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

Abstract

Stenotrophomonas maltophilia is an emerging global opportunistic pathogen, responsible for a wide range of human infections, including respiratory tract infections. Intrinsic multidrug resistance and propensity to form biofilms make S. maltophilia infections recalcitrant to treatment. Colistin is among the second-line options in case of difficult-to-treat S. maltophilia infections, with the advantage of being also administrable by nebulization. We investigated the potential synergism of colistin in combination with N-acetylcysteine (NAC) (a mucolytic agent with antioxidant and anti-inflammatory properties) against S. maltophilia grown in planktonic phase and biofilm. Eighteen S. maltophilia clinical isolates (comprising three isolates from cystic fibrosis (CF) and two trimethoprim-sulfamethoxazole (SXT)-resistant strains) were included. Checkerboard assays showed a synergism of colistin/NAC combinations against the strains with colistin Minimum Inhibitory Concentration (MIC) >2 µg/mL (n = 13), suggesting that NAC could antagonize the mechanisms involved in colistin resistance. Nonetheless, time–kill assays revealed that NAC might potentiate colistin activity also in case of lower colistin MICs. A dose-dependent potentiation of colistin activity by NAC was also clearly observed against S. maltophilia biofilms, also at sub-MIC concentrations. Colistin/NAC combinations, at concentrations likely achievable by topical administration, might represent a valid option for the treatment of S. maltophilia respiratory infections and should be examined further.

Effects of Tigecycline Combined with Azithromycin Against Biofilms of Multidrug-Resistant Stenotrophomonas maltophilia Isolates from a Patient in China

“…However, it is known that organisms such as S. maltophilia actually grow in the form of biofilms that are more resistant to bacteria than bacteria floating on airway epithelial cells. 8,36,37 Previous research showed levofloxacin prevented biofilm formation of S. maltophilia isolates, 38 however, according to our study, a refractory infection in pleural effusion was caused by S. maltophilia with high biofilm production, characterized by resistance to SXT, LVX, and ceftazidime. 11 The patient was treated using TGC at first, however, the effect was not good, and biofilm production in the isolates may have contributed to the poor efficacy.…”

“…However, it is known that organisms such as S. maltophilia actually grow in the form of biofilms that are more resistant to bacteria than bacteria floating on airway epithelial cells. 8 , 36 , 37 …”

“…[17][18][19] Briefly, overnight cultures of S. maltophilia were standardized to a 0.5 MacFarland standard (equivalent to 1.5 × 10 8 CFU/ mL), and then diluted (1:100) with fresh Luria Bertani broth. Aliquots (200 μ L) of standardized inocula were added to the wells of sterile flat-bottom 96-well polystyrene tissue culture plates (Thermo Fisher Scientific, USA) and incubated at 37°C over a series of time-points (2,4,6,8,10,12,24,36, and 48 h) in a closed and humidified plastic container. The medium was then discarded and non-adherent cells were removed by washing three times in sterilized ultrapure water.…”

The Urgent Need for Novel Antimicrobial Agents and Strategies to Fight Antibiotic Resistance

“…Ciacci et al demonstrated that N-acetylcysteine, in combination with colistin at concentrations likely achievable by topical administration, might represents a valid alternative for the treatment of respiratory infections caused by Stenotrophomonas maltophilia. Results from this study are very exciting, given the major role of S. maltophilia in difficult-to-treat respiratory tract infections in cystic fibrosis patients and, at the same time, the possibility to administer these two compounds via inhalation, likely reaching concentrations above the minimum inhibitory concentration (MIC) [10]. On the other hand, Richter et al showed the growth inhibitory effect of colistin plus chlorophyllin against Escherichia coli and Salmonella typhimurium.…”

“…Other contributions showed a remarkable antimicrobial effect, alone or in synergy with standard antibiotics, of some well-known agents that are generally regarded as non-toxic, such as lactic acid, N-acetylcysteine, and chlorophyllin [9][10][11], thus providing very interesting examples of possible drug repositioning. Specifically, Bardhan and colleagues reported on the antimicrobial activity of lactic acid, a natural product often present in naturally fermented substances, against MDR and carbapenem-resistant clinical strains of K. pneumoniae.…”