Pharmacodynamic and immunomodulatory effects of polymyxin B in combination with fosfomycin against KPC-2-producing Klebsiella pneumoniae

• Published in: International journal of antimicrobial agents 2022-04, Vol.59 (4), p.106566-106566, Article 106566
• Main Authors: Sharma, Rajnikant, Garcia, Estefany, Diep, John K., Lee, Vince H., Minhaj, Faisal, Jermain, Brian, Ellis-Grosse, Evelyn J., Abboud, Cely S., Rao, Gauri G.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - therapeutic use; Bacterial Proteins - metabolism; beta-Lactamases - metabolism; Carbapenem-Resistant Enterobacteriaceae - metabolism; Carbapenemase; Fosfomycin; Fosfomycin - pharmacology; Fosfomycin - therapeutic use; Humans; Immunity; Klebsiella Infections - drug therapy; Klebsiella Infections - microbiology; Klebsiella pneumoniae; Microbial Sensitivity Tests; Polymyxin B; Polymyxin B - pharmacology; Polymyxin B - therapeutic use; Pro-inflammatory cytokines
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2022.106566

•Host immunity plays an important role in clearance of bacterial infection.•Immunomodulatory and pharmacodynamic effects of polymyxin B and fosfomycin as mono- and combination therapy were evaluated.•Combination therapy led to a decrease in IL-6 and IL-8 as well as reduction in bacterial burden.•Our study highlights the need to further understand the interaction between the host immune system and infecting pathogen. Determining the role of the immune response in preventing antimicrobial resistance and optimising antibiotic regimens against carbapenemase-producing Klebsiella pneumoniae is a research gap that exists and needs to be further explored. The objective of this study was to determine the pharmacodynamic and immunomodulatory effects of fosfomycin alone and in combination with polymyxin B against KPC-2-producing K. pneumoniae clinical isolates. Six K. pneumoniae isolates were selected (polymyxin B MIC, 0.5–64 mg/L; fosfomycin MIC, 16–128 mg/L) to evaluate the pharmacodynamics of monotherapy and combination therapies in static time–kill studies. A mechanism-based model was used to characterise the joint activity of polymyxin B and fosfomycin. A549 human airway epithelial cells were infected with four isolates to evaluate the immunomodulatory effects of treatment. Our mechanism-based model indicated greater bacterial killing efficacy of fosfomycin with polymyxin B compared with monotherapy. In combination, polymyxin B was assumed to exert an outer membrane effect that resulted in an increase in the ability of fosfomycin to reach its target site. The mechanism-based model described the data well across all six strains, with R2 values ranging from 0.705–0.935. Combination therapy reduced K. pneumoniae-induced IL-6 and IL-8 but not TNFα expression. The reduction in cytokine expression was greater with polymyxin B than fosfomycin alone; combination therapy showed significantly greater reduction compared to either monotherapy. Our findings suggest that further research is needed to better understand immune-mediated killing in order to identify a strategy which harnesses the power of the immune response against these hard-to-treat bacteria.