Abstract
Whilst colistin (polymyxin E) represents the last mainstream treatment option for multidrug-resistant Gram-negative pathogens, details of its mechanism of action remain to be fully resolved. In this study, the effects of sub-inhibitory, inhibitory-bactericidal, and supra-bactericidal levels of colistin on the membrane integrity and morphology of Escherichia coli and Pseudomonas aeruginosa were investigated using potassium loss, flow cytometry, and scanning electron microscopy (SEM). Supra-bactericidal colistin concentrations induced just 4–12% intracellular potassium loss from bacteria after 24 h. Flow cytometry data suggested colistin might alter cell arrangement, and SEM confirmed the antibiotic causes bacterial aggregation. Filamentation was not detected in either species at any concentration or time-point up to 24 h. These results argue against the hypotheses that colistin kills bacteria by puncturing the cytoplasmic membrane or disrupting DNA synthesis. The colistin-induced bacterial aggregation detected has implications for the interpretation of MBC, time-kill, and other test results obtained with this antibiotic.
Highlights
Colistin is an antibiotic with a spectrum of activity that includes problematic carbapenem-resistant and extensively drug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli
To account for the fact that antibiotic-induced morphological changes can vary with antibiotic concentration (Alsteens et al 2008), inoculum density (Diver and Wise 1986), and test bacterial species (Wojnicz et al 2007), we examined the effects of sub-inhibitory, inhibitory, and bactericidal concentrations of colistin upon two species, E. coli and P. aeruginosa, using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values determined for assay-specific inoculum densities
Suspensions of P. aeruginosa treated with inhibitory-bactericidal (1.5 mg L−1; 1 × MIC and 1 × MBC) and supra-bactericidal (15 mg L− 1; 10 × MBC) levels of colistin, respectively, lost 3.8 and 4.0% of their total potassium pool within 1 h, these values remaining unchanged or almost unchanged (3.8 and 4.1%, respectively) when cells were examined at 24 h
Summary
Colistin (polymyxin E) is an antibiotic with a spectrum of activity that includes problematic carbapenem-resistant and extensively drug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli. Under suitable dosage regimens and with careful monitoring, it is accepted that the risk of colistin-induced kidney or nerve damage can be minimized (Kelesidis and Falagas 2015; Shields et al 2017), and the antibiotic has been returned to use as a last option or salvage therapy (Poirel et al 2017). Clinical indications include treatment of ventilator-associated pneumonia and lung infections in cystic fibrosis patients (Gu et al 2014; Liu et al 2015) as well as bacteraemia and urinary tract infections (Tängdén and Giske 2015; Bader et al 2017) caused by extensively drug resistant Gram-negative organisms. Transmissible colistin resistance emerged in 2011 and has spread worldwide, but its prevalence is still quite low (Giske 2015; Liu et al 2016; Baron et al 2016)
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