The Persistent Parasite: Diagnosis and Treatment of Resistant Trichomonas vaginalis Infection

Trichomonas vaginalis affects 5.3% of women globally.¹ It is associated with multiple adverse outcomes including pelvic inflammatory disease, infertility, HIV/STI acquisition/transmission, cervical cancer, and adverse birth outcomes.¹ 5-nitroimidazoles (metronidazole [MTZ], tinidazole [TDZ], secnidazole [SEC]) are the only drug class approved for treatment.² MTZ became available in 1960, with reports of drug resistance emerging two years later.¹ TDZ and SEC drug resistant cases have also been published.¹ Diagnosing and treating resistant T. vaginalis is challenging, particularly during pregnancy.

There are no population-based data on the prevalence of 5-nitroimidazole drug resistance, with most data coming from case studies, case series, and small observational studies. Resistance prevalence ranges from 2-10% among diverse populations.¹ However, the criteria used to define resistance across studies varies, limiting the ability for comparisons. Additionally, most studies are over a decade old. Updated 5-nitroimidazole resistance data among clinical T. vaginalis isolates are needed.

5-nitroimidazole resistance mechanisms in T. vaginalis are complex. These include altered enzymatic drug activation, modifications in metabolic functions of the parasite, and drug deactivation by coexisting vaginal microbes such as T. vaginalis virus and Mycoplasma hominis.³

Drug resistance should be considered when a patient has persistent T. vaginalis infection despite initial adequate treatment and re-infection from untreated sexual partner(s) has been ruled out.⁴ Currently, diagnosis of drug-resistant T. vaginalis infection is largely clinical, identified when patients have repeat positive testing after treatment. Drug resistance can be assessed in the laboratory by growing a clinical T. vaginalis isolate in Diamond’s media, adding serially diluted drug concentrations, and incubating the specimen under aerobic conditions.³ The lowest concentration of drug in which no motile trichomonads are observed defines the minimal lethal concentration (MLC). MLC cut-offs for MTZ, TDZ, and SEC drug resistance are shown in Table 1. Although laboratory-based resistance testing can increase the likelihood of cure in some individuals with persistent infection,² it is only available at select locations including the United States Centers for Disease Control and Prevention (CDC). A testing kit can be obtained by contacting the CDC Parasitology Lab at 1-404-718-4175 or parasiteslab@cdc.gov. Resistance testing is not yet available in the United Kingdom however the STI Reference Laboratory in England is beginning the validation process.

Table 1:

Minimal lethal concentration (MLC) cut-offs for 5-nitroimidizole drug resistance in T. vaginalis

5-nitroimidazole drug	T. vaginalis resistance (MLC)	Low-level resistance (MLC)	Moderate-level resistance (MLC)	High-level resistance (MLC)
Metronidazole	≥50 μg/mL	50 μg/mL	100, 200 μg/mL	≥400 μg/mL
Tinidazole	≥6.3 μg/mL	Not described	Not described	Not described
Secnidazole	≥12.5 μg/mL	Not described	Not described	Not described

Management of drug-resistant T. vaginalis infection is difficult and often requires multiple rounds of therapy after initial treatment with a first-line regimen (e.g., oral MTZ 500mg twice daily for 7 days, oral TDZ 2g single dose, oral SEC 2g single dose).² Resistance is relative in some cases, particularly among isolates with low-level resistance,² and higher doses of 5-nitroimidazoles for longer periods of time (e.g., MTZ or TDZ 2g orally twice daily for 7 days) may be sufficient.⁴ Additionally, TDZ and SEC have longer half-lives than MTZ and may be more effective than MTZ in resistant cases.⁴ SEC is approved for T. vaginalis treatment since 2021 but is not yet recommended by any major treatment guidelines.² If patients fail a 7-day regimen of high-dose oral MTZ or TDZ, drug resistance testing is recommended,² in addition to combination therapy with high-dose oral TDZ 2–3g daily in divided doses plus either intravaginal TDZ 500mg twice daily for 14 days or 6.25% intravaginal paromomycin cream 4g nightly for 14 days.⁴ Intravaginal TDZ and paromomycin require compounding and paromomycin can cause vaginal ulceration, limiting its use. Data are limited for several stand-alone non-5-nitroimidazole intravaginal treatments, however, they are not recommended without expert consultation: boric acid, povidone iodine, paromomycin, and furazolidone.⁴

Importantly, neither TDZ nor SEC are recommended in pregnant women with T. vaginalis, limiting treatment to oral MTZ.⁴ Pregnancy-related changes in MTZ metabolism may reduce treatment efficacy, contributing to persistent infection.⁵

In summary, drug-resistant T. vaginalis infections are a major challenge in clinical practice. Expanding the capability for laboratory assessment of drug resistance is essential in improving outcomes. This includes making antimicrobial resistance testing more accessible and investing in the development of molecular tests with the capability of identifying resistance markers. The development of non 5-nitroimidazole treatment options, particularly during pregnancy, should also be prioritized.