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Osteomyelitis-relevant antibiotics at clinical concentrations show limited effectivity against acute and chronic intracellular S. aureus infections in osteocytes

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dc.contributor.authorZelmer, A.R.
dc.contributor.authorYang, D.
dc.contributor.authorGunn, N.J.
dc.contributor.authorSolomon, L.B.
dc.contributor.authorNelson, R.
dc.contributor.authorKidd, S.P.
dc.contributor.authorRichter, K.
dc.contributor.authorAtkins, G.J.
dc.contributor.editorde Jonge, B.L.
dc.date.issued2024
dc.description.abstractOsteomyelitis caused by Staphylococcus aureus can involve the persistent infection of osteocytes. We sought to determine if current clinically utilized antibiotics were capable of clearing an intracellular osteocyte S. aureus infection. Rifampicin, vancomycin, levofloxacin, ofloxacin, amoxicillin, oxacillin, doxycycline, linezolid, gentamicin, and tigecycline were assessed for their minimum inhibitory concentration (MIC) and minimum bactericidal concentrations against 12 S. aureus strains, at pH 5.0 and 7.2 to mimic lysosomal and cytoplasmic environments, respectively. Those antibiotics whose bone estimated achievable concentration was commonly above their respective MIC for the strains tested were further assayed in a human osteocyte infection model under acute and chronic conditions. Osteocyte-like cells were treated at 1×, 4×, and 10× the MIC for 1 and 7 days following infection (acute model), or at 15 and 21 days of infection (chronic model). The intracellular effectivity of each antibiotic was measured in terms of CFU reduction, small colony variant formation, and bacterial mRNA expression change. Only rifampicin, levofloxacin, and linezolid reduced intracellular CFU numbers significantly in the acute model. Consistent with the transition to a non-culturable state, few if any CFU could be recovered from the chronic model. However, no treatment in either model reduced the quantity of bacterial mRNA or prevented non-culturable bacteria from returning to a culturable state. These findings indicate that S. aureus adapts phenotypically during intracellular infection of osteocytes, adopting a reversible quiescent state that is protected against antibiotics, even at 10× their MIC. Thus, new therapeutic approaches are necessary to cure S. aureus intracellular infections in osteomyelitis.
dc.description.statementofresponsibilityAnja R. Zelmer, Dongqing Yang, Nicholas J. Gunn, L. Bogdan Solomon, Renjy Nelson, Stephen P. Kidd, Katharina Richter, Gerald J. Atkins
dc.identifier.citationAntimicrobial Agents and Chemotherapy, 2024; 68(10):0080824-1-0080824-14
dc.identifier.doi10.1128/aac.00808-24
dc.identifier.issn0066-4804
dc.identifier.issn0066-4804
dc.identifier.orcidZelmer, A.R. [0000-0003-2684-5637]
dc.identifier.orcidYang, D. [0000-0002-5471-6288] [0000-0002-5765-9370]
dc.identifier.orcidSolomon, L.B. [0000-0001-6254-2372]
dc.identifier.orcidNelson, R. [0000-0002-2051-5998]
dc.identifier.orcidKidd, S.P. [0000-0002-2118-1651]
dc.identifier.orcidRichter, K. [0000-0003-2979-8215]
dc.identifier.orcidAtkins, G.J. [0000-0002-3123-9861]
dc.identifier.urihttps://hdl.handle.net/2440/143658
dc.language.isoen
dc.publisherAmerican Society for Microbiology
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2011042
dc.rights© 2024 American Society for Microbiology. All Rights Reserved.
dc.source.urihttp://dx.doi.org/10.1128/aac.00808-24
dc.subjectintracellular S. aureus infection; chronic osteomyelitis; intracellular antibiotic treatment
dc.subject.meshOsteocytes
dc.subject.meshHumans
dc.subject.meshStaphylococcus aureus
dc.subject.meshStaphylococcal Infections
dc.subject.meshOsteomyelitis
dc.subject.meshOxacillin
dc.subject.meshAmoxicillin
dc.subject.meshOfloxacin
dc.subject.meshRifampin
dc.subject.meshDoxycycline
dc.subject.meshVancomycin
dc.subject.meshGentamicins
dc.subject.meshAnti-Bacterial Agents
dc.subject.meshMicrobial Sensitivity Tests
dc.subject.meshLevofloxacin
dc.subject.meshLinezolid
dc.subject.meshTigecycline
dc.titleOsteomyelitis-relevant antibiotics at clinical concentrations show limited effectivity against acute and chronic intracellular S. aureus infections in osteocytes
dc.typeJournal article
pubs.publication-statusPublished

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