Potentiation of antimicrobial activity of colistin with antibiotics of different groups against multidrug- and extensively drug-resistant strains of Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa

Abstract

Objective. To reveal antibiotics being capable of potentiating the antimicrobial activity of colistin against multidrug- and extensively drug-resistant strains of Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. Materials and Methods. The minimum inhibitory concentrations (MIC) of colistin alone and in combination with fixed concentrations of antibiotics of different groups were determined for 272 multidrug- and extensively drug-resistant strains of K. pneumoniae, A. baumannii and P. aeruginosa. Bactericidal activity of colistin, carbapenems, clarithromycin and their combinations were also determined at fixed PK/PD breakpoint concentrations of antibiotics. Results. Potentiation of colistin antibacterial activity in the presence of fixed concentration of rifampicin (0.5 mg/L) was observed as a 4–16-fold MIC decrease for K. pneumoniae and A. baumannii. In the presence of fixed concentrations of azithromycin (2 mg/L) or clarithromycin (1 mg/L), the colistin MICs decreased 64–512 times for K. pneumoniae, 4–32 times for A. baumannii, 16–64 times for P. aeruginosa. Two- or more-fold reduction of MIC of colistin in the presence of 1 mg/L clarithromycin was observed for 85.2% of K. pneumoniae, 86.3% of A. baumannii and 60.2% of P. aeruginosa strains. In the presence of 1 mg/L clarithromycin and 8 mg/L meropenem, the potentiation effect was enhanced and was observed for an even larger percent of isolates: 96.1% K. pneumoniae, 98.0% A. baumannii and 61.3% P. aeruginosa. Colistin-based combinations with clarithromycin-meropenem and clarithromycin-doripenem were bactericidal against most isolates of A. baumannii and P. aeruginosa (91.4–100%), and against colistin-sensitive K. pneumoniae (95.3%) and colistin-resistant K. pneumoniae (79.1%). Conclusions. The ability of macrolides to significantly potentiate the colistin antimicrobial activity against both colistin-sensitive and colistin-resistant strains of K. pneumoniae, A. baumannii and P. aeruginosa was shown. This potentiation effect was enhanced in the presence of carbapenems. The most potent bactericidal activity was revealed with dual and triple combinations of colistin-clarithromycin and colistinclarithromycin-carbapenems.

Azithromycin possesses biofilm–inhibitory activity and potentiates non-bactericidal colistin methanesulfonate (CMS) and polymyxin B against Klebsiella pneumonia

“…We therefore hypothesized that AZM or other macrolides which have no effect against K. pneumoniae liquid cultures or colonies [26], might instead be effective against biofilm-forming K. pneumoniae cells (the ability to form biofilms is common among K. pneumoniae isolates (e.g., 63-94% [27][28][29]) and MDR and biofilm-formation appear unlinked [29]). Moreover, we suggest that AZM or other macrolides acting as an anti-biofilm therapeutic agent might enhance the bactericidal effectiveness of CMS in a combined anti-Klebsiella therapy, as macrolides have been shown to potentiate CMS against both K. pneumoniae and P. aeruginosa [30]. Previously we have discussed the range of different aggregations bacteria form and key differences between classical biofilms, colonies, and liquid cultures [31].…”

Azithromycin possesses biofilm–inhibitory activity and potentiates non-bactericidal colistin methanesulfonate against Klebsiella pneumonia

“…We therefore hypothesized that AZM or other macrolides which have no effect against K. pneumoniae liquid cultures or colonies [26], might instead be effective against biofilm-forming K. pneumoniae cells (the ability to form biofilms is commonplace amongst K. pneumoniae isolates (e.g., 63 - 94% [27-29]) and MDR and biofilm-formation appear unlinked [29]). Moreover, we suggest that AZM or other macrolides acting as an anti-biofilm therapeutic agent might enhance the bactericidal effectiveness of CMS in a combined anti- Klebsiella therapy, as macrolides have been shown to potentiate CMS against both K. pneumoniae and P. aeruginosa [30]. Previously we have discussed the range of different aggregations bacteria form and key differences between classical biofilms, colonies, and liquid cultures [31].…”