A continuum of bacterial coexistence equilibrium states sustains mcr-mediated colistin resistance at the human-animal interface.

Colistin represents one of the last therapeutic options against multidrug-resistant gram-negative bacteria; however, the ecological mechanisms sustaining plasmid-mediated resistance at the human-animal interface remain poorly understood. We develop a deterministic Ordinary Differential Equation model of mcr-mediated resistance dynamics in cohabiting human and animal bacterial populations, calibrated with field isolates of E. coli and K. pneumoniae from rural communities in Ecuador. Using normal hyperbolicity theory, we prove the existence of a normally attracting invariant manifold (NAIM) that supports a continuum of coexistence equilibria. This structure, absent from classical single-equilibrium AMR models, rigorously explains why mcr-mediated resistance persists as a stable ecological state governed by host carrying capacity rather than as a transient pharmacological response. Numerical simulations reproduce the empirically observed prevalence contrast between E. coli (90%) and K. pneumoniae (19.5%) as a consequence of species-specific growth and gene-transfer kinetics, not differential colistin exposure. Intervention analysis reveals that colistin restriction alone fails to shift the endemic equilibrium. We show that reducing inter-species bacterial transfer can unintentionally increase human antimicrobial resistance when resistance is higher in humans than in animals. By disrupting the dilution effect provided by susceptible animal-associated bacteria, contact-reduction measures may produce a biphasic response and exacerbate endemic resistance. These results reorient the One Health strategy away from exclusive pharmacological restriction and toward ecological interventions targeting bacterial carrying capacity and microbiota restoration as the primary levers for sustained resistance control.