Journal of Antimicrobial Chemotherapy最新文献

Background: Even though the doravirine/dolutegravir combination is not mentioned by guidelines, real-life data has begun to emerge on its use. We aimed to describe the durability of doravirine/dolutegravir in a multicentre Italian cohort of elderly people with HIV (EPWH).

Methods: We included all EPWH who ever started the doravirine/dolutegravir combination in six Italian centres and were followed up until treatment discontinuation (TD) for any reason (virological failure, death, treatment interruption for other reasons) on 31 March 2024. Descriptive statistics were used to describe the study population; Kaplan-Meier curves and Cox regression analyses were used to estimate incidence and associated predictors of time to TD.

Results: We included 157 people; 61.1% were male, the median age was 59 years (IQR: 55-64), 75.2% had multimorbidity, 38.9% were on polypharmacy, and 91.1% had HIV-RNA of <50 copies/mL. No genotype resistance test was available for 19.4% of people who started doravirine/dolutegravir. The main reasons for starting doravirine/dolutegravir were high cardiovascular risk (51.6%), simplification (52.9%) and drug-drug interactions (25.5%). During a median follow-up of 27.85 (IQR: 22.92-31.79) months, 8 (5.1%) participants experienced TD (2 toxicities, 2 virological failures, 2 switches to long-acting drugs, 1 death and 1 transferred). The incidence of TD was 2.27 per 100 person-years of follow-up. Multivariable Cox regression analyses did not show any factors as predictors of TD.

Conclusions: In this multicentre cohort of EPWH with clinical complexity, the doravirine/dolutegravir combination showed good durability over time. TD probability was very low, and no significant factors seem to predict it, likely due to the limited number and heterogeneity of cases of TD.

Background: Treatment of chronic hepatitis B infection requires lifelong administration of nucleos(t)ide analogues with a high barrier to resistance and effective viral suppression. The major limitation of lifelong therapy is the possible selection of drug-resistant hepatitis B virus (HBV) strains. International Liver Society guidelines recommend that hepatitis B resistance testing must be performed by a reference laboratory.

Objectives: Performance of the deep sequencing-based ViroKey® SQ FLEX Genotyping Assay for the determination of HBV genotypes and resistance profiles were evaluated.

Patients and methods: Plasma samples collected from patients with chronic hepatitis B have been sequenced by two methods including Sanger (population) sequencing of a portion of the P/S overlapping gene and the deep sequencing-based ViroKey® SQ FLEX Genotyping Assay (Vela Diagnostics).

Results: A high concordance rate with population sequencing was found regardless of HBV genotypes. Deep sequencing with the Sentosa platform was more sensitive than population sequencing in detecting minor variant populations.

Conclusions: The deep sequencing-based ViroKey® SQ FLEX Genotyping Assay can be confidently used in clinical practice for hepatitis B genotyping and resistance testing.

Background: Staphylococcus epidermidis is a ubiquitous member of the healthy skin and mucous microbiota but is also an opportunistic pathogen responsible for various infections, often treated with antibiotics like rifampicin. Resistance to rifampicin in S. epidermidis arises primarily through nonsynonymous mutations in the rpoB gene.

Objectives: To investigate the prevalence of rpoB mutations and their association with phenotypic rifampicin resistance in clinical S. epidermidis isolates from Denmark, France, and Sweden.

Methods: All clinical isolates (N = 942) were whole-genome sequenced to identify mutations in rpoB and subsequently linked to phenotypic rifampicin resistance based on antimicrobial susceptibility testing.

Results: A total of 64 (6.8%) isolates were resistant to rifampicin. They carried all mutational changes in the rifampicin resistance-determining region (RRDR). Among 12 identified nonsynonymous mutations, 11 were exclusively observed in resistant strains, including novel mutations not previously described in S. epidermidis.

Conclusions: This study highlights the diverse genetic variants of rpoB associated with rifampicin resistance in clinical S. epidermidis isolates, including novel mutations. The strong correlation between mutational changes in RRDR and phenotypic resistance reinforces the role of rpoB mutations as a primary mechanism of resistance in clinical isolates.

Objectives: To identify the role and function of mepR variants in conferring resistance to tigecycline in clinical Staphylococcus aureus.

Methods: The identification of the mepR and mepA variants in S. aureus DMB26a was performed by whole-genome sequencing and Blast alignment. The effects of the mepRD and mepAD variants of DMB26a on tigecycline susceptibility were evaluated through deletion and complementation analyses, as well as the determination of gene expression levels by RT-qPCR. Minimal inhibitory concentrations (MICs) for DMB26a and its mutants were determined by antimicrobial susceptibility testing.

Results: A mepR variant, designated mepRD, and a mepA variant, designated mepAD, were identified in the clinical tigecycline-resistant S. aureus isolate DMB26a, which showed 78.72% and 84.92% amino acid identity to the MepR and MepA proteins of S. aureus NCTC 8325-4, respectively. Our findings revealed that deletion of mepA in the tigecycline-susceptible S. aureus RN4220 did not lead to a decrease in the MIC of tigecycline, and that there was also no change in the tigecycline MIC after the complementation with mepAD. Furthermore, we constructed a mepR + mepA deletion strain of S. aureus RN4220 and complemented it with mepRD + mepAD. In that case, a 4-fold increase in the tigecycline MIC was observed in S. aureus RN4220ΔmepR + mepA-pLI50_mepRD + mepAD compared with S. aureus RN4220ΔmepR + mepA. In addition, the relative expression of mepAD was increased 6-fold under the regulation of mepRD.

Conclusions: This study provides the identification of a mepR variant contributing indirectly to tigecycline resistance via mediating increased expression of mepA in a clinical S. aureus isolate.

Background: Pseudomonas aeruginosa clinical isolates that lack motility do not express type IV pilin, yet the biological roles of this absence in the infection process remain poorly understood.

Objectives: We asked whether the absence of motility in these bacteria is associated with increased antibiotic persistence.

Methods: In this study, we analysed type IV PilD protein sequences in the database and conducted antibiotic-tolerant persister cell assays.

Results: We found that PilD variants were common in P. aeruginosa clinical isolates. Our results revealed that inactivation of PilD resulted in a significantly higher level of surviving persister cells following ciprofloxacin treatment. This PilD-mediated persistence did not involve previously described mechanisms, such as phenazine pyocyanin, biofilm or stringent response.

Conclusions: Our findings connect the non-motility of clinical P. aeruginosa isolates with the survival of persister cells, highlighting the clinical significance for the development of strategies to eradicate P. aeruginosa infections.

Objectives: Staphylococcus aureus is an important zoonotic pathogen that has often been seen in animals through the prism of the MRSA clonal complex (CC) 398 in pigs and in-contact humans. The goal of this study was first to assess the prevalence of MRSA, and second to look for MSSA CC398 in cats, dogs and horses in France.

Methods: Clinical S. aureus isolates (n = 479) were collected from 186 cats, 143 dogs and 150 horses during 2022-2023 all over the French territory. Antibiograms were performed on all isolates. MRSA and MSSA CC398 isolates were subject to WGS. Core genome (cg) MLST-based and SNP-based phylogenetic analyses were performed using published methodologies, and characterization of the isolates was performed using publicly available tools.

Results: Sixty-six MRSA isolates were identified in 14 cats (7.5%), 9 dogs (6.3%) and 43 horses (28.7%). The epidemiology of MRSA in cats and dogs remained stable since a previous study in 2015, with the presence of both CC398 and human-associated clones. In horses, in contrast, an important increase in MRSA (from 10% to 28.7%) was observed, potentially attributable to the emergence of the ST612 clones. In parallel, CC398 MSSA, a clone usually described as animal-independent, was found in 24.2% of the cat isolates.

Conclusions: Our study, which is leading the way to a genomic surveillance of S. aureus in France, revealed the emergence of both MRSA ST612 in horses and MSSA CC398 in cats. These clones should be closely monitored to avoid their zoonotic spread and to understand their dynamics of transmission between humans and animals.

Objectives: External quality assurance (EQA) is an objective tool to assess laboratories' diagnostic performance and their adherence to recognized international standards. External Quality Assessment in Asia (EQASIA) is an EQA network in South and South-East Asia established in 2020 with the aim of improving the quality of bacteriology diagnostics across all One Health sectors in the region. The aim of this paper is to provide a comprehensive overview of the EQA results collected from the EQASIA network and to assess improvements among the participating laboratories.

Methods: Six EQA rounds were conducted between 2021 and 2023, each composed of different panels of WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) and The Food and Agriculture Organization of the United Nations (FAO) priority pathogens of interest to both the human and animal health sector.

Results: Between 24 and 32 laboratories signed up for six EQA rounds (EQA1-6). Participating laboratories were able to isolate and correctly identify most of the isolates across the EQA panels except for the Campylobacter spp. and Enterococcus spp. panels. The overall performance of laboratories across the six EQAs was between 75% and 100% (average 93.3% and median 93.6%). The obtained results showed a significant improvement in laboratories' performance over time.

Conclusions: Laboratory capacity development and quality assurance in a microbiology laboratory are of particular importance especially in the context of antimicrobial resistance (AMR) and One Health surveillance. The EQASIA programme has the potential to validate laboratories' performance in detecting important One Health pathogens, generating reliable data for effective surveillance to curb AMR.

Background: Subcutaneous (SC) administration of antibiotics is a practical alternative to IV administration. Cefazolin is widely used for skin and soft tissue infections and other complex infections by IV administration.

Methods: In this prospective, cross-over self-controlled study, a single dose of SC cefazolin was administered to 15 stable inpatients established on IV cefazolin as part of their management plan. The equivalent dose of cefazolin was diluted in 50 mL of normal saline via gravity feed over 30 min. Venous blood samples were collected at baseline and 0.5, 1, 2, 4 and 8 h following both the SC and IV doses. Antibiotic concentrations were measured using UPLC-MS/MS. Pharmacokinetic data were analysed using a non-linear mixed-effects modelling approach. Pain scores and infusion site reactions (oedema/erythema) were evaluated.

Results: SC cefazolin was well tolerated. The bioavailability of SC administration was 74.8% (95% CI 66.7%-81.7%). Slower absorption from SC tissue was associated with a BMI of ≥30. Lower peak, and higher trough concentrations were observed with SC administration. Although lower bioavailability was observed with SC administration, the PTA for unbound drug concentrations greater than the MIC for more than 90% of the time between doses was higher for SC compared with IV administration at MICs between 0.25 and 4 mg/L. Simulated SC doses of 3 g twice daily had similar PTA to standard IV dosing of 2 g three times daily. A simulated 6 g continuous 24 h infusion of SC cefazolin had a favourable pharmacokinetic profile.

Conclusion: SC cefazolin appears to be well tolerated, with an improved pharmacokinetic profile compared with IV administration. Either 3 g twice daily, or 6 g as a 24 h SC infusion could be considered for future evaluation.