{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:35:07Z","timestamp":1790800507469,"version":"4.1.0"},"reference-count":33,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T00:00:00Z","timestamp":1717459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T00:00:00Z","timestamp":1717459200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["NRF-2018R1D1A1B07040831"],"award-info":[{"award-number":["NRF-2018R1D1A1B07040831"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["RS-2023-00246999"],"award-info":[{"award-number":["RS-2023-00246999"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Health and Welfare","award":["HI23C0299"],"award-info":[{"award-number":["HI23C0299"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2024,6,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Methicillin-resistant\n              <jats:italic>Staphylococcus aureus<\/jats:italic>\n              (MRSA) infections are often difficult to treat because of their biofilm-forming ability and antimicrobial resistance. We investigated the effects of sub-minimal inhibitory concentrations (MICs) of antibiotics on MRSA biofilm formation. Clinical MRSA isolates were grown with sub-MICs (1\/256\u20131\/2 \u00d7 MICs) of nafcillin, vancomycin, ciprofloxacin, and rifampin. The biofilm biomass was measured using crystal violet staining. Of the 107 MRSA isolates tested, 63 (58.9%) belonged to sequence type 5 (ST5), and 44 (41.1%) belonged to ST72. The MIC\n              <jats:sub>50<\/jats:sub>\n              \/MIC\n              <jats:sub>90<\/jats:sub>\n              values of nafcillin, vancomycin, ciprofloxacin, and rifampin were 256\/512, 1\/2, 64\/512, and 0.008\/0.03 mg\/L, respectively. The sub-MICs of nafcillin, vancomycin, ciprofloxacin, and rifampin promoted biofilm formation in 75 (70.1%), 49 (45.8%), 89 (83.2%), and 89 (83.2%) isolates, respectively. At sub-MICs of nafcillin, the factors associated with strong biofilm induction were the ST5 strain (\n              <jats:italic>P<\/jats:italic>\n              = 0.001) and\n              <jats:italic>agr<\/jats:italic>\n              dysfunction (\n              <jats:italic>P<\/jats:italic>\n              = 0.005). For the sub-MICs of ciprofloxacin, the associated factors were the ST5 strain (\n              <jats:italic>P<\/jats:italic>\n              = 0.002), staphylococcal protein A type t002 strain (\n              <jats:italic>P<\/jats:italic>\n              &lt; 0.001), and ciprofloxacin resistance (\n              <jats:italic>P<\/jats:italic>\n              &lt; 0.001). Among the sub-MICs of rifampin, only ST5 was associated with strong biofilm induction (\n              <jats:italic>P<\/jats:italic>\n              = 0.006). Because the sub-MICs of rifampin were much lower than clinically relevant concentrations, we further tested the capability of biofilm induction in 0.03\n              <jats:inline-formula>\n                <jats:alternatives>\n                  <jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"spectrum.03412-23.im001.tif\"\/>\n                  <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" display=\"inline\" overflow=\"scroll\">\n                    <mml:mo>-<\/mml:mo>\n                  <\/mml:math>\n                <\/jats:alternatives>\n              <\/jats:inline-formula>\n              32 mg\/L of rifampin. At these concentrations, rifampin-induced biofilm formation was rare in rifampin-susceptible MRSA [1.0% (1 of 100)] but common in rifampin-resistant MRSA [71.4% (5 of 7),\n              <jats:italic>P<\/jats:italic>\n              &lt; 0.001]. Induction of biofilm biomass at sub-MICs of antibiotics is common in clinical MRSA isolates and is differentially affected by the MRSA strain and antibiotic class.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>Bacteria can be exposed to sub-MICs of antibiotics at the beginning and end of a dosing regimen, between doses, or during low-dose therapies. Growing evidence suggests that sub-MICs of antimicrobials can stimulate MRSA biofilm formation and alter the composition of the biofilm matrix. Pevious studies have found that sub-MICs of oxacillin, methicillin, and amoxicillin promote biofilm formation in some community-acquired MRSA (CA-MRSA). We evaluated biofilm induction by sub-MICs of four different classes of antibiotics in 44 CA-MRSA and 63 healthcare-associated MRSA (HA-MRSA) strains. Our study indicated that sub-MICs of nafcillin, vancomycin, ciprofloxacin, and rifampin frequently promote biofilm induction in clinical MRSA isolates. Strong biofilm induction in sub-MICs of nafcillin, ciprofloxacin, and rifampin was more frequent in HA-MRSA than in CA-MRSA. Antibiotic-induced biofilm formation depends on the antibiotic class, MRSA strain, and antibiotic resistance. Our results emphasize the importance of maintaining effective bactericidal concentrations of antibiotics to treat biofilm-related infections.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.03412-23","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T13:01:38Z","timestamp":1713877298000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Effects of sub-inhibitory concentrations of nafcillin, vancomycin, ciprofloxacin, and rifampin on biofilm formation of clinical methicillin-resistant\n            <i>Staphylococcus aureus<\/i>"],"prefix":"10.1128","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4630-1242","authenticated-orcid":false,"given":"Ki-Ho","family":"Park","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University College of Medicine, Kyung Hee University Hospital, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dokyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul, South Korea"},{"name":"Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, South Korea"},{"name":"Center for Converging Humanities, Kyung Hee University, Seoul, South Korea"},{"name":"Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, Graduate School, Kyung Hee University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minji","family":"Jung","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University Hospital, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Youn","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University Hospital, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Mi","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University College of Medicine, Kyung Hee University Hospital, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8951-5032","authenticated-orcid":true,"given":"Mi Suk","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University College of Medicine, Kyung Hee University Hospital, Seoul, South 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