Models of antimicrobial pressure on intestinal bacteria of the treated host populations

Abstract

Antimicrobial drugs are used to treat pathogenic bacterial infections in animals and humans. The by-stander enteric bacteria of the treated host's intestine can become exposed to the drug or its metabolites reaching the intestine in antimicrobially active form. We consider which processes and variables need to be accounted for to project the antimicrobial concentrations in the host's intestine. Those include: the drug's fraction (inclusive of any active metabolites) excreted in bile; the drug's fractions and intestinal segments of excretion via other mechanisms; the rates and intestinal segments of the drug's absorption and re-absorption; the rates and intestinal segments of the drug's abiotic and biotic degradation in the intestine; the digesta passage time through the intestinal segments; the rates, mechanisms, and reversibility of the drug's sorption to the digesta and enteric microbiome; and the volume of luminal contents in the intestinal segments. For certain antimicrobials, the antimicrobial activity can further depend on the aeration and chemical conditions in the intestine. Model forms that incorporate the inter-individual variation in those relevant variables can support projections of the intestinal antimicrobial concentrations in populations of treated host, such as food animals. To illustrate the proposed modeling framework, we develop two examples of treatments of bovine respiratory disease in beef steers by oral chlortetracycline and injectable third-generation cephalosporin ceftiofur. The host's diet influences the digesta passage time, volume, and digesta and microbiome composition, and may influence the antimicrobial loss due to degradation and sorption in the intestine. We consider two diet compositions in the illustrative simulations. The examples highlight the extent of current ignorance and need for empirical data on the variables influencing the selective pressures imposed by antimicrobial treatments on the host's intestinal bacteria.

Ceftiofur formulation differentially affects the intestinal drug concentration, resistance of fecal Escherichia coli, and the microbiome of steers

“…coli and the microbiome, it suggests to us that this property produced clinically relevant differences in the GI PK parameters. Further, these concentrations were dramatically lower than predicted through mathematical models [38], demonstrating the need for empirical data. Here, the intestinal concentrations were above MIC 90 for E .…”

Faecal concentrations of ceftiofur metabolites in finisher pigs administered intramuscularly with ceftiofur

“…We measured the concentrations of ceftiofur metabolites in faeces of finisher pigs that were treated with ceftiofur hydrochloride by intramuscular injection for 3 days for production‐related diseases and fed one of three diets differing in fibre level and source. The faecal samples were collected 6–8 hr post injection, which corresponds to the peak faecal concentrations of ceftiofur metabolites (Volkova et al., 2017). The diets were based on corn grain and soybean‐meal and supplemented with dried distiller's grains with solubles, a byproduct of ethanol production from corn grain, or with sugar beet pulp, a byproduct of sugar beet processing to achieve a higher level of NDF.…”

Modeling the Effect of Tylosin Phosphate on Macrolide-Resistant Enterococci in Feedlots and Reducing Resistance Transmission

“…TYL, tylosin phosphate. parameterized for this purpose: (1) a pharmacokinetic model to determine the concentration of TYL reaching commensal bacteria within the large intestine (Cazer et al, 2014;Volkova et al, 2017), (2) a pharmacodynamic model to simulate the effect of TYL on the growth of susceptible and resistant Enterococcus populations (Volkova et al, 2016;Cazer et al, 2017), and (3) a bacterial metapopulation dynamics model incorporating bacterial growth within and movement between cattle host, water trough, feed bunk, and pen environment (Ayscue et al, 2009). One model simulation represents treating one pen of animals and the resultant changes to the Enterococcus subpopulations.…”

“…Localized increased sorption could be achieved through dietary modification or supplementation with TYL binders that are pH activated. TYL excretion rates can be similarly modified with diet; models show reduced antimicrobial intestinal concentrations with hay-based diets compared with grain-based diets (Volkova et al, 2017). TYL feeding trials have observed an effect of days on feed or diet changes on enterococci concentrations (Davedow et al, 2020; Schmidt et al, 2020)…”