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Background Escherichia coli is one of the most common causes of healthcare-associated infections (HAIs); multidrug resistance reduces available options for antibiotic treatment. We examined factors associated with the spread of multidrug-resistant E. coli phenotypes responsible for device- and procedure-related HAIs from acute care hospitals, long-term acute care hospitals, and inpatient rehabilitation facilities, using isolate and antimicrobial susceptibility data reported to the National Healthcare Safety Network during 2013–2017. Methods We used multivariable logistic regression to examine associations between co-resistant phenotypes, patient and healthcare facility characteristics, and time. We also examined the geographic distribution of co-resistant phenotypes each year by state and by hospital referral region to identify hot spots. Results A total of 96 672 E. coli isolates were included. Patient median age was 62 years, and 60% were female; more than half (54%) were reported from catheter-associated urinary tract infections. From 2013 to 2017, 35% of the isolates were nonsusceptible to fluoroquinolones (FQs), 17% to extended-spectrum cephalosporins (ESCs), and 13% to both ESCs and FQs. The proportion of isolates co-resistant to ESCs and FQs was higher in 2017 (14%) than in 2013 (11%) (P <.0001); overall prevalence and increases were heterogeneously distributed across healthcare referral regions. Co-resistance to FQs and ESCs was independently associated with male sex, central line–associated bloodstream infections, long-term acute care hospitals, and the 2016–2017 (vs 2013–2014) reporting period. Conclusions Multidrug resistance among E. coli causing device- and procedure-related HAIs has increased in the United States. FQ and ESC co-resistant strains appear to be spreading heterogeneously across hospital referral regions. [ABSTRACT FROM AUTHOR]