Gastric stability and oral bioavailability of colistin sulfate in pigs challenged or not with Escherichia coli O149: F4 (K88)

Abstract

The aim of the present study was to investigate the in vitro gastric stability of colistin sulfate (CS) and its antimicrobial activity against Escherichia coli and to study the impact of ETEC O149: F4 (K88) infection in pigs on CS intestinal absorption. The stability profile of CS was evaluated in a simulated gastric fluid (SGF). Antimicrobial activity of CS and its degradation products were examined in a 96-well polystyrene microplate model. The effect of experimental infection with ETEC O149: F4 on CS intestinal absorption was determined by quantification of CS systemic concentration using a validated LC-MS/MS method. A rapid degradation of CS accompanied by an increase in CS antimicrobial activity by comparison with non-degraded CS (P<0.0001) was observed in SGF. Additionally, CS levels were not quantifiable in systemic circulation using a highly sensitive method and concurrent oral challenge did not affect CS absorption in an induction model of subclinical post-weaning diarrhea (PWD).

Colistin in Pig Production: Chemistry, Mechanism of Antibacterial Action, Microbial Resistance Emergence, and One Health Perspectives

“…Colistin (polymyxin E) is a polymyxin antibiotic produced by Paenibacillus polymyxa var colistinus (Tambadou et al, 2015) consisting of a cyclic heptapeptide ring with three positively charged amine groups, a tail tripeptide moiety with two positively charged amine groups, and a hydrophobic acyl chain tail ( Figure 1 ; Li et al, 2006; Bergen et al, 2012; Azzopardi et al, 2013; Dijkmans et al, 2015; Rhouma et al, 2015). Colistin is an amphipathic molecule, with hydrophobicity mainly attributable to the fatty acyl moiety and hydrophilicity due to the five L -diaminobutyric acid ( L -Dab) amino groups (Li et al, 2006).…”

“…In fact, no pure colistin A and B reference standards are commercially available (Dotsikas et al, 2011) and no certificates of analysis that include chemical characterization are available in veterinary medicine to adequately establish the purity of the marketed CS formulations (Rhouma et al, 2016a). CS is a polypeptide antibiotic with a chemical structure characterized by the presence of multiple peptide bonds documented to predispose CS to chemical and enzymatic degradation (Chihara et al, 1973; Rhouma et al, 2015). In fact, in pig simulated gastric fluid (SGF), CS led to the formation of degradation products that have a significant antimicrobial activity compared to non-degraded CS (Rhouma et al, 2015).…”

“…CS is a polypeptide antibiotic with a chemical structure characterized by the presence of multiple peptide bonds documented to predispose CS to chemical and enzymatic degradation (Chihara et al, 1973; Rhouma et al, 2015). In fact, in pig simulated gastric fluid (SGF), CS led to the formation of degradation products that have a significant antimicrobial activity compared to non-degraded CS (Rhouma et al, 2015). …”

“…Unlike for human medicine, only a few studies have been conducted in pigs to evaluate the PK of colistin following oral (Guyonnet et al, 2010; Rhouma et al, 2015, 2016b) or intramuscular (IM) administration (Lin et al, 2005; Tang et al, 2009; He et al, 2011; Table 1 ). These studies were performed using CS, since this is the only form of colistin approved in swine medicine, and were conducted in healthy pigs.…”

“…It is reasonable to think that the PK can be different in sick animals. The oral CS PK data in pigs were obtained using either a high-pressure liquid chromatography (HPLC) assay (Guyonnet et al, 2010) or a LC coupled with the tandem mass spectrometry (HPLC–MS/MS) method (Rhouma et al, 2015, 2016b). CS PK data in pigs after parenteral administration were obtained using mostly microbiological assays (Lin et al, 2005; Tang et al, 2009; Table 1 ); these data should be viewed with caution because of the limited sensitivity of this method and the descriptions of the experiment conditions.…”