Mechanisms of drug resistance to T. vaginalis

Trichomonas vaginalis is the most common non-viral sexually transmitted infection in the world, yet drug resistance varies, according to a systematic literature review in the journal Parasitology.

The two specific drugs in the class of 5-nitroimidazoles approved by the US Food and Drug Administration to treat T. vaginalis are metronidazole and tinidazole, drugs that are structurally similar.

Resistance to metronidazole is between 2.2% and 9.6%, whereas tinidazole resistance is only 0% to 2%. But the true prevalence of this resistance is not known because trichomoniasis is not currently a nationally reportable disease.

“T. vaginalis disproportionately affects African Americans and is associated with increased risk of HIV acquisition, adverse birth outcomes, infertility and other adverse reproductive morbidities,” said co-author Jan Novak, MSc, PhD, a professor of microbiology at the University of Alabama at Birmingham.

For the literature review, the authors searched PubMed, ScienceDirect and Embase for English language articles on drug resistance, with 58 articles for inclusion.

The most surprising finding is that despite the first observation of metronidazole resistance in 1960s, shortly after the drug became available, “we still do not fully understand the mechanisms of this resistance,” Dr. Novak said.

“In addition, some T. vaginalis isolates are clinically more resistant than others with similar MLC values to metronidazole for unknown reasons.” The infection-causing T. vaginalishas two genotypes, with greater resistance seen in type 2 than type 1 populations.

T. vaginalis isolates exhibiting minimal lethal concentrations (MLCs) ≤25 μg/mL are considered metronidazole-sensitive. “An MLC of 50 μg/mL represents low-level resistance, MLCs of 100 to 200 μg/mL moderate-level resistance and MLCs ≥400 μg/mL high-level resistance,” Dr. Novak told Contemporary OB/GYN.

Metronidazole resistance observed clinically “is usually due to aerobic resistance that is facilitated by altered expression of enzymes involved in energy production and free-radical scavenging enzymes or ‘oxygen scavenging’ within the trichomonads,” he said.

“Specifically, increased intracellular oxygen concentrations, due to deficient oxygen scavenging, enable development of aerobic resistance.”

Dr. Novak said clinical treatment failure due to metronidazole may be more of a function of drug tolerance rather than developed drug resistance. “T. vaginalis isolates unresponsive to current recommended doses of metronidazole can often be treated by increasing dosages and duration of treatment,” he said.

Standard treatment of T. vaginalis in the United States is currently a 2-g single dose of oral metronidazole or tinidazole; an alternative regimen is 500 metronidazole mg orally twice daily for 7 days.

“Therapeutic approaches for metronidazole/tinidazole-resistant-trichomoniasis include the use of higher doses of metronidazole/tinidazole, extending the duration of treatment or additional topical intravaginal medications,” Dr. Novak said.

However, because many T. vaginalis cases are difficult to treat, he recommended management in consultation with infectious disease specialists, noting that “significant side effects in patients receiving high-dose therapy are a major limiting factor to favorable outcomes.”

Attaining a more complete understanding of the mechanisms of 5-nitroimidazole resistance in T. vaginalis will potentially allow the development of alternative methods of treatment using medications outside of the 5-nitroimidazole class. Dr. Novak is hopeful that new technologies will provide additional tools and resources for future study of resistance.

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Dr. Novak reports no relevant financial disclosures.

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Reference

1. Graves KJ, Novak J, Secor WE, Kissinger PJ, Schwebke JR, Muzny, CA. A systematic review of the literature on mechanisms of 5-nitroimidazole resistance in Trichomonas vaginalis. Parasitology. Published online July 30, 2020. doi:10.1017/S0031182020001237