Repositioning rafoxanide to treat Gram-negative bacilli infections.

Abstract

OBJECTIVES:

Repurposing drugs provides a new approach to the fight against MDR Gram-negative bacilli (MDR-GNB). Rafoxanide, a veterinary antihelminthic drug, has shown antibacterial activity in vitro against Gram-positive bacteria. We aimed to analyse the in vitro and in vivo efficacy of rafoxanide in combination with colistin against colistin-susceptible (Col-S) and colistin-resistant (Col-R) GNB.

METHODS:

A collection of Col-S and Col-R Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae were used. Chequerboard and time-kill curve analyses were performed to determine the synergy between rafoxanide and colistin. Changes in membrane structure and permeability were analysed using transmission electron microscopy and fluorescence assays. A murine peritoneal sepsis model using Col-R strains of these pathogens was performed to study the efficacy of rafoxanide (10 mg/kg/24 h, IV), colistimethate sodium (CMS) (20 mg/kg/8 h, intraperitoneally) and rafoxanide (10 mg/kg/24 h, IV) plus CMS (20 mg/kg/8 h, intraperitoneally) for 72 h.

RESULTS:

Rafoxanide showed MICs ≥256 mg/L for all Col-S and Col-R strains. Chequerboard and time-kill curve analyses showed that rafoxanide (1 mg/L) is more synergistic with colistin against Col-R than Col-S strains. Col-R, but not Col-S, strains treated with rafoxanide demonstrated higher membrane permeabilization. Transmission electron microscopy visualization confirmed that Col-R strains suffer morphological changes. In the murine peritoneal sepsis model with Col-R strains, rafoxanide plus CMS, compared with CMS alone, increased mouse survival to 53.8% and 73.3%, and reduced bacterial loads in tissues and blood between 2.34 and 4.99 log10 cfu/g or mL, respectively.

CONCLUSIONS:

Rafoxanide repurposing, as monotherapy and in combination with CMS, may address the urgent need for new treatments for infections caused by MDR-GNB.

• Authors: Andrea Miró-Canturri, Rafael Ayerbe-Algaba, Ángel Rodríguez Villodres, Jerónimo Pachón, Younes Smani
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 75 Issue 7 Pg. 1895-1905 (07 01 2020) ISSN: 1460-2091 [Electronic] England
• PMID: 32240294 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Anti-Bacterial Agents
• Rafoxanide
• Colistin

Topics

• Acinetobacter baumannii
• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Colistin (pharmacology)
• Drug Resistance, Multiple, Bacterial
• Drug Synergism
• Gram-Negative Bacteria
• Mice
• Microbial Sensitivity Tests
• Rafoxanide (pharmacology)