Methicillin-resistant and susceptible Staphylococcus aureus: tolerance, immune evasion and treatment

  • GBD 2019 Antimicrobial Resistance Collaborators. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the global burden of disease study 2019. Lancet 400, 2221–2248 (2022). This important study is the first comprehensive assessment of antimicrobial resistance, establishing the contribution of MRSA as one of the most important causes of death due to antimicrobial-resistant infection.

  • van der Vaart, T. W. et al. The utility of risk factors to define complicated Staphylococcus aureus bacteremia in a setting with low methicillin-resistant S. aureus prevalence. Clin. Infect. Dis. 78, 846–854 (2024).

    PubMed 

    Google Scholar 

  • Bai, A. D. et al. Staphylococcus aureus bacteraemia mortality: a systematic review and meta-analysis. Clin. Microbiol. Infect. 28, 1076–1084 (2022).

    CAS 
    PubMed 

    Google Scholar 

  • Piewngam, P. & Otto, M. Staphylococcus aureus colonisation and strategies for decolonisation. Lancet Microbe 5, e606–e618 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kuehnert, M. J. et al. Prevalence of Staphylococcus aureus nasal colonization in the United States, 2001–2002. J. Infect. Dis. 193, 172–179 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • von Eiff, C., Becker, K., Machka, K., Stammer, H. & Peters, G. Nasal carriage as a source of Staphylococcus aureus bacteremia. N. Engl. J. Med. 344, 11–16 (2001).

    Google Scholar 

  • Albrich, W. C. & Harbarth, S. Health-care workers: source, vector, or victim of MRSA? Lancet Infect. Dis. 8, 289–301 (2008).

    PubMed 

    Google Scholar 

  • Kirkland, K. B. & Weinstein, J. M. Adverse effects of contact isolation. Lancet 354, 1177–1178 (1999).

    CAS 
    PubMed 

    Google Scholar 

  • Stelfox, H. T., Bates, D. W. & Redelmeier, D. A. Safety of patients isolated for infection control. JAMA 290, 1899–1905 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • Leonhardt, K. K. et al. Clinical effectiveness and cost benefit of universal versus targeted methicillin-resistant Staphylococcus aureus screening upon admission in hospitals. Infect. Control Hosp. Epidemiol. 32, 797–803 (2011).

    PubMed 

    Google Scholar 

  • Huang, S. S. et al. Impact of routine intensive care unit surveillance cultures and resultant barrier precautions on hospital-wide methicillin-resistant Staphylococcus aureus bacteremia. Clin. Infect. Dis. 43, 971–978 (2006).

    PubMed 

    Google Scholar 

  • van Trijp, M. J. et al. Successful control of widespread methicillin-resistant Staphylococcus aureus colonization and infection in a large teaching hospital in the Netherlands. Infect. Control Hosp. Epidemiol. 28, 970–975 (2007).

    PubMed 

    Google Scholar 

  • Rammelkamp, C. H. & Maxon, T. Resistance of Staphylococcus aureus to the action of penicillin. Exp. Biol. Med. 51, 3 (1942).

    Google Scholar 

  • Harkins, C. P. et al. Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice. Genome Biol. 18, 130 (2017).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Jernigan, J. A. et al. Multidrug-resistant bacterial infections in U.S. hospitalized patients, 2012–2017. N. Engl. J. Med. 382, 1309–1319 (2020). This important epidemiological study of 890 US hospitals determined that MRSA is the most frequent multidrug-resistant pathogen encountered in the US health-care system.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • GBD 2021 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050. Lancet 404, 1199–1226 (2024).

    Google Scholar 

  • Howden, B. P. et al. Staphylococcus aureus host interactions and adaptation. Nat. Rev. Microbiol. 21, 380–395 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cheung, G. Y. C., Bae, J. S. & Otto, M. Pathogenicity and virulence of Staphylococcus aureus. Virulence 12, 547–569 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Skabytska, Y. et al. Cutaneous innate immune sensing of Toll-like receptor 2-6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells. Immunity 41, 762–775 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • Patot, S. et al. The TIR homologue lies near resistance genes in Staphylococcus aureus, coupling modulation of virulence and antimicrobial susceptibility. PLoS Pathog. 13, e1006092 (2017).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Shimada, T. et al. Staphylococcus aureus evades lysozyme-based peptidoglycan digestion that links phagocytosis, inflammasome activation, and IL-1β secretion. Cell Host Microbe 7, 38–49 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Thammavongsa, V., Missiakas, D. M. & Schneewind, O. Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death. Science 342, 863–866 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rooijakkers, S. H. et al. Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nat. Immunol. 10, 721–727 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wilke, G. A. & Bubeck Wardenburg, J. Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus α-hemolysin-mediated cellular injury. Proc. Natl Acad. Sci. USA 107, 13473–13478 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tromp, A. T. et al. Human CD45 is an F-component-specific receptor for the staphylococcal toxin Panton–Valentine leukocidin. Nat. Microbiol. 3, 708–717 (2018).

    CAS 
    PubMed 

    Google Scholar 

  • Tam, K. et al. Targeting leukocidin-mediated immune evasion protects mice from Staphylococcus aureus bacteremia. J. Exp. Med. 217, e20190541 (2020).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Jorch, S. K. et al. Peritoneal GATA6+ macrophages function as a portal for Staphylococcus aureus dissemination. J. Clin. Invest. 129, 4643–4656 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cruz, A. R. et al. Staphylococcal protein A inhibits complement activation by interfering with IgG hexamer formation. Proc. Natl Acad. Sci. USA 118, e2016772118 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gerlach, D. et al. Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity. Nature 563, 705–709 (2018).

    CAS 
    PubMed 

    Google Scholar 

  • Hanzelmann, D. et al. Toll-like receptor 2 activation depends on lipopeptide shedding by bacterial surfactants. Nat. Commun. 7, 12304 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, X. & Alonzo, F. 3rd Bacterial lipolysis of immune-activating ligands promotes evasion of innate defenses. Proc. Natl Acad. Sci. USA 116, 3764–3773 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, H. et al. Staphylococcus aureus epicutaneous exposure drives skin inflammation via IL-36-mediated T cell responses. Cell Host Microbe 22, 653–666 e655 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Matsumoto, M. et al. Interaction between Staphylococcus Agr virulence and neutrophils regulates pathogen expansion in the skin. Cell Host Microbe 29, 930–940 e934 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Voisin, B. et al. Macrophage-mediated extracellular matrix remodeling controls host Staphylococcus aureus susceptibility in the skin. Immunity 56, 1561–1577 e1569 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Beesetty, P. et al. Tissue specificity drives protective immunity against Staphylococcus aureus infection. Front. Immunol. 13, 795792 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee, B., Olaniyi, R., Kwiecinski, J. M. & Wardenburg, J. B. Staphylococcus aureus toxin suppresses antigen-specific T cell responses. J. Clin. Invest. 130, 1122–1127 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Van Roy, Z. et al. Tissue niche influences immune and metabolic profiles to Staphylococcus aureus biofilm infection. Nat. Commun. 15, 8965 (2024).

    PubMed 
    PubMed Central 

    Google Scholar 

  • de Vor, L., Rooijakkers, S. H. M. & van Strijp, J. A. G. Staphylococci evade the innate immune response by disarming neutrophils and forming biofilms. FEBS Lett. 594, 2556–2569 (2020).

    PubMed 

    Google Scholar 

  • Ricciardi, B. F. et al. Staphylococcus aureus evasion of host immunity in the setting of prosthetic joint infection: biofilm and beyond. Curr. Rev. Musculoskelet. Med. 11, 389–400 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Arciola, C. R., Campoccia, D. & Montanaro, L. Implant infections: adhesion, biofilm formation and immune evasion. Nat. Rev. Microbiol. 16, 397–409 (2018).

    CAS 
    PubMed 

    Google Scholar 

  • Pettygrove, B. A. et al. Delayed neutrophil recruitment allows nascent Staphylococcus aureus biofilm formation and immune evasion. Biomaterials 275, 120775 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, M. et al. Staphylococcus aureus SaeRS impairs macrophage immune functions through bacterial clumps formation in the early stage of infection. npj Biofilms Microbiomes 10, 102 (2024).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Staats, A. et al. Synovial fluid-induced aggregation occurs across Staphylococcus aureus clinical isolates and is mechanistically independent of attached biofilm formation. Microbiol. Spectr. 9, e0026721 (2021).

    PubMed 

    Google Scholar 

  • He, L. et al. Resistance to leukocytes ties benefits of quorum sensing dysfunctionality to biofilm infection. Nat. Microbiol. 4, 1114–1119 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bhattacharya, M. et al. Leukocidins and the nuclease nuc prevent neutrophil-mediated killing of Staphylococcus aureus biofilms. Infect. Immun. 88, e00372–20 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bhattacharya, M. et al. Staphylococcus aureus biofilms release leukocidins to elicit extracellular trap formation and evade neutrophil-mediated killing. Proc. Natl Acad. Sci. USA 115, 7416–7421 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Scherr, T. D. et al. Staphylococcus aureus biofilms induce macrophage dysfunction through leukocidin AB and alpha-toxin. mBio 6, e01021–15 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Thurlow, L. R. et al. Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. J. Immunol. 186, 6585–6596 (2011).

    CAS 
    PubMed 

    Google Scholar 

  • Yamada, K. J. et al. Monocyte metabolic reprogramming promotes pro-inflammatory activity and Staphylococcus aureus biofilm clearance. PLoS Pathog. 16, e1008354 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Heim, C. E. et al. Myeloid-derived suppressor cells contribute to Staphylococcus aureus orthopedic biofilm infection. J. Immunol. 192, 3778–3792 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • Aldrich, A. L., Horn, C. M., Heim, C. E., Korshoj, L. E. & Kielian, T. Transcriptional diversity and niche-specific distribution of leukocyte populations during Staphylococcus aureus craniotomy-associated biofilm infection. J. Immunol. 206, 751–765 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • Heim, C. E., Vidlak, D. & Kielian, T. Interleukin-10 production by myeloid-derived suppressor cells contributes to bacterial persistence during Staphylococcus aureus orthopedic biofilm infection. J. Leukoc. Biol. 98, 1003–1013 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tebartz, C. et al. A major role for myeloid-derived suppressor cells and a minor role for regulatory T cells in immunosuppression during Staphylococcus aureus infection. J. Immunol. 194, 1100–1111 (2015).

    CAS 
    PubMed 

    Google Scholar 

  • Stoll, H. et al. Staphylococcal enterotoxins dose-dependently modulate the generation of myeloid-derived suppressor cells. Front. Cell Infect. Microbiol. 8, 321 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Heim, C. E. et al. Lactate production by Staphylococcus aureus biofilm inhibits HDAC11 to reprogramme the host immune response during persistent infection. Nat. Microbiol. 5, 1271–1284 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mba Medie, F. et al. Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients. Proc. Natl Acad. Sci. USA 116, 20087–20096 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Chang, Y.-L. et al. Human DNA methylation signatures differentiate persistent from resolving MRSA bacteremia. Proc. Natl Acad. Sci. USA 118, e2000663118 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Van Roy, Z., Shi, W., Kak, G., Duan, B. & Kielian, T. Epigenetic regulation of leukocyte inflammatory mediator production dictates Staphylococcus aureus craniotomy infection outcome. J. Immunol. 211, 414–428 (2023).

    PubMed 

    Google Scholar 

  • Lacey, K. A. et al. Secreted mammalian DNases protect against systemic bacterial infection by digesting biofilms. J. Exp. Med. 220, e20221086 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rosenberg, G., Riquelme, S., Prince, A. & Avraham, R. Immunometabolic crosstalk during bacterial infection. Nat. Microbiol. 7, 497–507 (2022).

    CAS 
    PubMed 

    Google Scholar 

  • Arumugam, P. & Kielian, T. Metabolism shapes immune responses to Staphylococcus aureus. J. Innate Immun. 16, 12–30 (2024).

    CAS 
    PubMed 

    Google Scholar 

  • Horn, C. M. et al. Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis/HIF1a axis. J. Clin. Invest. 134, e174051 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dietrich, O. et al. Dysregulated immunometabolism is associated with the generation of myeloid-derived suppressor cells in Staphylococcus aureus chronic infection. J. Innate Immun. 14, 257–274 (2022).

    CAS 
    PubMed 

    Google Scholar 

  • Van Roy, Z. et al. Single-cell profiling reveals a conserved role for hypoxia-inducible factor signaling during human craniotomy infection. Cell Rep. Med. 5, 101790 (2024).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Vozza, E. G. et al. Staphylococcus aureus suppresses the pentose phosphate pathway in human neutrophils via the adenosine receptor A2aR to enhance intracellular survival. mBio 15, e0257123 (2024).

    PubMed 

    Google Scholar 

  • Reynolds, M. B. et al. Type I interferon governs immunometabolic checkpoints that coordinate inflammation during staphylococcal infection. Cell Rep. 43, 114607 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wise, A. D. et al. Mitochondria sense bacterial lactate and drive release of neutrophil extracellular traps. Cell Host Microbe 33, 341–357 e349 (2025).

    CAS 
    PubMed 

    Google Scholar 

  • Lesbats, J. et al. Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses. Nature 640, 524–533 (2025).

    CAS 
    PubMed 

    Google Scholar 

  • Tomlinson, K. L. et al. Staphylococcus aureus induces an itaconate-dominated immunometabolic response that drives biofilm formation. Nat. Commun. 12, 1399 (2021). This paper reports how. S. aureus–immune metabolic crosstalk promotes biofilm formation by inducing host itaconate, which inhibits S. aureus glycolysis, which reprogrammes S. aureus metabolism to favour extracellular polysaccharide production.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Peace, C. G. & O’Neill, L. A. The role of itaconate in host defense and inflammation. J. Clin. Invest. 132, e148548 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tomlinson, K. L. et al. Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst. Cell Rep. 42, 112064 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Makowski, L., Chaib, M. & Rathmell, J. C. Immunometabolism: from basic mechanisms to translation. Immunol. Rev. 295, 5–14 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Vuscan, P., Kischkel, B., Joosten, L. A. B. & Netea, M. G. Trained immunity: general and emerging concepts. Immunol. Rev. 323, 164–185 (2024).

    CAS 
    PubMed 

    Google Scholar 

  • Wong Fok Lung, T. et al. Staphylococcus aureus small colony variants impair host immunity by activating host cell glycolysis and inducing necroptosis. Nat. Microbiol. 5, 141–153 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Ferreira, A. V. et al. Dimethyl itaconate induces long-term innate immune responses and confers protection against infection. Cell Rep. 42, 112658 (2023).

    CAS 
    PubMed 

    Google Scholar 

  • Carlile, S. R. et al. Staphylococcus aureus induced trained immunity in macrophages confers heterologous protection against Gram-negative bacterial infection. iScience 27, 111284 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Radhouani, M. et al. Eosinophil innate immune memory after bacterial skin infection promotes allergic lung inflammation. Sci. Immunol. 10, eadp6231 (2025).

    CAS 
    PubMed 

    Google Scholar 

  • Wu, S. W., de Lencastre, H. & Tomasz, A. Recruitment of the mecA gene homologue of Staphylococcus sciuri into a resistance determinant and expression of the resistant phenotype in Staphylococcus aureus. J. Bacteriol. 183, 2417–2424 (2001).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fuda, C. et al. Shared functional attributes between the mecA gene product of Staphylococcus sciuri and penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus. Biochemistry 46, 8050–8057 (2007).

    CAS 
    PubMed 

    Google Scholar 

  • Tsubakishita, S., Kuwahara-Arai, K., Sasaki, T. & Hiramatsu, K. Origin and molecular evolution of the determinant of methicillin resistance in staphylococci. Antimicrob. Agents Chemother. 54, 4352–4359 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Crisostomo, M. I. et al. The evolution of methicillin resistance in Staphylococcus aureus: similarity of genetic backgrounds in historically early methicillin-susceptible and -resistant isolates and contemporary epidemic clones. Proc. Natl Acad. Sci. USA 98, 9865–9870 (2001).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Centers for Disease Control and Prevention. Reduced susceptibility of Staphylococcus aureus to vancomycin — Japan, 1996. MMWR Morb. Mortal. Wkly Rep. 46, 624–626 (1997).

  • Centers for Disease Control and Prevention. Vancomycin-resistant Staphylococcus aureus — Pennsylvania, 2002. MMWR Morb. Mortal. Wkly Rep. 51, 902 (2002).

    Google Scholar 

  • Sakoulas, G. et al. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J. Clin. Microbiol. 42, 2398–2402 (2004).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Holmes, N. E. et al. Antibiotic choice may not explain poorer outcomes in patients with Staphylococcus aureus bacteremia and high vancomycin minimum inhibitory concentrations. J. Infect. Dis. 204, 340–347 (2011).

    CAS 
    PubMed 

    Google Scholar 

  • Cui, L. et al. Cell wall thickening is a common feature of vancomycin resistance in Staphylococcus aureus. J. Clin. Microbiol. 41, 5–14 (2003).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cui, L., Murakami, H., Kuwahara-Arai, K., Hanaki, H. & Hiramatsu, K. Contribution of a thickened cell wall and its glutamine nonamidated component to the vancomycin resistance expressed by Staphylococcus aureus Mu50. Antimicrob. Agents Chemother. 44, 2276–2285 (2000).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gomes, D. M., Ward, K. E. & LaPlante, K. L. Clinical implications of vancomycin heteroresistant and intermediately susceptible Staphylococcus aureus. Pharmacotherapy 35, 424–432 (2015).

    PubMed 

    Google Scholar 

  • Yun, J. H. et al. Risk factors for vancomycin treatment failure in heterogeneous vancomycin-intermediate Staphylococcus aureus bacteremia. Microbiol. Spectr. 12, e0033324 (2024).

    PubMed 

    Google Scholar 

  • Claeys, K. C. et al. Pneumonia caused by methicillin-resistant Staphylococcus aureus: does vancomycin heteroresistance matter? Antimicrob. Agents Chemother. 60, 1708–1716 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chang, S. et al. Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. N. Engl. J. Med. 348, 1342–1347 (2003).

    PubMed 

    Google Scholar 

  • Kwun, M. J., Novotna, G., Hesketh, A. R., Hill, L. & Hong, H. J. In vivo studies suggest that induction of VanS-dependent vancomycin resistance requires binding of the drug to d-Ala-d-Ala termini in the peptidoglycan cell wall. Antimicrob. Agents Chemother. 57, 4470–4480 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cong, Y., Yang, S. & Rao, X. Vancomycin resistant Staphylococcus aureus infections: a review of case updating and clinical features. J. Adv. Res. 21, 169–176 (2020).

    PubMed 

    Google Scholar 

  • MacFarquhar, J. K. et al. Identification and characterization of vancomycin-resistant Staphylococcus aureus CC45/USA600, North Carolina, USA, 2021. Emerg. Infect. Dis. 31, 194–196 (2025).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Blechman, S. E. & Wright, E. S. Vancomycin-resistant Staphylococcus aureus (VRSA) can overcome the cost of antibiotic resistance and may threaten vancomycin’s clinical durability. PLoS Pathog. 20, e1012422 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wagner, J. L. et al. Counting the cost of daptomycin versus vancomycin in hospitalized patients: a cost minimization analysis. Open Forum Infect. Dis. 11, ofae217 (2024).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Pogliano, J., Pogliano, N. & Silverman, J. A. Daptomycin-mediated reorganization of membrane architecture causes mislocalization of essential cell division proteins. J. Bacteriol. 194, 4494–4504 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Muller, A. et al. Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains. Proc. Natl Acad. Sci. USA 113, E7077–E7086 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Bayer, A. S., Schneider, T. & Sahl, H. G. Mechanisms of daptomycin resistance in Staphylococcus aureus: role of the cell membrane and cell wall. Ann. N. Y. Acad. Sci. 1277, 139–158 (2013).

    CAS 
    PubMed 

    Google Scholar 

  • Ernst, C. M. & Peschel, A. MprF-mediated daptomycin resistance. Int. J. Med. Microbiol. 309, 359–363 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • Gasch, O. et al. Emergence of resistance to daptomycin in a cohort of patients with methicillin-resistant Staphylococcus aureus persistent bacteraemia treated with daptomycin. J. Antimicrob. Chemother. 69, 568–571 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • Sharma, M., Riederer, K., Chase, P. & Khatib, R. High rate of decreasing daptomycin susceptibility during the treatment of persistent Staphylococcus aureus bacteremia. Eur. J. Clin. Microbiol. Infect. Dis. 27, 433–437 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • Moise, P. A., North, D., Steenbergen, J. N. & Sakoulas, G. Susceptibility relationship between vancomycin and daptomycin in Staphylococcus aureus: facts and assumptions. Lancet Infect. Dis. 9, 617–624 (2009).

    CAS 
    PubMed 

    Google Scholar 

  • Fowler, V. G. Jr. et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N. Engl. J. Med. 355, 653–665 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • Swaney, S. M., Aoki, H., Ganoza, M. C. & Shinabarger, D. L. The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob. Agents Chemother. 42, 3251–3255 (1998).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gu, B., Kelesidis, T., Tsiodras, S., Hindler, J. & Humphries, R. M. The emerging problem of linezolid-resistant Staphylococcus. J. Antimicrob. Chemother. 68, 4–11 (2013).

    CAS 
    PubMed 

    Google Scholar 

  • Stefani, S., Bongiorno, D., Mongelli, G. & Campanile, F. Linezolid resistance in Staphylococci. Pharmaceuticals 3, 1988–2006 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Steward, C. D. et al. Testing for induction of clindamycin resistance in erythromycin-resistant isolates of Staphylococcus aureus. J. Clin. Microbiol. 43, 1716–1721 (2005).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Morosini, M. I., Diez-Aguilar, M. & Canton, R. Mechanisms of action and antimicrobial activity of ceftobiprole. Rev. Esp. Quimioter. 32, 3–10 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Vazquez, J. A. et al. Ceftaroline fosamil for the treatment of Staphylococcus aureus bacteremia secondary to acute bacterial skin and skin structure infections or community-acquired bacterial pneumonia. Infect. Dis. Clin. Pract. 23, 39–43 (2015).

    Google Scholar 

  • Holland, T. L., Bayer, A. S. & Fowler, V. G. Persistent methicilin-resistant Staphylococcus aureus bacteremia: resetting the clock for optimal management. Clin. Infect. Dis. 75, 1668–1674 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liapikou, A., Cilloniz, C. & Torres, A. Ceftobiprole for the treatment of pneumonia: a European perspective. Drug Des. Dev. Ther. 9, 4565–4572 (2015).

    CAS 

    Google Scholar 

  • Holland, T. L. et al. Ceftobiprole for treatment of complicated Staphylococcus aureus bacteremia. N. Engl. J. Med. 389, 1390–1401 (2023).

    CAS 
    PubMed 

    Google Scholar 

  • Long, S. W. et al. PBP2a mutations causing high-level ceftaroline resistance in clinical methicillin-resistant Staphylococcus aureus isolates. Antimicrob. Agents Chemother. 58, 6668–6674 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, H. et al. Global trends of antimicrobial susceptibility to ceftaroline and ceftazidime-avibactam: a surveillance study from the ATLAS program (2012–2016). Antimicrob. Resist. Infect. Control 9, 166 (2020).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Pfaller, M. A. et al. Ceftobiprole activity against Gram-positive and -negative pathogens collected from the United States in 2006 and 2016. Antimicrob. Agents Chemother. 63, e01566-18 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • Conlon, B. P. et al. Persister formation in Staphylococcus aureus is associated with ATP depletion. Nat. Microbiol. 1, 16051 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zalis, E. A. et al. Stochastic variation in expression of the tricarboxylic acid cycle produces persister cells. mBio 10, e01930–19 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rowe, S. E. et al. Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection. Nat. Microbiol. 5, 282–290 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Walters, M. C. et al. Contributions of antibiotic penetration, oxygen limitation, and low metabolic activity to tolerance of Pseudomonas aeruginosa biofilms to ciprofloxacin and tobramycin. Antimicrob. Agents Chemother. 47, 317–323 (2003).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pabst, B., Pitts, B., Lauchnor, E. & Stewart, P. S. Gel-entrapped Staphylococcus aureus bacteria as models of biofilm infection exhibit growth in dense aggregates, oxygen limitation, antibiotic tolerance, and heterogeneous gene expression. Antimicrob. Agents Chemother. 60, 6294–6301 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Freiberg, J. A. et al. Restriction of arginine induces antibiotic tolerance in Staphylococcus aureus. Nat. Commun. 15, 6734 (2024). This paper shows how limitation of an essential nutrient can inhibit protein synthesis and lead to antibiotic tolerance in biofilms, both in vitro and in a mouse infection model.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ledger, E. V. K. & Edwards, A. M. Growth arrest of Staphylococcus aureus induces daptomycin tolerance via cell wall remodelling. mBio 14, e0355822 (2023).

    PubMed 

    Google Scholar 

  • Ledger, E. V. K., Mesnage, S. & Edwards, A. M. Human serum triggers antibiotic tolerance in Staphylococcus aureus. Nat. Commun. 13, 2041 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim, W. et al. A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 556, 103–107 (2018). This study is a great example of how persisters can be targeted by antibiotics with mechanisms of action that are not reliant on active antibiotic targets, in this case the retinoid antibiotics destabilize the membrane resulting in death of actively growing bacteria and persister cells.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Conlon, B. P. et al. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503, 365–370 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Allison, K. R., Brynildsen, M. P. & Collins, J. J. Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473, 216–220 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Radlinski, L. C. et al. Chemical induction of aminoglycoside uptake overcomes antibiotic tolerance and resistance in Staphylococcus aureus. Cell Chem. Biol. 26, 1355–1364.e4 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Silverman, J. A., Mortin, L. I., Vanpraagh, A. D., Li, T. & Alder, J. Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact. J. Infect. Dis. 191, 2149–2152 (2005).

    CAS 
    PubMed 

    Google Scholar 

  • Rowe, S. E., Beam, J. E. & Conlon, B. P. Recalcitrant Staphylococcus aureus infections: obstacles and solutions. Infect. Immun. 89, e00694–20 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sakoulas, G. et al. Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus. J. Mol. Med. 92, 139–149 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • Peyrusson, F. et al. Intracellular Staphylococcus aureus persisters upon antibiotic exposure. Nat. Commun. 11, 2200 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Surewaard, B. G. et al. Identification and treatment of the Staphylococcus aureus reservoir in vivo. J. Exp. Med. 213, 1141–1151 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Barcia-Macay, M., Seral, C., Mingeot-Leclercq, M. P., Tulkens, P. M. & Van Bambeke, F. Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages. Antimicrob. Agents Chemother. 50, 841–851 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lehar, S. M. et al. Novel antibody-antibiotic conjugate eliminates intracellular S. aureus. Nature 527, 323–328 (2015).

    CAS 
    PubMed 

    Google Scholar 

  • Kahl, B. C., Becker, K. & Loffler, B. Clinical significance and pathogenesis of staphylococcal small colony variants in persistent infections. Clin. Microbiol. Rev. 29, 401–427 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Flannagan, R. S., Heit, B. & Heinrichs, D. E. Intracellular replication of Staphylococcus aureus in mature phagolysosomes in macrophages precedes host cell death, and bacterial escape and dissemination. Cell Microbiol. 18, 514–535 (2016).

    CAS 
    PubMed 

    Google Scholar 

  • Abuaita, B. H., Schultz, T. L. & O’Riordan, M. X. Mitochondria-derived vesicles deliver antimicrobial reactive oxygen species to control phagosome-localized Staphylococcus aureus. Cell Host Microbe 24, 625–636 e625 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gaupp, R., Ledala, N. & Somerville, G. A. Staphylococcal response to oxidative stress. Front. Cell Infect. Microbiol. 2, 33 (2012).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Helaine, S., Conlon, B. P., Davis, K. M. & Russell, D. G. Host stress drives tolerance and persistence: the bane of anti-microbial therapeutics. Cell Host Microbe 32, 852–862 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Antimicrobial Resistance, C. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399, 629–655 (2022).

    Google Scholar 

  • Holland, T. L., Arnold, C. & Fowler, V. G. Jr. Clinical management of Staphylococcus aureus bacteremia: a review. JAMA 312, 1330–1341 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Tong, S. Y. C. et al. The Staphylococcus aureus network adaptive platform trial protocol: new tools for an old foe. Clin. Infect. Dis. 75, 2027–2034 (2022). The CAMERA2 trial demonstrated that combination therapy with either daptomycin or vancomycin and an antistaphylococcal β-lactam did not improve clinical outcomes in patients with. S. aureus bacteraemia.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dolby, H. W., Clifford, S. A., Laurenson, I. F., Fowler, V. G. & Russell, C. D. Heterogeneity in Staphylococcus aureus bacteraemia clinical trials complicates interpretation of findings. J. Infect. Dis. 226, 723–728 (2022).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Westgeest, A. C. et al. Global differences in the management of Staphylococcus aureus bacteremia: no international standard of care. Clin. Infect. Dis. 77, 1092–1101 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rose, W., Fantl, M., Geriak, M., Nizet, V. & Sakoulas, G. Current paradigms of combination therapy in methicillin-resistant Staphylococcus aureus (MRSA) bacteremia: does it work, which combination, and for which patients? Clin. Infect. Dis. 73, 2353–2360 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tong, S. Y. C. et al. Effect of vancomycin or daptomycin with vs without an antistaphylococcal beta-lactam on mortality, bacteremia, relapse, or treatment failure in patients with MRSA bacteremia: a randomized clinical trial. JAMA 323, 527–537 (2020).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Grillo, S. et al. Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial. Nat. Med. 29, 2518–2525 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pujol, M. et al. Daptomycin plus fosfomycin versus daptomycin alone for methicillin-resistant Staphylococcus aureus bacteremia and endocarditis: a randomized clinical trial. Clin. Infect. Dis. 72, 1517–1525 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • Thwaites, G. E. et al. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 391, 668–678 (2018). This paper reports that ARREST showed no benefit in adjunctive rifampin in the treatment of MRSA bacteraemia.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Osmon, D. R. et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin. Infect. Dis. 56, e1–e25 (2013).

    PubMed 

    Google Scholar 

  • Aydin, O. et al. Rifampin-accompanied antibiotic regimens in the treatment of prosthetic joint infections: a frequentist and Bayesian meta-analysis of current evidence. Eur. J. Clin. Microbiol. Infect. Dis. 40, 665–671 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • Scheper, H. et al. Outcome of debridement, antibiotics, and implant retention for staphylococcal hip and knee prosthetic joint infections, focused on rifampicin use: a systematic review and meta-analysis. Open Forum Infect. Dis. 8, ofab298 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • El Zein, S. et al. Rifampin based therapy for patients with Staphylococcus aureus native vertebral osteomyelitis: a systematic review and meta-analysis. Clin. Infect. Dis. 78, 40–47 (2024).

    CAS 
    PubMed 

    Google Scholar 

  • Baddour, L. M. et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 132, 1435–1486 (2015).

    CAS 
    PubMed 

    Google Scholar 

  • Delgado, V. et al. 2023 ESC guidelines for the management of endocarditis. Eur. Heart J. 44, 3948–4042 (2023).

    PubMed 

    Google Scholar 

  • Chuard, C., Herrmann, M., Vaudaux, P., Waldvogel, F. A. & Lew, D. P. Successful therapy of experimental chronic foreign-body infection due to methicillin-resistant Staphylococcus aureus by antimicrobial combinations. Antimicrob. Agents Chemother. 35, 2611–2616 (1991).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lucet, J. C. et al. Treatment of experimental foreign body infection caused by methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 34, 2312–2317 (1990).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ryder, J. H. et al. Deconstructing the dogma: systematic literature review and meta-analysis of adjunctive gentamicin and rifampin in staphylococcal prosthetic valve endocarditis. Open Forum Infect. Dis. 9, ofac583 (2022).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Zasowski, E. J. et al. Multicenter observational study of ceftaroline fosamil for methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob. Agents Chemother. 61, e02015-16 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Geriak, M. et al. Clinical data on daptomycin plus ceftaroline versus standard of care monotherapy in the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob. Agents Chemother. 63, e02483-18 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • McCreary, E. K. et al. Multicenter cohort of patients with methicillin-resistant Staphylococcus aureus bacteremia receiving daptomycin plus ceftaroline compared with other MRSA treatments. Open Forum Infect. Dis. 7, ofz538 (2020).

    PubMed 

    Google Scholar 

  • Ulloa, E. R. et al. Cefazolin and ertapenem salvage therapy rapidly clears persistent methicillin-susceptible Staphylococcus aureus bacteremia. Clin. Infect. Dis. 71, 1413–1418 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Kalil, A. C., Holubar, M., Deresinski, S. & Chambers, H. F. Is daptomycin plus ceftaroline associated with better clinical outcomes than standard of care monotherapy for Staphylococcus aureus bacteremia? Antimicrob. Agents Chemother. 63, e00900-19 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nannini, E. C. et al. Inoculum effect with cefazolin among clinical isolates of methicillin-susceptible Staphylococcus aureus: frequency and possible cause of cefazolin treatment failure. Antimicrob. Agents Chemother. 53, 3437–3441 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • S. aureus Network Adaptive Platform Trial Group. Cefazolin versus (flu)cloxacillin for the treatment of penicillin-resistant, methicillin-susceptible Staphylococcus aureus bacteraemia: a randomised controlled trial within the S. aureus network adaptive platform (SNAP). In Proc. 35th Congress of the European Society of Clinical Microbiology and Infectious Diseases 4889 (ESCMID, 2025).

  • Iversen, K. et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N. Engl. J. Med. 380, 415–424 (2019). The POET study is one of the few RCTs to examine the efficacy of oral antibiotics for the treatment of left-sided endocarditis and showing that oral therapy is non-inferior to intravenous antibiotics.

    CAS 
    PubMed 

    Google Scholar 

  • Kaasch, A. J. et al. Efficacy and safety of an early oral switch in low-risk Staphylococcus aureus bloodstream infection (SABATO): an international, open-label, parallel-group, randomised, controlled, non-inferiority trial. Lancet Infect. Dis. 24, 523–534 (2024). The SABATO trial shows that oral switch is non-inferior to intraveous antibiotics in low-risk patients with S. aureus bacteraemia.

    PubMed 

    Google Scholar 

  • Li, H. K. et al. Oral versus intravenous antibiotics for bone and joint infection. N. Engl. J. Med. 380, 425–436 (2019). The OVIVA trial demonstrates that oral therapy is non-inferior to intravenous therapy for the treatment of bone and joint infections.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, K. et al. Bacteriophage therapy for drug-resistant Staphylococcus aureus infections. Front. Cell Infect. Microbiol. 14, 1336821 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Strathdee, S. A., Hatfull, G. F., Mutalik, V. K. & Schooley, R. T. Phage therapy: from biological mechanisms to future directions. Cell 186, 17–31 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ferry, T. et al. Phage therapy as adjuvant to conservative surgery and antibiotics to salvage patients with relapsing S. aureus prosthetic knee infection. Front. Med. 7, 570572 (2020).

    Google Scholar 

  • Ramirez-Sanchez, C. et al. Successful treatment of Staphylococcus aureus prosthetic joint infection with bacteriophage therapy. Viruses 13, 1182 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Doub, J. B. et al. Salphage: salvage bacteriophage therapy for recalcitrant MRSA prosthetic joint infection. Antibiotics 11, 616 (2022).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Schoeffel, J. et al. Successful use of salvage bacteriophage therapy for a recalcitrant MRSA knee and hip prosthetic joint infection. Pharmaceuticals 15, 177 (2022).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Petrovic Fabijan, A. et al. Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat. Microbiol. 5, 465–472 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Staphylococcus aureus phage product candidate. Armata Pharmaceuticals https://www.armatapharma.com/pipeline/ap-sa02/ (2025).

  • Fowler, V. G. Jr et al. Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis. J. Clin. Invest. 130, 3750–3760 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fowler, V. G. Jr. et al. Exebacase in addition to standard-of-care antibiotics for Staphylococcus aureus bloodstream infections and right-sided infective endocarditis: a phase 3, superiority-design, placebo-controlled, randomized clinical trial (DISRUPT). Clin. Infect. Dis. 78, 1473–1481 (2024). This is the first RCT to examine the efficacy of adjunctive phage lysin for treatment of S. aureus bacteraemia and right-sided endocarditis.

    CAS 
    PubMed 

    Google Scholar 

  • FDA news release: “FDA approves new antibiotic for three different uses”. FDA https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibiotic-three-different-uses (2024).

  • Dunne, M. W. et al. Extended-duration dosing and distribution of dalbavancin into bone and articular tissue. Antimicrob. Agents Chemother. 59, 1849–1855 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Turner, N. A. et al. Dalbavancin for treatment of Staphylococcus aureus bacteremia: the DOTS randomized clinical trial. JAMA https://doi.org/10.1001/jama.2025.12543 (2025).

  • O’Brien, E. C. & McLoughlin, R. M. Considering the ‘Alternatives’ for next-generation anti-Staphylococcus aureus vaccine development. Trends Mol. Med. 25, 171–184 (2019).

    PubMed 

    Google Scholar 

  • Wong Fok Lung, T. et al. Staphylococcus aureus adaptive evolution: recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development. Front. Cell Infect. Microbiol. 12, 1060810 (2022).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Caldera, J. R. et al. The characteristics of pre-existing humoral imprint determine efficacy of S. aureus vaccines and support alternative vaccine approaches. Cell Rep. Med. 5, 101360 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tsai, C. M. et al. Non-protective immune imprint underlies failure of Staphylococcus aureus IsdB vaccine. Cell Host Microbe 30, 1163–1172 e1166 (2022). This report provides evidence that prior S. aureus exposure elicits non-productive antibody responses that blunt opsonophagocytosis with an IsdB vaccine platform, which highlights the importance of understanding immune baseline and antigen experience in the context of S. aureus vaccine design.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Teymournejad, O., Li, Z., Beesetty, P., Yang, C. & Montgomery, C. P. Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy. npj Vaccines 8, 3 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tsai, C. M. et al. Pathobiont-driven antibody sialylation through IL-10 undermines vaccination. J. Clin. Invest. 134, e179563 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kelly, A. M. et al. IL-10 inhibition during immunization improves vaccine-induced protection against Staphylococcus aureus infection. JCI Insight 9, e178216 (2024).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Poolman, J. T. et al. A SpA+ LukAB vaccine targeting Staphylococcus aureus evasion factors restricts infection in two minipig infection models. npj Vaccines 10, 78 (2025).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pulendran, B. Integrated organ immunity: a path to a universal vaccine. Nat. Rev. Immunol. 24, 81–82 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bagnoli, F. et al. Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus. Proc. Natl Acad. Sci. USA 112, 3680–3685 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fritz, S. A. & Bubeck Wardenburg, J. A path forward for Staphylococcus aureus vaccine development. J. Exp. Med. 221, e20240002 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, X., Schneewind, O. & Missiakas, D. Engineered human antibodies for the opsonization and killing of Staphylococcus aureus. Proc. Natl Acad. Sci. USA 119, e2114478119 (2022).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Buckley, P. T. et al. Multivalent human antibody–centyrin fusion protein to prevent and treat Staphylococcus aureus infections. Cell Host Microbe 31, 751–765 e711 (2023).

    CAS 
    PubMed 

    Google Scholar 

  • Weems, J. J. Jr. et al. Phase II, randomized, double-blind, multicenter study comparing the safety and pharmacokinetics of tefibazumab to placebo for treatment of Staphylococcus aureus bacteremia. Antimicrob. Agents Chemother. 50, 2751–2755 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rupp, M. E. et al. Phase II, randomized, multicenter, double-blind, placebo-controlled trial of a polyclonal anti-Staphylococcus aureus capsular polysaccharide immune globulin in treatment of Staphylococcus aureus bacteremia. Antimicrob. Agents Chemother. 51, 4249–4254 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Salgado-Pabon, W. & Schlievert, P. M. Models matter: the search for an effective Staphylococcus aureus vaccine. Nat. Rev. Microbiol. 12, 585–591 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • AR-301: Human anti-S. aureus mAb for therapeutic treatment of VAP. Aridis Pharmaceuticals https://www.aridispharma.com/ar-301/ (2023).

  • Aridis Pharmaceuticals announces first quarter 2023 financial results and business update. US Securities and Exchange Commission https://www.sec.gov/Archives/edgar/data/1614067/000149315223020618/ex99-1.htm (2023).

  • Francois, B. et al. Efficacy and safety of suvratoxumab for prevention of Staphylococcus aureus ventilator-associated pneumonia (SAATELLITE): a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial. Lancet Infect. Dis. 21, 1313–1323 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • AR-320: long-acting human anti-S. aureus for prevention of VAP. Aridis Pharmaceuticals https://www.aridispharma.com/ar-320/ (2021).

  • Shinefield, H. et al. Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis. N. Engl. J. Med. 346, 491–496 (2002).

    PubMed 

    Google Scholar 

  • Millar, E. V. et al. Safety, immunogenicity, and efficacy of NDV-3A against Staphylococcus aureus colonization: a phase 2 vaccine trial among US army infantry trainees. Vaccine 39, 3179–3188 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hassanzadeh, H. et al. Efficacy of a 4-antigen Staphylococcus aureus vaccine in spinal surgery: the Staphylococcus aureus suRgical inpatient vaccine efficacy (STRIVE) randomized clinical trial. Clin. Infect. Dis. 77, 312–320 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fowler, V. G. et al. Effect of an investigational vaccine for preventing Staphylococcus aureus infections after cardiothoracic surgery: a randomized trial. JAMA 309, 1368–1378 (2013). This study uncovers the pitfalls in S. aureus vaccine design and surprisingly results in increased mortality in the vaccinated group relative to the unvaccinated participants.

    CAS 
    PubMed 

    Google Scholar 

  • Karauzum, H. et al. Lethal CD4 T cell responses induced by vaccination against Staphylococcus aureus bacteremia. J. Infect. Dis. 215, 1231–1239 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • McNeely, T. B. et al. Mortality among recipients of the Merck V710 Staphylococcus aureus vaccine after postoperative S. aureus infections: an analysis of possible contributing host factors. Hum. Vaccin. Immunother. 10, 3513–3516 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Seok, J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 110, 3507–3512 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bernard, L. et al. Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial. Lancet 385, 875–882 (2015).

    CAS 
    PubMed 

    Google Scholar 

  • Bernard, L. et al. Antibiotic therapy for 6 or 12 weeks for prosthetic joint infection. N. Engl. J. Med. 384, 1991–2001 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • US National Library of Medicine. Clinicaltrials.gov https://www.clinicaltrials.gov/study/NCT00217841 (2006).

  • US National Library of Medicine. Clinicaltrials.gov https://clinicaltrials.gov/study/NCT02357966?tab=results (2024).

  • AR-301: human anti-S. aureus mAb for therapeutic treatment of VAP. Aridis Pharmaceuticals https://www.aridispharma.com/ar-301/ (2022).

  • Benjamin, D. K. et al. A blinded, randomized, multicenter study of an intravenous Staphylococcus aureus immune globulin. J. Perinatol. 26, 290–295 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • DeJonge, M. et al. Clinical trial of safety and efficacy of INH-A21 for the prevention of nosocomial staphylococcal bloodstream infection in premature infants. J. Pediatr. 151, 260–265 (2007).

    CAS 
    PubMed 

    Google Scholar 

  • Weisman, L. E. et al. A randomized study of a monoclonal antibody (pagibaximab) to prevent staphylococcal sepsis. Pediatrics 128, 271–279 (2011).

    PubMed 

    Google Scholar 

  • US National Library of Medicine. Clinicaltrials.gov https://clinicaltrials.gov/study/NCT02940626?tab=results (2019).

  • Scott, W. K. et al. Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia. PLoS Genet. 14, e1007667 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Rasmussen, G. et al. Expression of HLA-DRA and CD74 mRNA in whole blood during the course of complicated and uncomplicated Staphylococcus aureus bacteremia. Microbiol. Immunol. 61, 442–451 (2017).

    CAS 
    PubMed 

    Google Scholar 

  • DeLorenze, G. N. et al. Polymorphisms in HLA class II genes are associated with susceptibility to Staphylococcus aureus infection in a white population. J. Infect. Dis. 213, 816–823 (2016).

    CAS 
    PubMed 

    Google Scholar 

  • Cyr, D. D. et al. Evaluating genetic susceptibility to Staphylococcus aureus bacteremia in African Americans using admixture mapping. Genes Immun. 18, 95–99 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Krogman, A. et al. HLA-DR polymorphisms influence in vivo responses to staphylococcal toxic shock syndrome toxin-1 in a transgenic mouse model. HLA 89, 20–28 (2017).

    CAS 
    PubMed 

    Google Scholar 

  • Weiss, S. et al. Toxin exposure and HLA alleles determine serum antibody binding to toxic shock syndrome toxin 1 (TSST-1) of Staphylococcus aureus. Front. Immunol. 14, 1229562 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Guimaraes, A. O. et al. A prognostic model of persistent bacteremia and mortality in complicated Staphylococcus aureus bloodstream infection. Clin. Infect. Dis. 68, 1502–1511 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • Volk, C. F. et al. Interleukin (IL)-1β and IL-10 host responses in patients with Staphylococcus aureus bacteremia determined by antimicrobial therapy. Clin. Infect. Dis. 70, 2634–2640 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Rose, W. E. et al. Elevated serum interleukin-10 at time of hospital admission is predictive of mortality in patients with Staphylococcus aureus bacteremia. J. Infect. Dis. 206, 1604–1611 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

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