{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T23:31:19Z","timestamp":1793662279378,"version":"4.5.1"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"Korea government (MSIT)","doi-asserted-by":"publisher","award":["2020R1F1A1067794"],"award-info":[{"award-number":["2020R1F1A1067794"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background: Treatment of device-related infections by drug-resistant Staphylococcus aureus can be challenging, and combination therapy has been proposed as a potential solution. We compared the effectiveness of levofloxacin\u2013rifampin and ciprofloxacin\u2013rifampin combinations in killing methicillin-resistant S. aureus (MRSA) using a time\u2013kill assay. Methods: We randomly selected 15 vancomycin-susceptible S. aureus (VSSA) strains, 3 vancomycin-intermediate S. aureus (VISA) strains, and 12 heterogeneous VISA (hVISA) strains from the Asian Bacterial Bank. Time\u2013kill experiments were performed in duplicate for each isolate. Viable bacterial counts were determined at 0 h, 4 h, 8 h, and 24 h for the ciprofloxacin\u2013 and levofloxacin\u2013rifampin combinations at 1\u00d7 MIC and 0.5\u00d7 MIC. We compared synergistic and antagonistic interactions between the two combinations. Results: The viable bacterial count significantly decreased after 24 h of exposure to ciprofloxacin\u2013rifampin and levofloxacin\u2013rifampin combinations, with synergy observed more frequently in isolates exposed to ciprofloxacin\u2013rifampin (43.3%) than levofloxacin\u2013rifampin (20.0%) (p = 0.0082). The synergistic interactions of both combinations were more frequently observed in resistant strains with high MICs of ciprofloxacin (\u226516 mg\/L) and levofloxacin (\u22658 mg\/L). Levofloxacin tended to exhibit more frequent antagonistic interactions with rifampin than ciprofloxacin, although there was no statistical difference in antagonism between the two combinations. Conclusions: Our study demonstrated that ciprofloxacin exhibits superior synergistic activity against MRSA strains, including VISA\/hVISA, when combined with rifampin compared with levofloxacin. High MICs of fluoroquinolones were found to predict synergism. Our results suggest that ciprofloxacin may be a more effective choice than levofloxacin for combination therapy with rifampin in the treatment of MRSA infections.<\/jats:p>","DOI":"10.3390\/antibiotics12040711","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T03:59:55Z","timestamp":1680753595000},"page":"711","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Comparing the Synergistic and Antagonistic Interactions of Ciprofloxacin and Levofloxacin Combined with Rifampin against Drug-Resistant Staphylococcus aureus: A Time\u2013Kill Assay"],"prefix":"10.3390","volume":"12","author":[{"given":"Yu Ri","family":"Kang","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"},{"name":"Asia Pacific Foundation for Infectious Diseases (APFID), Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doo Ryeon","family":"Chung","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"},{"name":"Asia Pacific Foundation for Infectious Diseases (APFID), Seoul 06351, Republic of Korea"},{"name":"Center for Infection Prevention and Control, Samsung Medical Center, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hoon","family":"Ko","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungmin","family":"Huh","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"},{"name":"Asia Pacific Foundation for Infectious Diseases (APFID), Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Young","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"},{"name":"Center for Infection Prevention and Control, Samsung Medical Center, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheol-In","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7464-9780","authenticated-orcid":false,"given":"Kyong Ran","family":"Peck","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1128\/CMR.00042-09","article-title":"Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: Resistance mechanisms, laboratory detection, and clinical implications","volume":"23","author":"Howden","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tuon, F.F., Suss, P.H., Telles, J.P., Dantas, L.R., Borges, N.H., and Ribeiro, V.S.T. (2023). Antimicrobial treatment of Staphylococcus aureus biofilms. Antibiotics, 12.","DOI":"10.3390\/antibiotics12010087"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"i37","DOI":"10.1093\/jac\/dku254","article-title":"Impact of bacterial biofilm on the treatment of prosthetic joint infections","volume":"69","author":"Jacqueline","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"ofac582","DOI":"10.1093\/ofid\/ofac582","article-title":"Adjunctive rifampin following debridement and implant retention for staphylococcal prosthetic joint infection: Is it effective if not combined with a fluoroquinolone?","volume":"9","author":"Hewlett","year":"2022","journal-title":"Open Forum. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1128\/CMR.00034-09","article-title":"Rifampin combination therapy for nonmycobacterial infections","volume":"23","author":"Forrest","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1128\/AAC.34.6.1014","article-title":"Comparative efficacies of ciprofloxacin, pefloxacin, and vancomycin in combination with rifampin in a rat model of methicillin-resistant Staphylococcus aureus chronic osteomyelitis","volume":"34","author":"Dworkin","year":"1990","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1128\/AAC.33.8.1184","article-title":"Ciprofloxacin and rifampin, alone and in combination, for therapy of experimental Staphylococcus aureus endocarditis","volume":"33","author":"Kaatz","year":"1989","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"dlaa114","DOI":"10.1093\/jacamr\/dlaa114","article-title":"Treatment of methicillin-resistant Staphylococcus aureus (MRSA): Updated guidelines from the UK","volume":"3","author":"Brown","year":"2021","journal-title":"JAC Antimicrob. Resist."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1186\/s13018-020-01877-2","article-title":"Rifampin combination therapy in staphylococcal prosthetic joint infections: A randomized controlled trial","volume":"15","author":"Karlsen","year":"2020","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ma, H., Cheng, J., Peng, L., Gao, Y., Zhang, G., and Luo, Z. (2020). Adjunctive rifampin for the treatment of Staphylococcus aureus bacteremia with deep infections: A meta-analysis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0230383"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/S0140-6736(17)32456-X","article-title":"Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): A multicentre, randomised, double-blind, placebo-controlled trial","volume":"391","author":"Thwaites","year":"2018","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1093\/cid\/ciq146","article-title":"Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children","volume":"52","author":"Liu","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e01746-18","DOI":"10.1128\/AAC.01746-18","article-title":"Role of rifampin against staphylococcal biofilm infections in vitro, in animal models, and in orthopedic-device-related infections","volume":"63","author":"Zimmerli","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3681","DOI":"10.1128\/AAC.00458-08","article-title":"Antagonistic effect of rifampin on the efficacy of high-dose levofloxacin in staphylococcal experimental foreign-body infection","volume":"52","author":"Murillo","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e00550-17","DOI":"10.1128\/mSphere.00550-17","article-title":"Convergent evolution driven by rifampin exacerbates the global burden of drug-resistant Staphylococcus aureus","volume":"3","author":"Monk","year":"2018","journal-title":"mSphere"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1007\/s11999-015-4300-3","article-title":"Rifamycin derivatives are effective against staphylococcal biofilms in vitro and elutable from PMMA","volume":"473","author":"Shiels","year":"2015","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.jbspin.2012.09.008","article-title":"Optimizing combination rifampin therapy for staphylococcal osteoarticular infections","volume":"80","author":"Coiffier","year":"2013","journal-title":"Jt. Bone Spine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1111\/j.1469-0691.2005.01230.x","article-title":"Use of rifampicin and ciprofloxacin combination therapy after surgical debridement in the treatment of early manifestation prosthetic joint infections","volume":"11","author":"Berdal","year":"2005","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/S0140-6736(89)91083-0","article-title":"Treatment of right-sided Staphylococcus aureus endocarditis in intravenous drug users with ciprofloxacin and rifampicin","volume":"2","author":"Dworkin","year":"1989","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1093\/cid\/ciab426","article-title":"If, when, and how to use rifampin in acute staphylococcal periprosthetic joint infections, a multicentre observational study","volume":"73","author":"Beldman","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1001\/jama.279.19.1537","article-title":"Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: A randomized controlled trial. Foreign-Body Infection (FBI) Study Group","volume":"279","author":"Zimmerli","year":"1998","journal-title":"JAMA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1007\/s10096-015-2404-z","article-title":"Influence of daily dosage and frequency of administration of rifampicin-levofloxacin therapy on tolerance and effectiveness in 154 patients treated for prosthetic joint infections","volume":"34","author":"Nguyen","year":"2015","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.ijantimicag.2016.05.021","article-title":"Short- versus long- duration levofloxacin plus rifampicin for acute staphylococcal prosthetic joint infection managed with implant retention: A randomised clinical trial","volume":"48","author":"Euba","year":"2016","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ijantimicag.2017.04.011","article-title":"Moxifloxacin plus rifampin as an alternative for levofloxacin plus rifampin in the treatment of a prosthetic joint infection with Staphylococcus aureus","volume":"51","author":"Tornero","year":"2018","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1128\/AAC.43.2.421","article-title":"Comparative activities of clinafloxacin, grepafloxacin, levofloxacin, moxifloxacin, ofloxacin, sparfloxacin, and trovafloxacin and nonquinolones linozelid, quinupristin-dalfopristin, gentamicin, and vancomycin against clinical isolates of ciprofloxacin-resistant and -susceptible Staphylococcus aureus strains","volume":"43","author":"Jones","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1128\/AAC.41.8.1662","article-title":"Levofloxacin versus ciprofloxacin, flucloxacillin, or vancomycin for treatment of experimental endocarditis due to methicillin-susceptible or -resistant Staphylococcus aureus","volume":"41","author":"Entenza","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1128\/AAC.41.6.1293","article-title":"In vitro activities of ciprofloxacin and rifampin alone and in combination against growing and nongrowing strains of methicillin-susceptible and methicillin-resistant Staphylococcus aureus","volume":"41","author":"Bahl","year":"1997","journal-title":"Antimirob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1128\/AAC.43.11.2742","article-title":"Efficacy of levofloxacin for experimental aortic-valve endocarditis in rabbits infected with viridans group streptococcus or Staphylococcus aureus","volume":"43","author":"Chambers","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","unstructured":"(2023, March 30). FDA in Brief: FDA Warns that Fluoroquinolone Antibiotics Can Cause Aortic Aneurysm in Certain Patients, Available online: https:\/\/www.fda.gov\/news-events\/fda-brief\/fda-brief-fda-warns-fluoroquinolone-antibiotics-can-cause-aortic-aneurysm-certain-patients."},{"key":"ref_31","unstructured":"(2023, March 30). Quinolone- and Fluoroquinolone-Containing Medicinal Products. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/referrals\/quinolone-fluoroquinolone-containing-medicinal-products."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"819","DOI":"10.2165\/00003088-200342090-00003","article-title":"Pharmacokinetic interactions with rifampicin: Clinical relevance","volume":"42","author":"Niemi","year":"2003","journal-title":"Clin. Pharmacokinet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"992","DOI":"10.3346\/jkms.2010.25.7.992","article-title":"Bloodstream infections and clinical significance of healthcare-associated bacteremia: A multicenter surveillance study in Korean hospitals","volume":"25","author":"Son","year":"2010","journal-title":"J. Korean Med. Sci."},{"key":"ref_34","unstructured":"Clinical and Laboratory Standards Institute (CLSI) (2019). Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Ninth Informational Supplement M100-S29, CLSI."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1093\/jac\/47.4.399","article-title":"A modified population analysis profile (PAP) method to detect hetero-resistance to vancomycin in Staphylococcus aureus in a UK hospital","volume":"47","author":"Wootton","year":"2001","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1128\/JCM.38.3.1008-1015.2000","article-title":"Multilocus sequence typing for characterization of methicillin-resistant and methicillin-susceptible clones of Staphylococcus aureus","volume":"38","author":"Enright","year":"2000","journal-title":"J. Clin. Microbiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1128\/AAC.46.7.2155-2161.2002","article-title":"Multiplex PCR strategy for rapid identification of structural types and variants of the mec element in methicillin-resistant Staphylococcus aureus","volume":"46","author":"Oliveira","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5442","DOI":"10.1128\/JCM.41.12.5442-5448.2003","article-title":"Typing of methicillin-resistant Staphylococcus aureus in a university hospital setting by using novel software for spa repeat determination and database management","volume":"41","author":"Harmsen","year":"2003","journal-title":"J. Clin. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Garcia, L.S. (2010). Clinical Microbiology Procedures Handbook, American Society of Microbiology. [3rd ed.].","DOI":"10.1128\/9781555817435"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4495","DOI":"10.1128\/AAC.00237-09","article-title":"In vitro 24-h time-kill studies of vancomycin and linezolid in combination versus methicillin-resistant Staphylococcus aureus","volume":"53","author":"Singh","year":"2009","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/4\/711\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:10:55Z","timestamp":1760123455000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/4\/711"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,6]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["antibiotics12040711"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics12040711","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,6]]}}}