{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T01:19:41Z","timestamp":1776388781855,"version":"3.51.2"},"reference-count":27,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T00:00:00Z","timestamp":1743811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Advanz Pharma Switzerland Sarl"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background: The presence of biofilms and low antimicrobial concentrations in bone tissue make prosthetic joint infections (PJI) difficult to treat. Ceftobiprole (CTO) has a potential role in MRSA PJI. This study evaluated the efficacy of ceftobiprole and daptomycin (DAP) alone and in combination against MRSA biofilms at expected bone tissue concentrations. We assessed whether CTO-DAP outperformed DAP combined with a non-anti-MRSA beta-lactam (cefazolin [CZO]). Methods: A dynamic in vitro PK\/PD biofilm model (CDC biofilm reactor) was used to simulate concentrations expected in cortical bone at a standard dosing of DAP (10 mg\/kg\/24 h), CTO (500 mg\/8 h), and CZO (2 g\/8 h), and assess performance against a 48-h MRSA biofilm from two clinical isolates that cause PJI (MRSA-1811 and MRSA-1733). Time\u2013kill curves using the log change method (\u0394log10 CFU\/cm2) assessed antimicrobial efficacy over 56 h. Resistance emergence was monitored. Results: Although both monotherapies were active, neither reached bactericidal levels nor was one superior to the other (\u0394log10 CFU\/cm2 CTO vs. DAP: \u22121.44 \u00b1 0.25 vs. \u22121.50 \u00b1 0.01 [p = 0.686] and \u22121.55 \u00b1 0.74 vs. \u22120.56 \u00b1 0.36 [p = 0.108] for MRSA-1811 and MRSA-1733, respectively). Only in the MRSA-1811 isolate did the CTO-DAP combination improve the activity of each monotherapy, without achieving a synergistic effect (\u0394log10 CFU\/cm2: CTO-DAP \u22122.087 \u00b1 0.048 vs. CTO \u22121.436 \u00b1 0.249 [p = 0.013] and vs. DAP \u22121.503 \u00b1 0.011 [p = 0.006]). No combination therapy (CTO-DAP vs. DAP-CZO) outperformed the other in either strain. No resistant bacterial subpopulations appeared with any antibiotic regimen. Conclusions: At clinically relevant concentrations, ceftobiprole and daptomycin showed similar activity against MRSA biofilms. The CTO-DAP combination showed comparable efficacy to DAP-CZO.<\/jats:p>","DOI":"10.3390\/antibiotics14040386","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T11:24:39Z","timestamp":1744025079000},"page":"386","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Efficacy of Ceftobiprole and Daptomycin at Bone Concentrations Against Methicillin-Resistant Staphylococcus aureus Biofilm: Results of a Dynamic In Vitro PK\/PD Model"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5945-5953","authenticated-orcid":false,"given":"Mikel","family":"Manche\u00f1o-Losa","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n \u201ci + 12\u201d del Hospital 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9582-3162","authenticated-orcid":false,"given":"Mar\u00eda \u00c1ngeles","family":"Mel\u00e9ndez-Carmona","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n \u201ci + 12\u201d del Hospital 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Lumbreras","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n \u201ci + 12\u201d del Hospital 12 de Octubre, 28041 Madrid, Spain"},{"name":"CIBER de Enfermedades Infecciosas CIBERINFEC, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Medicine, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaime","family":"Lora-Tamayo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n \u201ci + 12\u201d del Hospital 12 de Octubre, 28041 Madrid, Spain"},{"name":"CIBER de Enfermedades Infecciosas CIBERINFEC, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Medicine, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/nrmicro.2016.34","article-title":"Distinguishing Between Resistance, Tolerance and Persistence to Antibiotic Treatment","volume":"14","author":"Brauner","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1111\/1469-0691.12003","article-title":"Antimicrobial Treatment Concepts for Orthopaedic Device-Related Infection","volume":"18","author":"Sendi","year":"2012","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jinf.2018.07.014","article-title":"Clinical Outcome and Risk Factors for Failure in Late Acute Prosthetic Joint Infections Treated with Debridement and Implant Retention","volume":"78","author":"Sebillotte","year":"2019","journal-title":"J. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1302\/0301-620X.102B7.BJJ-2019-1628.R1","article-title":"2020 Frank Stinchfield Award: Identifying Who Will Fail Following Irrigation and Debridement for Prosthetic Joint Infection: A Machine Learning-Based Validated Tool","volume":"102-B","author":"Shohat","year":"2020","journal-title":"Bone Jt. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.eimc.2016.08.012","article-title":"Executive Summary of Management of Prosthetic Joint Infections. Clinical Practice Guidelines by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)","volume":"35","author":"Ariza","year":"2017","journal-title":"Enfermedades Infecc. Microbiol. Cl\u00ednica"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.ijantimicag.2013.05.005","article-title":"Daptomycin: The Role of High-Dose and Combination Therapy for Gram-Positive Infections","volume":"42","author":"Gould","year":"2013","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3806","DOI":"10.1128\/AAC.00127-12","article-title":"Efficacy of Daptomycin-Cloxacillin Combination in Experimental Foreign-Body Infection Due to Methicillin-Resistant Staphylococcus aureus","volume":"56","author":"Murillo","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ijantimicag.2013.09.013","article-title":"Evaluation of the In Vitro Activities of Ceftobiprole and Comparators in Staphylococcal Colony or Microtitre Plate Biofilm Assays","volume":"43","author":"Abbanat","year":"2014","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3789","DOI":"10.1128\/AAC.49.9.3789-3793.2005","article-title":"Intensive Therapy with Ceftobiprole Medocaril of Experimental Foreign-Body Infection by Methicillin-Resistant Staphylococcus aureus","volume":"49","author":"Vaudaux","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1128\/AAC.00638-07","article-title":"Efficacies of Ceftobiprole Medocaril and Comparators in a Rabbit Model of Osteomyelitis Due to Methicillin-Resistant Staphylococcus aureus","volume":"52","author":"Yin","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1093\/jac\/dku236","article-title":"Potent Synergy of Ceftobiprole plus Daptomycin against Multiple Strains of Staphylococcus aureus with Various Resistance Phenotypes","volume":"69","author":"Barber","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Grayson, M.L., Cosgrove, S.E., Crowe, S.M., Hope, W., McCarthy, J.S., Mills, J., Mouton, J.W., and Paterson, D.L. (2018). Kucers\u2019 the Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal, Antiparasitic and Antiviral Drugs, Taylor & Francis Group, LLC. [7th ed.].","DOI":"10.1201\/9781498747967"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2165\/00003088-200948020-00002","article-title":"Penetration of Antibacterials into Bone","volume":"48","author":"Landersdorfer","year":"2009","journal-title":"Clin. Pharmacokinet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s40121-014-0055-5","article-title":"Evaluation of High-Dose Daptomycin Versus Vancomycin Alone or Combined with Clarithromycin or Rifampin Against Staphylococcus aureus and S. epidermidis in a Novel In Vitro PK\/PD Model of Bacterial Biofilm","volume":"4","author":"Vidaillac","year":"2015","journal-title":"Infect. Dis. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hidalgo-Tenorio, C., Pitto-Robles, I., Arn\u00e9s Garc\u00eda, D., De Novales, F., Morata, L., Mendez, R., De Pablo, O., L\u00f3pez De Medrano, V., Lleti, M., and Vizcarra, P. (2023). Cefto Real-Life Study: Real-World Data on the Use of Ceftobiprole in a Multicenter Spanish Cohort. Antibiotics, 12.","DOI":"10.20944\/preprints202306.1477.v1"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5576","DOI":"10.1128\/AAC.02681-14","article-title":"Comparative Efficacies of Cloxacillin-Daptomycin and the Standard Cloxacillin-Rifampin Therapies against an Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus","volume":"58","author":"Murillo","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e03726-22","DOI":"10.1128\/spectrum.03726-22","article-title":"Synergistic Combinations of FDA-Approved Drugs with Ceftobiprole against Methicillin-Resistant Staphylococcus aureus","volume":"11","author":"Sharma","year":"2023","journal-title":"Microbiol. Spectr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4497","DOI":"10.1128\/AAC.00386-15","article-title":"Evaluation of Ceftaroline Alone and in Combination against Biofilm-Producing Methicillin-Resistant Staphylococcus aureus with Reduced Susceptibility to Daptomycin and Vancomycin in an In Vitro Pharmacokinetic\/Pharmacodynamic Model","volume":"59","author":"Barber","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.5194\/jbji-7-11-2022","article-title":"Local Antibiotic Treatment with Calcium Sulfate as Carrier Material Improves the Outcome of Debridement, Antibiotics, and Implant Retention Procedures for Periprosthetic Joint Infections after Hip Arthroplasty\u2014A Retrospective Study","volume":"7","author":"Reinisch","year":"2022","journal-title":"J. Bone Jt. Infect."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"38","DOI":"10.7150\/jbji.17234","article-title":"Ceramic Biocomposites as Biodegradable Antibiotic Carriers in the Treatment of Bone Infections","volume":"2","author":"Ferguson","year":"2017","journal-title":"J. Bone Jt. Infect."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e01879-21","DOI":"10.1128\/AAC.01879-21","article-title":"Phage Activity against Planktonic and Biofilm Staphylococcus aureus Periprosthetic Joint Infection Isolates","volume":"66","author":"Totten","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e144","DOI":"10.1093\/cid\/ciaa705","article-title":"Phage Therapy for Limb-Threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-Biofilm Activity","volume":"73","author":"Cano","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_23","unstructured":"Clinical and Laboratory Standards Institute (CLSI) (2022). Performance Standards for Antimicrobial Susceptibility Testing, Clinical and Laboratory Standards Institute. [32nd ed.]."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1128\/JCM.37.6.1771-1776.1999","article-title":"The Calgary Biofilm Device: New Technology for Rapid Determination of Antibiotic Susceptibilities of Bacterial Biofilms","volume":"37","author":"Ceri","year":"1999","journal-title":"J. Clin. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1093\/jac\/dku151","article-title":"Activity of Colistin Combined with Doripenem at Clinically Relevant Concentrations Against Multidrug-Resistant Pseudomonas Aeruginosa in an In Vitro Dynamic Biofilm Model","volume":"69","author":"Murillo","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1093\/jac\/15.suppl_A.125","article-title":"In-Vitro Model for Simultaneous Simulation of the Serum Kinetics of Two Drugs with Different Half-Lives","volume":"15","author":"Blaser","year":"1985","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_27","unstructured":"Onaghise, O. (2020). Pharmaceutical Microbiology Manual, Food and Drug Administration Office of Regulatory Affairs."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/14\/4\/386\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:11:00Z","timestamp":1760029860000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/14\/4\/386"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,5]]},"references-count":27,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["antibiotics14040386"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics14040386","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,5]]}}}