Journal of Antimicrobial Chemotherapy最新文献

Background: Antimicrobial stewardship (AMS) programmes are led by multi-professional teams and are central to optimizing antimicrobial use and minimizing inappropriate use. Although frameworks exist that describe the knowledge and skills relating to antimicrobial resistance (AMR) and AMS for generalist healthcare professionals, there is a need to provide a framework for AMS specialists working in the NHS that supports the development of flexible capabilities rather than granular competencies.

Objectives: To develop a multi-professional capability framework to recognize and develop the specialist knowledge and skills of AMS staff across all sectors of healthcare, including adult and paediatric services, at all levels of post-foundation specialist practice.

Methods: A modified Delphi approach was adopted. Initial capability statements were derived from a literature review. An expert panel of UK-based AMS professionals participated in two Delphi survey rounds to assess the importance of each capability statement and map level of delivery against level of practice. Descriptors of practice and professional development resources were identified through follow-up workshops and consultation.

Results: From 922 source statements, 45 capability statements were agreed and structured into four domains: AMS Professional Practice, Leadership and Management, Education, and Research and Quality Improvement. Consensus was reached across all statements following two Delphi rounds. Descriptors of practice and development resources were identified to support benchmarking and professional development across all levels of specialist practice.

Conclusions: This multi-professional capability framework defines AMS specialist practice relevant to all NHS sectors, supporting professional development, career progression, and strategic workforce planning across all professional groups.

Objectives: Optimal antimicrobial exposure in epithelial lining fluid (ELF) is critical for meropenem efficacy in pneumonia, yet ELF pharmacokinetic data remain scarce, particularly in children. To address this, we aimed to develop a model capable of predicting meropenem concentrations in both plasma and ELF for evaluating pharmacodynamic target attainment under clinical dosing strategies.

Methods: A physiologically based pharmacokinetic (PBPK) model was developed to simulate unbound meropenem concentrations in plasma and ELF. An empirical penetration coefficient (ρ) was incorporated to link lung intracellular concentrations to ELF concentrations, modelled as a function of clinical and inflammatory covariates. Following validation, the percentage of time over a dosing interval that the free drug concentration remains above the MIC(%ƒT > MIC), of meropenem plasma and ELF were related to in-hospital mortality. Monte Carlo simulations were conducted to assess the PTA for 40%ƒT >  MIC under varying regimens, MIC ranges (0.25-16 mg/L) and penetration scenarios.

Results: The PBPK model accurately predicted meropenem exposures in both plasma and ELF. ELF penetration was significantly influenced by physiological and pathological factors. ELF %ƒT >  MIC showed higher interindividual variability compared with that of plasma and was more strongly correlated with survival in both adult (P = 0.073) and paediatric patients (P = 0.013). Although prolonging the infusion improved ELF target attainment for susceptible pathogens (MIC ≤4 mg/L) with adequate penetration, it failed against high-MIC strains or with poor lung penetration.

Conclusions: These findings underscore the importance of targeting infection-site pharmacokinetics over plasma exposure for better therapeutic efficacy in pneumonia. The model can be used to optimize dosing strategies.

Background: Considerable inter-individual variability in the pharmacokinetics of long-acting injectable (LAI) rilpivirine and cabotegravir has been reported. Here, we sought to evaluate intra- and inter-individual variability of rilpivirine and cabotegravir plasma trough concentrations and to assess the influence of demographic factors and body composition on drug exposure in people with HIV (PWH) receiving LAI therapy.

Methods: This retrospective observational study included PWH treated with LAI rilpivirine and cabotegravir for ≥16 months, with at least three consecutive plasma trough concentration assessments. Body composition was estimated by bioelectrical impedance analysis. Associations between drug levels and clinical variables were analysed using univariate and multivariate regression analysis.

Results: Forty-eight PWH were included (mean age 47 ± 15 years, 17% females). Rilpivirine and cabotegravir showed moderate intra-individual variability in trough concentrations (28-30%), with <1% of samples below the therapeutic threshold. Cabotegravir trough concentrations were significantly higher in women than in men (3285 ± 921 versus 2096 ± 775 ng/mL; P < 0001) and in participants aged >65 years compared with younger individuals (2826 ± 455 ng/mL versus 2119 ± 1006 ng/mL; P = 0044); in addition, cabotegravir levels inversely correlated with skeletal muscle mass (r = -0.45; P = 0.008) and bone mass (r = -0.47; P = 0006). On the contrary, rilpivirine concentrations showed no significant associations with demographic or body composition variables. Multivariate analysis confirmed age, sex and muscle mass as independent predictors of cabotegravir exposure.

Conclusions: Sex, age and muscle mass significantly influence cabotegravir-but not rilpivirine-trough concentrations in PWH receiving LAI therapy. Therapeutic drug monitoring combined with body composition assessment may help to optimize dosing interval adjustment.

Objectives: Pseudomonas aeruginosa (Pa) stands as a dangerous multidrug-resistant human pathogen, and the associated antibiotic resistance mechanisms, governed by diverse molecular processes, present a persistent challenge in eradicating bacterial infections, especially in patients with cystic fibrosis. The search for novel antibiotic resistance markers has led researchers to explore the field of metabolomics. This study aims to discern alterations in metabolite levels resulting from varied antibiotic resistance profiles in Pa strains isolated from clinical patients.

Methods: In-depth analysis of intracellular metabolites from Pa strains was conducted. Following bacterial cultivation and extraction, LC-MS measurements were performed, and subsequent data analysis used a combination of statistical and chemometric methodologies.

Results: A total of 45 metabolites were identified under positive ionization mode. Statistically significant variations were discerned across all comparisons involving the 14 antibiotics investigated, primarily manifesting as alterations in amino acid pathways and their derivatives. The chemometric outcomes revealed a distinct clustering of samples corresponding to the specific antibiotics tested.

Conclusion: The presented findings show noteworthy shifts in bacterial metabolic pathways, laying the groundwork for further investigations. These initial insights promise to delineate avenues towards comprehensive explorations into antibiotic resistance in bacteria. This study provides a foundation for future investigations aimed at unravelling the intricate dynamics of antibiotic resistance in Pa.

Invasive fungal infections continue to represent an important cause of morbidity and mortality in severely ill and immunocompromised patients. Liposomal amphotericin B (LAmB) has a significantly improved toxicity profile versus conventional amphotericin B deoxycholate and is recommended for a wide range of medically important opportunistic fungal pathogens. Although rates are significantly lower than with older formulations, nephrotoxicity with LAmB remains a concern. Risk factors for renal toxicity with LAmB include higher doses, longer duration of treatment, concomitant use of nephrotoxic agents and the presence of pre-existing kidney disease. Appropriate patient screening, individualized risk assessment, and patient monitoring may reduce the risk of renal toxicity. The prophylactic use of intravenous saline fluids is also recommended with LAmB to reduce the risk of nephrotoxicity. In addition, magnesium and potassium supplementation should be considered to reduce the risk of hypomagnesaemia and hypokalaemia, respectively. Alternate dosing strategies, including intermittent dosing and, for certain fungal infections, single-dose high-dose induction therapy, may be useful in minimizing nephrotoxicity, but additional research is necessary.

Long-acting glycopeptide antibiotics (LGPs), such as dalbavancin and oritavancin, are a novel class of antibiotic agents effective in the treatment of Gram-positive infections. The long half-life and relative ease of administration of LGPs make them a valuable treatment option for patients experiencing barriers to healthcare access. However, challenges for effective use remain, and disproportionately affect patients who would most benefit. These include high upfront costs, cost siloing, impractical and inconsistent medication approval processes and limited integration into existing multidisciplinary models of care. There is a clear need to improve funding arrangements, institutional workflows and models of care to promote safe and equitable access to LGPs, in line with processes developed for other high-cost medications.

Objective: To evaluate the reliability of different antimicrobial-susceptibility testing methods for determining the susceptibility of Staphylococcus aureus to eravacycline.

Methods: Using broth microdilution (BMD) as the reference method, disk diffusion (DD) and MIC test strips (MTS) were employed to test 422 S. aureus isolates (256 MSSA and 166 MRSA). Interpretive breakpoints for eravacycline followed the ChinaCAST criteria (MIC ≤ 0.25 mg/L or inhibition zone diameter ≥ 20 mm = susceptible). BMD results were used to calculate categorical agreement (CA), essential agreement (EA), major errors (ME), and very major errors (VME) for each comparator method.

Results: The susceptibility rates to eravacycline were 93.6% (BMD), 96.9% (MTS) and 93.1% (DD). Compared with BMD, MTS yielded CA 96.7%, EA 63.0% and VME 3.3%, whereas DD showed CA 98.1%, ME 1.2% and VME 0.7%. Stratified analysis revealed that MRSA was the main source of VME (7.8% for MTS and 1.8% for DD). Disk diffusion showed excellent agreement with BMD (κ = 0.85, 95% CI 0.74-0.95), whereas MTS yielded good agreement (κ = 0.64, 95% CI 0.46-0.81).

Conclusion: Under the conditions of this study, disk diffusion demonstrated excellent categorical agreement with BMD and can serve as an alternative method for routine laboratory detection of eravacycline susceptibility.

Objectives: Cefiderocol is a new siderophore cephalosporin for treating severe bacterial infections by Gram-negative pathogens in adults. Significant elimination of the drug will probably occur as a result of kidney replacement therapy, but there are currently insufficient pharmacokinetic data to guide dosing during prolonged intermittent kidney replacement therapy (PIKRT) or the use of the pathogen adsorber Seraph 100.

Materials and methods/case reports: Pharmacokinetic data were obtained from two critically ill patients undergoing PIKRT and hemoperfusion with the pathogen adsorber Seraph 100. Cefiderocol levels in plasma and dialysate samples were quantified using liquid chromatography with tandem mass spectrometry to evaluate the impact of extracorporeal therapy modalities on cefiderocol pharmacokinetics.

Results: The median cefiderocol dialyser clearance was 80.94 (38.7-87) mL/min, while the Seraph 100 showed no significant clearance [-1.8 (-7.9 to 3.6) mL/min]. The cefiderocol concentration in the total spent dialysate suggests a total elimination of 1350 and 400 mg of cefiderocol, or 68% and 40% of the administered dose.

Conclusion: Cefiderocol is substantially eliminated by PIKRT, but not during hemoperfusion with the Seraph 100. Consequently, dosage adjustments may be necessary depending on the intensity of the PIKRT procedure. Doses used for patients with normal renal function may be required to prevent underdosing during intensive PIKRT.

Despite a decrease in disease severity since the emergence of the severe acute respiratory syndrome coronavirus 2 Omicron variant, coronavirus disease-2019 (COVID-19) continues to pose a significant threat to patients with haematological malignancies (HM). Although repeated booster vaccinations enhance protection against severe illnesses in immunocompromised individuals, they remain at heightened risk of adverse outcomes. This underscores the crucial need for effective pharmacologic strategies to prevent and treat infection. This review examines current strategies for preventing severe COVID-19 in patients with HM, focusing on pre-exposure prophylaxis and early treatment of COVID-19. New monoclonal antibodies have been developed, offering effective pre-exposure prophylaxis. Antiviral agents and monoclonal antibodies demonstrated efficacy in limiting severe COVID-19 outcomes in patients with HM, though some patients, particularly the elderly, remain at risk of critical illness and death. Prolonged infection over months is also common, particularly in patients with lymphoid malignancies. Sustained viral shedding and ongoing mutation may be associated with chronic symptoms and is the likely source of several novel variants of concern that prolonged the pandemic. While HM subtype and advanced age are risk factors for severe or persistent COVID-19, there are no accurate tools for predicting individual risk. Given this uncertainty, prompt medical consultation, timely prescription of antiviral agents, and close monitoring are essential to minimize the risk of adverse outcomes in this vulnerable population.