{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:22:50Z","timestamp":1792797770633,"version":"4.5.0"},"reference-count":91,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001702","name":"AO Foundation","doi-asserted-by":"publisher","award":["AOTrauma"],"award-info":[{"award-number":["AOTrauma"]}],"id":[{"id":"10.13039\/501100001702","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Orthopaedic device-related infection (ODRI) presents a significant challenge to the field of orthopaedic and trauma surgery. Despite extensive treatment involving surgical debridement and prolonged antibiotic therapy, outcomes remain poor. This is largely due to the unique abilities of Staphylococcus aureus, the most common causative agent of ODRI, to establish and protect itself within the host by forming biofilms on implanted devices and staphylococcal abscess communities (SACs). There is a need for novel antimicrobials that can readily target such features. Enzybiotics are a class of antimicrobial enzymes derived from bacteria and bacteriophages, which function by enzymatically degrading bacterial polymers essential to bacterial survival or biofilm formation. Here, we apply an enzybiotic-based combination regimen to a set of in vitro models as well as in a murine ODRI model to evaluate their usefulness in eradicating established S. aureus infection, compared to classical antibiotics. We show that two chimeric endolysins previously selected for their functional efficacy in human serum in combination with a polysaccharide depolymerase reduce bacterial CFU numbers 10,000-fold in a peg model and in an implant model of biofilm. The enzyme combination also completely eradicates S. aureus in a SAC in vitro model where classical antibiotics are ineffective. In an in vivo ODRI model in mice, the antibiofilm effects of this enzyme regimen are further enhanced when combined with a classical gentamicin\/vancomycin treatment. In a mouse model of methicillin-resistant S. aureus (MRSA) ODRI following a fracture repair, a combined local enzybiotic\/antibiotic treatment regimen showed a significant CFU reduction in the device and the surrounding soft tissue, as well as significant prevention of weight loss. These outcomes were superior to treatment with antibiotics alone. Overall, this study demonstrates that the addition of enzybiotics, which are distinguished by their extremely rapid killing efficacy and antibiofilm activities, can enhance the treatment of severe MRSA ODRI.<\/jats:p>","DOI":"10.3390\/antibiotics10101186","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T08:27:44Z","timestamp":1632904064000},"page":"1186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["An Enzybiotic Regimen for the Treatment of Methicillin-Resistant Staphylococcus aureus Orthopaedic Device-Related Infection"],"prefix":"10.3390","volume":"10","author":[{"given":"Eric T.","family":"Sumrall","sequence":"first","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marloes I.","family":"Hofstee","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2705-0812","authenticated-orcid":false,"given":"Daniel","family":"Arens","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4647-1011","authenticated-orcid":false,"given":"Christian","family":"R\u00f6hrig","sequence":"additional","affiliation":[{"name":"Micreos GmbH, 8820 W\u00e4denswil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Baertl","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"},{"name":"Department of Trauma Surgery, University Medical Center, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7148-9569","authenticated-orcid":false,"given":"Dominic","family":"Gehweiler","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3535-3861","authenticated-orcid":false,"given":"Mathias","family":"Schmelcher","sequence":"additional","affiliation":[{"name":"Micreos GmbH, 8820 W\u00e4denswil, Switzerland"},{"name":"Institute of Food, Nutrition and Health, ETH Z\u00fcrich, 8092 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J.","family":"Loessner","sequence":"additional","affiliation":[{"name":"Institute of Food, Nutrition and Health, ETH Z\u00fcrich, 8092 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8155-4202","authenticated-orcid":false,"given":"Stephan","family":"Zeiter","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7778-2480","authenticated-orcid":false,"given":"R. Geoff","family":"Richards","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2307-0397","authenticated-orcid":false,"given":"T. Fintan","family":"Moriarty","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1302\/2058-5241.1.000037","article-title":"Orthopaedic device-related infection: Current and future interventions for improved prevention and treatment","volume":"1","author":"Moriarty","year":"2016","journal-title":"EFORT Open Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1016\/j.injury.2011.10.015","article-title":"Prevalence of complications of open tibial shaft fractures stratified as per the Gustilo-Anderson classification","volume":"42","author":"Papakostidis","year":"2011","journal-title":"Injury"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1007\/s00402-019-03287-4","article-title":"General treatment principles for fracture-related infection: Recommendations from an international expert group","volume":"140","author":"Metsemakers","year":"2019","journal-title":"Arch. Orthop. Trauma Surg."},{"key":"ref_4","first-page":"805","article-title":"Late Outcomes of Trauma Patients with Infections during Index Hospitalization","volume":"67","author":"Czaja","year":"2009","journal-title":"J. Trauma Inj. Infect. Crit. Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/j.injury.2017.03.030","article-title":"Infection after fracture fixation of the tibia: Analysis of healthcare utilization and related costs","volume":"48","author":"Metsemakers","year":"2017","journal-title":"Injury"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1302\/2058-5241.4.180093","article-title":"Infection after fracture fixation","volume":"4","author":"Steinmetz","year":"2019","journal-title":"EFORT Open Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.injury.2013.02.027","article-title":"Predictors of poor outcomes following deep infection after internal fixation of ankle fractures","volume":"44","author":"Ovaska","year":"2013","journal-title":"Injury"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Rittmann, W.W., and Perren, S.M. (1975). Cortical Bone Healing after Internal Fixation and Infection: Biomechanics and Biology, Springer.","DOI":"10.1007\/978-3-642-65977-5"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"380","DOI":"10.3109\/17453674.2013.823589","article-title":"Prosthetic joint-associated infections treated with DAIR (debridement, antibiotics, irrigation, and retention): Analysis of risk factors and local antibiotic carriers in 91 patients","volume":"84","author":"Kuiper","year":"2013","journal-title":"Acta Orthop."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1007\/s11999-012-2500-7","article-title":"Aggressive early debridement for treatment of acutely infected cemented total hip arthroplasty","volume":"470","author":"Sukeik","year":"2012","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/cid\/cis803","article-title":"Diagnosis and management of prosthetic joint infection: Clinical practice guidelines by the Infectious Diseases Society of America","volume":"56","author":"Osmon","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"457","DOI":"10.3109\/17453674.2015.1026756","article-title":"75% success rate after open debridement, exchange of tibial insert, and antibiotics in knee prosthetic joint infections","volume":"86","author":"Holmberg","year":"2015","journal-title":"Acta Orthop."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1302\/0301-620X.99B11.BJJ-2017-0088.R1","article-title":"Outcomes following debridement, antibiotics and implant retention in the management of periprosthetic infections of the hip: A review of cohort studies","volume":"99-B","author":"Tsang","year":"2017","journal-title":"Bone Jt. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1016\/j.biomaterials.2005.11.044","article-title":"The significance of infection related to orthopedic devices and issues of antibiotic resistance","volume":"27","author":"Campoccia","year":"2006","journal-title":"Biomaterials"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1177\/039139880502801106","article-title":"Etiology of implant orthopedic infections: A survey on 1027 clinical isolates","volume":"28","author":"Arciola","year":"2005","journal-title":"Int. J. Artif. Organs"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41413-019-0061-z","article-title":"Evolving concepts in bone infection: Redefining \u201cbiofilm\u201d, \u201cacute vs. chronic osteomyelitis\u201d, \u201cthe immune proteome\u201d and \u201clocal antibiotic therapy\u201d","volume":"7","author":"Masters","year":"2019","journal-title":"Bone Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1111\/j.1574-695X.2010.00766.x","article-title":"New methods for the detection of orthopedic and other biofilm infections","volume":"61","author":"Costerton","year":"2011","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"50","DOI":"10.7150\/jbji.23423","article-title":"Current therapies in treatment and prevention of fracture wound biofilms: Why a multifaceted approach is essential for resolving persistent infections","volume":"3","author":"Blanchette","year":"2018","journal-title":"J. Bone Jt. Infect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrmicro2415","article-title":"The biofilm matrix","volume":"8","author":"Flemming","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/bit.21838","article-title":"Medical biofilms","volume":"100","author":"Bryers","year":"2008","journal-title":"Biotechnol. Bioeng."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1086\/377001","article-title":"Detection of Staphylococcus aureus biofilm on tampons and menses components","volume":"188","author":"Veeh","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1001\/jama.1995.03520440052036","article-title":"Molecular analysis of bacterial pathogens in otitis media with effusion","volume":"273","author":"Post","year":"1995","journal-title":"JAMA"},{"key":"ref_23","first-page":"107","article-title":"Multidrug tolerance of biofilms and persister cells","volume":"322","author":"Lewis","year":"2008","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1093\/jac\/22.6.777","article-title":"Resistance of bacterial biofilms to antibiotics: A growth-rate related effect?","volume":"22","author":"Brown","year":"1988","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_25","first-page":"235","article-title":"Staphylococcus aureus persisters tolerant to bactericidal antibiotics","volume":"22","author":"Lechner","year":"2012","journal-title":"J. Mol. Microbiol. Biotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1146\/annurev.micro.112408.134306","article-title":"Persister cells","volume":"64","author":"Lewis","year":"2010","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3871","DOI":"10.4049\/jimmunol.1701574","article-title":"Innate Immunity to Staphylococcus aureus: Evolving Paradigms in Soft Tissue and Invasive Infections","volume":"200","author":"Brandt","year":"2018","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e01005-16","DOI":"10.1128\/IAI.01005-16","article-title":"Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence","volume":"85","author":"Farnsworth","year":"2017","journal-title":"Infect. Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.tim.2011.01.007","article-title":"A play in four acts: Staphylococcus aureus abscess formation","volume":"19","author":"Cheng","year":"2011","journal-title":"Trends Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Cheng, A.G., McAdow, M., Kim, H.K., Bae, T., Missiakas, D.M., and Schneewind, O. (2010). Contribution of coagulases towards Staphylococcus aureus disease and protective immunity. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001036"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1146\/annurev-pathol-012615-044351","article-title":"Pathogenesis of Staphylococcus aureus Bloodstream Infections","volume":"11","author":"Thomer","year":"2016","journal-title":"Annu. Rev. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e00293-20","DOI":"10.1128\/IAI.00293-20","article-title":"Three-Dimensional In Vitro Staphylococcus aureus Abscess Communities Display Antibiotic Tolerance and Protection from Neutrophil Clearance","volume":"88","author":"Hofstee","year":"2020","journal-title":"Infect. Immun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1016\/j.ajpath.2014.11.030","article-title":"Pathogenesis of Staphylococcus aureus abscesses","volume":"185","author":"Kobayashi","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.2217\/fmb.12.97","article-title":"Bacteriophage endolysins as novel antimicrobials","volume":"7","author":"Schmelcher","year":"2012","journal-title":"Future Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.ijmm.2010.04.002","article-title":"Bacteriophage endolysins: A novel anti-infective to control Gram-positive pathogens","volume":"300","author":"Fischetti","year":"2010","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Lopetuso, L.R., Giorgio, M.E., Saviano, A., Scaldaferri, F., Gasbarrini, A., and Cammarota, G. (2019). Bacteriocins and Bacteriophages: Therapeutic Weapons for Gastrointestinal Diseases?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010183"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1073\/pnas.51.3.414","article-title":"Lysostaphin: A New Bacteriolytic Agent for the Staphylococcus","volume":"51","author":"Schindler","year":"1964","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.3390\/ph3041139","article-title":"Lysostaphin: A Staphylococcal Bacteriolysin with Potential Clinical Applications","volume":"3","author":"Bastos","year":"2010","journal-title":"Pharmaceuticals"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/B978-0-12-394438-2.00007-4","article-title":"Endolysins as antimicrobials","volume":"83","author":"Nelson","year":"2012","journal-title":"Adv. Virus Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"103245","DOI":"10.1016\/j.fm.2019.103245","article-title":"Effective removal of staphylococcal biofilms on various food contact surfaces by Staphylococcus aureus phage endolysin LysCSA13","volume":"84","author":"Cha","year":"2019","journal-title":"Food Microbiol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Gutierrez, D., Ruas-Madiedo, P., Martinez, B., Rodriguez, A., and Garcia, P. (2014). Effective removal of staphylococcal biofilms by the endolysin LysH5. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107307"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Pennone, V., Sanz-Gaitero, M., O\u2019Connor, P., Coffey, A., Jordan, K., van Raaij, M.J., and McAuliffe, O. (2019). Inhibition of L. monocytogenes Biofilm Formation by the Amidase Domain of the Phage vB_LmoS_293 Endolysin. Viruses, 11.","DOI":"10.3390\/v11080722"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Olsen, N.M.C., Thiran, E., Hasler, T., Vanzieleghem, T., Belibasakis, G.N., Mahillon, J., Loessner, M.J., and Schmelcher, M. (2018). Synergistic Removal of Static and Dynamic Staphylococcus aureus Biofilms by Combined Treatment with a Bacteriophage Endolysin and a Polysaccharide Depolymerase. Viruses, 10.","DOI":"10.3390\/v10080438"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1128\/jb.178.1.175-183.1996","article-title":"The intercellular adhesin involved in biofilm accumulation of Staphylococcus epidermidis is a linear beta-1,6-linked glucosaminoglycan: Purification and structural analysis","volume":"178","author":"Mack","year":"1996","journal-title":"J. Bacteriol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.3389\/fmicb.2015.01315","article-title":"Role of the Pre-neck Appendage Protein (Dpo7) from Phage vB_SepiS-phiIPLA7 as an Anti-biofilm Agent in Staphylococcal Species","volume":"6","author":"Gutierrez","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.copbio.2020.09.012","article-title":"Bacteriophage endolysins\u2014Extending their application to tissues and the bloodstream","volume":"68","author":"Schmelcher","year":"2021","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/nature01026","article-title":"A bacteriolytic agent that detects and kills Bacillus anthracis","volume":"418","author":"Schuch","year":"2002","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Fischetti, V.A. (2018). Development of Phage Lysins as Novel Therapeutics: A Historical Perspective. Viruses, 10.","DOI":"10.3390\/v10060310"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Abdelrahman, F., Easwaran, M., Daramola, O.I., Ragab, S., Lynch, S., Oduselu, T.J., Khan, F.M., Ayobami, A., Adnan, F., and Torrents, E. (2021). Phage-Encoded Endolysins. Antibiotics, 10.","DOI":"10.3390\/antibiotics10020124"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e00071-17","DOI":"10.1128\/CMR.00071-17","article-title":"Recombinant Endolysins as Potential Therapeutics against Antibiotic-Resistant Staphylococcus aureus: Current Status of Research and Novel Delivery Strategies","volume":"31","author":"Schmelcher","year":"2018","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1128\/AAC.00890-10","article-title":"A novel chimeric lysin shows superiority to mupirocin for skin decolonization of methicillin-resistant and -sensitive Staphylococcus aureus strains","volume":"55","author":"Pastagia","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1159\/000473872","article-title":"Successful Treatment of Chronic Staphylococcus aureus-Related Dermatoses with the Topical Endolysin Staphefekt SA.100: A Report of 3 Cases","volume":"9","author":"Totte","year":"2017","journal-title":"Case Rep. Dermatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.jconrel.2016.11.030","article-title":"Thermally triggered release of the bacteriophage endolysin CHAPK and the bacteriocin lysostaphin for the control of methicillin resistant Staphylococcus aureus (MRSA)","volume":"245","author":"Hathaway","year":"2017","journal-title":"J. Control Release"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"543","DOI":"10.4155\/tde-2017-0040","article-title":"Recent advances in therapeutic delivery systems of bacteriophage and bacteriophage-encoded endolysins","volume":"8","author":"Hathaway","year":"2017","journal-title":"Ther. Deliv."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1128\/AAC.01625-09","article-title":"Synergism between a novel chimeric lysin and oxacillin protects against infection by methicillin-resistant Staphylococcus aureus","volume":"54","author":"Daniel","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"E4960","DOI":"10.1073\/pnas.1801013115","article-title":"Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing","volume":"115","author":"Johnson","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1302\/0301-620X.102B7.BJJ-2019-1590.R1","article-title":"2020 John Charnley Award: The antimicrobial potential of bacteriophage-derived lysin in a murine debridement, antibiotics, and implant retention model of prosthetic joint infection","volume":"102-B","author":"Sosa","year":"2020","journal-title":"Bone Jt. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e01781-20","DOI":"10.1128\/mBio.01781-20","article-title":"Engineering of Long-Circulating Peptidoglycan Hydrolases Enables Efficient Treatment of Systemic Staphylococcus aureus Infection","volume":"11","author":"Sobieraj","year":"2020","journal-title":"mBio"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e02134-17","DOI":"10.1128\/AEM.02134-17","article-title":"Corrected and Republished from: Identification of Peptidoglycan Hydrolase Constructs with Synergistic Staphylolytic Activity in Cow\u2019s Milk","volume":"84","author":"Verbree","year":"2018","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1128\/JCM.01144-10","article-title":"LysGH15, a novel bacteriophage lysin, protects a murine bacteremia model efficiently against lethal methicillin-resistant Staphylococcus aureus infection","volume":"49","author":"Gu","year":"2011","journal-title":"J. Clin. Microbiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1074\/jbc.M509691200","article-title":"Cell wall-targeting domain of glycylglycine endopeptidase distinguishes among peptidoglycan cross-bridges","volume":"281","author":"Lu","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e00209-20","DOI":"10.1128\/mBio.00209-20","article-title":"Targeting Hidden Pathogens: Cell-Penetrating Enzybiotics Eradicate Intracellular Drug-Resistant Staphylococcus aureus","volume":"11","author":"Rohrig","year":"2020","journal-title":"mBio"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Boles, B.R., Thoendel, M., Roth, A.J., and Horswill, A.R. (2010). Identification of genes involved in polysaccharide-independent Staphylococcus aureus biofilm formation. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010146"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1073\/pnas.1814265116","article-title":"Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus","volume":"116","author":"Copin","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1039\/D0LC00294A","article-title":"Point-of-care testing system for digital single cell detection of MRSA directly from nasal swabs","volume":"20","author":"Schulz","year":"2020","journal-title":"Lab Chip"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2927","DOI":"10.3389\/fmicb.2018.02927","article-title":"Improved Biodistribution and Extended Serum Half-Life of a Bacteriophage Endolysin by Albumin Binding Domain Fusion","volume":"9","author":"Seijsing","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/978-1-4939-0703-8_12","article-title":"Use of bacteriophage cell wall-binding proteins for rapid diagnostics of Listeria","volume":"1157","author":"Schmelcher","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_68","first-page":"321","article-title":"Influence of fracture stability on Staphylococcus epidermidis and Staphylococcus aureus infection in a murine femoral fracture model","volume":"34","author":"Zeiter","year":"2017","journal-title":"Eur. Cells Mater."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"774","DOI":"10.22203\/eCM.v041a49","article-title":"A murine Staphylococcus aureus fracture-related infection model characterised by fracture non-union, staphylococcal abscess communities and myeloid-derived suppressor cells","volume":"41","author":"Hofstee","year":"2021","journal-title":"Eur. Cells Mater."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1111\/j.1365-2672.2012.05288.x","article-title":"Staphylococcus aureus biofilm formation and antibiotic susceptibility tests on polystyrene and metal surfaces","volume":"112","author":"Fille","year":"2012","journal-title":"J. Appl. Microbiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.1574-695X.2007.00357.x","article-title":"Osteomyelitis and the role of biofilms in chronic infection","volume":"52","author":"Brady","year":"2008","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.1128\/AEM.66.7.2951-2958.2000","article-title":"Gene cloning and expression and secretion of Listeria monocytogenes bacteriophage-lytic enzymes in Lactococcus lactis","volume":"66","author":"Gaeng","year":"2000","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_73","first-page":"207","article-title":"Staphylococcal biofilms","volume":"322","author":"Otto","year":"2008","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1046\/j.1365-2958.2002.02827.x","article-title":"Staphylococcus and biofilms","volume":"43","author":"Gotz","year":"2002","journal-title":"Mol. Microbiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1177\/039139880903200903","article-title":"Therapeutic potential of biofilm-dispersing enzymes","volume":"32","author":"Kaplan","year":"2009","journal-title":"Int. J. Artif. Organs"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/ja.2011.113","article-title":"Recombinant human DNase I decreases biofilm and increases antimicrobial susceptibility in staphylococci","volume":"65","author":"Kaplan","year":"2012","journal-title":"J. Antibiot."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e02008-17","DOI":"10.1128\/AAC.02008-17","article-title":"Novel Treatment of Staphylococcus aureus Device-Related Infections Using Fibrinolytic Agents","volume":"62","author":"Hogan","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1093\/cid\/cir308","article-title":"Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008","volume":"53","author":"Talan","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3721","DOI":"10.1128\/IAI.00442-12","article-title":"Abscess formation and alpha-hemolysin induced toxicity in a mouse model of Staphylococcus aureus peritoneal infection","volume":"80","author":"Rauch","year":"2012","journal-title":"Infect. Immun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e02270-19","DOI":"10.1128\/mBio.02270-19","article-title":"Staphylococcus aureus Exploits the Host Apoptotic Pathway to Persist during Infection","volume":"10","author":"Winstel","year":"2019","journal-title":"mBio"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1093\/jac\/dku552","article-title":"Evolutionarily distinct bacteriophage endolysins featuring conserved peptidoglycan cleavage sites protect mice from MRSA infection","volume":"70","author":"Schmelcher","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4621","DOI":"10.1128\/AAC.00126-14","article-title":"Intravitreal injection of the chimeric phage endolysin Ply187 protects mice from Staphylococcus aureus endophthalmitis","volume":"58","author":"Singh","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Abdelkader, K., Gerstmans, H., Saafan, A., Dishisha, T., and Briers, Y. (2019). The Preclinical and Clinical Progress of Bacteriophages and Their Lytic Enzymes: The Parts are Easier than the Whole. Viruses, 11.","DOI":"10.3390\/v11020096"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Windolf, C.D., Logters, T., Scholz, M., Windolf, J., and Flohe, S. (2014). Lysostaphin-coated titan-implants preventing localized osteitis by Staphylococcus aureus in a mouse model. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115940"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"eaaw1228","DOI":"10.1126\/sciadv.aaw1228","article-title":"Lysostaphin and BMP-2 co-delivery reduces S. aureus infection and regenerates critical-sized segmental bone defects","volume":"5","author":"Johnson","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.1128\/AAC.47.11.3407-3414.2003","article-title":"Lysostaphin disrupts Staphylococcus aureus and Staphylococcus epidermidis biofilms on artificial surfaces","volume":"47","author":"Wu","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_87","first-page":"191","article-title":"Lysostaphin as a potential therapeutic agent for staphylococcal biofilm eradication","volume":"54","author":"Walencka","year":"2005","journal-title":"Pol. J. Microbiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1128\/AAC.45.5.1431-1437.2001","article-title":"Mechanism and suppression of lysostaphin resistance in oxacillin-resistant Staphylococcus aureus","volume":"45","author":"Climo","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"6286","DOI":"10.1128\/JB.00457-06","article-title":"Staphylococcus aureus mutants with increased lysostaphin resistance","volume":"188","author":"Grundling","year":"2006","journal-title":"J. Bacteriol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.ijid.2019.02.005","article-title":"Antibiotic penetration into bone and joints: An updated review","volume":"81","author":"Thabit","year":"2019","journal-title":"Int. J. Infect. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"6199","DOI":"10.1128\/IAI.71.11.6199-6204.2003","article-title":"Phage lytic enzyme Cpl-1 as a novel antimicrobial for pneumococcal bacteremia","volume":"71","author":"Loeffler","year":"2003","journal-title":"Infect. Immun."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/10\/10\/1186\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:07:13Z","timestamp":1760166433000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/10\/10\/1186"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,29]]},"references-count":91,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["antibiotics10101186"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics10101186","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,29]]}}}