Increased prevalence of fluoroquinolones (FQs) therapy-induced FQ resistant microbes has become a major concern in both human and veterinary medicine. Antimicrobial resistance has emerged in pathogenic organisms, as well as commensal organisms. This includes the gastrointestinal tract, with Escherichia coli among the organisms for which MDR has emerged. Based upon our pervious work, resistance to FQs rapidly appears as part of MDR expressed in clinical E. coli isolates cultured from patients receiving FQs.
The purpose of this study was to demonstrate and characterize, emerging resistance, using fecal E. coli as sentinel organisms, after routine use of two popular antimicrobials. Purpose-bred drug free hound dogs (n= 8 per group) maintained on a standard diet were studied. Dogs were dosed with either amoxicillin (G1, 10 mg/kg every 12 hr), enrofloxacin (G2, 5 mg/kg every 24 hr) or not dosed (control; G3) until the resistance to the treatment drug emerged. Dogs were studied for a minimum of 7 and a maximum of 21 d. Fecal samples were collected per rectum at baseline (day that drug administration began; B), and every 3 days until resistance (>75% of CFU resistant; T). Drug was then discontinued and monitoring continued weekly up to 4 weeks, or until the resistance resolved (<25% of CFU resistant; E), whichever came first. Husbandry was implemented to minimize mechanical transmission. Outcome measures, determined at 3 time points (B, T and E), included: Total coliform counts, total E. coli counts, percent E. coli and percent E. coli resistant to either drug, MIC90 (using Etest®), and the presence of MDR (yes or no) based on a commercial 13 drug panel antibiogram.
No resistance was present in any dog at time B. Resistance to amoxicillin developed in both G1 (6 d; n=8) and G2 (9d; n=4), but not G3. Resistance to enrofloxacin emerged in G2 (D 9; n=4), but in neither G1 nor G3. MIC90 for resistant isolates exceeded the breakpoint MIC for either drug by at least 8 fold. MDR did not develop in association with amoxicillin resistance. In contrast, all isolates resistant to enrofloxacin exhibited MDR. Amoxicillin resistance generally resolved by 2 weeks after completion of amoxicillin therapy in both G1 and G2, whereas enrofloxacin resistance resolved in varied times from 1 to more than 4 weeks in G2. Interestingly, E. coli was undetectable by day 9 and remained undetectable in 4 G2 dogs. These data indicate that both antimicrobial therapies facilitated the emergence of high-level resistance using recommended dosing regimens, and that resistance to enrofloxacin tends to be associated with MDR. This may reflect the synthetic nature of FQs: baseline resistance is likely to be low because isolates are not exposed to FQs under natural conditions, but once exposed, resistance involves complex mechanisms leading to MDR. This study suggests that, use of FQ might be used judiciously due to its apparent facilitation of emergent MDR in E. coli.