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 and objectives: Self-administration of outpatient parenteral antimicrobial therapy (S-OPAT) aligns with the growing emphasis on patient and caregiver engagement in healthcare. Despite its potential benefits, S-OPAT use varies widely, suggesting that many eligible patients are not offered this option. Insight into S-OPAT decision-making is needed to improve its broader implementation and quality. The objectives of this study were to identify determinants that (i) influence healthcare professionals' (HCPs) decisions to offer S-OPAT and (ii) affect patients' and caregivers' acceptance or refusal of S-OPAT.

Methods: Semi-structured interviews were performed with HCPs involved in S-OPAT and with patients and caregivers who either self-administered OPAT or declined S-OPAT. Participants were recruited from four hospitals and six home care organizations. Transcripts were analysed using thematic analysis.

Results: Fifty-one interviews were conducted with HCPs, patients and caregivers. The determinants reported were related to cognitions or affect (e.g. emotions or personality traits, such as patients' reluctance to accept help), skills and capabilities (e.g. patients' perceived skills for S-OPAT, or the ability of HCPs to explain what S-OPAT entails) and collaboration and communication (e.g. between healthcare organizations and between patients and caregivers).

Conclusions: Decisions regarding S-OPAT are influenced by cognitive, skill-related, and collaborative determinants shaping inter-stakeholder cooperation. Addressing these determinants may help create a more person-centred approach and support further expansion of S-OPAT. We recommend increasing HCP awareness of S-OPAT, discussing S-OPAT with all patients or their caregivers, emphasizing the freedom to try S-OPAT, and tailoring the content, timing, and location of the S-OPAT offer to individual needs.

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: To estimate the prevalence of NRTI and integrase strand transfer inhibitor (INSTI), drug resistance mutations (DRMs) in antiretroviral therapy (ART)-experienced people with HIV-1 (PWH) switched to bictegravir/emtricitabine/tenofovir alafenamide fumarate (B/F/TAF) and among those with HIV-RNA ≤50 copies/mL to assess the association with risk of viral rebound (VR).

Methods: Data from the ARCA cohort were used to estimate resistance prevalence assuming a binomial distribution; 95% confidence intervals (CIs) were reported. Standard survival analysis with time-fixed covariate measured at B/F/TAF initiation was used to evaluate the association between detected resistance and risk of confirmed VR >50 copies/mL (2 consecutive values).

Findings: We included 1414 PWH (973-69%-in the VR analysis). Overall, 27% were female, median age was 53 years (IQR 44-59). Major NRTI-DRMs were detected in 25% (95% CI: 22.5, 27.1). Major INSTI-DRMs affecting bictegravir were rare (0.6%, 95% CI: 0.2, 1.4). The overall rate of VR by 36 months was 5.3% (95% CI: 3.7-6.9%), confirming that viral rebound on B/F/TAF is a rare event. After controlling for confounding, NRTI resistance was not associated with VR, whereas a history of INSTI virological failure (VF) and major INSTI-DRMs were associated with VR (aRH 2.68, 95% CI: 1.40, 5.12; and aRH 4.21, 95% CI: 1.18, 15.02, respectively).

Conclusions: In our cohort of PWH who were switched to B/F/TAF, NRTI-DRMs were common, but B/F/TAF remained effective in maintaining viral suppression despite their presence. However, previous failure to INSTI-based regimens and major INSTI-DRMs were risk factors for VR.

Objectives: This study investigated whether extracorporeal membrane oxygenation (ECMO) alters the pharmacokinetics or tissue penetration of vancomycin and linezolid, assessed the need for dose adjustments during ECMO support and evaluated the suitability of each drug for different infection sites.

Methods: Each Landrace pig underwent two sequential experiments, one without ECMO and one with ECMO, separated by more than 4 weeks. Blood samples were collected before and after intravenous infusion of vancomycin and linezolid and tissue samples were obtained immediately after the ECMO period. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using a non-compartmental model and tissue penetration rates were determined by comparing tissue concentrations with serum levels before euthanasia.

Results: ECMO did not significantly influence the pharmacokinetics of vancomycin or linezolid. Vancomycin penetration was highest in the kidney (390%) and alveolar epithelial lining fluid (120%), with lower levels in the lung, liver, spleen and skin (10%-20%) and minimal penetration in the small intestine and muscle (<10%). Linezolid demonstrated stronger tissue penetration, reaching 236% in alveolar epithelial lining fluid and 20%-30% in the kidney and liver.

Conclusions: ECMO does not affect the pharmacokinetics of vancomycin or linezolid, suggesting that dose adjustments are unnecessary. Both drugs demonstrate wide tissue distribution during ECMO and are suitable treatment options in this setting.

Bacterial topoisomerases are enzymes critical for maintaining genomic DNA integrity and ensuring bacterial cell survival, making them ideal targets for antibacterial agents. Bacterial topoisomerase inhibitors, such as quinolones and fluoroquinolones, target two enzymes, DNA gyrase and topoisomerase IV, and inhibit the control of DNA supercoiling/decatenation, leading to impaired DNA replication and bacterial cell death. Since their initial discovery, many quinolones and fluoroquinolones have been developed with activity against a wide range of bacterial species, contributing significantly to the treatment of various infectious diseases worldwide. Fluoroquinolones such as levofloxacin and ciprofloxacin remain important and effective therapeutic options today due to their broad-spectrum antibacterial activity, chemical stability and high bioavailability. However, side effects of fluoroquinolones have become a concern, leading to warnings being issued in the United States, Europe and the United Kingdom. Furthermore, in many countries, the prevalence of fluoroquinolone-resistant bacteria has been steadily increasing each year, which poses a serious threat to public health. The clinical development of new non-quinolone bacterial topoisomerase inhibitors (for example, zoliflodacin, gepotidacin and fobrepodacin) offers a promising solution to these issues and has the potential to play a crucial role in combating the growing problem of antimicrobial resistance. This review article will discuss the evolution of quinolone and fluoroquinolone antibacterial agents as key topoisomerase inhibitors, examine their current clinical applications and challenges to future development, and explore the potential of new topoisomerase inhibitors.

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.