Journal of Antimicrobial Chemotherapy最新文献

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.

Background: Although self-administered outpatient parenteral antimicrobial therapy (S-OPAT) has several advantages over nurse-administered therapy, it remains underused. A comprehensive understanding of the determinants of S-OPAT-the factors that hinder or promote its use-is essential to improve the quality of care and increase uptake.

Objective: This systematic review aimed to identify and synthesize determinants influencing the entire S-OPAT patient care pathway, from the offer of S-OPAT to its acceptance, training and performance, considering the perspectives of healthcare professionals, patients and their caregivers.

Methods: We systematically searched PubMed, Embase, PsycINFO and CINAHL for original articles published between January 2000 and July 2024 on determinants influencing decision-making and experiences regarding S-OPAT and other self-administered intravenous therapies. Determinants were thematically analysed to construct overarching themes. This review was registered in PROSPERO (CRD42022311294).

Results: In 23 studies reporting behavioural determinants (11 on S-OPAT), a total of 238 determinants were identified to influence the offer, acceptance, training and performance of self-administration. A limited number of studies explored determinants influencing the offer of S-OPAT and the caregiver's perspective. The overarching themes included stakeholders' cognitions or affect, collaboration and communication, context, resources and skills and capabilities, which influenced all steps in the patient care pathway. Many determinants were identified regarding cognitions or affect and collaboration and communication, stressing the importance of considering stakeholders' opinions on self-administration and improving transmural collaboration.

Conclusions: This review revealed key behavioural determinants shaping the success of S-OPAT. Targeting these factors can overcome implementation barriers and improve access, caregiver engagement and quality of care.

Background: Ceftazidime/avibactam (CZA) is recognized as an efficacious treatment modality against multidrug-resistant Pseudomonas aeruginosa. Nevertheless, it encounters the challenge of escalating antimicrobial resistance. Employing combination regimens involving ceftazidime/avibactam may confer advantages.

Methods: Checkerboard titration, time-kill assays, and an in vitro pharmacodynamic model were employed to investigate the effectiveness of ceftazidime/avibactam alone and in combination in vitro. Additionally, an intraperitoneal infection mouse model was established to assess the efficacy of combination therapy in vivo.

Results: In the in vitro pharmacodynamic model, administration of ceftazidime/avibactam plus polymyxin B resulted in a significant reduction in colony-forming units of all four strains, whereas ceftazidime/avibactam plus aztreonam only reduced the colonies of three strains. Significant or trending declines in mortality and tissue colony counts of infected mice were observed in groups treated with ceftazidime/avibactam plus polymyxin B. Conversely, ceftazidime/avibactam combined with aztreonam only reduced mortality and tissue colonies in MBL-positive P.aeruginosa-infected mice.

Conclusion: Combining ceftazidime/avibactam with polymyxin B might represent a potentially effective option against MDR-P.aeruginosa. Although the synergistic effect in vitro might not be readily apparent due to the potent bactericidal effect of aztreonam alone, the combination of ceftazidime/avibactam and aztreonam demonstrated promising synergistic effects on MBL-positive P.aeruginosa strains in vivo.

Background: Periprosthetic joint infections pose clinical and socioeconomic challenges. Gram-negative pathogens are associated with poorer outcomes compared with Gram-positive organisms. Rising antimicrobial resistance limits treatment options. The new combination of cefepime/enmetazobactam offers a promising carbapenem-sparing therapy.

Objectives: To investigate the distribution and the time above the minimum inhibitory concentration for cefepime and the time above the threshold concentration for enmetazobactam during the first and third dosing intervals in tissues relevant to periprosthetic joint infection, following either intermittent short-term infusion or continuous infusion in a preclinical, randomized porcine model.

Materials and methods: Sixteen pigs were randomized to receive cefepime/enmetazobactam either as a short-term infusion (2 g/0.5 g over 2 h) or continuous infusion (initial dosage of 1 g/0.25 g administered over 15 min followed by 2 g/0.5 g over 7 h and 45 min) in three dosing intervals of 8 h. Microdialysis was used to dynamically sample interstitial fluid concentrations of cefepime and enmetazobactam from cancellous bone, subcutaneous tissue and synovial fluid. Plasma samples were collected as reference. The following dosing interval targets were applied: for cefepime, 60% T > MIC of 8 mg/L and for enmetazobactam, 45% of T > Ct of 2 mg/L.

Results: All pigs reached the predetermined targets in all investigated compartments following both administration forms. For all targets, compartments, dosing intervals and administration forms, the mean T > MIC for cefepime was ≥92% and mean T > Ct for enmetazobactam was ≥99%.

Conclusion: Cefepime/enmetazobactam demonstrated robust tissue distribution, reaching the applied pharmacokinetic/pharmacodynamic targets in all investigated tissue compartments, regardless of the mode of administration. From a pharmacokinetic view, cefepime/enmetazobactam may prove useful in future Gram-negative periprosthetic joint infection settings.

Background: Antimicrobial resistance threatens oral treatment options for acute uncomplicated urinary tract infection (uUTI). Gepotidacin (Blujepa) is a novel oral triazaacenaphthylene antibiotic evaluated in Phase 3 trials versus nitrofurantoin.

Objectives: To pool Phase 3 randomized evidence comparing gepotidacin and nitrofurantoin for efficacy and safety in female uUTI.

Methods: PRISMA-compliant systematic review and random-effects meta-analysis of Phase 3 randomized controlled trials. Two investigators independently screened records (using Rayyan), extracted data and assessed risk of bias with RoB 2; certainty was rated with GRADE. Outcomes were pooled as risk ratios (RR) or mean differences with 95% confidence intervals (CI) using RevMan 5.4.

Results: Three trials (EAGLE-2, EAGLE-3 and EAGLE-J) including 3510 participants (gepotidacin n = 1853; nitrofurantoin n = 1657) were included. Gepotidacin increased composite therapeutic success versus nitrofurantoin (RR 1.20; 95% CI 1.10-1.31; I2 = 0%; P < 0.001) and improved microbiological eradication (RR 1.14; 95% CI 1.07-1.21; I2 = 2%; P < 0.001). Gastrointestinal adverse events were more frequent with gepotidacin (diarrhoea RR 5.51; 95% CI 4.08-7.45; nausea RR 2.49; 95% CI 1.56-3.97). Serious adverse events were rare and similar between groups. Certainty of evidence per outcome is presented in Table S2 (available as Supplementary data at JAC Online).

Conclusions: Gepotidacin provides superior composite and microbiological outcomes relative to nitrofurantoin for female uUTI but is associated with increased mild-to-moderate gastrointestinal toxicity. Long-term tolerability and resistance surveillance are recommended.

The therapeutic landscape of acute leukaemia (AL) has evolved profoundly with the introduction of targeted and differentiation agents, altering the epidemiology of invasive fungal disease (IFD). While antifungal prophylaxis with triazoles remains standard for patients receiving intensive chemotherapy, this paradigm may no longer apply to those treated with novel regimens. Targeted agents such as tyrosine kinase inhibitors, blinatumomab, inotuzumab ozogamycin, ivosidenib, gilteritinib, and venetoclax are associated with higher remission rates, shorter or absent neutropenia, and minimal mucosal injury-key determinants of IFD risk. As a result, the incidence of IFD appears markedly lower in such populations. Redefining antifungal prophylactic strategies must account for this therapeutic heterogeneity to avoid overexposure to antifungal drugs and misdirected research priorities. Updated, risk-adapted strategies-integrating treatment intensity, myelotoxicity, and drug interactions-are essential to define which AL patients truly benefit from primary antifungal prophylaxis in the modern era.

Background: Voriconazole is widely used for invasive fungal infections in critically ill patients, but its pharmacokinetics may be significantly altered by extracorporeal membrane oxygenation (ECMO). Data on the impact of different ECMO modes are limited.

Methods: We performed a retrospective observational study including all patients admitted to the ICU from January 2018 to May 2025 who were treated with voriconazole for suspected fungal infections. Voriconazole trough concentrations (Cmin) were compared between ECMO and non-ECMO patients. Multivariate linear regression was used to identify clinical predictors of Cmin, and subgroup analyses were performed by ECMO mode and other relevant covariates.

Results: A total of 166 patients (492 samples) were included, including 33 ECMO patients (111 samples) and 133 non-ECMO patients (381 samples). There was no significant difference in voriconazole trough concentrations between the ECMO and non-ECMO groups. When stratified by mode, VAV-ECMO was associated with significantly lower concentrations than non-ECMO (P = 0.004), whereas VV- and VA-ECMO were comparable to non-ECMO. In multivariate linear regression, increasing age and coadministration with amiodarone were associated with higher voriconazole Cmin, whereas lower albumin levels and concomitant CRRT were associated with reduced concentrations.

Conclusions: ECMO support did not significantly reduce voriconazole Cmin compared with the non-ECMO group. However, VAV-ECMO is associated with reduced voriconazole exposure, suggesting a configuration-specific rather than uniform ECMO effect. Routine therapeutic drug monitoring remains essential.

Objectives: To evaluate the in vitro activity of cefepime in association with a β-lactamase inhibitor (enmetazobactam) or β-lactam enhancer (BLE), zidebactam, against carbapenem-resistant Acinetobacter baumannii (CRAB) strains susceptible or resistant to sulbactam/durlobactam.

Material and methods: Twenty-one CRAB clinical isolates were characterized by WGS and AST to cefepime/enmetazobactam, cefepime/zidebactam and comparators was determined.

Results: Resistome analysis revealed that all CRAB carried blaOXA-23 carbapenemase genes, while blaADC-25 and blaOXA-66 β-lactamase genes were observed exclusively in sulbactam/durlobactam-resistant strains. Analysis of penicillin-binding protein genes demonstrated the presence of specific mutations within PBP3 (N392T) previously associated to the resistance to sulbactam/durlobactam. Phenotypic analysis revealed that cefepime/enmetazobactam did not exert antibacterial activity against CRAB, while cefepime/zidebactam displayed potent bactericidal activity against both sulbactam/durlobactam-susceptible and -resistant strains.

Conclusions: These results demonstrate that cefepime/zidebactam exhibited potent in vitro antibacterial activity against CRAB producing OXA carbapenemase and support its clinical use against both sulbactam/durlobactam-susceptible or -resistant isolates.