Successful Treatment of Persistent 5-Nitroimidazole–Resistant Trichomoniasis With an Extended Course of Oral Secnidazole Plus Intravaginal Boric Acid

Abstract

We describe a case of persistent 5-nitroimidazole–resistant trichomoniasis cured after 14 days of oral secnidazole and intravaginal boric acid. Secnidazole may be an important treatment option for resistant trichomoniasis, particularly in women who fail other regimens, including higher doses of oral metronidazole and tinidazole for longer durations of time.

In Brief

A woman with 5-nitroimidazole–resistant trichomoniasis was cured with a 14-day course of oral secnidazole and intravaginal boric acid after failing multiple treatment regimens for 30 months.

Trichomoniasis is a highly prevalent, nonviral sexually transmitted infection, affecting ~156 million people worldwide¹ and 3.7 million in the United States.² If not treated, trichomoniasis can lead to vaginitis, cervicitis, pelvic inflammatory disease, cervical cancer, and infertility in women.^3–5 Untreated trichomoniasis also can lead to adverse birth outcomes, including preterm birth, premature rupture of membranes, and low birth weight.^6,7 In men and women, it can also increase the risk for HIV and other sexually transmitted infections.^2,3,8

The 5-nitroimidazoles, metronidazole (MTZ) and tinidazole (TDZ), have been standard therapies for Trichomonas vaginalis for 40 years. Drug resistance associated with persistent trichomoniasis is problematic because of a lack of proven alternatives. We describe a case of persistent 5-nitroimidazole–resistant trichomoniasis successfully treated with an extended course of oral secnidazole (SEC) in combination with intravaginal boric acid. Secnidazole was approved by the US Food and Drug Administration for trichomoniasis treatment in women and men in 2021.⁹

A 33-year-old woman with polycystic ovarian syndrome, menorrhagia, iron deficiency anemia, and hyperlipidemia developed symptomatic (vaginal discharge and pruritus) persistent trichomoniasis. She had 1 sexual encounter 3 months before her diagnosis and no sexual activity since. She informed her partner of the diagnosis and the need for treatment; however, information on her partner's subsequent infection status or treatment was not available. Over the next 30 months, she failed 4 courses of oral MTZ at varying doses and durations, 5 courses of oral TDZ at varying doses and durations, and a 14-day course of high-dose, oral TDZ with intravaginal paromomycin (4 g of 6.25% intravaginal paromomycin cream nightly; Table 1). Latter attempts with oral MTZ and TDZ were combined with intravaginal boric acid. Treatment failures were confirmed by repeat positive wet mount and/or InPouch culture, which were readily available on site (Table 1). Drug susceptibility testing on her T. vaginalis isolate was originally performed at the Centers for Disease Control and Prevention (CDC) after she had received 6 courses of treatment. Test results revealed 5-nitroimidazole resistance to MTZ and TDZ. Minimum lethal concentrations (MLCs) of the isolate to MTZ and TDZ were 400 μg/mL (high-level resistance¹³) and 200 μg/mL (MLCs ≥25 μg/mL are considered resistant [E. Secor, CDC, personal communication]), respectively. Sixteen months later, after the patient received 5 additional treatment courses (Table 1), T. vaginalis susceptibility testing was repeated at the University of Alabama at Birmingham, which also included SEC resistance testing. Minimum lethal concentrations for MTZ, TDZ, and SEC were 400, 25, and 100 μg/mL, respectively.

TABLE 1 - Chronological Order of Treatments and Test Results

Date (MM/DD/YY)	Treatment	Duration, d	Test	Result
08/26/19	MTZ 2 g po	1	Wet mount	Trich+, many WBC, clue cells−
10/07/19	MTZ 2 g po	1	Wet mount	Trich+, moderate WBC, clue cells−
10/23/19	TDZ 1 g po once daily	2
11/07/19	TDZ 2 g po once daily	7	Wet mount	Trich+, many WBC, clue cells−
11/25/19	TDZ 2 g po once daily	7
12/12/19			Wet mount	Trich+, moderate WBC, clue cells−
01/07/20	TDZ 2 g po once daily	7	Culture	Trich+
01/29/20*			Wet mount	Trich+, rare WBC, clue cells−
03/05/20			Susceptibility testing results from trichomonas culture sent to the CDC	MLCs: MTZ 400 μg/mL, TDZ 200 μg/mL
07/22/20†	TDZ 1 g po TID + intravaginal paromomycin 4 g of 6.25% cream qhs	14
07/31/20			Culture (urine)‡	Trich− (17% sensitivity; urine NAAT not performed)‡
08/21/20	Intravaginal boric acid 600 mg bid§		Wet mount, culture	Wet mount: Trich+, negative WBC, clue cells− Culture: Trich+
09/28/20	Nitazoxanide 1 g po bid	14
10/24/20			Wet mount	Trich+, rare WBC, clue cells−
11/17/20	MTZ 2 g po once then 500 mg po bid	7
01/29/21	Intravaginal boric acid 600 mg bid	Ongoing¶	Culture	Trich+
02/01/21			Culture	Trich+
06/02/21			Wet mount, culture	Wet mount: Trich+, rare WBC, clue cells− Culture: Trich+
07/29/21			Susceptibility testing results from trichomonas culture at UAB	MLCs: MTZ 400 μg/mL, TDZ 25 μg/mL, SEC 100 μg/mL
01/11/22	MTZ 500 mg po bid	7	Wet mount‡	Trich−, few WBC, clue cells+
01/24/22			Trich NAAT	Trich+
02/24/22	SEC 2 g po + intravaginal boric acid 600 mg bid	14	Wet mount, culture	Wet mount: Trich−, few WBC, clue cells− Culture: Trich+
04/07/22∥			Wet mount, culture	Wet mount: Trich−, rare WBC, clue cells− Culture: Trich−
04/07/22∥			Trich NAAT	Trich−

*Initial infectious disease clinic appointment.

^†This date is approximate; the patient reported finishing the treatment course in the first part of August. The patient was having trouble getting intravaginal paromomycin because of cost, and there was a significant delay in starting this regimen.

^‡Suspected false negative as the patient continued to test positive for trichomonas multiple times afterward; sensitivity of vaginal wet mount for trichomonas is relatively low (44%–68%^10,11), as is sensitivity of trichomonas culture for urine specimens (centrifuged urine yielded a sensitivity of only 17% vs. culture of self-collected vaginal swabs in one study).¹²

^§The CDC was contacted for expert advice. Compounded formulation of intravaginal boric acid initially was prescribed; however, the patient was only able to obtain for a short period of time because of cost and had to switch to a noncompounded, commercial formulation.

^¶For symptom control.

^∥Test of cure after investigational treatment.

MLCs indicates minimum lethal concentrations; MTZ, metronidazole; NAAT, nucleic acid amplification test; qhs, every night at bedtime; SEC, secnidazole; TDZ, tinidazole; UAB, University of Alabama at Birmingham; WBC, white blood cells.

A single-patient, investigator-initiated protocol was developed to attempt treatment with a 14-day course of oral SEC 2 g once daily combined with intravaginal boric acid 600 mg bid. An extended course of SEC was used instead of a single 2-g dose given that the MLC of the T. vaginalis isolate to SEC was 100 μg/mL.¹⁴ This protocol was approved by the institutional review board of Wake Forest University Health Sciences. The patient provided written informed consent before any study-related activities were conducted. Physical examination, serum chemistries (i.e., electrolytes, glucose, blood urea nitrogen, creatinine, total protein, albumin, total bilirubin, liver enzymes), and complete blood count were performed at baseline. All results were within normal limits with the exception of glucose, which was slightly elevated (120 mg/dL) after nonfasted testing. The patient was counseled to take SEC per the product label (granules sprinkled over applesauce, yogurt, or pudding and swallowed without chewing within 30 minutes) for 14 days. Concomitant intravaginal boric acid was applied as a 600-mg suppository bid. Based on the results of previous studies, bid dosing was used to achieve optimal concentrations of intravaginal boric acid to achieve cure.^15,16 It is important to note that a compounded formulation of intravaginal boric acid 600 mg bid had been prescribed almost 1 year before the oral SEC protocol (Table 1); however, the patient only was able to obtain this formulation for a short period because of cost. She had switched to a noncompounded store-purchased commercial formulation, although she was not consistent with this treatment until the SEC treatment protocol started. The patient was counseled to avoid unprotected sexual intercourse during the study period.

Four weeks after the end of the SEC plus intravaginal boric acid treatment protocol, the patient was seen and reported successful completion of the investigational regimen. Her vaginal discharge and pruritus resolved completely. A test of cure was performed using vaginal wet mount, T. vaginalis culture, and a nucleic acid amplification test per protocol. All yielded negative results. Physical examination, serum chemistries, and complete blood count were repeated and notable only for known preexisting anemia. Serum chemistries were monitored out of an abundance of caution because of the investigative nature of the extended dosing regimen of SEC. She reported dysgeusia while on therapy, which resolved after therapy was completed.

Recently updated guidelines from the American College of Gynecologists and Obstetricians³ and CDC² recommend MTZ 500 mg orally bid for 7 days for all women with trichomoniasis. In the setting of persistent infection after treatment with the 7-day multidose oral MTZ regimen (and treatment noncompliance or reinfection from untreated sexual partner(s) have been ruled out), treatment with 2-g oral MTZ or TDZ once daily for 7 days is recommended.² If a patient fails this regimen, 2 additional options are recommended: (1) high-dose oral TDZ 2 to 3 g in divided doses plus paromomycin 4 g of 6.25% intravaginal cream nightly, both for 14 days, or (2) high-dose oral TDZ 2 to 3 g in divided doses plus intravaginal TDZ 500 mg bid, both for 14 days.²T. vaginalis drug resistance is relative rather than absolute and may be overcome with higher doses of drug for longer periods of time.¹⁷ Unfortunately, the patient failed the 7-day 500-mg oral MTZ, 7-day 2-g oral MTZ, 2-g oral TDZ, and high-dose oral TDZ with intravaginal paromomycin cream regimens. Thus, an alternative treatment option was needed.

Since the publication of the updated American College of Gynecologists and Obstetricians³ and CDC guidelines,² a single 2-g oral dose of SEC also has been US Food and Drug Administration approved for the treatment of trichomoniasis in women and men.⁹ Although SEC is not yet included in national treatment guidelines for trichomoniasis, it may be a valuable added treatment option based on its excellent efficacy and safety profile. Moreover, SEC is the only oral single-dose treatment option for bacterial vaginosis and trichomoniasis in women. As a single-dose oral treatment, SEC provides greater drug exposure than MTZ (7–8 hours) or TDZ (12–13 hours), owing to its longer half-life (17–19 hours). This may eliminate problems with nonadherence to multidose regimens. Data on the use of SEC in cases of persistent trichomonas infections are limited; to our knowledge, this is the first report of successful treatment of persistent drug-resistant trichomoniasis with multidose oral SEC in combination with intravaginal boric acid.

There is little precedent for extended durations of SEC for persistent/resistant T. vaginalis infections; however, there is an abundance of experience using multiday courses of other 5-nitroimidazoles (i.e., MTZ, TDZ).^18–20 Daily dosing of SEC would not be considered excessively frequent based on its pharmacokinetics profile. Daily dosing of SEC was selected for this patient to maintain therapeutic concentrations over the dosing interval without excessive accumulation. Relative to its half-life (17–19 hours), daily dosing of SEC is consistent with the recommended dosing intervals for other 5-nitroimidazoles. For instance, the half-life of MTZ is 7 to 8 hours, and MTZ is approved for dosing as often as every 6 hours.²¹

Drug resistance to 5-nitroimidazoles, particularly MTZ, in T. vaginalis was documented as early as 1962.²²T. vaginalis isolates with MTZ MLCs ≤25 μg/mL are considered susceptible. Isolates with MLCs of 50, 100 to 200, and ≥400 μg/mL have low-, moderate-, and high-level MTZ resistance, respectively.^13,23 Tinidazole isolates with MLCs <25 μg/mL are considered susceptible, whereas isolates with higher MLCs are considered resistant (E. Secor, CDC, personal communication). An interesting finding here was the reduced TDZ MLC observed after repeat T. vaginalis isolate susceptibility testing 16 months later. During most of 2021, after multiple failed treatments, the patient was maintained intermittently on intravaginal boric acid alone for symptom control (Table 1). It is possible some reversion to TDZ susceptibility occurred in the absence of selective TDZ drug pressure during that time,²⁴ or she was reinfected with a different strain of T. vaginalis. The latter is unlikely given that she denied any type of sexual intercourse after initial diagnosis of infection.

Prevalence estimates of resistance in T. vaginalis have previously ranged from 2.2% to 9.6% for MTZ and 0% to 2% for TDZ,^13,23 although updated estimates are needed. Compared with MTZ and TDZ, there are minimal data on SEC resistance in T. vaginalis. In one in vitro analysis of T. vaginalis isolates from 100 women, the mean (SD) MLCs for SEC and MTZ were 5.9 (13.2) and 13.5 (26.9) μg/mL.¹⁴ The median MLC for SEC was significantly lower versus MTZ (1.6 vs. 6.3 μg/mL).¹⁴ Rates of low-level resistance to SEC and MTZ were 4% and 7%, and no isolate showed moderate- or high-level resistance to SEC compared with 1% of isolates that showed moderate resistance to MTZ. These data suggest that SEC is more potent against T. vaginalis than MTZ. This is likely the best explanation for the success of multidose oral SEC in combination with intravaginal boric acid in our patient after failing several multidose 5-nitroimidazole regimens with MTZ and TDZ.

Intravaginal boric acid bid (as a compounded formulation) has been successful for trichomoniasis treatment in women with severe hypersensitivity reactions to 5-nitroimidazoles.¹⁶ The mechanism by which boric acid eradicates T. vaginalis is not well understood, although it may create a more acidic environment within the vaginal mucosa that may inactivate factors contributing to the pathogenicity of T. vaginalis, such as cell detaching factor, which is known to be acid labile.^25–27 However, compounded intravaginal boric acid was used consistently for up to 60 days in some reports.¹⁶ In our patient, it is unclear whether co-administration of commercial intravaginal boric acid with SEC for the 14-day treatment course contributed to treatment success.

This case demonstrates that multidose oral SEC may have an important role in the treatment of persistent trichomoniasis, perhaps in combination with intravaginal boric acid, particularly when patients fail other treatment regimens, including various combinations of oral MTZ and TDZ with intravaginal preparations. Additional in vivo data on clinical outcomes of multidose oral SEC treatment in the setting of 5-nitroimidazole resistance are needed.