Clinical Microbiology and Infection最新文献

Objectives: To report long-term clinical efficacy, safety, pharmacokinetics, immunogenicity and seroneutralization results of AZD7442 (monoclonal antibodies tixagevimab-cilgavimab) in patients hospitalized with COVID-19.

Methods: In this phase 3, double-blind, randomized, multicentre trial, hospitalized adults with PCR-confirmed SARS-CoV-2 infection were randomly assigned 1:1 to receive AZD7442 or placebo, and followed-up until day 456, with repeated blood sample collections until day 365. Clinical endpoints included clinical status, mortality, rehospitalization, SARS-CoV-2 reinfection, and adverse events. Antidrug antibodies and serum drug concentrations were measured. Analyses were performed on the modified intention-to-treat (mITT) populations, defined as participants who actually received the intervention.

Results: Between April 28, 2021, and June 23, 2022, 237 participants were randomly assigned to AZD7442 (n = 127) or placebo (n = 110), and 123 participants actually received AZD7442. Participants were infected with pre-Omicron variants in 58.8% (133/226) of cases, versus 33.2% (75/226) of Omicron BA1, BA2, or BA5, and 8% (18/226) missing data. There was no significant difference in the distribution of the 7-point ordinal scale between the AZD7442 and placebo groups, either on day 15 (primary endpoint) (OR = 0.93 [0.54-1.61], p 0.81), or any other time point. Significantly more rehospitalizations occurred between discharge and day 456 among participants who received AZD7442 in the global mITT population (OR = 2.04 [1.03-4.05], p 0.04), but not in the antigen-positive mITT population (OR = 1.78 [0.80-3.94], p 0.15). No significant differences were observed in mortality, SARS-CoV-2 reinfection, or adverse events. In the AZD7442 group, 12 of 87 participants (13.8%) had treatment-emergent antidrug antibodies versus 5 of 69 (7.2%) in the placebo group (OR = 2.02 [0.66-6.14], p 0.21). Serum drug concentrations were detectable up to day 365 for all sampled participants (35/35). Neutralizing antibody titres were significantly higher in the AZD7442 group up to day 180.

Conclusions: AZD7442 did not demonstrate any clinical benefit and was safe up to 15 months. This study also provides valuable data on the pharmacokinetics, immunogenicity, and neutralizing activity of AZD7442 in patients hospitalized with COVID-19.

Background: Gerald P. Bodey (1934-2020) was a pioneering haematologist who revolutionized the management of infectious complications in patients with haematological malignancies. Over 4 decades, he authored >800 peer-reviewed publications and established evidence-based practices that continue to save lives worldwide.

Objectives: To examine Bodey's seminal contributions to infectious diseases in immunocompromised hosts and their enduring impact on contemporary cancer care.

Sources: Beginning with his seminal paper on the relationship between infections and circulating neutrophils, this review synthesizes Dr. Bodey's research accomplishments from the 1960s through 2000s, organising his work into chronologically arranged principles that shaped modern oncology practice.

Content: Seven key principles emerge from Bodey's work: (1) the critical importance of autopsy data for understanding infection epidemiology; (2) quantitative risk assessment using neutrophil counts, establishing the 500 cells/mm³ threshold for empirical antibiotic therapy; (3) timely empirical antibiotic therapy in febrile neutropenic patients; (4) the necessity of studying antibiotics specifically in neutropenic populations; (5) environmental control strategies and prophylaxis; (6) recognition of fungal infections as persistent threats; and (7) mentorship and academic excellence in developing future leaders.

Implications: Bodey's foundational work established the framework for modern infection management in cancer patients. His quantitative approach to infection risk assessment and empirical antibiotic therapy became standard care for >5 decades. As cancer treatment evolves toward targeted therapies with novel immunosuppressive effects, Bodey's principles require adaptation but remain fundamentally relevant. His legacy demonstrates the importance of rigorous clinical research, mentorship, and patient-focused care in advancing medical knowledge and improving outcomes.

Objectives: Gonorrhoea, caused by Neisseria gonorrhoeae, is a significant public health challenge due to the rising incidence of antimicrobial resistant (AMR) strains. The Valencian Region, one of the top tourist destinations in Eastern Spain, has witnessed an increase of over 200% in the number of cases in recent years. Here, we aimed to investigate the impact of imported AMR lineages in shaping the local gonococcal population and generating sustained transmission events.

Methods: We analysed 1647 N. gonorrhoeae isolates collected in the Valencian Region between 2012 and 2024 with accompanying phenotypic antimicrobial susceptibility and epidemiological data. Genomic data was obtained through high-throughput sequencing and combined with 5894 genomes from national and international isolates. From these, information on typing and genetic AMR determinants was derived. Phylogenomic and statistical inference were used to investigate the local dynamics of this pathogen.

Results: Results revealed high levels of AMR, including 63.6% (n = 449/706) ciprofloxacin resistance, 17.7% (n = 195/1102) azithromycin resistance, and 8.4% (n = 66/783) reduced susceptibility or resistance to ceftriaxone. The two main circulating lineages were NG-STAR CC1615 and CC63, carrying 55.0% (n = 121/220) and 26.5% (n = 45/170) isolates with a mosaic mtr (mosaic mtrD and mtrR promoter), respectively. Phylodynamic analyses identified multiple introductions of AMR lineages into the region leading to sustained transmissions since the 1990s. These lineages significantly carried more isolates with mtr mosaics (OR = 4.17 [3.27-5.34]; p 1.26E-33) and phenotypic resistance to azithromycin (OR = 2.22 [1.60-3.06]; p 1.14E-06), among other antimicrobials.

Conclusions: This study highlights the dynamic evolution and dissemination of AMR N. gonorrhoeae at the local level, highlighting the role of international mobility, sexual networks, and antibiotic usage in shaping resistance patterns. Enhanced genomic surveillance, with special monitoring of mosaic mtr-carrying lineages, together with targeted public health interventions, will be key to curb local and regional spread of resistant gonococcal strains.

Objectives: The emergence of extensively drug-resistant Enterobacterales, particularly carbapenemase-producing Klebsiella pneumoniae, poses a serious global health threat. Cefiderocol (FDC), a sideromycin antibiotic, employs a 'Trojan horse' strategy by using bacterial iron transport systems to enter the cell and inhibit cell wall synthesis. Although initially promising, resistance to FDC has rapidly emerged in the clinics and in the environment, necessitating a comprehensive understanding of the underlying resistance mechanisms.

Methods: In this study, we used transposon-directed insertion-site sequencing in an extensively drug-resistant FDC-susceptible K. pneumoniae ST258 strain to systematically identify genetic networks that modulate FDC resistance.

Results: Our transposon-directed insertion-site sequencing analysis revealed 299 chromosomal genes significantly impacting FDC resistance, with 143 identified as conditionally resistant modulators (CRMs) and 156 as conditionally essential genes. CRMs notably included genes associated with FDC influx, such as the siderophore uptake genes cirA and tonB, and porin channels such as ompK36 and tolB. Importantly, we identified several CRMs involved in bacterial capsule synthesis and expression (e.g. csrD and glnD), suggesting that capsule overexpression is a novel resistance mechanism. Phenotypic characterization of cirA, csrD and glnD knockout mutants confirmed increased FDC resistance. Furthermore, disruption of csrD and glnD resulted in enhanced capsule production, increased resistance to human serum and, in particular, increased virulence in a Galleria mellonella infection model.

Conclusions: These results emphasize the multifactorial nature of FDC resistance, involving both impaired drug entry and capsule-mediated protection, with potentially pleiotropic effects on bacterial virulence. Our study elucidates key genetic determinants of FDC resistance and highlights the complex interplay between antibiotic resistance and bacterial pathogenicity.