Journal of Antimicrobial Chemotherapy最新文献

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.

Objective: Omadacycline, a novel aminomethylcycline antibiotic for community-acquired bacterial infections, lacks comprehensive real-world safety data. We evaluated its adverse drug reactions (ADRs) using the FDA Adverse Event Reporting System (FAERS).

Methods: A comprehensive analysis of post-marketing ADR reports submitted to FAERS between the first quarter of 2020 and the fourth quarter of 2024 was conducted. Disproportionality signals were assessed via four methods: reporting odds ratio (ROR), proportional reporting ratio, Bayesian confidence propagation neural network and multi-item gamma Poisson shrinker.

Results and conclusion: Among 4541 omadacycline-related reports, 577 distinct ADRs were identified. The most frequently reported ADRs were nausea (221 cases, 14.1%), vomiting (129), diarrhoea (93), dyspnoea (56) and rash (52). The strongest safety signals (ROR) included tooth discolouration (ROR = 184.33, 95% CI = 96.79-351.06), tongue discolouration (159.88, 101.76-251.25) and Mycobacterium avium complex infection (73.30, 40.15-133.78). Hepatic events (e.g. elevated transaminases) and mortality (49 cases) also demonstrated significant signals. Omadacycline is associated with gastrointestinal disturbances, dental discolouration and respiratory complications. Vigilance for hepatic injury and mortality is warranted, especially in elderly comorbid patients. Ongoing pharmacovigilance integrating real-world evidence is essential.

Objectives: Antimicrobial-resistant Neisseria gonorrhoeae is a serious threat to global health. Current N. gonorrhoeae antimicrobial susceptibility testing (AST) is laborious and time consuming (≥2 days) leading to overprescription of last-resort, broad-spectrum antibiotics. In this proof-of-principle study, we developed a fast (<8 h) phenotypic, impedance-based AST for N. gonorrhoeae against frontline and experimental antibiotics.

Methods: WHO N. gonorrhoeae reference strains F, K, O, V, X and Y were exposed to EUCAST susceptibility breakpoint concentrations of ceftriaxone, ciprofloxacin and azithromycin for up to 5 h and to doubling dilutions of antibiotics for 4 h. The % cell count of antibiotic exposed compared with unexposed control samples, as measured by an impedance-based Fast Antimicrobial Susceptibility Test (iFAST®), was used to differentiate between susceptible and non-susceptible strains. Responses to novel antimicrobial compounds, including zoliflodacin and gepotidacin, were also measured by iFAST® and compared with published MICs.

Results: The protocol reported susceptibility profiles concordant with published data for all strain-drug combinations after 4 h of exposure. Dose-response curves generated using iFAST® for most strain-drug combinations were in essential agreement with published Etest MIC values. Novel compounds assessed using iFAST® showed higher antimicrobial activity than ciprofloxacin in the high-level resistant strain WHO X.

Conclusions: iFAST® AST results were concordant with the current clinical standards and measured in under 8 h. This method is therefore promising for the development of a rapid and accurate phenotypic N. gonorrhoeae antimicrobial susceptibility test.

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.

Objectives: This study aimed to gain a better understanding of the role of insertional mutations in the integrase (IN)-coding sequence of 13 HIV-1-infected people.

Results: Here, we present the first documentation of amino acid insertion in the IN-coding sequence of HIV-1-infected people at positions 168, 253, 255 and 260. The consequences of these mutations in terms of viral replication and resistance to INSTIs were analysed using virological and biochemical assays and 3D modelling. Analysis of viral genomes by quantitative PCR demonstrated that insertional mutations reduce reverse transcription efficiency and had different impacts on viral integration. Taken together, we showed that mutants were delayed in their replication. Virological assays using two potent strand-transfer inhibitors (INSTIs), raltegravir and dolutegravir, demonstrated that no resistance to INSTIs was observed.

Conclusions: Our study has revealed that the mutations observed in people living with HIV-1 do not confer resistance to anti-integrase compounds but are detrimental to viral replication.

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: 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.