An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in apixaban concentration. A single 5-mg oral dose of apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on apixaban clearance.

The molecular processes underlying epidemic waves of methicillin-resistant Staphylococcus aureus (MRSA) are poorly understood1. While a major role has been attributed to the acquisition of virulence determinants by horizontal gene transfer2, there are insufficient epidemiological and functional data supporting that concept. We here report the spread of clones containing a previously extremely rare3,4 mobile genetic element-encoded gene, sasX. We demonstrate that sasX has a key role in MRSA colonization and pathogenesis, significantly enhancing nasal colonization, lung disease, and abscess formation, and promoting mechanisms of immune evasion. Moreover, we observed the recent spread of sasX from sequence type (ST) 239 to invasive clones belonging to other STs. Our study identifies sasX as a quickly spreading critical determinant of MRSA pathogenic success and a promising target for therapeutic interference. Importantly, our results provide proof-of-principle that horizontal gene transfer of key virulence determinants drives MRSA epidemic waves.

Widespread antibiotic resistance among important bacterial pathogens such as Staphylococcus aureus1 calls for alternative routes of drug development. Interfering with critical virulence determinants is considered a promising novel approach to control bacterial infection2. Phenol-soluble modulins (PSMs) are peptide toxins with multiple key roles in pathogenesis3–5 and a major impact on the ability of highly virulent S. aureus to cause disease3,6. However, targeting PSMs for therapeutic intervention is hampered by their multitude and diversity. Here, we report that an ABC transporter with previously unknown function is responsible for the export of all PSM classes, thus representing a single target to interfere simultaneously with the production of all PSMs. The transporter had a strong effect on virulence phenotypes, such as neutrophil lysis, and the development of S. aureus infection, similar in extent to the sum of all PSMs. Furthermore, it proved essential for bacterial growth. Moreover, it protected the producer from the antimicrobial activity of secreted PSMs and contributed to defense against PSM-mediated bacterial interference. Our study reveals a non-canonical, dedicated secretion mechanism for an important toxin class and identifies this mechanism as a comprehensive potential target for the development of drugs efficiently inhibiting growth and virulence of pathogenic staphylococci.