The antiplatelet agent ticagrelor (Brilinta/Brilique, AstraZeneca) demonstrated bactericidal activity against antibiotic-resistant gram-positive bacteria that pose a threat to human health, including methicillin-resistant Staphylococcus aureus (MRSA), and may represent a new class of antibiotic active against multidrug-resistant staphylococci or enterococci, new research suggests. The findings were published online May 8 in a research letter in JAMA Cardiology. "The antibacterial properties of ticagrelor do not seem to be related to its antiplatelet activity and are not seen with other antiplatelet agents, such as clopidogrel or prasugrel. Rather, they appear to be mediated through a different, novel mechanism," lead author Patrizio Lancellotti, MD, University of Liege Hospital, Belgium, told Medscape Medical News. "This new mechanism potentially opens the door to a new class of antibiotics, which are urgently needed, as more bacteria are becoming resistant to current drugs," he added. The researchers say their findings warrant further investigation, including randomized clinical trials comparing the protective activity of ticagrelor with that of other antiplatelet drugs against gram-positive bacterial infection in patients with cardiovascular disease. They suggest that a dual antiplatelet and antibacterial effect of ticagrelor might make it superior to other P2Y12 inhibitor antiplatelet agents in patients with cardiovascular disease who are at risk for gram-positive bacterial infections, such as infective endocarditis. They also indicate that the drug could be used in polymer coatings of implanted cardiac devices to lower the risk for infection. They say that because the antibacterial mechanism appears to be distinct from the antiplatelet activity, there is potential for a range of new ticagrelor-derived antibiotics, devoid of antiplatelet activity, for use against multidrug-resistant staphylococci or enterococci. Lower Infection-Related Deaths The researchers conducted their studies after noticing that among patients with acute coronary syndrome and pulmonary infections who were receiving intensive care, survival appeared more likely with ticagrelor than a different antiplatelet agent. The authors report findings from a post hoc analysis of the PLATO trial, which involved patients acute coronary syndrome. In that analysis, the risk for infection-related death was lower for patients who were treated with ticagrelor than for those treated with clopidogrel (Plavix, Sanofi-Aventis). More recently, in the XANTHIPPE study of possible antiplatelet effects on inflammation and immune responses, use of ticagrelor was associated with improved lung function in patients hospitalized for pneumonia. "We therefore wanted to investigate whether ticagrelor or its metabolites had antibacterial properties," Lancellotti said The researchers conducted a series of in vitro studies and found that the drug was highly active against S aureus, including MRSA. "MRSA is a huge problem, with few drugs available to treat it, but in the lab, ticagrelor killed MRSA more rapidly than vancomycin," Lancellotti noted. "It also showed good activity against Enterococcus, which can cause infective endocarditis or infections of cardiac devices and is often highly resistant to antibiotics so can be very difficult to treat," he added. The researchers report that ticagrelor and its metabolite, AR-C124910, demonstrated bactericidal activity against all gram-positive strains tested, including the drug-resistant strains glycopeptide intermediate S aureus (GISA), methicillin-resistant Staphylococcus epidermidis (MRSE), MRSA, and vancomycin-resistant E faecalis (VRE). The minimal bactericidal concentration was 20 μg/mL against methicillin-sensitive S aureus (MSSA), GISA, MRSA, and VRE; 30 μg/mL against MRSE; and 40 μg/mL against E faecalis and S agalactiae. At minimal bactericidal concentration, ticagrelor was superior to vancomycin, with rapid killing of late exponential-phase cultures of MRSA (time to kill 99.9% of the initial inoculum, 2 hours). Bactericidal activity was similar to that of the new antibiotic, daptomycin (Cubicin, Merck), recently introduced against resistant strains of S aureus. A subminimal bactericidal concentration of ticagrelor (10 μg/mL) combined with vancomycin (4 μg/mL) killed approximately 50% of the initial MRSA inoculum, displaying synergistic activity. Ticagrelor also increased the bactericidal activity of rifampin (multiple brands), ciprofloxacin (multiple brands), and vancomycin (multiple brands) in a disk diffusion assay. Other results showed that ticagrelor was effective against biofilm, the matrix produced by bacteria to protect them from antibiotics. "Staphylococcus is particularly efficient at producing a biofilm, which is one reason why it is so difficult to treat," Lancellotti commented. Ticagrelor inhibited MRSA, MRSE, and VRE biofilm formation in a dose-dependent manner. Biofilm mass was reduced by more than 85% after exposure to ticagrelor 20 μg/mL, the researchers report. In mice, conventional oral antiplatelet dosages of ticagrelor inhibited biofilm growth on implants preinfected with S aureus, and the drug inhibited the dissemination of bacteria to surrounding tissues, they add. They note that although bactericidal concentrations would not be reached systemically in patients who receive typical dosages of ticagrelor for treating cardiovascular disease, antibacterial activity at infection sites may still be achieved through local, possibly platelet-driven, drug accumulation. "The most suitable dose of ticagrelor for the antibacterial action is too high regarding its antiplatelet action, so it would have a high bleeding risk," Lancellotti told Medscape Medical News. "So, to obtain the antibacterial effect without the bleeding, we have changed the ticagrelor molecule slightly so it loses its antiplatelet effect but keeps the antibacterial action. We are also investigating different compounds based on ticagrelor." He added that going forward, the researchers would like to see more data from large randomized trials of ticagrelor specifically regarding infection rates. "Real-world registries of patients on the drug would also be desirable to see if they have fewer infections than similar patients taking other antiplatelet agents," he said. The work was supported by a grant from the European Research Council. Lancellotti and coauthor Cécile Oury, PhD, report a pending patent for a new use of triazolo (4,5-D) pyrimidine derivatives (including ticagrelor) for the prevention and treatment of bacterial infection. JAMA Cardiol. Published online May 8, 2019. Full text Source
