Bryan, Andrew

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.

Abstract Metagenomic sequencing of plasma has been advertised by Karius, Inc. as a way to diagnose a variety of infectious syndromes. Due to the lack of robust evidence of clinical utility, our laboratory began actively stewarding Karius testing. Microbiology Directors recommended cancelation of Karius orders when certain criteria were identified. We set out to review Karius test requests in a 52-month period of stewardship, during which we recommended cancellation on 21 of 57 orders (37%). Of Karius tests sent on samples with negative conventional testing, only 3 (7%) had positive results for Karius with plausible explanatory etiologies. Of these three cases, two were empirically covered for the positive finding without improvement and one case was never treated. Twelve (29%) had positive results that were noted by infectious diseases (ID) to reflect insignificant detections. Given the 4-fold higher detection of insignificant Karius results, we set out to systematically analyze the literature for the experience of insignificant detections at other centers. When we compared studies that included healthy controls or had clinical adjudication of positive Karius findings by ID physicians, we found a median of 17.5% of individual patients that had positive insignificant detections of potential pathogenic bacteria or fungi. The most frequently detected species were as likely to be clinically adjudicated to be insignificant as they were to be significant within the same studies. Overall, these findings highlight limited utility of Karius testing and a need for careful stewardship, not only to ensure it is sent on patients who may benefit, but also to ensure results of potential pathogens are interpreted cautiously.