Syphilis Relapse Still a Challenge Despite Treatments
(Recurrence requires intensified therapies and continuous research)
Recurrence of syphilis persists as a tough clinical problem, even following standard treatments. Factors such as immune status and treatment approaches affect the percentage of patients experiencing relapse.
Key Development
Relapses appearing early, within two years post-infection, often show as recurrent skin lesions, enlarged lymph nodes, and neuro-ophthalmic symptoms, like headaches or blurred vision. According to a study by the CDC, relapse rates are higher among those with compromised immunity or those who do not complete their treatment. For definitive diagnosis, doctors integrate serological evaluations like TPPA/TPHA and RPR/VDRL with clinical assessments to tell true relapse from reinfection.
Pathogenesis Factors
Several elements fuel the pathogenesis of relapse. One is that Treponema pallidum can survive in places where antibiotics don’t penetrate well, such as the central nervous system (CNS). Host immune dysregulation, especially driven by HIV, also impairs how well the body clears bacteria. Furthermore, antimicrobial resistance and high-risk sexual activity contribute to relapse-like situations or treatment failure.
Recommendations
Current guidelines emphasize risk-based treatment plans. Intensified regimens are specifically recommended for recurrent early syphilis, according to the CDC’s 2021 Sexually Transmitted Infections Treatment Guidelines. For those with recurrent secondary syphilis, the standard approach involves weekly intramuscular injections of 2.4 million units of benzathine penicillin G for three weeks. The WHO also promotes enhanced therapy for high-risk recurrences.
Treatment for Neuroinvasive Relapse
Neuroinvasive relapse requires intravenous aqueous penicillin G at 18–24 million units daily for 10–14 days for enough concentration in cerebrospinal fluid. A ceftriaxone regimen (2 g daily intravenously for 10–14 days) is recommended for penicillin-allergic patients with neurosyphilis.
Research Models
Preclinical models are essential in clarifying relapse mechanisms. Rabbit infection models accurately mimic chancre progression and reactivation of latent infections. Humanized mouse models have revealed how T. pallidum avoids immune responses.
Etiology and Epidemiology
Syphilis, caused by Treponema pallidum subsp. pallidum, is a systemic infection with a preference for neural and mucocutaneous tissues. Globally, the WHO estimates 7.1 million new syphilis cases each year, with higher rates in sub-Saharan Africa and South Asia. Transmission mainly occurs via sexual contact; however, vertical transmission, blood exposure, and iatrogenic routes also account for minor proportions. Contemporary data shows that China has over 500,000 cases annually, the highest incidence of bacterial STIs nationally.
Epidemiological Patterns
Figures from Tokyo (2019–2022) showed male predominance, where the male-to-female ratio was 3.8:1. Men who have sex with men (MSM) accounted for 62% of cases, showing the impact of high-risk sexual networks.
Definition of Recurrence
Recurrence is defined as the return of clinical or serological activity after proper antimicrobial therapy. Diagnostic criteria include reappearance of lesions, a fourfold increase in nontreponemal antibody titers, and exclusion of reinfection via molecular typing and partner tracing.
Clinical Presentation
Recurrent syphilis involves multiple systems with different phenotypic patterns. Primary recurrence often shows as painless genital or anal ulcers. Secondary recurrence presents as a generalized copper-red rash, often on the palms and soles, accompanied by lymphadenopathy. Neurologic issues, such as meningitis and cranial nerve palsies, may also occur.
Factors Influencing Recurrence
Recurrence is influenced by host-pathogen interactions. Risk factors include insufficient penicillin dosage, nonadherence to therapy, and bacterial persistence in immune-protected areas. Immunocompromised individuals, including those with HIV, have impaired pathogen clearance. Behavioral factors, like unprotected sex and multiple partners, increase reinfection risk. Antimicrobial resistance also plays a key role.
Treatment Strategies
Management of recurrent syphilis requires stage-specific antimicrobial regimens tailored to the host’s immunity and antibiotic resistance patterns. Penicillin-based regimens are first-line treatments.
Specific Regimens
The typical regimen for late syphilis and secondary recurrent syphilis involves 2.4 million units of intramuscular BPG weekly for 3 weeks. For neurosyphilis, intravenous aqueous penicillin G (18–24 million units daily for 10–14 days) is standard.
Alternative Therapies
For penicillin-allergic patients with neurosyphilis, ceftriaxone (2 g daily intravenously or intramuscularly for 10–14 days) is a recommended alternative. Doxycycline (100 mg orally twice daily for 30 days) can be used for non-pregnant, penicillin-allergic patients with late or recurrent syphilis, but requires close monitoring. Macrolides like azithromycin are contraindicated in areas with high resistance.
Management
Comprehensive management involves appropriate antibiotics and structured serological surveillance. For late latent syphilis, extended BPG regimens (3 weekly doses) are advised. For late recurrent syphilis, BPG 2.4 million units weekly for 3 weeks remains standard. Post-treatment surveillance includes quantitative nontreponemal testing at 6, 12, and 24 months.
Preclinical Models
Preclinical models are crucial for studying clinical strategies. Animal models, like rabbits, and in vitro culture systems are used.
Rabbit Models
Rabbits are highly susceptible to Treponema pallidum. Infections in rabbits mirror human infections, therefore, rabbits make great study subjects. Clinical symptoms, pathological changes, and serological responses are monitored to assess infection progression and treatment efficacy.
Mouse Model
The mouse model is cost-effective and reproducible. A syphilis infection model in C57BL/6 mice allows evaluation of colonization, dissemination, and immune responses.
In vitro Systems
In vitro culture systems help investigate Treponema pallidum biology and drug susceptibility. Recent advancements have enabled continuous in vitro growth using co-culture systems with cottontail rabbit epithelial cells.
Model Characteristics
The choice of preclinical model depends on the research question, resources, and ethics. In vitro models are simple and cost-effective. Animal models are pivotal for studying infection dynamics and immunity. Tissue culture models help study host-pathogen interactions. Bioinformatics-driven models identify therapeutic targets.
Applications of Preclinical Models
Preclinical models enhance diagnostic methods, assess new therapies, study pathogenesis, validate vaccine development, and inform public health policies. They enable validation of NAAT accuracy, assessment of antibiotic effectiveness, and investigation of immune evasion.
Limitations
Model organisms often differ from humans; in vitro cultivation of Treponema pallidum is difficult; and vaccine development faces many challenges. Ethical considerations and the difficulty of clinical translation also pose challenges.
Future Research
Future investigations should prioritize multifaceted approaches to advance global syphilis prevention and control. Critical research directions must focus on elucidating the mechanisms of relapse, refining therapeutic protocols, developing novel diagnostic modalities, and enhancing public health interventions. According to a 2023 study in the journal PLOS Pathogens, using genomic sequencing could help to personalize treatments and track the spread of antibiotic-resistant strains.
Data, Ethics, and Funding
The study confirmed that ethical approval and informed consent were waived since no humans or animals were part of the study. There was no funding to report, and the author declares no competing interests.
