New therapy from old drugs: synergistic bactericidal activity of sulfadiazine with colistin against colistin-resistant bacteria, including plasmid-mediated colistin-resistant mcr-1 isolates

The recent emergence of colistin (COL) resistance, particularly mcr-1 plasmid-mediated COL resistance in Gram-negative bacteria, has led to renewed interest in antibiotic combinations to overcome clinical therapeutic impasses. The aim of this study was to evaluate the potential of the synergistic and bactericidal activity of COL in combination with sulphonamide compounds, including sulfadiazine (SDI), sulfamethoxazole (SMX) and trimethoprim/sulfamethoxazole (SXT), as well as trimethoprim (TMP) against clinical COL-resistant bacterial strains, including strains with the plasmid-encoded mcr-1 gene. A collection of 55 COL-resistant and -susceptible strains from different origins (Laos, Thailand and France) was used in this study. Several in vitro methods were used to determine the potential of the synergistic activity of these combinations, including Etest on agar pre-treated plates, the Etest cross method and the chequerboard assay. A time-kill assay was performed to evaluate the potential bactericidal activity of combinations in addition to synergistic activity. Significant synergistic activity was observed with all combinations tested. The combination of COL + SDI presented the highest synergistic effect against the various species of COL-resistant strains (92.7%). For the other combinations, a synergistic effect was also observed but with lower frequency for COL + SMX (33.3%), COL + TMP (47.3%) and COL + SXT (31.5%). Synergy was observed independently of the COL resistance mechanism. These in vitro results suggest that the combination of COL + SDI would appear to be justifiable in patients with multidrug-resistant bacterial infections that cannot be treated with COL monotherapy.