Following burn injury, patients are at increased risk of infection and are often cited as having a high incidence of difficult-to-treat pathogens (DTp). The purpose of this study is to determine the incidence of DTp after burn injury, which factors are associated with their development, and subsequent outcomes. This single-center, retrospective study assessed patients with thermal or inhalation injury who had a positive culture resulting in initiation of treatment (i.e., excision, topical, or systemic antimicrobials). Demographic data, pathogen and resistance profiles, and prior exposure to topical and systemic antimicrobials were collected. Pathogens were considered DTp if they were multi-drug-resistant (MDR), extensively drug-resistant (XDR), methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase (ESBL)-producing, AmpC-producing, carbapenem-resistant, difficult-to-treat resistance (DTR) Pseudomonas sp., carbapenem-resistant Acinetobacter baumannii (CRAB), or Stenotrophomonas spp. Sixty-five patients who grew 376 pathogens were included in the final analysis. Two-hundred thirteen (56.7%) pathogens were considered DTp. Prior exposure to 7 of the 11 collected topical antimicrobials and 9 of 11 systemic antimicrobial classes were significantly associated with future development of a DTp. This remained true for six and eight, respectively, after controlling for significant covariates via logistic regression. As there were only four deaths, a Cox-proportional hazard analysis was not feasible. The Kaplan-Meier plot according to DTp revealed a clear divergence in mortality (Log rank p = 0.0583). In this analysis, exposure to topical and systemic antibiotics was associated with the development of DTp. The results from this pilot study will inform the next iteration of multicenter study.