Antimicrobial susceptibility of Treponema pallidum subspecies pallidum: an in-vitro study

The increasing incidence of syphilis and the limitations of first-line treatment with penicillin, particularly in neurosyphilis, neonatal syphilis, and pregnancy, highlight the need to expand the therapeutic repertoire for effective management of this disease. We assessed the in-vitro efficacy of 18...

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Published in:The Lancet. Microbe 2023-12, Vol.4 (12), p.e994-e1004
Main Authors: Tantalo, Lauren C, Lieberman, Nicole A P, Pérez-Mañá, Clara, Suñer, Clara, Vall Mayans, Marti, Ubals, Maria, González-Beiras, Camila, Rodríguez-Gascón, Alicia, Canut, Andrés, González-Candelas, Fernando, Mueller, John, Tapia, Kenneth, Greninger, Alexander L, Giacani, Lorenzo, Mitjà, Oriol
Format: Article
Language:English
Subjects:
Amoxicillin - pharmacology
Amoxicillin - therapeutic use
Animals
Anti-Bacterial Agents - pharmacology
Anti-Bacterial Agents - therapeutic use
Azithromycin - pharmacology
Azithromycin - therapeutic use
Ceftriaxone - pharmacology
Ceftriaxone - therapeutic use
Drug Resistance, Bacterial - genetics
Globus Pallidus
Humans
Infant, Newborn
Linezolid - pharmacology
Linezolid - therapeutic use
Macrolides - pharmacology
Macrolides - therapeutic use
Syphilis - drug therapy
Syphilis - epidemiology
Syphilis - microbiology
Treponema
Treponema pallidum - genetics
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Summary:The increasing incidence of syphilis and the limitations of first-line treatment with penicillin, particularly in neurosyphilis, neonatal syphilis, and pregnancy, highlight the need to expand the therapeutic repertoire for effective management of this disease. We assessed the in-vitro efficacy of 18 antibiotics from several classes on Treponema pallidum subspecies pallidum (T pallidum), the syphilis bacteria. Using the in-vitro culture system for T pallidum, we exposed the pathogen to a concentration range of each tested antibiotic. After a 7-day incubation, the treponemal burden was evaluated by quantitative PCR targeting the T pallidum tp0574 gene. The primary outcome was the minimum inhibitory concentration (MIC) at which the quantitative PCR values were not significantly higher than the inoculum wells. We also investigated the susceptibility of macrolide-resistant strains to high concentrations of azithromycin, and the possibility of developing resistance to linezolid, a proposed candidate for syphilis treatment. Amoxicillin, ceftriaxone, several oral cephalosporins, tedizolid, and dalbavancin exhibited anti-treponemal activity at concentrations achievable in human plasma following regular dosing regimens. The experiments revealed a MIC for amoxicillin at 0·02 mg/L, ceftriaxone at 0·0025 mg/L, cephalexin at 0·25 mg/L, cefetamet and cefixime at 0·0313 mg/L, cefuroxime at 0·0156 mg/L, tedizolid at 0·0625 mg/L, spectinomycin at 0·1 mg/L, and dalbavancin at 0·125 mg/L. The MIC for zoliflodacin and balofloxacin was 2 mg/L. Ertapenem, isoniazid, pyrazinamide, and metronidazole had either a poor or no effect. Azithromycin concentrations up to 2 mg/L (64 times the MIC) were ineffective against strains carrying mutations associated to macrolide resistance. Exposure to subtherapeutic doses of linezolid for 10 weeks did not induce phenotypic or genotypic resistance. Cephalosporins and oxazolidinones are potential candidates for expanding the current therapeutic repertoire for syphilis. Our findings warrant testing efficacy in animal models and, if successful, clinical assessment of efficacy. European Research Council.
ISSN:2666-5247
2666-5247
DOI:10.1016/S2666-5247(23)00219-7