Journal of Antimicrobial Chemotherapy最新文献

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: 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.

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.

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.

Background: Dalbavancin is a promising option for the treatment of complex gram-positive infections. However, the optimal dosing regimen to ensure adequate drug exposure during prolonged treatment courses remains debate.

Objectives: To evaluate whether an intravenous dalbavancin regimen of 1500 mg administered on days 1, 15 and 43 achieves validated serum concentration targets for infections requiring 12 weeks of treatment.

Methods: We conducted a retrospective bicentric study including patients who received three 1500 mg doses of dalbavancin intended to provide 12 weeks of treatment coverage between January 2020 and May 2024. Patients' characteristics, microbiological data, and dalbavancin concentrations measured before reinjection on days 15, 43 and 90 were collected. We targeted a total dalbavancin plasma concentration of ≥8.04 mg/L, validated for Staphylococcus spp. strains with a MIC ≤0.125 mg/L. Concentrations were compared according to body mass index (≥30 kg/m2) and albumin level (≥30 g/L).

Results: Forty-two patients (39 bone and joint infections and three vascular infections) were included. Dalbavancin serum trough concentrations exceeded 8.04 mg/L for all available measurements (76/76) across the different monitored time points during the 12-week treatment period. Although lower concentrations were observed in patients with hypoalbuminemia or obesity, all measured values remained above the target threshold.

Conclusions: These results suggest that a three-dose dalbavancin regimen administered on days 1, 15, and 43 may achieve validated pharmacokinetic targets and maintain therapeutic exposure over a 12-week period for staphylococcal infections with a dalbavancin MIC ≤0.125 mg/L. Therapeutic drug monitoring should be performed for patients with hypoalbuminemia or obesity until larger studies confirm these findings, and for strains with an MIC >0.125 mg/L.

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.