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 center dot 02 mg/L, ceftriaxone at 0 center dot 0025 mg/L, cephalexin at 0 center dot 25 mg/L, cefetamet and cefixime at 0 center dot 0313 mg/L, cefuroxime at 0 center dot 0156 mg/L, tedizolid at 0 center dot 0625 mg/L, spectinomycin at 0 center dot 1 mg/L, and dalbavancin at 0 center dot 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.
[1]Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA USA.
[2]Univ Washington, Dept Lab Med & Pathol, Seattle, WA USA.
[3]Hosp Badalona Germans Trias & Pujol, Inst Recerca Germans Trias & Pujol, Clin Pharmacol Unit, Badalona, Spain.
[4]Univ Autonoma Barcelona, Dept Pharmacol Therapeut & Toxicol, Barcelona, Spain.
[5]Hosp Badalona Germans Trias & Pujol, Fight Infect Dis Fdn, Sexually Transmitted Infect & Skin Neglected Trop, Barcelona, Spain.
[6]Univ Cent Catalunya, Univ Vic, Vic, Spain.
[7]Univ Basque Country UPV EHU, Fac Pharm, Pharmacokinet Nanotechnol & Gene Therapy Grp Pharm, Vitoria, Spain.
[8]Bioaraba Microbiol Infect Dis Antimicrobial Agents, Vitoria, Spain.
[9]Araba Univ Hosp, Microbiol Serv, Osakidetza Basque Hlth Serv, Vitoria, Spain.
[10]Univ Valencia, Joint Res Unit Infect & Publ Hlth FISABIO, Valencia, Spain.
[11]Univ Valencia, Inst Integrat Syst Biol, CSIC, Paterna, Spain.
[12]CIBER Epidemiol & Publ Hlth, Madrid, Spain.
[13]Innoviva Specialty Therapeut, Waltham, MA USA.
[14]Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA USA.
[15]Univ Papua New Guinea, Sch Med & Hlth Sci, Port Moresby, Papua N Guinea.
[16]Univ Washington, Dept Global Hlth, Seattle, WA 98104 USA.
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