Fang, Ferric C.

Abstract Objectives Carbapenem resistance is a growing public health crisis with regional variability in incidence. We characterized the susceptibility of carbapenem-resistant Gram-negative rods (CR-GNRs) from the Pacific Northwest to five reserve beta-lactam agents including cefiderocol and aztreonam-avibactam. Methods A panel of 162 CR-GNRs from unique patients were tested against cefiderocol, aztreonam-avibactam, ceftazidime-avibactam, meropenem-vaborbactam and ceftolozane-tazobactam, with a subset of isolates derived from patients with bacteraemia (n = 55). Whole-genome sequencing (WGS) was performed on representative Stenotrophomonas maltophilia isolates displaying a range of cefiderocol MICs (n = 9). Results Among all isolates, the MIC50 and MIC90 to cefiderocol was 0.25 and 4 mg/L, respectively, compared with 4 and >64 mg/L for aztreonam-avibactam. Overall, 98.3% of S. maltophilia (n = 60), 91.2% of Enterobacterales (n = 34) and 88.5% of Pseudomonas aeruginosa (n = 26) isolates were susceptible to cefiderocol, while 78.6% of other non-fermenters had MICs ≤4 mg/L. Aztreonam-avibactam and cefiderocol exhibited similar activity against Enterobacterales and S. maltophilia, but aztreonam-avibactam was less active against other organisms. WGS of S. maltophilia isolates with elevated cefiderocol MICs identified disruptive mutations in PBP-encoding genes (mrcB/PBP1b and pbpC/PBP1c) that were not observed in highly susceptible isolates. The bacteraemia cohort had many comorbidities and a 29% 30 day all-cause mortality. In this cohort, cefiderocol demonstrated the highest in vitro activity as extrapolated from MICs, followed by ceftazidime-avibactam, aztreonam-avibactam, meropenem-vaborbactam and ceftolozane-tazobactam, respectively. Conclusions Cefiderocol exhibited the greatest in vitro activity against various CR-GNRs species in a Pacific Northwest population enriched for severely ill patients. Susceptibility to other agents was more variable among tested organisms.

AbstractIn this article, the editors of Clinical Infectious Diseases review some of the most important lessons they have learned about the epidemiology, clinical features, diagnosis, treatment and prevention of SARS-CoV-2 infection and identify essential questions about COVID-19 that remain to be answered.