Clinical data suggest that ticagrelor alters infection outcomes compared to patients taking other antiplatelet medications

In the PLATO trial, over 18,000 patients with ACS were treated with 1 year of either ticagrelor or clopidogrel [7]. In a post hoc analysis of patients, adverse events were studied including rates of bacteremia/sepsis [8]. Although the rates of these infections were similar in both groups, there were fewer deaths due to sepsis/bacteremia in the ticagrelor group (7 versus 23; p = 0.003).

The PLATO study renewed interest regarding infectious outcomes in patients following ACS. A total of 3 retrospective studies were published comparing patients on clopidogrel and ticagrelor. Among 9,518 patients treated with ticagrelor or clopidogrel (matched using propensity scoring), there were significantly fewer hospital readmissions due to infection with ticagrelor (6.11%) than with clopidogrel (10.53%) (HR 0.736, 95% CI 0.64 to 0.85; p < 0.001) [9]. In another propensity-matched retrospective study, 1.4% of 1,356 patients treated with ticagrelor compared to 3.6% of 1,356 patients treated with clopidogrel had gram-positive infections (HR 0.37; 95% CI 0.22 to 0.63; p < 0.001) [10]. Last, a third retrospective study including over 26,000 patients measured the occurrence of SAB during the first year after initiation of either ticagrelor or clopidogrel [11]. Patients treated with ticagrelor had significantly fewer episodes of SAB with absolute risk reduction of −0.19% (95% CI −0.32% to −0.05%; p = 0.006).

Notably, the findings from PLATO were a post hoc analysis, and these retrospective studies were correlative and not designed to determine cause and effect. However, these data in sum suggest that there may be mechanisms by which ticagrelor mitigates infection risk and, potentially, SAB.

Ticagrelor has direct activity against S. aureus, albeit at supraphysiologic concentration

When evaluated with in vitro time–kill assays, ticagrelor was effective against methicillin-resistant S. aureus (MRSA), methicillin-susceptible S. aureus (MSSA), Staphylococcus epidermidis, Streptococcus agalactiae, and Enterococcus faecalis [12]. It was not effective against 2 gram-negative pathogens, Escherichia coli and Pseudomonas aeruginosa. However, its antibacterial activity occurred at supraphysiologic concentrations. The minimum inhibitory concentration (MIC) of ticagrelor against MRSA was 20 μg/mL, whereas the physiologic concentration of ticagrelor at dosing for ACS in humans is between 0.8 and 1.2 μg/mL [12]. Another study also found that ticagrelor inhibited a clinical isolate of MSSA but only at supraphysiologic concentrations (MIC 64 μg/mL) [13]. Further, the combination of ticagrelor with the antimicrobials cefazolin or ertapenem was only additive rather than synergistic.

If concentrations of ticagrelor required for direct antistaphylococcal activity are not achievable clinically, how does ticagrelor exert an antibacterial effect at physiologic doses? In a murine model in which MRSA-inoculated polyurethane disks were implanted in the flanks of immunocompetent mice, those treated with ticagrelor at physiologic dosing had significantly decreased bacterial burden of their infected implant, suggesting that another mechanism in vivo may be driving the antistaphylococcal activity of ticagrelor [12]. In sum, these results indicate that direct antibacterial activity of ticagrelor is unlikely to account for its apparent activity in vivo.

Ticagrelor improves host platelet–mediated killing of S. aureus and decreases host thrombocytopenia

Platelets engage in the clearance of S. aureus by secretion of antimicrobial peptides and phagocytosis of bacteria as well as recruitment of other lymphocytes [2–5]. In vitro, ticagrelor at physiologic concentration significantly enhanced the ability of human platelets to kill MRSA, whereas aspirin (another antiplatelet drug) did not [14]. The same effect was reproducible against MSSA [13]. Under microscopy, platelets incubated with S. aureus developed significant structural damage, although platelets treated with ticagrelor were relatively preserved, suggesting that ticagrelor may have a protective/stabilizing effect on platelets in the setting of S. aureus exposure [14].

In an observational prospective study of 49 consecutive patients with SAB, thrombocytopenia correlated with increased mortality [14]. Notably, isolates from SAB patients with more severe thrombocytopenia produced more α-toxin [14], an exotoxin that increases hepatic clearance of platelets through platelet desialylation. Mice infected with α-toxin–deficient S. aureus mutants had decreased thrombocytopenia and bacterial burden compared with mice infected with wild-type S. aureus. However, mice pretreated with physiologic concentrations of ticagrelor had decreased thrombocytopenia and improved survival during wild-type SAB [14].

In a clinical case report, a 60-year-old man with refractory SAB and thrombocytopenia despite 5 days of antibiotic therapy was started on ticagrelor [13]. Within 24 hours, his bacteremia resolved and platelet count improved. Discontinuation of ticagrelor led to recurrent thrombocytopenia, which then reversed with the resumption of ticagrelor. The patient was treated with 3 months of ticagrelor in addition to standard antibiotic therapy without further infection recurrence.

In sum, these in vitro and in vivo studies suggest that ticagrelor can enhance platelet-mediated killing of S. aureus as well as mitigate S. aureus–induced thrombocytopenia likely by preventing α-toxin–related desialylation. Given the role of platelets in innate immunity, maintaining platelet counts may contribute to improved outcomes in SAB as an additional benefit to ticagrelor therapy.

Antiplatelet therapy inhibits S. aureus binding to host endothelial tissues

Among other adherence mechanisms, S. aureus binds platelets via interactions between its clumping factor A (clfA) and host platelet von Willebrand factor and fibrinogen [15]. Activated platelets bind to the exposed extracellular matrix of damaged host endovascular tissue (such as heart valves). Therefore, preventing platelet aggregation on host endothelium by inhibiting platelet activation may mitigate SAB and its infectious complications. For example, S. aureus mutants lacking clfA were 50% less likely to cause endocarditis than wild-type strains in a SAB rat model [16].

In ex vivo perfusion reactors, precoating bovine jugular veins with fibrinogen stimulated both human platelet and S. aureus surface binding [17]. However, the platelet α_IIbβ3 antagonist eptifibatide decreased S. aureus adhesion, likely due to inhibition of platelets. Likewise, the effect of antiplatelet therapy with aspirin and ticagrelor on S. aureus adhesion in the presence of human blood (including platelets) was tested under shear conditions [17]. Treatment with both aspirin and ticagrelor independently decreased S. aureus attachment to the lumen of bovine jugular veins; the combination of the 2 resulted in significantly less adhesion than aspirin alone. Dual antiplatelet therapy was also found in vivo to decrease endocarditis in a rat model of SAB due to inhibition of platelet binding [18]. Preventing S. aureus binding to platelets and therefore minimizing contact with host tissues may be another mechanism by which ticagrelor and other antiplatelet drugs mitigate infection.