Background: Streptococcus pneumoniae is a gram-positive opportunistic pathogen, and infection risks of S. pneumoniae can be profoundly augmented by its acquired multidrug-resistance (MDR). The rapid development of MDR in S. pneumoniae was attributed to the international dissemination of a small number of multidrug-resistant “clones.” Clonal complex (CC) 271 is a prevalent MDR CC in the world and the most prevalent CC in China. However, the evolutionary trajectories of multidrug-resistant S. pneumoniae CC271 in China still are largely unknown. Methods: We investigated a collection of 1312 S. pneumoniae isolates collected from 28 tertiary hospitals in China from 2007 to 2020. Recombination prediction and recombination-masked phylogenetic analysis were combined to determine the population structure and mode of evolution of CC271. Data from the Global Pneumococcal Sequencing program (GPS) were combined to understand the global distribution of clones identified in this study. Bayesian analysis were recruited to analysis the evolutionary dynamics of dominant clones within CC271 in China. Results: The phylogenomic analysis resulted in the discovery of two globally distributed clones, ST271-A and ST271-B. ST271-A was a derivative of ST236 and an ancestor of ST271-B and ST320, refining the internal phylogenetic relationship of CC271. ST271-B was the most dominant clone in China, with higher β-lactam resistance especially for cephalosporins comparing to other MDR clones. Bayesian skyline plot showed a rapid expansion of 19F ST271-B from 1995 to 2000, which correlates with the widespread use of cephalosporins in the 1990s in China. 19A ST320, a vaccine-escape clone, is the second largest population in China. The Bayesian skyline plot showed that the 19A ST320 began to expand rapidly around 2001, which appeared to coincide with the prevalence of 19A after application of PCV7 in 2000 in the USA. We also observed frequent transmission of 19A ST320 between countries. It suggests that mass vaccination in some countries could affect the prevalence of clones in unvaccinated countries in the context of high-frequency international transmission. Conclusions: Our results refined the internal phylogenetic relationship of CC271, showing that the 19F ST271-B and 19A ST320 evolved independently from ST271-A, with different histories and driving forces for their evolution and dissemination in China.

Eravacycline is a broad-spectrum fluorocycline currently approved for complicated intra-abdominal infections (cIAIs). In lung-infection models, it is effective against methicillin-resistant Staphylococcus aureus (MRSA) and tetracycline-resistant MRSA. As such, we aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to evaluate eravacycline’s pulmonary distribution and kinetics. Data were extracted from a Phase I study ( NCT01989949 ) which assessed the bronchopulmonary disposition of intravenous eravacycline to construct the population PK model that could adequately describe the drug’s pulmonary kinetics. Eravacycline lung PK was best described by a three-compartment model with allometric scaling, with the epithelial lining fluid (ELF) component parameterized as the ELF distribution ratio ( R a t i o = C f r e e , E L F C f r e e , c e n t r a l , unbound concentration in ELF over central compartment). The estimated ELF distribution ratio was 8.26 (95% confidence interval = 6.8–9.8). Besides allometrically scaled weight, no other significant covariate was found. MIC ₉₀ was 0.5 mg/L ( Escherichia coli ), 2 mg/L ( Klebsiella pneumoniae ), 0.5 mg/L ( Acinetobacter baumannii ), and 0.12 mg/L ( S. aureus ). At the approved cIAI dosage or higher (1 mg/kg or 1.5 mg/kg q12h), a PK/PD cutoff value of 2 mg/L was appropriate for E. coli , while a lower value of 1 mg/L was selected for K. pneumoniae , A. baumannii , and S. aureus . For lower doses, the cutoff value was reduced to 0.5 mg/L for K. pneumoniae , A. baumannii , and S. aureus . The study showed eravacycline was widely distributed into the lungs with promising antibacterial efficacy, thus justifying further investigations into its uses for pulmonary infections.

This study investigated the antitumor effects of foretinib on triple-negative breast cancer cells MDA-MB-231 xenograft tumors in vivo underlying phosphorylated mesenchymal to epithelial transition (p-MET)/ hepatocyte growth factor (HGF)-related mechanism, as well as its pharmacokinetic characteristics. The MDA-MB-231 human breast cancer cell line was used for in vitro experiments, and the tumor xenograft model was established for in vivo experiments. MDA-MB-231 xenograft mice received oral foretinib (15 or 50 mg/kg/day) or vehicle for 18 days. The xenograft tumors were collected. Protein expressions of p-MET and HGF were examined with Western blotting and immunohistochemical staining. The mRNA expression of MET was examined with real-time PCR. Blood samples were collected from the mice treated with foretinib under different doses of 2, 10, and 50 mg/kg, and the pharmacokinetic profiles of foretinib were evaluated. We found that foretinib treatment caused a significant inhibition in tumor growth in a dose-dependent manner, whereas the continuous administration did not result in weight loss in treated nude mice. In both MDA-MB-231 cells and xenograft tumors, foretinib suppressed the expression of p-MET and HGF. These findings reveal that the decrease of p-MET and HGF may play an important role in the anti-breast cancer properties of foretinib.

Background: The clinical use of carbapenems is facing challenges due to increased carbapenemase-producing Escherichia coli (CP-EC) infections over the past decade. Meanwhile, whole-genome sequencing (WGS) is an important method for bacterial epidemiological research. We aim to provide more gene-based surveys to explore the genomics and occurrence of CP-EC in China.Methods: A total of 780 Escherichia coli isolates were collected by the China Antimicrobial Resistance Surveillance Trial (CARST) from 2019 to 2020. An antibacterial susceptibility test was performed by using the agar dilution method. CP-EC were detected by the modified carbapenem inactivation method (mCIM), EDTA-modified carbapenem inactivation method (eCIM), and polymerase chain reaction (PCR). Homology analysis was performed by multilocus sequence typing (MLST). A conjugation experiment was performed to verify the transferability of plasmids carrying carbapenemase genes. WGS was conducted to explore the gene-environment of the carbapenemase gene.Result: Of the 780 Escherichia coli isolates, 31 isolates were insensitive to carbapenem with a rate of 4%. Among them, 13 CP-EC isolates had transferability of the bla_NDM gene. These isolates belonged to nine distinct sequence types (STs), with some correlation. We found that two (2/13, 15.4%) of the CP-EC isolates that were collected from blood specimens were highly pathogenic and also showed high transferability of the bla_NDM gene. In addition, eight (8/13, 61.5%) of the CP-EC isolates were found to be multidrug-resistant.Conclusion: With the increasing use of carbapenem, CP-EC isolates accounted for nearly half of the total carbapenem-insensitive Escherichia coli isolates. Our findings highlight the urgent need to pay attention to CP-EC isolates in bloodstream infections and ESBL-producing CP-EC isolates. Based on the One Health concept, we suggest various measures, including the development of bacterial vaccines, antibiotic management, and establishment of better medical environments, to avoid the outbreak of CP-EC.

Corrigendum: Molecular epidemiology and comparative genomics of carbapenemase-producing Escherichia coli isolates from 19 tertiary hospitals in China from 2019 to 2020

Streptococcus pneumoniae poses a significant health threat with rising antimicrobial resistance. In China, long-term, age-stratified data on its molecular epidemiology remain limited. This study investigates resistance trends and serotype distribution across pediatric, adult, and elderly populations over 14 years. A total of 1312 clinical isolates collected during seven two‑year surveillance phases (2007-2020) from 24 hospitals across China were analyzed using whole-genome sequencing for serotype prediction, multilocus sequence typing (MLST), and Global Pneumococcal Sequence Clustering (GPSC); antibacterial susceptibility was performed using agar dilution method. Serotypes 19 F and 19 A consistently accounted for the largest proportion of isolates throughout the study period. PCV13 serotype coverage was highest in children (85.8%) and increased nationally from 64.5% to 77.9% over 14 years. MLST identified ST271 and ST320 as the most prevalent clones, often associated with serotypes 19 F and 19 A, respectively. AMR was severe, with > 90% macrolide resistance nationwide. Penicillin non-susceptibility (using non‑meningitis oral breakpoints) increased markedly, especially among pediatric isolates, which also showed higher β-lactam resistance. Fluoroquinolones retained high susceptibility (>97% of isolates susceptible). The resistance gene erm(B) was detected in 96.3% of isolates. S. pneumoniae in China exhibits persistent high resistance to macrolides and increasing β-lactam non-susceptibility, particularly in children. Dominant clones and serotypes showed no statistically significant change in proportional trends over the 14 years. PCV13 serotype coverage remains high, yet actual vaccine uptake is low; this suggests a missed opportunity for preventing infections caused by vaccine serotypes, highlighting the potential benefit of increased immunization efforts.