ISTH 2019

"We describe, for the first time, the bactericidal activity of ticagrelor against antibiotic-resistant Gram-positive bacteria," presented Dr Cécile Oury, Senior Research Associate, University of Liège, Belgium, as she explained her team’s unprecedented findings at the International Society on Thrombosis and Haemostasis (ISTH) 2019 Congress.

The results could provide an explanation as to why sub-analyses of clinical trials have revealed a reduced likelihood of infection-related death in patients receiving ticagrelor versus other P2Y12 inhibitors.

"The potential clinical link with this discovery is coming from the sub-analysis of the PLATO trial, showing that patients treated with ticagrelor compared to clopidogrel were at lower risk of [infection-related] death," claimed Dr Oury. Similarly, the 2018 XANTHIPPE study found that ticagrelor was associated with improved lung function versus placebo in patients hospitalised for pneumonia.

"So, how did we perform this study? First, we tested ticagrelor and its metabolites [AR-C124910] against several bacteria in vitro," explained Dr Oury. The antiplatelet's bactericidal efficacy was tested in methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-sensitive S aureus (MSSA), glycopeptide intermediate S aureus (GISA), methicillin-resistant S aureus (MRSA), and vancomycin-resistant Enterococcus faecalis (VRE) using time-kill assays.

"We discovered that ticagrelor and its main metabolite had antibacterial activity against all Gram-positive bacteria tested, and, most importantly, also against all the strains that were resistant to antibiotics."

Ticagrelor 5 mcg/mL demonstrated a rapid mode of action, promptly delaying MRSA growth. The agent killed late exponential-phase cultures of MRSA (minimal bactericidal concentration (MBC): 20 mcg/mL), showing similar efficacy to the last-resort antibiotic daptomycin. It also demonstrated superiority to vancomycin against MRSA, MRSE and VRE.

"We also found a synergistic effect when you combine ticagrelor with other antibiotics," she added, "using sub-MBC doses of ticagrelor and vancomycin led to improved activity against MRSA…it also suggests that ticagrelor may act through different mechanisms to vancomycin." The observation was also made with rifampicin and ciprofloxacin. Resistance to ticagrelor did not emerge, according minimal inhibitory concentration over 2 weeks, unlike with ofloxacin and rifampicin (independent experiments).

"We then performed an in vivo study in mice, assessing the effect of typical doses of ticagrelor on bacteria grown on implants that have been pre-infected with S aureus," she continued, "treating the mice with ticagrelor inhibited biofilm growth, in vivo."

Dr Oury speculated on what the results could mean for clinical practice: "Our results mean that ticagrelor might be superior to other P2Y12 inhibitors in patients with cardiovascular disease [CVD] at risk of Gram-positive bacterial infections, for example, endocarditis."

The findings also suggest that ticagrelor-derived molecules - with antiplatelet activity removed - could be a viable new class of antibiotics with activity against resistant strains of staphylococci and enterococci.

"Obviously, the bactericidal concentrations that were needed to have the in vitro effect are not reached in the blood, but, we can hypothesise that local antibacterial activity could still be possible through local accumulation at infection sites."

Thinking about next steps for ticagrelor, one of the most widely prescribed drugs worldwide, Dr Oury concluded, "We hope that these results will stir up the initiation of new randomised clinical trials that will compare the effect of ticagrelor versus other P2Y12 inhibitors."