Pharmacokinetics of Colistin in the Gastrointestinal Tract of Poultry Following Dosing via Drinking Water and Its Bactericidal Impact on Enteric.

Abstract

Colistin, a last-line antibiotic of major importance in veterinary medicine and of critical importance in human medicine, is authorized to treat gastrointestinal (enteric) infections caused by non-invasivein multiple veterinary species including poultry. Its use in veterinary medicine has been implicated in the widespread prevalence of mobilized colistin resistance. The objectives of this study were to determine the intestinal content reached in broiler chickens during 72-h treatment with colistin, to evaluate the associated impact on intestinaldensity, and to select less susceptiblepopulations. In this study, 94 broiler chickens were administered a dose of 75,000 IU/kg/day via drinking water. Intestinal samples were collected pre-, during-, and post-dosing. Luminal intestinal content was assessed for colistin content by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), andwere isolated and enumerated on UriSelect agar™. Minimum inhibitory concentration (MIC, for eight isolates per intestine per animal) was determined, and when higher than the epidemiological cutoff (ECOFF 2 mg/l), isolates were screened for mobilized colistin resistance (mcr)-1 to 5. Colistin content increased during treatment to a maximum of 5.09 mg/kg. During this time, the total population ofshowed an almost 1,000-fold reduction. An apparent increase in the relative abundance ofwith an MIC ≥ ECOFF, either mcr-negative (6.25-10.94%) or mcr-1-positive (4.16-31.25%) was observed, although this susceptibility shift was not maintained post-treatment. Indeed, following cessation of dosing, colistin was eliminated from the intestine, and content was below the limit of quantification (LOQ, 1.1 mg/kg) within 4 h, and the median MIC ofisolates returned below baseline thereafter. Few isolates with a lower susceptibility (mcr-1-positive or negative) were however observed at the end of the study period, indicating maintained sub-populations in the chicken gut. The results of this study show a limited impact on long-term maintenance of less susceptiblepopulations as a direct result of colistin treatment in individual birds.