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Published on: January 24, 2025
Antimicrobial susceptibility of Treponema pallidum subspecies pallidum: an in-vitro study
Lauren C Tantalo1, Nicole A P Lieberman2, Clara Pérez-Mañá3
1Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA.
Background:
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.
Methods:
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.
Findings:
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.
Interpretation:
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.
Funding:
European Research Council.
Insights
New antibiotics like cephalosporins and oxazolidinones show promise for treating syphilis, especially drug-resistant strains. Further research is needed to confirm their effectiveness in clinical settings.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Syphilis incidence is rising globally.
- Penicillin, the primary treatment, has limitations, particularly for neurosyphilis, neonatal syphilis, and during pregnancy.
- There is an urgent need for alternative antibiotics to manage syphilis effectively.
Purpose of the Study:
- To evaluate the in vitro efficacy of 18 different antibiotics against Treponema pallidum subspecies pallidum (T. pallidum), the causative agent of syphilis.
- To identify potential alternative treatments for syphilis, addressing limitations of current therapies.
Main Methods:
- Utilized an in vitro culture system to expose T. pallidum to a range of concentrations for 18 antibiotics.
- Assessed bacterial burden using quantitative PCR targeting the T. pallidum tp0574 gene after 7 days of incubation.
- Determined Minimum Inhibitory Concentrations (MICs) and investigated resistance development to azithromycin and linezolid.
Main Results:
- Amoxicillin, ceftriaxone, oral cephalosporins (cephalexin, cefetamet, cefixime, cefuroxime), tedizolid, spectinomycin, and dalbavancin demonstrated anti-treponemal activity at clinically relevant concentrations.
- Minimum Inhibitory Concentrations (MICs) were established for active agents, with ceftriaxone showing high potency (0.0025 mg/L).
- Macrolide-resistant strains were unaffected by high azithromycin concentrations, while linezolid did not induce resistance after prolonged exposure.
Conclusions:
- Cephalosporins and oxazolidinones show potential as alternative therapeutic options for syphilis.
- These findings support further investigation, including animal models and clinical trials, to assess the efficacy of these promising antibiotics.
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