IMPORTANCEEstimates of the incidence of overall antibiotic-associated adverse drug events (ADEs) in hospitalized patients are generally unavailable.OBJECTIVE To describe the incidence of antibiotic-associated ADEs for adult inpatients receiving systemic antibiotic therapy. DESIGN, SETTING, AND PARTICIPANTSRetrospective cohort of adult inpatients admitted to general medicine wards at an academic medical center.EXPOSURES At least 24 hours of any parenteral or oral antibiotic therapy.MAIN OUTCOMES AND MEASURES Medical records of 1488 patients were examined for 30 days after antibiotic initiation for the development of the following antibiotic-associated ADEs: gastrointestinal, dermatologic, musculoskeletal, hematologic, hepatobiliary, renal, cardiac, and neurologic; and 90 days for the development of Clostridium difficile infection or incident multidrug-resistant organism infection, based on adjudication by 2 infectious diseases trained clinicians. RESULTSIn 1488 patients, the median age was 59 years (interquartile range, 49-69 years), and 758 (51%) participants were female. A total of 298 (20%) patients experienced at least 1 antibiotic-associated ADE. Furthermore, 56 (20%) non-clinically indicated antibiotic regimens were associated with an ADE, including 7 cases of C difficile infection. Every additional 10 days of antibiotic therapy conferred a 3% increased risk of an ADE. The most common ADEs were gastrointestinal, renal, and hematologic abnormalities, accounting for 78 (42%), 45 (24%), and 28 (15%) 30-day ADEs, respectively. Notable differences were identified between the incidence of ADEs associated with specific antibiotics.CONCLUSIONS AND RELEVANCE Although antibiotics may play a critical role when used appropriately, our findings underscore the importance of judicious antibiotic prescribing to reduce the harm that can result from antibiotic-associated ADEs.

Background Bacterial infections may complicate viral pneumonias. Recent reports suggest that bacterial co-infection at time of presentation is uncommon in coronavirus disease 2019 (COVID-19); however, estimates were based on microbiology tests alone. We sought to develop and apply consensus definitions, incorporating clinical criteria to better understand the rate of co-infections and antibiotic use in COVID-19. Methods A total of 1016 adult patients admitted to 5 hospitals in the Johns Hopkins Health System between March 1, 2020, and May 31, 2020, with COVID-19 were evaluated. Adjudication of co-infection using definitions developed by a multidisciplinary team for this study was performed. Both respiratory and common nonrespiratory co-infections were assessed. The definition of bacterial community-acquired pneumonia (bCAP) included proven (clinical, laboratory, and radiographic criteria plus microbiologic diagnosis), probable (clinical, laboratory, and radiographic criteria without microbiologic diagnosis), and possible (not all clinical, laboratory, and radiographic criteria met) categories. Clinical characteristics and antimicrobial use were assessed in the context of the consensus definitions. Results Bacterial respiratory co-infections were infrequent (1.2%); 1 patient had proven bCAP, and 11 (1.1%) had probable bCAP. Two patients (0.2%) had viral respiratory co-infections. Although 69% of patients received antibiotics for pneumonia, the majority were stopped within 48 hours in patients with possible or no evidence of bCAP. The most common nonrespiratory infection was urinary tract infection (present in 3% of the cohort). Conclusions Using multidisciplinary consensus definitions, proven or probable bCAP was uncommon in adults hospitalized due to COVID-19, as were other nonrespiratory bacterial infections. Empiric antibiotic use was high, highlighting the need to enhance antibiotic stewardship in the treatment of viral pneumonias.

Background As cefiderocol is increasingly being prescribed in clinical practice, it is critical that we understand key mechanisms contributing to acquired resistance to this agent. Methods We report the case of a patient with acute lymphoblastic leukemia with an NDM-5 producing Escherichia coli intra-abdominal infection where resistance to cefiderocol evolved approximately 2 weeks after initiating cefiderocol therapy. Through WGS investigations, mRNA expression studies, and EDTA inhibition analysis, we investigate the role of increased NDM-5 production and genetic mutations contributing to the development of cefiderocol resistance using 5 sequential clinical E. coli isolates obtained from the patient. Results blaNDM-5 genes were identified in all 5 isolates. Cefiderocol MICs were 2, 4, and >32 mcg/mL for isolates 1-2, 3, 4-5, respectively. WGS showed that isolates 1-3 contained a single copy of the blaNDM-5 gene, whereas isolates 4 and 5 had 5 copies and 10 copies of the blaNDM-5 gene on an IncFIA/FIB/IncFII plasmid, respectively. These findings correlated with NDM-5 mRNA expression analysis in which isolates 4 and 5 expressed NDM 1.7x and 2.8x greater than isolate 1. Synergy testing with the combination of ceftazidime-avibactam and aztreonam demonstrated expansion of the zone of inhibition between the disks for all isolates. The patient was eventually successfully treated with this combination and remained infection free 10 months later. Conclusions Our patient’s case suggests that increased copy numbers of bla NDM genes through translocation events is used by Enterobacterales to evade cefiderocol-mediated cell death. The frequency of increased NDM expression in contributing to cefiderocol resistance needs investigation.

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Our study supports recent guidance identifying vancomycin as a vesicant, among a subset of antimicrobial agents, and removal of pH criteria for identification of vesicants.