Serum bactericidal activity of colistin and azidothymidine combinations against mcr-1-positive colistin-resistant Escherichia coli

Abstract

To examine the serum bactericidal activity of colistin sulphate (CS) and azidothymidine (AZT) combinations, time-kill curves were performed in native and heat-inactivated human serum with five colistin-resistant and four colistin-susceptible Gram-negative strains. Serum samples were spiked according to median and minimum plasma peak concentrations measured in a phase 1 clinical study in which seven healthy subjects received three (q12h) 1-h intravenous infusions of 4, 2 and 2 MIU colistin methanesulfonate (CMS) co-administered with 200, 100 and 100 mg AZT, respectively. This trial was performed to assess pharmacokinetics and safety of CMS/AZT combination therapy. Minimum bactericidal concentrations of CS in native, but not heat-inactivated, serum were strongly reduced compared with Mueller-Hinton broth for all tested Enterobacteriaceae, except one colistin-resistant (serum-resistant) strain. For colistin-susceptible strains, the minimum CS concentration after 2 MIU CMS was already bactericidal in native and heat-inactivated serum. Median, but not minimum, CS concentrations after 2 MIU CMS were sufficient to kill the serum-resistant, colistin-resistant Escherichia coli strain in native serum. In heat-inactivated serum, even the median CS concentration after 2 MIU CMS was not bactericidal for all colistin-resistant strains. In general, combinations with AZT accelerated killing of colistin-resistant E. coli or showed bactericidal activity even if the substances alone were not bactericidal. Thus, combination with AZT potentiates the bactericidal effect of colistin against colistin-resistant E. coli. Although the dosage of 2 MIU CMS plus AZT may be sufficient to treat infections with colistin-susceptible strains, for infections caused by colistin-resistant E. coli, dosing should be further optimised.

Effect of Different Media on the Bactericidal Activity of Colistin and on the Synergistic Combination With Azidothymidine Against mcr-1-Positive Colistin-Resistant Escherichia coli

“…According to EUCAST and CLSI guidelines, our study demonstrated that all the mcr-1-positive E. coli strains tested are resistant to colistin as confirmed in previous studies (Poirel et al, 2016;Hu et al, 2018;Loose et al, 2018). We showed for the first time, that MIC values for the mcr-1-positive strains, but not colistin-susceptible strains, significantly increased up to 16-fold in AU compared to CMHB.…”

“…of colistin-resistant E. coli (Hu et al, 2018;Loose et al, 2018). Since FIC indices calculations are based on MIC values measured by microbroth dilutions in CAMHB with an inoculum 10 5 CFU/mL (Hu et al, 2018), we were interested to ask whether using a higher inoculum or different growth media could have an influence on the synergistic activity between colistin and azidothymidine.…”

“…Since the development of new antibiotics is decreasing, it is mandatory to find solutions to break the resistance to or enhance the antimicrobial activity of older antibiotics by co-administration of appropriate drugs, otherwise not used for antibiotic therapy. Recently, we have demonstrated that colistin in combination with the antiviral drug azidothymidine enhanced the colistin activity against colistin-resistant Enterobacteriaceae (Hu et al, 2018;Loose et al, 2018).…”

Effect of Different Levels of Multienzymes on Immune Response, Blood Hematology and Biochemistry, Antioxidants Status and Organs Histology of Broiler Chicks Fed Standard and Low-Density Diets

“…This test is used to measure the bactericidal activity of the serum during antimicrobial treatment against bacteria isolated from the same patient. This test has been widely used in patients with infective endocarditis, osteomyelitis, bacteremia, or other serious bacterial infections (43,44). The turbidimetric method of Engstad et al (45) was used to measure the serum lysozyme activity.…”

Drug Repurposing to Fight Colistin and Carbapenem-Resistant Bacteria

“…Patented in 2014 (Hu and Coates, 2014), it has been enrolled in a Phase 1 clinical trial. Results showed that the association had a bactericidal activity on plasma concentration on mcr-1 positive strains and that it was well tolerated by the healthy volunteers involved in the study (Loose et al, 2018). Further human studies can be undertaken to confirm these results, but they confirm that AZT can be a recovery therapy against MDR bacteria and thus help clinicians avoid therapeutic impasses.…”