International Journal of Antimicrobial Agents最新文献

The rising prevalence of drug resistance has emerged as a major obstacle to global tuberculosis (TB) control, necessitating the development of novel host-directed strategies. In this study, we conducted a cell-based screening of a G-protein-coupled receptor-related compound library and identified amodiaquine hydrochloride (CAS), a conventional antimalarial drug, as a potent inducer of autophagic killing of intracellular Mycobacterium tuberculosis (Mtb). Further mechanistic investigation revealed that CAS reduced the phosphorylation of PI3K, AKT and mTOR in Mtb-infected macrophages, thereby promoting ULK1 activation and autophagic induction. In vivo studies using the BALB/c mouse model demonstrated that CAS treatment significantly reduced bacterial load in lungs. Taken together, our findings highlight CAS as a novel host-directed therapeutic agent capable of enhancing the intracellular clearance of Mtb by triggering autophagy in macrophages.

Objectives: This study evaluated the in vitro activity of sulbactam/durlobactam and comparators against carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream isolates from Italy and investigated genomic mechanisms underlying resistance.

Methods: A total of 110 consecutive CRAB isolates (2021-2023) were tested for susceptibility to sulbactam/durlobactam, cefiderocol, colistin, and comparators. Whole-genome sequencing (WGS) was performed on sulbactam/durlobactam-resistant isolates to characterize β-lactamase genes, outbreak dynamics, and mutations in penicillin-binding proteins (PBPs).

Results: Sulbactam/durlobactam inhibited 88.7% of isolates (MIC₅₀ = 2 mg/L; MIC₉₀ > 64 mg/L), while 12.7% were resistant. Cefiderocol and colistin showed 91.8% and 96.4% susceptibility rates, respectively. All resistant isolates carried bla_OXA-23, and three also harbored bla_NDM-1. WGS revealed close clonal relationships (average nucleotide identity > 99%) among bla_NDM-1 positive isolates (ST231) and among OXA-23-only isolates (ST837/ST369), indicating local outbreak dynamics. Comparative PBP analysis identified recurrent substitutions P112S and G137R (PBP1b), N392T and A515V (PBP3), and S329N (PBP5). Structural correlation suggests these mutations reduce β-lactam binding and may contribute to resistance, particularly when combined with NDM-1.

Conclusions: This study provides early evidence of sulbactam/durlobactam resistance in treatment-naïve CRAB from Italy, driven by NDM-1 co-production and PBP alterations. The coexistence of epidemic ST231 and ST837/ST369 clones highlights the need for continuous genomic surveillance and prudent antibiotic stewardship to prevent dissemination of resistant A. baumannii lineages.

Objectives: The aim of this study was to develop and validate a risk score to predict the occurrence of bloodstream infections (BSI) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) among colonised intensive care unit (ICU) patients, in order to support early clinical decision-making and antimicrobial stewardship.

Methods: Prospective observational study including adult patients admitted to ICU with CRAB colonisation at any site at the University Hospital of Pisa, Italy (June 2020-June 2023). The primary outcome measure was BSI caused by CRAB. A multivariable regression analysis was performed to identify factors independently associated with CRAB-BSI. Regression coefficients were used to develop a risk score for CRAB-BSI. Discrimination was evaluated using the area under the receiver operating characteristic curve (AUC-ROC).

Results: Among 283 colonised patients, 103/283 (36.4%) developed a BSI caused by CRAB. Median (IQR) time from colonisation to BSI was 4 days (1-8 days). On multivariable analysis, burns (OR: 8.219, 95% CI: 3.591-18.812, P < 0.001), number of colonised sites (per-site: OR: 2.197, 95% CI: 1.363-3.541, P = 0.001), respiratory tract colonisation (OR: 4.285, 95% CI: 2.179-8.426, P < 0.001), and cardiovascular disease (OR: 1.940, 95% CI: 1.068-3.524, P = 0.029) were independently associated with increased risk of BSI. The score ranged from 1 to 9 points. The AUC of the model was 0.817 (95% CI: 0.764-0.869, P < 0.001). The negative predictive value (NPV) was 97.8% in patients without septic shock and 72.2% in those who developed septic shock.

Conclusions: The rate of CRAB-BSI among colonised patients is considerable. The proposed score may be useful, after external validation, for a rational empirical use of new antibiotics.

Objectives: The global crisis of antimicrobial resistance (AMR) demands a paradigm shift in traditional drug discovery, and artificial intelligence (AI) is uniquely positioned to lead this transformation.

Methods: We highlight how AI and machine learning (ML) can accelerate the discovery of novel antimicrobials by enabling de novo drug design, virtual screening, identification of new drug targets, and elucidation of antimicrobial mechanisms.

Results: AI/ML is revolutionizing resistance prediction by integrating diverse genomic and phenotypic data for rapid diagnostics, real-time surveillance, and personalized antimicrobial therapy.

Conclusions: Despite data limitations and the 'black-box' challenge of model interpretability, the potential of AI to combat AMR hinges on sustained investment, data-sharing, and unprecedented interdisciplinary collaboration worldwide. The strategic deployment of AI and ML is thus a crucial element in the battle plan for the war against drug-resistant pathogens.

Background: Treatment regimens and clinical outcomes for post-kala-azar dermal leishmaniasis (PKDL) vary across South Asia and Eastern Africa. We evaluated the skin target site pharmacokinetics (PK) of miltefosine, liposomal amphotericin B (LAmB) and paromomycin and associated pharmacodynamics (PD) on skin parasite reduction and lesion healing, to determine PK/PD factors driving regional differences in clinical outcomes.

Methods: In South Asia, participants (n = 126) received LAmB alone or with miltefosine. In Eastern Africa, participants (n = 110) received LAmB or paromomycin with miltefosine. Skin drug concentrations were compared to the in vitro EC₅₀ of Leishmania donovani to assess PK target attainment, then correlated with skin parasite load and lesion score to evaluate pharmacokinetic-pharmacodynamic (PK-PD) relationships.

Results: Antileishmanial drug distribution varied in skin. Miltefosine showed the highest skin-to-plasma ratio, with medians of 1.19 (IQR: 0.78-1.88) in South Asia vs. 1.58 (1.1-2.08) in Eastern Africa (P < 0.05). Combining paromomycin or LAmB with miltefosine improved PK target attainment and reduced variability. In South Asia, macular or mixed (macular and papular/nodular) lesions predominated (93%) and were associated with ≥6-fold higher baseline parasite load and lesion score versus Eastern Africa, where papular and maculopapular lesions were more common (97%). By treatment end, parasite loads dropped ≥99% in both regions, with ≤7% above the transmission threshold. Lesion scores decreased by 11% in South Asia and 93% in Eastern Africa.

Conclusions: Similar skin PK target attainment and relative parasite reduction were achieved for all regimens. Regional differences in parasite load and lesion score at baseline and lesion healing rates, suggest disease presentation is the primary factor affecting clinical outcomes.