Pharmacokinetics and Pharmacodynamics of Colistin Combined With Isopropoxy Benzene Guanidine Against mcr-1-Positive Salmonella in an Intestinal Infection Model

Abstract

Plasmid-borne colistin resistance mediated by mcr-1 is a growing problem, which poses a serious challenge to the clinical application of colistin for Gram-negative bacterial infections. Drug combination is one of the effective strategies to treat colistin-resistant bacteria. Here, we found a guanidine compound, namely, isopropoxy benzene guanidine (IBG), which boosted the efficacy of colistin against mcr-1-positive Salmonella. This study aimed to develop a pharmacokinetics/pharmacodynamics (PK/PD) model by combining colistin with IBG against mcr-1-positive Salmonella in an intestinal infection model. Antibiotic susceptibility testing, checkerboard assays and time-kill curves were used to investigate the antibacterial activity of the synergistic activity of the combination. PK studies of colistin in the intestine were determined through oral gavage of single dose of 2, 4, 8, and 16 mg/kg of body weight in broilers with intestinal infection. On the contrary, PD studies were conducted over 24 h based on a single dose ranging from 2 to 16 mg/kg. The inhibitory effect Imax model was used for PK/PD modeling. The combination of colistin and IBG showed significant synergistic activity. The AUC0−24h/MIC index was used to evaluate the relationship between PK and PD, and the correlation was >0.9085. The AUC0−24h /MIC targets in combination required to achieve the bacteriostatic action, 3-log10 kill, and 4-log10 kill of bacterial counts were 47.55, 865.87, and 1894.39, respectively. These results can facilitate the evaluation of the use of IBG as a potential colistin adjuvant in the treatment of intestinal diseases in broilers caused by colistin-resistant Salmonella.

Ex vivo pharmacokinetic/pharmacodynamic of hexahydrocolupulone against Clostridium perfringens in broiler chickens

“…The MBC was determined as the concentration at which a 99.9% reduction in the bacterial counts was achieved. The agar method was employed to determine the MPC of hexahydrocolupulone ( 24 ). The C. perfringens strains with a concentration of 10 10 CFU/mL were inoculated to agar plates that contained varying concentrations of hexahydrocolupulone (1 MIC, 2 MIC, 4 MIC, 8 MIC, 16 MIC, and 32 MIC).…”

Flufenamic Acid, a Promising Agent for the Sensitization of Colistin-Resistant Gram-Negative Bacteria to Colistin

“…The in vitro synergistic efficacy of colistin and FFA was examined using a checkerboard assay approach using a modified version of a protocol employed in a previous report ( 36 ). Briefly, serial dilutions of FFA and colistin were mixed in 96-well plates to generate a range of dilution combinations.…”

Metabolite Identification of Isopropoxy Benzene Guanidine in Rat Liver Microsomes by Using UHPLC-Q-TOF-MS/MS

“…Guanidine-containing compounds also have good antibacterial activity against drug-resistant bacteria [ 10 , 11 ]. Isopropoxy benzene guanidine (IBG) is a novel guanidine compound that not only exhibits effective antibacterial activity against Gram-positive bacteria but also restores the sensitivity of Gram-negative bacteria to colistin as an antibiotic adjuvant [ 12 , 13 , 14 , 15 ]. IBG is expected to be a new antibacterial drug for bacterial infections.…”