In vitro synergism of colistin in combination with N-acetylcysteine against Acinetobacter baumannii grown in planktonic phase and in biofilms

Abstract

ObjectivesTo investigate the potential synergism of colistin in combination with N-acetylcysteine against Acinetobacter baumannii strains grown in planktonic phase or as biofilms.MethodsSixteen strains were investigated, including nine colistin-susceptible (MIC range 0.5–1 mg/L) and seven colistin-resistant (MIC range 16–256 mg/L) strains. Synergism of colistin in combination with N-acetylcysteine was investigated by chequerboard assays. The activity of colistin/N-acetylcysteine combinations was further evaluated by time–kill assays with planktonic cultures (three colistin-resistant strains and one colistin-susceptible strain) and by in vitro biofilm models (three colistin-resistant and three colistin-susceptible strains).ResultsChequerboard assays revealed a relevant synergism of colistin/N-acetylcysteine combinations with all colistin-resistant strains, whereas no synergism was observed with colistin-susceptible strains. Time–kill assays showed a concentration-dependent potentiation of colistin activity by N-acetylcysteine against colistin-resistant strains, with eradication of the culture by combinations of N-acetylcysteine at 8000 mg/L plus colistin at 2 or 8 mg/L. A static effect during the first 8 h of incubation was demonstrated with the colistin-susceptible strain exposed to 0.25 × MIC colistin plus 8000 mg/L N-acetylcysteine. A remarkable antibiofilm synergistic activity of 8 mg/L colistin plus 8000 mg/L N-acetylcysteine was demonstrated with all colistin-resistant and colistin-susceptible strains. The effects were greater with colistin-resistant strains (marked reduction of viable biofilm cells was observed at sub-MIC colistin concentrations).Conclusions N-acetylcysteine, at concentrations achievable by topical administration, was shown to revert the colistin-resistant phenotype in A. baumannii, and to exert a relevant activity against biofilms of colistin-susceptible and colistin-resistant A. baumannii strains.

In Vitro Synergism of Colistin and N-acetylcysteine against Stenotrophomonas maltophilia

“…Nonetheless, apart from intrinsic resistance of BCC, colistin is not recommended as first-line treatment option for other relevant CF pathogens (e.g., S. maltophilia and Achromobacter xylosoxidans ), due to lack of clinical breakpoints and high rates of organisms with high Minimum Inhibitory Concentration (MIC) values [21]. Recently, it has been shown that colistin/NAC combinations exert a relevant antimicrobial and antibiofilm synergistic activity against Acinetobacter baumannii [22]. In particular, high NAC concentrations (potentially achievable by topical administration) can revert the colistin resistance phenotype in this pathogen [22].…”

“…Recently, it has been shown that colistin/NAC combinations exert a relevant antimicrobial and antibiofilm synergistic activity against Acinetobacter baumannii [22]. In particular, high NAC concentrations (potentially achievable by topical administration) can revert the colistin resistance phenotype in this pathogen [22].…”

<p>Small Molecule Adjuvants Potentiate Colistin Activity and Attenuate Resistance Development in <em>Escherichia coli</em> by Affecting <em>pmr</em>AB System</p>

“… 17 In addition, N-acetylcysteine, a mucolytic agent, also synergized with colistin against Col S and Col R A. baumannii grown in planktonic phase and in biofilms. 16 These findings suggest that the combination of colistin with other membrane-active compounds or drugs can result in synergistic interaction by facilitating the colistin effect on bacterial membranes. 51 In this study, we only tested the synergistic potential of SMs against three APEC strains (O78, O1, and O2); however, these SMs were previously found to be effective against multiple APEC strains, including antibiotic-resistant and biofilm protected APEC; 23 therefore, we believe that these SMs may potentiate the activity of colistin against diverse E. coli and possibly against other Gram-negative pathogens.…”

“…One potential approach to ameliorate colistin resistance is the use of antibiotic adjuvants (or potentiators) which can increase the efficacy of colistin, ultimately requiring lower doses of colistin for treatments. 13 , 14 In previous studies, 2-aminoimidazoles (2-AIs), 13 ( E )-2-hexenal, 15 indole, 15 N-acetylcysteine, 16 resveratrol, 17 niclosamide, 18 and pentamidine 19 were identified as colistin adjuvants against different Gram-negative pathogens. Importantly, colistin adjuvants can also reverse the colistin resistance so that the colistin is effective against the previously resistant bacteria.…”

Synergistic activity of colistin combined with PFK-158 against colistin-resistant and colistin-susceptible Gram-negative bacteria

“…A large quantity of previous studies have reported the synergistic activity of colistin combined with other antibiotics against colistin-resistant or carbapenem-resistant strains [18,19,20]. Besides, a few studies based on colistin in combination with the nonantibiotics were also performed previously [21,22,23]. In this study, we evaluated the synergistic activity of colistin combined with PFK-158 against colistin-resistant and colistin-susceptible Gram-negative bacteria.…”