Metronidazole-resistant trichomoniasis: Two Canadian cases

Abstract

Metronidazole-resistant trichomoniasis is a health burden for patients, and limited access to susceptibility testing and treatment is a challenge for Canadian clinicians. These cases emphasize the burden of metronidazole resistance in our population. Herein we describe two cases of metronidazole-resistant trichomoniasis. In one case, a patient underwent five courses of therapy to treat a persistent Trichomonas vaginalis infection. International culture and susceptibility testing revealed resistance to metronidazole and susceptibility to tinidazole. The patient was subsequently lost to follow-up. In another case, a patient was treated with six courses of therapy before their infection had cleared. International culture and susceptibility testing indicated resistance to metronidazole and intermediate resistance to tinidazole. In both cases, metronidazole treatment, either alone or in addition to another therapy, was attempted an average of 3.5 times in escalating dose regimens before switching to tinidazole. Tinidazole proved to be an effective second-line therapy when tolerated by the patient. Until susceptibility testing is available in Canada, clinicians should be aware of access to international susceptibility testing of T. vaginalis to appropriately identify metronidazole-resistant cases and make timely and informed decisions regarding treatment.

Introduction

Trichomonas vaginalis is estimated to be the most prevalent non-viral sexually transmitted infection (STI) worldwide (1). Among women aged 15–49 years, the estimated global prevalence of trichomoniasis was 5.3% (95% CI 4.0%–7.2%) in 2016. In comparison, the global prevalence of chlamydia was estimated at 3.8% (3.3%–4.5%), and the global prevalence of gonorrhea was estimated at 0.9% (0.7%–1.1%) in the same year (1). T. vaginalis, a flagellated parasite, most commonly infects the squamous epithelium of the urogenital tract and is a cause of vaginitis and non-gonococcal urethritis. Trichomoniasis may have an impact on a woman’s reproductive health and lead to adverse pregnancy outcomes because it is associated with premature rupture of membranes, pre-term delivery and low birth weight (2). In addition, trichomoniasis has been shown to increase acquisition of human immunodeficiency virus (HIV), herpes simplex virus type 2 (HSV-2) and human papilloma virus (HPV) (3). The only effective therapies for trichomoniasis are the 5-nitroimidazoles such as metronidazole or tinidazole. In Canada, only metronidazole is approved for use. Recommended dosing is either 2 g once orally or 500 mg orally, twice daily for 7 days with higher cure rates reported for the 7-day regimen (4,5). However, the prevalence of metronidazole-resistant T. vaginalis in vitro has been shown to be as high as 9.6% (6). Over time, there has been increasing awareness of metronidazole-resistant trichomoniasis among clinicians. It is not known if this is due to an increase in resistance among trichomonas strains or due to increased susceptibility testing (7).

Although no publications have shown a geographic pattern in metronidazole resistance on a worldwide scale, a study analyzing 560 women from 6 cities in the United States concluded that the prevalence of resistance did not vary significantly by geographical location (8).

Another 5-nitroimidazole derivative, tinidazole, has become especially important for second-line therapy in cases of metronidazole resistance. Although cross-resistance among metronidazole and tinidazole has been reported, a study of 104 T. vaginalis samples found tinidazole to be more effective than metronidazole (9). Furthermore, Sobel and Brown successfully treated 22/24 metronidazole-resistant trichomoniasis cases with high dose oral and intravaginal tinidazole. Two dosing regimens were used: oral tinidazole 500 mg 4 times daily for 14 days with vaginal tinidazole 500 mg twice daily for 14 days (total dose, 42 g), and oral tinidazole 1 g 3 times daily for 14 days with vaginal tinidazole 500 mg 3 times daily for 14 days (total dose, 63 g) (10). Other studies have shown similar results (7,9).

Canadian clinicians face unique challenges in treating persistent or recurring trichomonas infections. First, antimicrobial resistance testing for T. vaginalis is not available in Canada; consequently, some Canadian experts organize culture and susceptibility testing through labs in the United States, but transport of collection kits and specimens may cause delays in diagnosis and treatment. Second, pre-formulated tinidazole is not available in Canada; therefore, only compounded tinidazole can be used. This compounded formulation may come at a considerable cost to the patient, further emphasizing the importance of knowing antimicrobial susceptibilities prior to initiating therapy.

We report two cases of Trichomonas vaginalis vaginitis with confirmed resistance to metronidazole. Patient consent to report case details was obtained.

Case Description

Case 1

In 2014, a 43- to 47-year-old female from Manitoba was diagnosed with a T. vaginalis infection, confirmed by rapid antigen testing (RAT). She was treated with metronidazole (unspecified). Information regarding initial treatment doses, sexual practices of the patient and partner treatment was not reported, as a transition in care providers during later treatment courses resulted in incomplete data. More than 4 weeks later, the patient presented with ongoing symptoms and wet mount confirmed trichomoniasis. The patient was prescribed a second course of metronidazole. Later, results of a Pap test revealed persistent T. vaginalis; however, symptom-status was unspecified. She was treated with a 7-day course of metronidazole (unspecified dose) (see Table 1). The patient returned to a physician and it was determined that the trichomoniasis was ongoing, although diagnostic method was unspecified. The fourth course of treatment given was oral metronidazole 2 g for 5 days (see Table 2). Results of culture and susceptibility testing returned from a lab through an infectious diseases physician in Alabama, USA indicating resistance to metronidazole (minimum lethal concentration [MLC] 50 μg/mL) and susceptibility to tinidazole (MLC 12.5 μg/mL). The patient was then treated with oral tinidazole 2 g once daily for 5 days, which is only available in compounded form from a specialized compounding pharmacy. No test of cure was done to ensure clearance of infection as the patient was lost to follow-up. Patient compliance was high during all treatment courses.

Table 1:

Treatments 1–3

Case	Demographics	Diagnostic method	Treatment 1	Cure	Diagnostic method	Treatment 2	Cure	Diagnostic method	Treatment 3	Cure
1	Sex: Female	Rapid antigen testing	Metronidazole*	–	Wet mount	Metronidazole*	–	Positive on Pap test	Metronidazole* × 7 d	–
	Age: 43–47 y
	Ethnicity: African
	Province: MB
	Comorbidities: unspecified
2	Sex: Female	Nucleic acid amplification test	Metronidazole 500 mg PO BID x 7 d. Partner treated same	–	Rapid antigen testing	Metronidazole 2 g PO once	–	Unknown	Topical clindamycin* x 3 days, metronidazole 500 mg PO BID x 14 d	–
	Age: 33–37 y
	Ethnicity: Indigenous
	Province: SK
	Comorbidities: HTN, substance use, PCOS

^* Dose unspecified

MB = Manitoba, Canada; PO = orally; BID = twice daily; SK = Saskatchewan, Canada; HTN = Hypertension; PCOS = Polycystic ovary syndrome

Table 2:

Treatments 4–6

Case	Diagnostic method	Treatment 4	Cure	Culture & susceptibility (C&S) results	Treatment 5	Cure	C&S results	Treatment 6	Cure
1	Unknown	Metronidazole 2 g PO x 5 d	–	Metronidazole MLC: 50 μg/mL (resistant) and tinidazole MLC: 12.5 μg/mL for (sensitive)	Tinidazole 2 g PO OD x 5 d	Unknown. Patient lost to follow-up
2	Unknown	Tinidazole 2 g PO OD x 7 d. Course not completed, patient intolerance (nausea, fatigue, neuropathy)	–	–	Boric acid 600 mg PV qhs x 14 d	–	Metronidazole MLC: 400 µg/mL (resistant), tinidazole MLC: 50 µg/mL (intermediate resistance). CDC recommends high dose tinidazole. Boric acid trialled at higher dose due to tinidazole intolerance	Boric acid 600 mg PV BID x 28 d	Yes. NAAT negative

^*Dose unspecified

C&S = culture & sensitivity; PO = orally; OD = once daily; PV = vaginally; BID = twice daily; MLC = Minimum lethal concentration; CDC = Centers for Disease Control and Prevention; NAAT = Nucleic acid amplification testing

Case 2

In 2017, a 33- to 37-year-old female from Saskatchewan was diagnosed with a T. vaginalis infection. This was confirmed by nucleic acid amplification testing (NAAT). She was originally treated with oral metronidazole 500 mg twice daily for 7 days. Sexual partner(s) were also treated. The patient initially became asymptomatic, but then returned 3–4 weeks later with recurring symptoms and was treated with metronidazole 2 g orally once after confirmation with RAT. One to two weeks later, the patient had ongoing symptoms. Trichomonas infection was confirmed, although the diagnostic method was unspecified. She received topical clindamycin (dose unspecified) for 3 days and oral metronidazole 500 mg twice daily for 14 days. The reason for treatment with clindamycin was not provided. The patient continued to be symptomatic and therefore, treatment with oral tinidazole 2 g once daily for 7 days was initiated from a specialized compounding pharmacy. Due to drug intolerance including nausea, fatigue and neuropathy, the patient was unable to complete the course. A fifth course of therapy was then trialled with boric acid. Dosing was 600 mg vaginally, every night at bedtime for 14 days. The patient’s culture and susceptibility results returned from the Centers for Disease Control and Prevention (CDC) in the United States and revealed resistance to metronidazole (MLC 400 µg/mL) and intermediate resistance to tinidazole (MLC 50 µg/mL). The CDC recommended high-dose oral tinidazole 1 g 3 times daily for 14 days and paromomycin PV (dose unspecified). The patient’s symptoms relapsed at which point the CDC recommended boric acid 600 mg vaginally, twice daily for 28 days due to intolerance to tinidazole. After completing this sixth course of treatment, follow-up NAAT testing was negative. Patient compliance was high during all treatment courses. Data regarding sexual practices of the patient were not available. It is also unknown if the patient’s partner received more than one treatment dose.

Discussion

As described in these cases, metronidazole-resistant trichomoniasis is a challenge for patients and providers alike. In both cases, metronidazole therapy was attempted either alone or in addition to other therapies an average of 3.5 times in escalating dose regimens before attempting tinidazole therapy. Metronidazole therapy dosing was often not reported, which limits the ability to determine the effectiveness of the therapy. In cases where dosing was specified, the dose met or exceeded the suggestions made by the Canadian guidelines on STIs (4). Culture and susceptibility testing was often delayed, presumably owing to the difficulty in accessing these tests within Canada. Treatment delay has potential consequences for a patient because untreated trichomonas vaginitis may impact quality of life as well as increase an individual’s risk of acquiring and transmitting STIs including HIV, HSV-2, and HPV (3). Additionally, multiple courses of therapy result in increased physician office visits and can be costly to the patient and the health care system. In these cases, culture and susceptibility testing proved to be useful as it confirmed that metronidazole was not effective and guided management toward other therapies such as tinidazole and boric acid. Non-metronidazole therapies in particular are difficult to access and are often only available through special access programs or compounding pharmacies, often coming at a considerable financial cost to the patient.

In patients with T. vaginalis vaginitis, who appear to fail standard treatment and in whom re-infection has been ruled out or is unlikely, the possibility of metronidazole resistance should be considered. While Canada does not have access to such testing, the US CDC has generously provided access to Canadian clinicians, which can be organized through local laboratories. In the spirit of “choosing wisely,” susceptibility testing is important to appropriately identify metronidazole-resistant trichomoniasis cases and direct appropriate treatment early in the treatment course. This would minimize the number of visits and the number of unnecessary exposures to antimicrobials required to achieve cure. Moreover, improved understanding of the burden of resistant trichomonas in Canada may expedite evaluation of second-line therapies such as tinidazole and boric acid which would be an initial step toward improved access to these therapies for Canadian patients. Finally, these cases demonstrate that metronidazole-resistant trichomoniasis has been identified in multiple Canadian provinces. Given that trichomoniasis is a transmissible infection that affects patient health, appropriate recognition, and treatment of resistant strains of trichomonas is an important public health measure.

Conclusion

Metronidazole-resistant trichomoniasis is a burden for Canadian patients. Until susceptibility testing is available in Canada, clinicians should be aware of access to international susceptibility testing to make timely and informed decisions regarding treatment. Commercially available pre-formulated tinidazole would provide Canadian patients and clinicians with access to a broader range of therapies. Overall, T. vaginalis is a risk to our patients’ health and ensuring that we are treating it appropriately is a priority.

Ethics Approval:

These two cases are part of a larger series. The University of Manitoba review board approved this study [HREB HS22813(H2019:176)].

Informed Consent:

Informed consent was received from the patients.

Funding:

No funding was received for this work.

Disclosures:

The authors have nothing to disclose.

Peer Review:

This manuscript has been peer reviewed.

ANIMAL STUDIES:

N/A