Objective Candida auris is a globally emerging pathogen associated with significant mortality. This pathogen frequently is misidentified by traditional biochemical methods and is resistant to commonly used antifungals. The echinocandins currently are recommended as the first-line treatment for C. auris infections. The objective of this work is to demonstrate the challenges associated with C. auris in the real-world setting. Methods A 54-year-old male presented to our institution for concerns of sepsis on multiple occasions over a 5-month period. Eleven urine cultures were positive over this timeframe for yeast (9 unidentified Candida isolates and 2 C. lusitaniae isolates). On day 27, the patient developed echinocandin-susceptible candidemia, which was initially identified as C. haemulonii but later accurately identified as C. auris at an outside mycology reference laboratory. Approximately 10 weeks later, the patient had a recurrence of candidemia, this time caused by an echinocandin-resistant C. auris strain. Results Genomic DNA sequencing performed at the outside mycology reference laboratory identified a single serine to proline base pair change at position 639 (S639P) in the hotspot 1 region of the FKS1 gene of the echinocandin-resistant strain. Conclusions Our experiences highlight 4 major concerns associated with C. auris: misidentification, persistent colonization, infection recurrence despite the receipt of appropriate initial therapy, and development of resistance.

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Objectives: The production of a metallo-(L1) and serine-(L2) β-lactamase precludes the use of β-lactams for the treatment of Stenotrophomonas maltophilia infections. Pre-clinical data suggest cefiderocol is the first approved β-lactam with reliable activity against S. maltophilia, but data against strains resistant to current first -line agents are limited and no studies have assessed cefiderocol-based combinations. The objective of this study was to evaluate and compare the in vitro activity of cefiderocol alone and in combination with levofloxacin, minocycline, polymyxin B, and trimethoprim-sulfamethoxazole (TMP-SMZ) against a collection of highly resistant clinical S. maltophilia isolates. Methods: The minimum inhibitory concentrations (MICs) of 37 S. maltophilia isolates not susceptible to levofloxacin and/or TMP-SMZ were determined for cefiderocol, ceftazidime, levofloxacin, minocycline, polymyxin B, and TMP-SMZ. Nine strains with varying MICs to cefiderocol were then tested in time-kill experiments alone and in combination with comparators. Results: The only agents with susceptibility rates exceeding 40% were cefiderocol (100%) and minocycline (97.3%). Cefiderocol displayed the lowest MIC50 and MIC90 values (0.125 and 0.5 mg/L, respectively). In time-kill experiments, synergy was observed when cefiderocol was combined with levofloxacin, minocycline, polymyxin B, and TMP-SMZ against 4/9 (44.4%), 6/9 (66.7%), 5/9 (55.5%), and 6/9 (66.7%) isolates, respectively. Conclusions: These data suggest that cefiderocol displays potent in vitro activity against S. maltophilia, including strains resistant to currently preferred agents. Future dynamic and in vivo studies of cefiderocol alone and in combination are warranted to further define cefiderocol's synergistic capabilities and place in therapy for S. maltophilia infections.

Stenotrophomonas maltophilia is difficult to treat due to the production of multiple intrinsic and acquired mechanisms of resistance. Trimethoprim-sulfamethoxazole (TMP-SMZ) and the fluoroquinolones have traditionally been considered the drugs of choice but are plagued by increasing resistance and adverse drug effects. The objective of this study was to evaluate the in vitro activities of 12 clinically relevant antimicrobials against clinical S. maltophilia isolates nonsusceptible to levofloxacin and/or TMP-SMZ. A diverse panel of 41 clinical S. maltophilia isolates collected through the SENTRY Antimicrobial Surveillance Program from 2008 to 2018 was evaluated against ceftazidime, ceftazidime-avibactam, chloramphenicol, delafloxacin, levofloxacin, moxifloxacin, eravacycline, minocycline, omadacycline, polymyxin B, and tigecycline. MICs were determined in triplicate via reference broth microdilution and interpreted according to CLSI guidelines where available. MIC distributions and susceptibilities were also compared across infection type, acquisition setting, and geographic origin. Susceptibilities to levofloxacin and TMP-SMZ were 29.3% and 36.6%, respectively. Minocycline displayed the highest susceptibility rate overall (92.7%) and the lowest MIC90 value (4 mg/liter) of any of the 12 agents tested. Only 3 isolates were resistant to levofloxacin, TMP-SMZ, and minocycline. Polymyxin B and tigecycline were the second most active agents. No significant differences were observed in MIC distributions across the 3 strata evaluated. These data demonstrate that few antimicrobials, old or new, maintain reliable activity against resistant S. maltophilia. The role of minocycline in the treatment of infections due to S. maltophilia warrants further clinical investigation given its potent in vitro activity and favorable adverse effect profile.

Metallo-β-lactamase (MBL)-producing Enterobacteriaceae, particularly those that coharbor serine β-lactamases, are a serious emerging public health threat given their rapid dissemination and the limited number of treatment options. Preclinical and anecdotal clinical data support the use of aztreonam in combination with ceftazidime-avibactam against these pathogens, but other aztreonam-based combinations have not been explored. The objective of this study was to evaluate the in vitro activity and compare synergy between aztreonam in combination with ceftazidime-avibactam and meropenem-vaborbactam against serine and MBL-producing Enterobacteriaceae via time-kill analyses. Eight clinical Enterobacteriaceae strains (4 Escherichia coli and 4 Klebsiella pneumoniae) coproducing NDM and at least one serine β-lactamase were used for all experiments. Drugs were tested alone, in dual β-lactam combinations, and in triple-drug combinations against all strains. All strains were resistant to ceftazidime-avibactam and meropenem-vaborbactam and 7/8 (87.5%) strains were resistant to aztreonam. Aztreonam combined with ceftazidime-avibactam was synergistic against all 7 aztreonam-resistant strains. Aztreonam combined with meropenem-vaborbactam was synergistic against all aztreonam-resistant strains with the exception of an OXA-232-producing K. pneumoniae strain. Neither triple combination was synergistic against the aztreonam-susceptible strain. These data suggest that aztreonam plus meropenem-vaborbactam has similar activity to aztreonam plus ceftazidime-avibactam against Enterobacteriaceae producing NDM and other non-OXA-48-like serine β-lactamases. Confirmation of these findings in future in vitro and in vivo models is warranted.