Clinical Microbiology and Infection最新文献

Background: Following intense efforts to revive the dry antibiotic research and development pipeline, a few highly awaited antibiotics with activity against multidrug-resistant (MDR) bacteria were recently approved.

Objectives: We aim to highlight gaps in the evidence generated for new antibiotics by the time of their approval and to review the consequent limitations of treatment guidelines for priority MDR bacteria. We also report on the availability of the new antibiotics, reimbursement strategies allowing the use of these antibiotics in hospitals, and antibiotic stewardship efforts.

Sources: We searched PubMed for phase 3 randomized controlled trials, guidelines, and publications on access, usage, regulatory aspects and antimicrobial stewardship of antibiotics approved for use against MDR bacteria between 2013 and 2023. Other sources included governmental and professional documents regarding policies for reimbursement and use of the new antibiotics.

Content: Several gaps in the evidence available regarding the new antibiotics are described related to the trials' target populations, comparators, management algorithm within the trial, non-inferiority hypotheses, and assessment of resistance development within the studies. We highlight the risk of current guidelines to increase the usage of new antibiotics and consequently accelerate resistance development. Updated mapping of antibiotic availability reveals critical inequality in access to the new antibiotics. Finally, strategies used nationally in Europe to provide access to the new antibiotics are not sufficiently balanced by antibiotic stewardship efforts to calibrate the judicious use of the new antibiotics.

Implications: Antibiotic resistance is an immediate threat. The present review highlights areas where more systematic and uniform strategies across countries and geographical regions are warranted to improve evidence, availability, and use of new broad-spectrum antibiotics.

Objectives: Cefepime-enmetazobactam is a new β-lactam/βlactamase inhibitor combination with broad-spectrum activity against multidrug-resistant Enterobacterales, including extended-spectrum β-lactamase producers. This study evaluated the in vitro activity of cefepime-enmetazobactam towards a collection of carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa and Acinetobacter baumannii compared to the other β-lactam/β-lactamase inhibitor combinations.

Methods: The MIC of cefepime, cefepime-enmetazobactam, ceftazidime, ceftazidime-avibactam, meropenem, meropenem-vaborbactam, imipenem, imipenem-relebactam, and ertapenem were determined by broth microdilution on 2212 CRE, including 2089 carbapenemase producers (1000 OXA-48-like, 49 KPC, 697 NDM, 180 VIM, 1 IMP, 9 IMI, and 158 multiple carbapenemases) and 123 CRE that do not produce carbapenemase received at the French National Reference Centre (from March 1, 2023 to August 31, 2023), 50 P. aeruginosa, and 30 A. baumannii. All strains were fully sequenced.

Results: We confirmed the absence of inhibitory activity of enmetazobactam towards metallo-β-lactamases. Cefepime-enmetazobactam and ceftazidime-avibactam exhibited a similar susceptibility (96.7% vs. 99.5%, respectively) on OXA-48-producers. Cefepime-enmetazobactam exhibited 66.9% and 63.3% susceptibility for CRE non-EPC and KPC, whereas those rates rose to 96.7%/95.9%, 93.4%/95.9%, and 95.9%/98.0% for ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam, respectively. Low MICs (≤0.25 mg/L) were obtained for ceftazidime-avibactam-resistant KPC variants. Cefepime-enmetazobactam did not display a significant added value when compared with cefepime alone on Pseudomonas aeruginosa and Acinetobacter baumannii.

Discussion: OXA-48 producers displayed high susceptibility to cefepime-enmetazobactam, which is similar to ceftazidime-avibactam, including for OXA-48 producers that coproduce a ceftazidime hydrolyzing enzyme (extended-spectrum β-lactamases or AmpC). In vivo experiments have to be implemented to confirm if cefepime-enmetazobactam might be a relevant alternative to ceftazidime-avibactam for the treatment of infections caused by OXA-48 producers.

Objectives: To determine the proportion of individuals with detectable antigen in plasma or serum after SARS-CoV-2 infection and the association of antigen detection with postacute sequelae of COVID-19 (PASC) symptoms.

Methods: Plasma and serum samples were collected from adults participating in four independent studies at different time points, ranging from several days up to 14 months post-SARS-CoV-2 infection. The primary outcome measure was to quantify SARS-CoV-2 antigens, including the S1 subunit of spike, full-length spike, and nucleocapsid, in participant samples. The presence of 34 commonly reported PASC symptoms during the postacute period was determined from participant surveys or chart reviews of electronic health records.

Results: Of the 1569 samples analysed from 706 individuals infected with SARS-CoV-2, 21% (95% CI, 18-24%) were positive for either S1, spike, or nucleocapsid. Spike was predominantly detected, and the highest proportion of samples was spike positive (20%; 95% CI, 18-22%) between 4 and 7 months postinfection. In total, 578 participants (82%) reported at least one of the 34 PASC symptoms included in our analysis ≥1 month postinfection. Cardiopulmonary, musculoskeletal, and neurologic symptoms had the highest reported prevalence in over half of all participants, and among those participants, 43% (95% CI, 40-45%) on average were antigen-positive. Among the participants who reported no ongoing symptoms (128, 18%), antigen was detected in 28 participants (21%). The presence of antigen was associated with the presence of one or more PASC symptoms, adjusting for sex, age, time postinfection, and cohort (OR, 1.8; 95% CI, 1.4-2.2).

Discussion: The findings of this multicohort study indicate that SARS-CoV-2 antigens can be detected in the blood of a substantial proportion of individuals up to 14 months after infection. While approximately one in five asymptomatic individuals was antigen-positive, roughly half of all individuals reporting ongoing cardiopulmonary, musculoskeletal, and neurologic symptoms were antigen-positive.

Objectives: For the prevention of hand, foot, and mouth disease (HFMD), enterovirus A71 (EV-A71) vaccines have been used in China since 2016. To better inform vaccination strategies, we assess the real-world effectiveness of EV-A71 vaccination in China.

Methods: The analysis was based on surveillance data of HFMD caused by EV-A71 in children under the age of 5 in China, along with meteorological and demographic data. The seasonal autoregressive integrated moving average model and the interrupted time series analysis were used to estimate the effectiveness of the EV-A71 vaccination on the EV-A71 HFMD incidence and to predict the counterfactual cases with no EV-A71 vaccine.

Results: Between 2010 and 2018, 6 712 613 cases of HFMD caused by EV-A71 were reported in children under 5 years old in 260 Chinese cities. During 2017-2018, the EV-A71 vaccination was associated with a reduction in EV-A71 HFMD incidence, with a relative risk of 0.83 (95% CI, 0.81-0.86), and an estimated reduction of 297 946 (95% CI, 250 534-346 658) cases. However, this association varied across cities (I² = 85.6%, p < 0.001) and the effectiveness of the EV-A71 vaccination decreased as population density increased. Higher vaccination coverage was associated with greater effectiveness of the EV-A71 vaccination and an earlier point in EV-A71 case reduction. Specifically, when the vaccination coverage exceeded ∼20%, the relative risk was rapidly reduced to below 0.71 (95% CI, 0.69-0.72).

Discussion: Our study demonstrated that the EV-A71 vaccination was associated with a reduction in the incidence of EV-A71 HFMD, but the association varied with regions and was influenced by vaccination coverage and population density. To optimize EV-A71 HFMD prevention, increasing vaccination coverage (>20%) is recommended for children under 5 years old.