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Cited by 47Syphilis Diagnosis and TreatmentHistorical Medical Research and TreatmentsAntibiotics Pharmacokinetics and Efficacy

Efficacy of linezolid on Treponema pallidum, the syphilis agent: A preclinical study

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Haynes, Austin M., Giacani, Lorenzo, Mayans, Marti Vall, Ubals, Maria, Nieto, Carles, Pérez-Mañá, Clara, Quintó, Llorenç, Romeis, Emily +1 more·2021·EBioMedicine
DOI 10.1016/j.ebiom.2021.103281PMC PMC7973135
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Abstract

BACKGROUND: Penicillin G, the current standard treatment for syphilis, has important drawbacks, but virtually no preclinical or clinical studies have been performed to identify viable alternatives. We tested, both in vitro and in vivo, three marketed antibiotics with adequate pharmacological properties to treat syphilis. METHODS: We used an in vitro culturing system of T. pallidum to perform drug susceptibility testing and applied quantitative PCR targeting the tp0574 gene to measure bacterial growth. To confirm in vivo efficacy, fifteen rabbits were infected intradermally with T. pallidum at eight sites each and randomly allocated to an experimental treatment (linezolid, moxifloxacin, clofazimine) or a control arm (benzathine penicillin G [BPG], untreated). The primary outcome was treatment efficacy defined as the time to lesion healing measured from the date of treatment start. Secondary outcomes were absence of treponemes or treponemal mRNA in injection sites, absence of seroconversion, and cerebrospinal fluid (CSF) abnormalities and negative rabbit infectivity tests (RIT). FINDINGS: Linezolid showed in vitro bactericidal activity at concentrations of 0.5 µg/mL or higher. When administered orally to experimentally infected rabbits, it induced healing of early lesions at a time similar to BPG (hazard ratio 3.84; 95% CI 2.05-7.17; p < 0.0001 compared to untreated controls). In linezolid-treated animals, dark-field microscopy and qPCR assessment showed no presence of treponemes after day 3 post-treatment start, serologic test did not convert to positive, CSF had no abnormalities, and RIT was negative. Moxifloxacin and clofazimine failed to inhibit bacterial growth in vitro and could not cure the infection in the rabbit model. INTERPRETATION: Linezolid, a low-cost oxazolidinone, has in vitro and in vivo activity against T. pallidum, with efficacy similar to BPG in treating treponemal lesions in the animal model. Our findings warrant further research to assess the efficacy of linezolid as an alternative to penicillin G to treat syphilis in human clinical trials. FUNDING: European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 850450).

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Authors
Haynes, A. M., Giacani, L., Mayans, M. V., Ubals, M., Nieto, C., Pérez-Mañá, C., Quintó, L., Romeis, E., & Mitjà, O.
Affiliations
  • University of Washington (US)
  • Manhiça Health Research Centre (MZ)
Corresponding author
Giacani, Lorenzo
ORCID
Venue
EBioMedicine
Publisher
Elsevier BV
Published
2021-03
Volume
65
Pages
103281
ISSN
2352-3964 (ISSN-L)
DOI
10.1016/j.ebiom.2021.103281
PMC
PMC7973135
OpenAlex
W3137927043
Cited by
47
References
2
Citations by year
2026: 11 · 2025: 11 · 2024: 11 · 2023: 10 · 2022: 1 · 2021: 3
FWCI
3.93
Type
journal article
Language
en
Open access
Licence
Locations
  • EBioMedicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
European Research Council
Topics
  • Health Sciences › Medicine › Physiology › Syphilis Diagnosis and Treatment
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Historical Medical Research and Treatments
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Keywords
linezolid, Treponema pallidum, syphilis, oxazolidinones, moxifloxacin, clofazimine, benzathine penicillin G, antibiotic susceptibility, rabbit model, seroconversion, cerebrospinal fluid abnormalities, drug repurposing
MeSH terms
Linezolid, Moxifloxacin, Animals, Clofazimine, Disease Models, Animal, Drug Evaluation, Preclinical, Male, Microbial Sensitivity Tests, Penicillin G Benzathine, Rabbits, ROC Curve, Syphilis, Treponema pallidum, Area Under Curve

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