Introduction: Catheter associated urinary tract infections (UTI) are among the most common types of nosocomial infections in human hospitals, with Pseudomonas aeruginosa being one of the commonly isolated pathogens. P. aeruginosa is of particular interest due to its frequent association with antimicrobial resistance. Ertapenem is a once daily dosed broad‐spectrum carbapenem antibiotic typically reserved for resistant bacterial infections. We hypothesized that concurrent use of a non‐specific immunostimulant (Zelnate™) along with ertapenem treatment would improve clearance of P. aeruginosa in a sheep model of UTI. Furthermore, we hypothesized that the use of ertapenem would select for emergence of isolates that are resistant to broader spectrum carbapenem antibiotics. Materials and Methods: Ten cull ewes were housed in an isolation facility (BSL‐2). All ewes had an indwelling urinary catheter placed and were challenged via catheter with Pseudomonas aeruginosa. Ewes were divided into 3 treatment groups: ertapenem (4), ertapenem + Zelnate™ (4), and negative control (2). Multiple urine and plasma samples were collected over a 14 day study period that included sampling of a single dose of ertapenem as well as steady‐state concentrations. Urine and plasma concentrations were quantified via LC‐MS. Antimicrobial resistance was evaluated using broth dilution MIC assays as well as a commercial test for carbapenemases. Results: There was a two‐fold drop in bacterial shedding within 1.5 h for the ertapenem and ertapenem + Zelnate™ groups. One‐way ANOVA results showed a significant difference in average bacterial shedding levels between the control group and the ertapenem + Zelnate™ group (p = 0.004), but no significant differences between the control and the ertapenem group (p = 0.12). MIC testing for ertapenem, imipenem, and meropenem showed that the majority of isolates had an increase in MIC in comparison to the original strain. Carbapenamase testing was negative for all urine samples. Conclusions: Our results indicate that ertapenem use selects for P. aeruginosa isolates with cross‐resistance to meropenem and imipenem. Zelnate™ along with ertapenem decrease bacterial shedding in comparison to antibiotherapy alone.