Comparative In Vitro Activities of First and Second-Generation Ceragenins Alone and in Combination with Antibiotics Against Multidrug-Resistant Klebsiella pneumoniae Strains

Abstract

Objectives: The ceragenins, or CSAs, were designed to mimic the activities of antimicrobial peptides and represent a new class of antimicrobial agent. The aim of this study was to comparatively investigate the antimicrobial activities of first/second generation ceragenins and various antibiotics against multidrug-resistant (MDR) Klebsiella pneumoniae, including colistin-resistant bacteria. Also, the synergistic effects of two ceragenins with colistin or meropenem were investigated with six K. pneumoniae strains presenting different resistant patterns. Methods: Minimal inhibition concentrations (MICs) were determined by the microdilution method according to the CLSI. Antibiotic combination studies were evaluated by the time–kill curve method. Results: MIC50 and MIC90 values of tested ceragenins ranged from 8 to 32 mg/L and 16 to 128 mg/L. Overall, among the ceragenins tested, CSA-131 showed the lowest MIC50 and MIC90 values against all microorganisms. The MICs of the ceragenins were similar or better than tested antibiotics, except for colistin. Synergistic activities of CSA-131 in combination with colistin was found for strains both at 1× MIC and 4× MIC. No antagonism was observed with any combination. Conclusions: First-generation ceragenins CSA-13 and CSA-44 and second-generation ceragenins CSA-131, CSA-138 and CSA-142 have significant antimicrobial effects on MDR K. pneumoniae. Mechanisms allowing resistance to clinical comparator antibiotics like colistin did not impact the activity of ceragenins. These results suggest that ceragenins may play a role in treating infections that are resistant to known antibiotics.

<p>NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131</p>

“…Although the antibiotics/chemotherapeutics mentioned above have been recommended in the treatment of infections caused by NDM-1 producing strains, our results demonstrated that these drugs were ineffective in eradicating strains tested due to the high levels of resistance. It should be underlined that our data are in agreement with those of Ozbek-Celik et al, 38 who reported that MICs values for meropenem-resistant clinical isolates of K. pneumoniae were 0.5-32 µg/mL for CSA-13 and CSA-44 (MIC 90 , 32 µg/mL) and 0.5-16 µg/mL in the case of CSA-131 (MIC 90 , 32 µg/mL). In addition, Bozkurt Guzel et al 40 also determined the antimicrobial activity of CSA-13 against E. coli ATCC 25922 with the MIC value 4 µg/ mL.…”

“…Therefore, CSAs can be considered as a new approach to eradicate MDR pathogens. 16,20,29,38,39 Moreover, bacteria are unable to achieve high levels of resistance to CSAs. It should be pointed out that ceragenins appear to be well tolerated and exhibits no degradation in the presence of bacterial and host proteases, making these properties a significant area of the antimicrobial research.…”

New β-Lactam Antibiotics and Ceragenins – A Study to Assess Their Potential in Treatment of Infections Caused by Multidrug-Resistant Strains of Pseudomonas aeruginosa

“…CSA-13 is the most studied ceragenin. Others, such as CSA-44, CSA-131, CSA-138, and CSA-142, 25 have been designed and tested in order to optimize antimicrobial activity and to increase the safety of use.…”

Characterization of Endophytic Streptomyces griseorubens MPT42 and Assessment of Antimicrobial Synergistic Interactions of Its Extract and Essential Oil from Host Plant Litsea cubeba

“…These processes make antibiotic-like substances diffusive inside bacterial cells, where they might then inhibit metabolic processes, protein and/or DNA synthesis, etc., leading to cell death [3,29,37]. Although combinations of different types or generations of antibiotics have shown synergistic effects [38,39], the use of an appropriate EO in combination with antibiotics against bacterial pathogens could bring advantageous alternatives to reducing the use of conventional antibiotics as well as the emergence of multidrug-resistant bacteria [40]. For instance, streptomycin and kanamycin combined with lemongrass (Cymbopogon citratus) EO exhibited synergistic or additive effect against S. Typhimurium [37].…”