Platelets are a critical immune defense against Staphylococcus aureus bloodstream infections. Staphylococcus aureus α-toxin is a virulence factor that decreases platelet viability and accelerates platelet clearance. It has been shown that ticagrelor blocks α-toxin–mediated platelet injury and resulting thrombocytopenia, protecting mice in a lethal S. aureus sepsis model. We now present the use of ticagrelor as adjunctive therapy in a patient with a S. aureus endovascular infection and thrombocytopenia, associated with restoration of platelet count and bacteremia clearance. Ticagrelor enhanced platelet killing of the S. aureus bloodstream isolate from the treated patient in vitro.

Neutrophils possess a diverse repertoire of pathogen clearance mechanisms, one of which is the formation of neutrophil extracellular traps (NETs). NETs are complexes of histone proteins and DNA coated with proteolytic enzymes that are released extracellularly to entrap pathogens and aid in their clearance, in a process known as NETosis. Intravascular NETosis may drive a massive inflammatory response that has been shown to contribute to morbidity and mortality in many infectious diseases, including malaria, dengue fever, influenza, bacterial sepsis, and severe acute respiratory syndrome coronavirus 2 infection. In this review we seek to (1) summarize the current understanding of NETs, (2) discuss infectious diseases in which NET formation contributes to morbidity and mortality, and (3) explore potential adjunctive therapeutics that may be considered for future study in treating severe infections driven by NET pathophysiology. This includes drugs specifically targeting NET inhibition and US Food and Drug Administration–approved drugs that may be repurposed as NET inhibitors.

Besides antistaphylococcal beta-lactams and source control, there are limited validated antimicrobial salvage options in patients with prolonged methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, including infective endocarditis (IE). MSSA IE cases treated with ertapenem (ETP) plus cefazolin (CZ) were compared with matched IE cases treated with standard beta-lactam monotherapy. The bactericidal activity of ETP plus CZ was also compared with nafcillin (NAF), CZ, and ETP alone using an in vitro MSSA biofilm model. The median duration of bacteremia experienced by patients (n = 12) while on CZ or NAF was 4 days (range 1–16 days) compared with 1 day (range 1–3 days) for patients (n = 5) treated with ETP + CZ (P = .01, Mann-Whitney U test). Cefazolin and NAF alone or in combination did not achieve biofilm eradication at clinically relevant concentrations. However, the addition of ETP to CZ led to bactericidal eradication within biofilms at standard dosing. Ertapenem reduces CZ concentrations required to eradicate MSSA biofilms to those achievable in vivo by standard dosing, translating into shorter bacteremia duration in patients with MSSA endocarditis. Larger studies are needed to investigate ETP plus CZ therapy in the treatment of biofilm-related MSSA infections such as endocarditis.

Outpatient treatment of Pseudomonas aeruginosa infections is challenged by increasing rates of resistance to fluoroquinolones, the only class of antibiotics which offers an established oral route of administration against this organism. Azithromycin does not demonstrate activity against P. aeruginosa when evaluated under standard methods of susceptibility testing with bacteriologic media. However, growing evidence shows that azithromycin is very active against P. aeruginosa when using physiologic media that recapitulate the in vivo milieu and is supported by animal models of infection and various clinical settings, including cystic fibrosis. We present three cases of outpatient management of P. aeruginosa otolaryngological infections successfully treated with oral azithromycin, 500 mg daily ranging from 3–8 weeks, where use of fluoroquinolones was not possible due to either resistance or patient intolerance. We review the previous data supporting this clinical approach, in the hope that this will alert clinicians to this treatment option and to inspire a more thorough clinical trial evaluation of azithromycin in this environment of growing medical need.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with high rates of treatment failure, even when antibiotics showing in vitro susceptibility are used. Early optimization of therapy is crucial to reduce morbidity and mortality. Building on our previous research on carbapenem therapy for methicillin-susceptible S aureus bacteremia, we examined the utility of adjunctive carbapenems (ertapenem or meropenem) to enhance the efficacy of ceftaroline or vancomycin for treatment of MRSA. Methods: The effectiveness of combination therapy versus monotherapy against MRSA was assessed using checkerboard, time-kill, and human whole blood killing assays, as well as a murine bacteremia model. Additionally, we performed transcriptomic analysis and conducted human platelet and antimicrobial peptide killing assays on MRSA pretreated with subtherapeutic concentrations of ceftaroline and carbapenems. The supernatants from these MRSA isolates were used to treat platelets, and cytotoxicity was assessed via lactate dehydrogenase release assays. Results: Although not used for MRSA, we identified striking in vitro and in vivo synergy between carbapenems and ceftaroline or vancomycin. MRSA pretreated with subtherapeutic ceftaroline-carbapenem therapy revealed transcriptional shifts indicative of reduced antibiotic resistance, virulence, and host immune evasion. Supernatants from these MRSA isolates also caused less platelet injury compared to monotherapy. Furthermore, MRSA pretreated with ceftaroline and carbapenems demonstrated increased susceptibility to killing by human platelets and the antimicrobial peptide LL-37. Conclusions: The therapeutic success of adjunctive carbapenems appears driven by multiple mechanisms, including direct drug–drug synergy with first-line anti-MRSA agents, attenuation of resistance and virulence factors, and enhancement of immune-mediated killing, each warranting further investigation.