Journal of Antimicrobial Chemotherapy最新文献

Objectives: While tigecycline has been associated with hypofibrinogenaemia, limited data with eravacycline suggest this may also occur with this agent. However, the incidence and clinical significance of this finding are not well defined.

Methods: This is a retrospective cohort study of hospitalized adults who received at least two doses of eravacycline between 1 August 2018 and 1 October 2024 and had two or more fibrinogen levels monitored while on therapy. The primary outcome was ≥50% reduction in fibrinogen while on eravacycline. Secondary outcomes included ≥25% reduction in fibrinogen, time to 50% fibrinogen reduction, development of hypofibrinogenemia (<200 mg/dL) and bleeding events.

Results: Thirty-nine patients were included with 17 (44%) being solid organ transplant recipients and 11 (28%) patients not considered to be immunocompromised. Eravacycline was primarily used to treat nontuberculosis mycobacterial infections (82%). The median (IQR) duration of eravacycline therapy was 12 (8-22) days. Thirty-three per cent of patients met the primary outcome of ≥50% decrease in fibrinogen with a median (IQR) time to 50% decrease in fibrinogen of 10 (8-11) days. A substantially higher number, 79%, experienced ≥25% reduction in fibrinogen. Hypofibrinogenaemia developed in 18 (49%) patients. A total of four (10%) patients experienced minor bleeding events.

Discussion: A majority of eravacycline-treated patients experienced at least a 25% decrease in fibrinogen levels. Although the decreased fibrinogen levels did not result in major clinically significant bleeding, fibrinogen levels should be monitored at baseline and at least weekly. Patients should also be monitored for any signs and symptoms of bleeding.

Background: Critically ill patients are exposed to important pharmacokinetic alteration that can lead to under- or over-exposure. In addition, children and neonates undergo physical growth and organ maturation that alter drug pharmacokinetics, especially children with sickle cell disease who frequently experience organ dysfunctions. The aim of the study was to describe cefotaxime and desacetyl-cefotaxime pharmacokinetics and optimize dosing regimens in this population.

Methods: We performed a pharmacokinetic analysis of cefotaxime and its metabolite desacetyl-cefotaxime via a population approach. Trough concentrations and steady-state concentrations were then simulated using several doses and were compared to pharmacological targets: 100% fT > 4 × MIC and Cτ or CSS < 60 mg/L.

Results: A total of 797 cefotaxime and desacetyl-cefotaxime observations were collected from 242 children and neonates, including 50 with sickle cell disease (SCD). Cefotaxime data was best described by a two-compartment model with first-order absorption and elimination. A supplemental compartment was linked to the cefotaxime central compartment to describe desacetyl-cefotaxime pharmacokinetics. Allometric scaling with bodyweight, eGFR and Sickle cell status turned out to be significant in the model. Post-menstrual age was used to describe organ maturation functions for neonates. Simulations showed that probability of attaining targets was systematically better through continuous perfusion. Doses were suggested up to 300 mg/kg/day according to covariates.

Conclusion: We identified bodyweight, SCD status and eGFR as significant covariate that influence cefotaxime PK. Continuous infusion was the most performant way to achieve the pharmacological target in critically ill children and neonates, making a first necessary step towards individualized prescription in this fragile population.

Objectives: VRE resistant to potential therapeutic agents such as linezolid are an increasing concern in Canada and worldwide. Infections produced by these isolates have limited treatment options and are associated with poor clinical outcomes. We report an isolate of vancomycin-resistant Enterococcus faecium (VREfm); identified through the Canadian surveillance program, CANWARD, which exhibited linezolid resistance (LVREfm); and carried the optrA and cfr(D) genes on a linear plasmid.

Methods: Antimicrobial susceptibility testing was performed by broth microdilution and MICs were interpreted by 2025 CLSI breakpoints. WGS was performed to characterize resistance determinants and the associated plasmid.

Results: In 2021, a single LVREfm isolate was recovered from a blood culture of a 67-year-old male patient admitted to an ICU. The isolate was XDR but remained susceptible dose dependent to daptomycin (MIC = 2 mg/L). MLST identified the isolate as ST817, a sequence type not commonly found in our national collection.Vancomycin resistance was mediated by the vanA gene cluster, while linezolid resistance determinants included optrA, cfr(D) and the 23S rRNA gene mutation, G2576T. Vancomycin and linezolid resistance genes were co-located on a linear plasmid that exhibited over 94% sequence identity to previously described linear plasmids from India and the USA. Notably, the plasmid also encoded four toxin-antitoxin systems, potentially contributing to its stability and persistence.

Conclusions: This case highlights the appearance of linezolid resistance in VRE mediated by linear plasmids in Canada and underscores the importance of ongoing genomic surveillance to track the dissemination of MDR determinants in clinical settings.

Background: Pluralibacter gergoviae is a gram-negative bacillus in the Enterobacteriaceae family. Although rarely associated with human infections, its resistance to preservatives and presence in hospital-use products raise concerns about nosocomial transmission.

Objectives: To describe the clinical and microbiological profiles of P. gergoviae infections.

Methods: A comprehensive search was conducted in multiple databases and grey literature without time restrictions. Eligibility criteria included: (1) studies reporting human infections by P. gergoviae and (2) patients with confirmed infections. Data were synthesized narratively and summarized as frequencies and proportions. Univariate and multivariate analyses assessed risk factors for multidrug resistance (MDR) and mortality.

Results: Of 371 articles retrieved, 16 met the inclusion criteria, and 18 additional studies were identified through grey literature and manual search, totalling 34 studies. Three described outbreaks, two in neonatal intensive care units (NICUs). Overall, 196 patients were identified, predominantly male (59%), with 66% of infections being healthcare-associated. Most were admitted to ICUs (74%), especially NICUs (70%). Bloodstream infections were most common, followed by periodontitis and urinary tract infections. Phenotypic methods were primarily used for identification. MDR was reported in 33% of strains; ESBL and carbapenemase production in 35% and 23% of cases, respectively. The most frequent carbapenemase genes were blaKPC, blaNDM, and blaIMP. Mortality occurred in 11% of cases, and all MDR-related deaths were associated with blaKPC. Prior antibiotic use was significantly associated with mortality (P = 0.039; OR: 13).

Conclusions: Pluralibacter gergoviae is rare but clinically relevant, with MDR potential and impact on vulnerable populations, particularly in NICU settings.

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.