Synergy between Mecillinam and Ceftazidime/Avibactam or Avibactam against Multi-Drug-Resistant Carbapenemase-Producing Escherichia coli and Klebsiella pneumoniae

Background: Carbapenemase-producing Klebsiella pneumoniae and Escherichia coli have become a significant global health challenge. This has created an urgent need for new treatment modalities. We evaluated the efficacy of mecillinam in combination with either avibactam or ceftazidime/avibactam against carbapenemase-producing clinical isolates. Materials and methods: Nineteen MDR clinical isolates of K. pneumoniae and E. coli were selected for the presence of blaKPC, blaNDM, blaOXA or blaIMP based on whole-genome sequencing and phenotypic susceptibility testing. We tested the synergy between mecillinam and avibactam or ceftazidime/avibactam. We used time–kill studies in vitro and a mouse peritonitis/sepsis model to confirm the synergistic effect. We investigated avibactam’s impact on mecillinam´s affinity for penicillin-binding proteins with a Bocillin assay, and cell changes with phase-contrast and confocal laser scanning microscopy. Results: Mecillinam combined with ceftazidime/avibactam or avibactam substantially reduced MICs (from up to >256 µg/mL to <0.0016 µg/mL) for 17/18 strains. Significant log-CFU reductions were confirmed in time–kill and in vivo experiments. The Bocillin assay did not reveal changes. Conclusion: Mecillinam in combination with avibactam or ceftazidime/avibactam has a notable effect on most types of CPEs, both in vitro and in vivo. The mecillinam/avibactam combination treatment could be a new efficient antibiotic treatment against multi-drug-resistant carbapenemase-producing Gram-negative pathogens

Biomarkers for iron metabolism among patients hospitalized with community-acquired pneumonia caused by infection with SARS-CoV-2, bacteria, and influenza

Ferritin, the central iron storage protein, has attracted attention as a biomarker of severe COVID‐19. Few studies have investigated regulators of iron metabolism in the context of COVID‐19. The aim was to evaluate biomarkers for iron metabolism in the acute phase response to community‐acquired pneumonia (CAP) caused by SARS‐CoV‐2 compared with CAP caused by bacteria or influenza virus in hospitalized patients. A cross‐sectional study of 164 patients from the Surviving Pneumonia Cohort recruited between January 8, 2019 and May 26, 2020. Blood samples were collected at admission and analyzed for levels of C‐reactive protein (CRP), ferritin, soluble transferrin receptor, erythroferrone, and hepcidin. Median (IQR) hepcidin was higher in SARS‐CoV‐2 with 143.8 (100.7–180.7) ng/mL compared with bacterial and influenza infection with 78.8 (40.1–125.4) and 53.5 (25.2–125.8) ng/mL, respectively. The median ferritin level was more than 2‐fold higher in patients with SARS‐CoV‐2 compared with the other etiologies (p < 0.001). Patients with SARS‐CoV‐2 had lower levels of erythroferrone and CRP compared with those infected with bacteria. Higher levels of hepcidin and lower levels of erythroferrone despite lower CRP levels among patients with SARS‐CoV‐2 compared with those infected with bacteria indicate alterations in iron metabolism in patients with SARS‐CoV‐2 infection