-DRVs, 57 P-LA-DRVs and 45 S/P-LA-DRVs, no significant association with VF was observed.

Conclusions: Our findings indicate that pre-existing IN and RT DRM, including low-abundance and secondary/polymorphic variants, did not compromise the virological efficacy of dolutegravir-based triple therapy in ART-naïve individuals, supporting the high resistance barrier of dolutegravir and the lack of need for baseline resistance testing.

Invasive aspergillosis (IA) crude mortality has shown a sustained reduction over the past decades, demonstrated in randomized controlled clinical trials of new antifungal agents and across large population surveys. New diagnostic tools and integrated management approaches have driven faster, more targeted initiation of appropriate antifungal therapy. In parallel, improvements in the identification of periods at highest risk for IA and in practices for management of the underlying disease processes predisposing to immunosuppression, including immunomodulatory therapies, have progressed. Given the highly complex and interconnected relationship between the underlying disease and its treatment and the predisposition to IA that the underlying disease creates, it is difficult to separate out which mortality improvements could be attributable to improved management of IA and which to better management of the underlying disease. The reductions in IA mortality have been sustained despite increases in the number of older, more vulnerable patients with more severe underlying disease undergoing treatment for acute haematological disorders and haematopoietic cell transplantation. This gradual and subtle move to a higher risk, more co-morbid patient population may have obscured any impact from the management developments other than antifungal therapy over this period, including better fungal diagnosis and supportive care. The overwhelming single factor contributing to a reduction in IA mortality over the past years appears to have been the routine adoption of mould-active antifungals, azoles in particular. Any impact of consensus definitions used to classify disease, improvements in diagnostic tools and earlier targeted strategies, remains difficult to measure based on available data. However, recently, the use of mould-active azoles has become threatened by the emergence of azole resistance in Aspergillus fumigatus, the frequent co-occurrence of Aspergillus species and Mucorales species, and difficult to handle drug-drug interactions, thereby fuelling an ongoing search for novel antifungal agents.

Objectives: To search for colistin heteroresistance (CHR) prevalence in Acinetobacter baumannii bloodstream isolates, and to investigate potential molecular contributors to CHR using WGS.

Methods: A total of 267 A. baumannii isolates were recovered from bloodstream infections between January 2014 and July 2018 at a tertiary care hospital in Türkiye. Antimicrobial susceptibility to colistin was assessed using the broth microdilution method. CHR was evaluated by population analysis profiling (PAP). WGS was performed on a representative heteroresistant strain (A325) to investigate putative CHR-associated mechanisms.

Results: Thirty-five isolates (13.9%) were classified as colistin-resistant. CHR was identified in 86 of 267 isolates (32.2%) using PAP. Comparative genomic analysis of the colistin-susceptible main population and the colistin-resistant subpopulation of isolate A325 revealed identical mutational profiles in known resistance-associated genes, with the exception of a partial deletion in the lpxD gene between codons 2 and 75, identified exclusively in the resistant subpopulation. Notably, tetracyclines, macrolides and aminoglycosides were fully inactive in the colistin-susceptible main population, whereas an inhibition zone around these antibiotic discs was observed with the colistin-resistant subpopulation.

Conclusions: This study demonstrates a high prevalence of both colistin resistance and CHR among A. baumannii bloodstream isolates. The identification of a partial lpxD deletion in the resistant subpopulation of the colistin-heteroresistant isolate suggests a potential contributory role of LPS-related alterations in CHR. Inverse antimicrobial activity profiles between populations highlight distinct resistance mechanisms potentially shaped by evolutionary trade-offs and collateral sensitivity.