Treponematoses Therapy

@article{nokey,

title = {Evaluation of Dual Path Platform optical density in relation to RPR titers and serological response in syphilis: a cross-sectional and longitudinal study},

author = {Buezo, Sara and Escrig-Sarreta, Roser and Ouchi, Dan; {(…)} and Mitjà, Oriol},

doi = {10.1016/j.ijid.2026.109106},

year  = {2026},

date = {2026-09-06},

urldate = {2026-09-06},

journal = {International Journal of Infectious Diseases },

abstract = {The Dual Path Platform (DPP) detects treponemal and lipoidal antibodies at the point of care, with an automated reader generating quantitative optical density (OD) values. We assessed the association between DPP OD and RPR titers and post-treatment DPP OD trajectories according to serological cure.

Methods: We conducted an observational study comprising cross-sectional and longitudinal analyses. The cross-sectional analysis assessed the association between DPP OD and RPR titers in anonymized serum samples. The longitudinal analysis assessed post-treatment changes in DPP OD according to RPR-based serological cure.

Results: The cross-sectional analysis included 1,222 samples. DPP OD increased with RPR titer, with a quadratic model showing attenuation of the increase at higher titers. Differences between consecutive RPR categories were significant through 1:64 but not at higher titers, with substantial overlap between categories. The longitudinal analysis included 118 participants. Mean DPP OD declined from 89.1 at baseline to 32.4 at week 12, 20.8 at week 24, and 17.0 at week 48. DPP OD declined after treatment in cases with serological cure and increased during recurrent RPR increases.

Conclusions: DPP OD was quantitatively associated with RPR titer and longitudinal changes reflected RPR-based serological response, supporting further evaluation as a complementary approach for treatment monitoring. },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokeyh,

title = {High increase of Nichols-like clade circulating Treponema pallidum subsp. pallidum in Barcelona from 2021 to 2023},

author = {Patricia Nadal-Barón and Jesús Trejo-Zahinos and Maider Arando and Alicia Barberan-Masegosa and Marta Bernat-Sole and Arantxa (…) Pérez-Ugarte and Yannick. Hoyos-Mallecot},

doi = {10.1038/s41598-024-74355-y},

year  = {2024},

date = {2024-10-08},

urldate = {2024-10-08},

journal = {SCIENTIFIC REPORTS},

volume = {14},

issue = {1},

abstract = {Worldwide, more than 90% of contemporary syphilis strains belong to SS14-like clade. This study aimed to describe the molecular profile of circulating Treponema pallidum subsp. pallidum (TPA) strains in Barcelona, Spain, from 2021 to 2023 building upon our report in 2015 which showed that 94.8% of typed strains belonged to the SS14 clade. Multilocus sequence typing (MLST) was conducted on TPA-positive samples obtained from swab samples by sequencing the tp0136, tp0548, and tp0705 loci. Strains were classified as Nichols-like or SS14-like clade. Macrolide and tetracycline resistance‑associated mutations were determined through analysis of 23S rDNA and 16S rRNA gene sequences. Of the 96 typeable samples, 47.9% belonged to SS14-like and 52.1% to the Nichols-like. Fourteen haplotypes were identified, with ST26 representing 43.8% of the samples, distributed across 11 haplotypes in the SS14-like and 3 haplotypes in the Nichols-like. All the samples showed macrolide resistance-associated mutations, while none exhibited tetracycline-associated mutations. Our findings revealed a substantial shift in the proportion of TPA clades within the Barcelona population from 2021 to 2023, characterized by a higher proportion of Nichols-like strains compared to 2015 and international trends. The varying temporal and geographical trends underscore the need for regular surveillance to understand regional variations in syphilis and strengthen control programs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokeym,

title = {Oral linezolid compared with benzathine penicillin G for treatment of early syphilis in adults (Trep-AB Study) in Spain: a prospective, open-label, non-inferiority, randomised controlled trial},

author = {Maria Ubals and Patricia Nadal-Barón and Maider Arando and Angel Rivero and Adrià Mendoza and Victor (…) Descalzo Jorro and Oriol. Mitjà},

doi = {10.1016/S1473-3099(23)00683-7},

year  = {2024},

date = {2024-04-02},

urldate = {2024-04-02},

journal = {The Lancet Infectious Diseases},

volume = {24},

issue = {4},

pages = {404-416},

abstract = {Background 

Management of syphilis, a sexually transmitted infection (STI) with increasing incidence, is challenged by drug shortages, scarcity of randomised trial data, an absence of non-penicillin alternatives for pregnant women with penicillin allergy (other than desensitisation), extended parenteral administration for neurosyphilis and congenital syphilis, and macrolide resistance. Linezolid was shown to be active against Treponema pallidum, the causative agent of syphilis, in vitro and in the rabbit model. We aimed to assess the efficacy of linezolid for treating early syphilis in adults compared with the standard of care benzathine penicillin G (BPG). 

Methods 

We did a multicentre, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid for treating early syphilis compared with BPG. We recruited participants with serological or molecular confirmation of syphilis (either primary, secondary, or early latent) at one STI unit in a public hospital and two STI community clinics in Catalonia (Spain). Participants were randomly allocated in a 1:1 ratio using a computer-generated block randomisation list with six participants per block, to receive either oral linezolid (600 mg once per day for 5 days) or intramuscular BPG (single dose of 2·4 million international units) and were assessed for signs and symptoms (once per week until week 6 and at week 12, week 24, and week 48) and reagin titres of non-treponemal antibodies (week 12, week 24, and week 48). The primary endpoint was treatment response, assessed using a composite endpoint that included clinical response, serological response, and absence of relapse. Clinical response was assessed at 2 weeks for primary syphilis and at 6 weeks for secondary syphilis following treatment initiation. Serological cure was defined as a four-fold decline in rapid plasma reagin titre or seroreversion at any of the 12-week, 24-week, or 48-week timepoints. The absence of relapse was defined as the presence of different molecular sequence types of T pallidum in recurrent syphilis. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference in rates of treatment response was higher than –10%. The primary analysis was done in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05069974) and was stopped for futility after interim analysis. 

Findings Between Oct 20, 2021, and Sept 15, 2022, 62 patients were assessed for eligibility, and 59 were randomly assigned to linezolid (n=29) or BPG (n=30). In the per-protocol population, after 48 weeks' follow-up, 19 (70%) of 27 participants (95% CI 49·8 to 86·2) in the linezolid group had responded to treatment and 28 (100%) of 28 participants (87·7 to 100·0) in the BPG group (treatment difference –29·6, 95% CI –50·5 to –8·8), which did not meet the non-inferiority criterion. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (five [17%] of 29, 95% CI 5·8 to 35·8 in the linezolid group vs five [17%] of 30, 5·6 to 34·7, in the BPG group). No serious adverse events were reported during follow-up. 

Interpretation 

The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis.},

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pubstate = {published},

tppubtype = {article}

}

@article{nokeyr,

title = {Antimicrobial susceptibility of Treponema pallidum subspecies pallidum: an in-vitro study},

author = {Lauren Tantalo and Nicole Lieberman and Clara Perez-Mañà and Clara Suñer and Martí Vall-Mayans and Maria Ubals and Oriol (…) Mitjà},

doi = {10.1016/S2666-5247(23)00219-7},

year  = {2023},

date = {2023-12-04},

urldate = {2023-12-04},

journal = {The Lancet Microbe},

volume = {4},

issue = {12},

abstract = {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.},

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pubstate = {published},

tppubtype = {article}

}

@article{NIETO2023SUBCUT,

title = {Syphilis vaccine: challenges, controversies and opportunities},

author = {Carlos Ávila-Nieto and Núria Pedreño-Lopez and Oriol Mitjà and Bonaventura Clotet and Julà Blanco and Jorge Carrillo},

doi = {https://doi.org/10.3389/fimmu.2023.1126170},

year  = {2023},

date = {2023-01-01},

journal = {Frontiers in Immunology},

volume = {14},

abstract = {Syphilis is a sexually or vertically (mother to fetus) transmitted disease caused by the infection of Treponema pallidum subspecie pallidum (TPA). The incidence of syphilis has increased over the past years despite the fact that this bacterium is an obligate human pathogen, the infection route is well known, and the disease can be successfully treated with penicillin. As complementary measures to preventive campaigns and early treatment of infected individuals, development of a syphilis vaccine may be crucial for controlling disease spread and/or severity, particularly in countries where the effectiveness of the aforementioned measures is limited. In the last century, several vaccine prototypes have been tested in preclinical studies, mainly in rabbits. While none of them provided protection against infection, some prototypes prevented bacteria from disseminating to distal organs, attenuated lesion development, and accelerated their healing. In spite of these promising results, there is still some controversy regarding the identification of vaccine candidates and the characteristics of a syphilis-protective immune response. In this review, we describe what is known about TPA immune response, and the main mechanisms used by this pathogen to evade it. Moreover, we emphasize the importance of integrating this knowledge, in conjunction with the characterization of outer membrane proteins (OMPs), to expedite the development of a syphilis vaccine that can protect against TPA infection.},

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pubstate = {published},

tppubtype = {article}

}

@article{MITJA2023100737,

title = {Treatment of bacterial sexually transmitted infections in Europe: gonorrhoea, Mycoplasma genitalium, and syphilis},

author = {Oriol Mitjà and Clara Suñer and Lorenzo Giacani and Martí Vall-Mayans and George-Sorin Tiplica and Jonathan D. C. Ross and Catriona S. Bradshaw},

doi = {https://doi.org/10.1016/j.lanepe.2023.100737},

issn = {2666-7762},

year  = {2023},

date = {2023-01-01},

journal = {The Lancet Regional Health - Europe},

volume = {34},

pages = {100737},

abstract = {This review explores the therapeutic challenges of sexually transmitted infections (STI) in Europe, which include increasing antimicrobial resistance and limited progress in drug discovery. We primarily focus on gonorrhoea, Mycoplasma genitalium, and syphilis infections. For gonorrhoea with escalating resistance rates we explore the possibility of combining ceftriaxone with another antibiotic or using alternative antibiotics to mitigate resistance emergence, and we provide insights on the ongoing evaluation of new antimicrobials, like gepotidacin and zoliflodacin. In the case of M. genitalium, which exhibits high resistance rates to first and second-line treatments, we emphasize the importance of resistance-guided therapy in regions with elevated resistance levels, and highlight the limited alternative options, such as pristinamycin and minocycline. Furthermore, we address the challenges posed by syphilis, where the primary treatment consists of penicillin or doxycycline, with challenges arising in neurosyphilis, allergy, pregnancy, and supply shortages and discuss the ongoing evaluation of alternative antimicrobials (e.g., ceftriaxone, cefixime, linezolid). Our findings identify priority actions and provide concrete solutions for long-term effective management of STIs and antimicrobial resistance mitigation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{GOKENGIN2023100738,

title = {Prevention strategies for sexually transmitted infections, HIV, and viral hepatitis in Europe},

author = {Deniz Gökengin and Teymur Noori and Andrea Alemany and Carlo Bienkowski and Geoffroy Liegon and Ahmet Çağkan (…) İnkaya and Jean-Michel. Molina},

doi = {https://doi.org/10.1016/j.lanepe.2023.100738},

issn = {2666-7762},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {The Lancet Regional Health - Europe},

volume = {34},

pages = {100738},

abstract = {The current prevention efforts for STIs, HIV and viral hepatitis in the WHO European Region, especially in the Central and Eastern subregions, are hindered by healthcare disparities, data gaps, and limited resources. In this comprehensive narrative review, we aim to highlight both achievements and persisting challenges while also exploring new developments that could significantly impact the prevention of these infections in the near future. While pre-exposure prophylaxis (PrEP) for HIV has been broadly approved and implemented in 38 out of 53 countries in the region, challenges remain, including cost, limited licensing, and incomplete adherence. We explore innovative approaches like on-demand PrEP, long-acting injectable cabotegravir, and intravaginal rings that have shown promising results, alongside the use of six-monthly lenacapavir, the outcomes of which are pending. Additionally, the potential of doxycycline post-exposure prophylaxis has been discussed, revealing efficacy in reducing chlamydia and syphilis risk, but effectiveness against gonorrhoea being contingent on tetracycline resistance rates, and the need of further data to determine potential resistance development in other bacteria and its impact on the gut microbiome. We examine successful vaccination campaigns against HBV and HPV, the ongoing development of vaccines for chlamydia, syphilis, herpesvirus, and gonorrhoea, and challenges in HIV vaccine research, including lines of research with significant potential like sequential immunization, T-cell responses, and mRNA technology. This review underscores the research endeavors that pave the way for a more resilient and robust approach to combating STIs, HIV, and viral hepatitis in the region.},

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pubstate = {published},

tppubtype = {article}

}

@article{MITJA2023100742,

title = {Epidemiology and determinants of reemerging bacterial sexually transmitted infections (STIs) and emerging STIs in Europe},

author = {Oriol Mitjà and Valeska Padovese and Cinta Folch and Isotta Rossoni and Michael Marks and Miquel Angel (…) Rodríguez Arias and Jordi. Casabona},

doi = {https://doi.org/10.1016/j.lanepe.2023.100742},

issn = {2666-7762},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {The Lancet Regional Health - Europe},

volume = {34},

pages = {100742},

abstract = {In this scoping review, we offer a comprehensive understanding of the current and recent epidemiology, challenges, and emerging issues related to bacterial sexually transmitted infections (STIs) in the WHO European Region. We endeavour in collating data from both EU/EEA and non- EU/EEA countries, thereby giving a complete picture of the region which highlights the higher notification rates in Northern and Western countries than other regions, likely due to differences in testing, access to testing, and surveillance capacity. We provide an up-to-date review on the current knowledge of determinants and persistent inequities in key populations as well as the use of molecular epidemiology for identifying transmission networks in gonorrhoea and syphilis, and detecting chlamydia mutations that evade molecular diagnosis. Finally, we explore the emerging STIs in the region and the evolving transmission routes of food and waterborne diseases into sexual transmission. Our findings call for harmonized STI surveillance systems, proactive strategies, and policies to address social factors, and staying vigilant for emerging STIs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Fernandez2021,

title = {Multilocus sequence typing of Treponema pallidum subsp. pallidum in Barcelona},

author = {Candela Fernández-Naval and Maider Arando and Mateu Espasa and Andrés Antón and Miguel Fernández-Huerta and Aroa (…) Juliana Esperalba. Silgado},

doi = {https://doi.org/10.2217/fmb-2021-0037},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Future Microbiology},

volume = {16},

number = {13},

pages = {967-976},

abstract = {Aim: To implement the multilocus sequence typing (MLST) methodology in syphilis samples previously characterized by enhanced CDC typing (ECDCT) and macrolide resistance. Materials & methods: MLST was performed on genital ulcer and blood samples by analyzing a region of the tp0136, tp0548 and tp0705 loci using Sanger sequencing. Results: Up to 59/85 (69.4%) of genital ulcer and 4/39 (10.3%) of whole blood samples were fully typed. The most frequent profiles were 1.3.1 (56%) and 1.1.1 (11%). All the 1.3.1 samples typed carried the A2058G mutation, responsible for macrolide resistance. MLST and ECDCT showed similar overall typing yields. Conclusion: Several allelic profiles of T. pallidum subsp. pallidum were identified and classified into two major genetic clades in Barcelona. Our results were similar to that described in Europe.},

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pubstate = {published},

tppubtype = {article}

}

@article{Haynes2021,

title = {Efficacy of linezolid on Treponema pallidum, the syphilis agent: A preclinical study},

author = {Austin M. Haynes and Lorenzo Giacani and Marti Vall Mayans and Maria Ubals and Carles Nieto and Clara Pérez-Mañá and Llorenç Quintó and Emily Romeis and Oriol Mitjà},

doi = {10.1016/j.ebiom.2021.103281},

issn = {2352-3964},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {EBioMedicine},

volume = {65},

publisher = {Elsevier},

abstract = {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 textitin vitro and textitin vivo, three marketed antibiotics with adequate pharmacological properties to treat syphilis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Hoyos-Mallecotsextrans-2020-054779,

title = {Drassanes Exprés: a public and confidential testing service for asymptomatic STIs with same-day result notification},

author = {Yannick Hoyos-Mallecot and Jorge Nestor Garcia and Elena Sulleiro and Juliana Esperalba and Paula Salmeron and Francesc (…) Zarzuela and Mateu. Espasa},

doi = {10.1136/sextrans-2020-054779},

issn = {1368-4973},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Sexually Transmitted Infections},

publisher = {The Medical Society for the Study of Venereal Disease},

abstract = {Background STIs are a major public health concern. Screening programmes for asymptomatic users are key components of STI control. Traditional limitations of screening programmes include low population coverage and delays in treatments, thus reducing the expected impact on STI control. In our centre, the normal time from test to results was 4 days, and 7 days until treatment was established.To reduce time to treatment and to increase population coverage, we developed ‘Drassanes Exprés’, a testing service for asymptomatic STIs. The objectives of this study were to provide a guide for the implementation of a service with these characteristics and to evaluate the results of this intervention.Methods The Drassanes Exprés programme was launched in Spain on 07 November 2016 as a public, confidential and free-of-charge testing service for asymptomatic STIs, with same-day result notification. For this walk-in service, confidentiality was obtained by registering all information into the Laboratory Internal Software instead of the Electronic Patient Records. Samples were processed in a point-of-care laboratory and result notification was provided via mail or short message service.Information about workflow, screening protocols and result interpretation is detailed. Additionally, demographic characteristics, STI prevalence, and time from patients’ sample collection to notification and treatment are analysed.Results Between 07 November 2016 and 07 November 2019, 13 993 users attended the Drassanes Exprés screening programme. Of these, 0.5% were transgender people, 29.3% women, 45.2% men who have sex with men and 25.1% men who have sex with women. The median age was 31 years (range: 26–39 years). Overall, 14.6% of users tested positive for at least one STI. The most prevalent infection was Chlamydia trachomatis (8.3%), followed by Neisseria gonorrhoeae (5.7%), syphilis (1.8%), HIV (0.4%) and hepatitis C virus (0.2%). The median time from test to results was 2.4 hours (range: 2–3.1 hours). Of 2049 users diagnosed with an STI, treatment was achieved in 97.0% of cases; the average time to treatment was 2.0 days.Conclusions Drassanes Exprés is the first public programme for rapid, asymptomatic, STI screening and treatment in Spain. Assessing high-risk practices and providing confidentiality, easy access and rapid results/treatments are key elements in the development of STI screening programmes.Data are available upon reasonable request. All data relevant to the study are included in the article, however more detailed protocols are available upon request.},

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}