Secnidazole: a treatment for trichomoniasis in adolescents and adults

ABSTRACT

Introduction

Single-dose 2-g oral secnidazole (SEC), newly approved by the U.S. Food and Drug administration (FDA) for treatment of trichomoniasis, is a potent 5-nitroimidazole with selective toxicity against various micro-organisms. It has been used internationally to treat trichomoniasis, bacterial vaginosis, and other infections for decades. Trichomoniasis is the most common non-viral sexually transmitted infection worldwide and is associated with significant morbidity. In comparison to the only other FDA-approved treatments for trichomoniasis in the United States – metronidazole and tinidazole – SEC has favorable pharmacokinetics, including a longer half-life and a lower minimal lethal concentration.

Areas covered

This work summarizes the chemistry and pharmacology of SEC and reviews the evidence on its efficacy, tolerability, and safety for the treatment of trichomoniasis.

Expert opinion

SEC is an efficacious, well tolerated, and safe treatment for patients aged ≥12 years with trichomoniasis. Single-dose administration makes it a favorable treatment option, especially in cases where adherence to multi-dose treatment regimens may be low.

KEYWORDS:

• Trichomoniasis
• Trichomonas vaginalis
• secnidazole
• 5-nitroimidazoles
• metronidazole
• tinidazole
• sexually transmitted infections

1. Introduction

Trichomoniasis is the most prevalent non-viral sexually transmitted infection (STI) worldwide, affecting approximately 156 million people globally, including 5.3% of women and 0.6% of men aged 15–49 years [1] and 3.7 million people in the United States [2]. As a non-reportable STI, reliable prevalence estimates are limited, but a recent population-based epidemiological study found US-based prevalence rates of 2.1% in women and 0.5% in men [3,4]. Significant health disparities exist for T. vaginalis infection: prevalence rates are 9.6% in African American women, 1.4% in Hispanic women, and 0.8% in non-Hispanic White women. Additionally, unlike rates of chlamydia and gonorrhea, T. vaginalis prevalence rates are as high or higher among women aged >24 years as they are for women aged <24 years [5]. Risk factors for trichomoniasis include multiple recent sexual partners and lower socioeconomic status [6]. Women with bacterial vaginosis (BV) have an increased risk for T. vaginalis [7]. Male sexual partners of T. vaginalis-infected women also are likely to be infected [8].

Trichomoniasis is associated with many adverse gynecologic outcomes, including vaginitis, cervicitis, pelvic inflammatory disease, cervical cancer, and infertility [9–11,12,13]. Women with trichomoniasis are also at higher risk for adverse birth outcomes such as preterm birth, premature rupture of membranes, and low birth weight infants [14,15]. Coinfection with BV and T. vaginalis is common [16]. In men, trichomoniasis is associated with epididymitis, non-gonococcal urethritis, and prostatitis [8] and may also lead to infertility [17]. In both men and women, trichomoniasis significantly increases the risk of transmission and acquisition of human immunodeficiency virus (HIV) and other STIs (e.g. chlamydia, gonorrhea, herpes simplex virus, and syphilis) [2,9,18].

As many as 85% of patients with trichomoniasis are asymptomatic [2]. Symptomatic patients generally present with abnormal vaginal discharge, in addition to vaginal and cervical inflammation [2]. Diagnostic testing for trichomoniasis in women seeking care for vaginal discharge is recommended by the Centers for Disease Control and Prevention (CDC). Annual screening for all women with HIV, including those who are pregnant [2] is also recommended. Additionally, annual screening is a consideration for men and women seeking care in high-prevalence settings (e.g. STD clinics and correctional facilities) and for asymptomatic women at high risk for infection (e.g. multiple sexual partners, drug misuse, transactional sex, and/or a history of STIs or incarceration) [2].

Treatment of trichomoniasis is recommended to alleviate symptoms, reduce the risk for adverse reproductive outcomes, and prevent the acquisition and transmission of HIV and other STIs. Recently updated national guidelines published by the American College of Gynecologists and Obstetricians (ACOG) in 2020 and the CDC in 2021 now recommend multi-dose metronidazole (MTZ) 500 mg orally twice daily for 7 days for the treatment of all infected women, although a single, oral dose of MTZ 2-g remains the recommended treatment for men [2,9]. This change in national guideline recommendations in women is based on a recent meta-analysis [19] and clinical trial data [20] in infected women, showing that single-dose MTZ is not as efficacious as is multi-dose MTZ for the treatment of T. vaginalis. However, single-dose MTZ continues to be the recommended regimen for men, as there are no rigorous head-to-head data comparing the 2 MTZ dosing regimens in men. For the first time ever, the recommended treatment for an STI (e.g. T. vaginalis) differs based on gender, which can present unique management challenges [21]. 5-nitroimidazoles (MTZ, tinidazole [TDZ], and secnidazole [SEC]) are the only class of antimicrobial medications known to be effective against T. vaginalis.

Drug resistance to 5-nitroimidazoles, particularly MTZ, in T. vaginalis was documented as early as 1962 [22]. T. vaginalis isolates with minimal lethal concentrations (MLCs) ≤25 μg/mL are MTZ sensitive. In contrast, T. vaginalis isolates with MLCs >50 μg/mL, 100–200 μg/mL, and ≥400 μg/mL have low-level, moderate-level, and high-level resistance, respectively [23].

Prevalence estimates of 5-nitroimidazole resistance in T. vaginalis vary but are higher with MTZ (2.2–9.6%) than TDZ (0–2%) [23,24]. A recent systematic review of the literature on mechanisms of 5-nitroimidazole resistance in T. vaginalis found that resistance can be aerobic or anaerobic [23]. Resistance is relative rather than absolute (i.e. it may be overcome with higher doses of drug for longer periods of time) [23,25]. Resistance is facilitated by altered expression and activation of enzymes and proteins involved in T. vaginalis energy production and oxygen scavenging. T. vaginalis infection with Mycoplasma hominis or T. vaginalis virus also has been associated with resistance [23].

Since publication of updated national guidelines [2], a single, 2-g oral dose of SEC, a second-generation 5-nitroimidazole, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of trichomoniasis in both women and men. This drug offers an additional therapeutic option for T. vaginalis infection with the same dosing regimen in both women and men. It also offers the advantage of single-dose treatment, eliminating issues with non-adherence that could occur when using multi-dose MTZ regimens. SEC is also FDA approved for the treatment of BV, making it an effective, single-dose treatment for concurrent BV and T. vaginalis infections. This review presents an overview of the chemistry, pharmacology, tolerability, safety, efficacy, and drug resistance of SEC for the treatment of trichomoniasis in women and men. It also compares SEC to other 5-nitroimidazoles, MTZ and TDZ, in terms of efficacy, safety, and other attributes. Finally, it outlines unmet therapeutic needs and provides expert commentary on the use of SEC for the treatment of trichomoniasis based on recently updated treatment guidelines.

2. Overview of secnidazole

SEC has been used since the late 1960s [26] to treat various bacterial and parasitic infections in many countries. It was FDA approved in 2017 to treat BV in the US [27,28]. Dating back to 1976, studies have shown that SEC is an effective treatment for trichomoniasis [29]. Recent data have also shown the efficacy of SEC to treat trichomoniasis as well as its safety and favorable pharmacokinetic and pharmacodynamic properties (PK/PD) [30,31].

2.1. Chemistry and microbiology

SEC is in the 5-nitroimidazole class of drugs and is a potent antimicrobial [32]. Structurally, SEC is an analogue of MTZ and TDZ, the other 5-nitroimidazoles used to treat T. vaginalis (Figure 1) [33]. The slight variation in the molecular structure of SEC is likely responsible for its longer half-life compared with MTZ and TDZ [32]. SEC has selective toxicity against numerous anaerobic, Gram-positive, and Gram-negative bacteria as well as protozoa. It enters the pathogen in an inactive form through passive diffusion and is subsequently activated through reduction of the 5-nitroimidazole group by nitroreductase enzymes, ultimately damaging DNA and causing cell death [23, 33–35].

Figure 1. Chemical structure of secnidazole, metronidazole, and tinidazole.

2.2. Pharmacodynamics

As part of the clinical trial program, a thorough phase 1, four-period, crossover study was conducted to evaluate the effect of SEC on the QTc interval. Healthy adults (N = 52) were randomized to four treatment arms: 2-g proposed therapeutic dose, 6-g supratherapeutic dose, placebo, or positive control (moxifloxacin 400 mg) [36]. Results of the study demonstrated that neither dose of SEC caused a clinically meaningful effect on the QTc interval [36].

2.3. Pharmacokinetics and metabolism

In vitro and PK studies showed that the half-life of SEC ranges from 17 to 19 hours [37], which is considerably longer than MTZ (7–8 h) [38] and TDZ (12–13 h) [39]. These studies also demonstrated that the half-life of SEC is longer in men versus women (20 vs 14 h) [39]. Other PK data showed no clinically meaningful differences in SEC exposure (maximum serum concentration and area under the concentration-time curve [AUC]) between men and women [39].

SEC has similar antimicrobial properties compared with other 5-nitroimidazoles. Both SEC and MTZ have equipotent activity against T. vaginalis, as measured by their minimal inhibitory concentration (MIC) and minimal trichomonacidal concentration (MTC) levels [30]. In one study, SEC had a minimal lethal concentration (MLC) 56% lower than that of MTZ against T. vaginalis, suggesting that SEC may be more toxic to this pathogen [30].

The mean peak plasma concentration (C_max) after a SEC 2-g dose is 45.4 mcg/mL. The mean systemic exposure (AUC_0-inf) is 1331.6 mcg•hr/mL. SEC reaches peak plasma concentration (T_max) in 4 hours and remains above the MIC for several days (Figure 2).

Figure 2. A single 2-g oral dose of secnidazole reaches peak plasma concentrations at 4 h, and with its long half-life, remains above the minimum inhibitory concentration for several days as opposed to oral metronidazole 500 mg, which requires repeat dosing. (Adapted from Lupin Pharmaceuticals [data on file] and Ashiq B, et al. 2011 [40]).

SEC can be taken without regard to timing of meals. There was no significant difference in C_max or AUC when SEC was taken with a high-fat meal compared to applesauce under fasting conditions. The type of food (pudding, applesauce, yogurt) also did not affect absorption.

SEC has a half-life of approximately 17 hours. SEC has a total body clearance of approximately 25 mL/min and a renal clearance of approximately 3.9 mL/min. SEC is metabolized in vitro via oxidation by the human hepatic CYP450 enzyme. SEC excretion in urine is approximately 15% of a 2-g oral dose.

2.4. Drug interaction studies

SEC does not affect the efficacy of oral contraceptives. In a phase 2 study, healthy women received concomitant administration of SEC 2-g with an oral contraceptive containing ethinyl estradiol (EE) and norethindrone (NE). The effect on EE was a 29% decrease in the C_max and no significant effect on the AUC [41]. The effect on NE was not significant, showing a 13% and 16% increase in C_max and AUC, respectively. There was no effect on the C_max or AUC of EE or NE when SEC 2-g was administered 1 day before the oral contraceptive.

Certain antibiotics may reduce the efficacy of bowel preparation for colonoscopy by direct drug chelation with magnesium (sodium picosulfate, magnesium hydroxide, anhydrous citric acid). SEC should be administered either 2 hours before or 6 hours after bowel preparation.

2.5. Administration and dosage

SEC is administered as a single oral dose of 2-g, off-white to slightly yellowish granules with 4.8 g net weight, packed in a unit-of-use, child-resistant foil packet. The entire contents of the SEC packet should be sprinkled onto a standard serving of applesauce, yogurt, or pudding. The granules will not dissolve. The entire mixture should be consumed within 30 minutes without chewing or crunching the granules. A glass of water may be taken after the administration of SEC to aid in swallowing.

The recommended dosage of SEC for the treatment of BV in adult women is a single 2-g packet of granules taken once orally, without regard to the timing of meals. The recommended dosage of SEC for the treatment of trichomoniasis in adult women and men (aged ≥18 years) is a single 2-g packet of granules taken once orally, without regard to the timing of meals. Because trichomoniasis is a STI, ideally, sexual partners should be treated with the same dose and at the same time. There is no guidance on dosing of SEC in patients with renal or hepatic impairment, but it appears no adjustments are necessary.

3. Clinical efficacy

3.1. Summary of efficacy in women

A multicenter, randomized, double-blind, placebo-controlled, delayed-treatment trial was conducted to evaluate the efficacy of single, oral dose of SEC for the treatment of trichomoniasis in women [31]. A total of 147 women (aged 15–65 years) were enrolled across 10 centers in the US. The women were randomly assigned (1:1) to receive either SEC 2-g or placebo. The modified intent-to-treat (mITT) population consisted of all randomized patients who tested positive for T. vaginalis by culture and negative for other STIs. In the mITT population of 131 patients, 90.8% were African American, and the median age was 36 years. A majority of women (84.7% [111/131]) reported baseline clinical symptoms of vaginal itching, discharge, or odor. A test-of-cure (TOC) visit occurred 6–12 days after the initial dosing at baseline. At the TOC visit, patients were given the opposite treatment from baseline (SEC patients received placebo and vice versa) with a return visit 7–12 days later to ensure all patients received appropriate treatment according to the standard of care. To minimize the risk of reinfection, participants were counseled to abstain from sexual activity during the study.

In the mITT population, microbiological cure (negative for T. vaginalis by culture) at the TOC visit was significantly higher in the SEC (92.2%) versus placebo group (1.5%) (Table 1).

Table 1. Microbiological cure rate in women with trichomoniasis at the TOC visit (mITT*)

	Secnidazole 2-g	Placebo	Treatment difference
	n/N (%)	n/N (%)	(95% CI)^†
Microbiological cure^‡	59/64 (92.2)	1/67 (1.5)^§	90.7 (80.7, 96.5)
			p < 0.001^¶

CI: confidence interval; mITT: modified intent to treat population; STI; sexually transmitted infection; TOC: test of cure. *Defined as all randomized patients who were culture positive for T. vaginalis and negative for other STIs. ^†Exact CI from Score Method. ^‡InPouch^TM TV test negative for T. vaginalis; patients with no test results were assumed to be positive (1 SEC- and 3 placebo-treated patients).

^§In placebo-treated patients with a positive T. vaginalis culture at TOC, receiving delayed SEC showed a comparable microbiological cure rate 7–12 days later (88.9% [56/63]); 95% CI: 78.4%, 95.4%) compared with the 92.2% cure rate for patients initially treated with SEC. ^¶P-value derived using a Cochran–Mantel–Haenszel test adjusted for clinical symptoms (present/absent) of trichomoniasis at baseline.

3.2. Summary of efficacy in men

A single oral 2-g dose of SEC was assessed in four open-label trials in men (one comparative study with MTZ and ornidazole [ORZ] in men only [42] and three single-arm studies in men and women [38,43,44]) (Table 2). ORZ is another 5-nitroimidazole used to treat trichomoniasis, amebiasis, and giardiasis in other countries, but it is not approved in the US.

Table 2. Studies of SEC in men

Citation(Location)	Treatment	M/F	Cure rate	Adverse events
Siboulet 1977 [43] (France)	SEC 2 g SD PO	76/104	95.6%*	Nausea/gastralgia: 9% Gastric burning: 1%
Videau 1978 [38] (France)	SEC 2 g SD PO	56/84	97.1%^†	Nausea: 4%
Özbilgin 1994 [42] (Turkey)	SEC 2 g SD PO MTZ 250 mg TID PO (7 d) ORZ 500 g BID PO (5 d)	30/0 29/0 26/0	100% 100% 100%	NR
Dyudyun 2016 [44] (Ukraine)	SEC 2 g SD PO^§ SEC 2 g MD PO (3 d)^¶	49/38	97.0%^‡	Dyspepsia: 0.5% Metallic taste: NR

BID: twice daily; F: female; M: male; MD: multiple doses; MTZ: metronidazole; NR: not reported; ORZ: ornidazole; PO: by mouth; SD: single dose; SEC: secnidazole; TID: thrice daily.

*Microbiological cure (wet mount and culture: Siboulet, Videau; wet mount, culture, and molecular test: Dyudyun). ^†Symptomatic cure. ^‡Microbiological and symptomatic cure. ^§Treatment for patients experiencing their first occurrence of T. vaginalis. ^¶Treatment for patients with persistent trichomoniasis.

Parasitological evaluation was performed pre- and post-treatment and reported cure rates ranged from 91.7% (165/180) to 100% (30/30) at time points ranging from 2 to 20 days after treatment (n = 437; 211 men and 226 women).

3.3. Summary of efficacy in adolescents

Secnidazole is FDA approved for BV in postmenarchal adolescent girls aged ≥12 years and for trichomoniasis in adolescent girls and boys aged ≥12 years.

The safety and efficacy of SEC for the treatment of BV have been established in female patients aged 12–17 years based on data from a multicenter, open-label safety study of 40 female pediatric patients with BV [45] and on data from controlled studies in adult women [27,28,46].

The safety and efficacy of SEC for the treatment of trichomoniasis have been established in male and female patients aged 12–17 years based on the extrapolation of clinical trial data from adult women with trichomoniasis [31], four open-label studies in men with trichomoniasis [38 ,42–44], and an open-label safety study of female patients with BV [45].

4. Post-marketing surveillance

4.1. Safety

In the US-based clinical trial, SEC was safe and well tolerated [31]. Eleven patients (14.9%) in the SEC group and 16 patients (21.9%) in the placebo group reported adverse reactions (Table 3). Symptomatic vulvovaginal candidiasis was reported by two patients (2.7%) in the SEC group and none of the patients in the placebo group.

Table 3. Summary of TEAEs* (SAF)

	Secnidazole 2-g (n = 74)		Placebo (n = 73)
	Patients^† n (%)	Events, n	Patients^† n (%)	Events, n
Any TEAE	11 (14.9)	13	16 (21.9)	20
Nausea	2 (2.7)	2	3 (4.1)	3
Abdominal pain	1 (1.4)	1	1 (1.4)	1
Diarrhea	1 (1.4)	1	2 (2.7)	2
Vomiting	1 (1.4)	1	1 (1.4)	1
Vulvovaginal candidiasis	2 (2.7)	2	0	0
Vulvovaginalmycotic infection	1 (1.4)	1	0	0
Productive cough	1 (1.4)	1	0	0
Upper-airwaycough syndrome	1 (1.4)	1	0	0
Myalgia	1 (1.4)	1	0	0
Back pain	0	0	1 (1.4)	1
Headache	1 (1.4)	1	5 (6.8)	5
Vulvovaginal pruritus	1 (1.4)	1	0	0
Dysmenorrhea	0	0	2 (2.7)	2
Irregular Menstruation	0	0	1 (1.4)	1
Thirst	0	0	1 (1.4)	1
Pruritus	0	0	1 (1.4)	1

TEAE: treatment-emergent adverse event; SAF: safety population; TOC: test of cure. *Includes all TEAEs during the primary phase (start date on or before the TOC visit). ^†Patients experiencing multiple TEAEs are counted only once within a given cell.

In studies outside the US, dysgeusia was reported during the use of SEC and other 2-g formulations of SEC [44,47]. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

5. Drug resistance

Compared to MTZ and TDZ [23,24], there are minimal data on SEC resistance in T. vaginalis. The prevalence of in vitro aerobic MTZ and SEC resistance in archived T. vaginalis isolates from 100 women was recently determined [30]. The mean (SD) MLC for SEC was 5.9 (13.2) µg/mL; the mean (SD) MLC for MTZ was 13.5 (26.9) µg/mL. The median MLC for SEC was significantly lower (1.6 µg/mL) than that for MTZ (6.3 µg/mL). Of the 100 T. vaginalis isolates, 96% had a lower MLC for SEC than for MTZ, while three isolates had similar MLCs for both medications (p < 0.0001). Only one T. vaginalis isolate had a higher MLC for SEC (3.1 µg/mL) than for MTZ (1.6 µg/mL). The prevalence of low-level resistance to SEC was 4%, while that for MTZ was 7%. None of the isolates demonstrated moderate- or high-level SEC resistance, while 1% of the isolates demonstrated moderate MTZ resistance. Overall, these data suggest that SEC has superior efficacy in vitro compared to MTZ against T. vaginalis. Given that drug resistance in T. vaginalis has been found to be relative and not absolute [25], additional in vivo data on clinical outcomes of treatment in the setting of drug resistance, particularly for infections with low-level in vitro resistance, are needed.

6. Comparison to other 5-nitroimidazoles

In 2010, an open-label study compared MTZ 2-g single oral dose and MTZ 500 mg twice-daily oral dose for 7 days for the treatment of trichomoniasis in HIV-infected women [48]. Overall, the efficacy rates were 83.2% in the single-dose MTZ group and 91.5% the multi-dose group. Of the 244 women with HIV and trichomoniasis in this study, 66.8% also had BV coinfection at baseline. In the single-dose MTZ group, women with BV were 4.2 times more likely to be positive for T. vaginalis at TOC compared to women without BV [49].

A similar open-label study was conducted in 2018 comparing MTZ 2-g single oral dose and MTZ 500 mg twice-daily oral dose for 7 days for the treatment of trichomoniasis in HIV-negative women [20]. Efficacy rates were 81.4% in the single-dose MTZ group and 89.4% in the multi-dose group. This study also showed a high rate of BV co-infection at baseline (48.3%). With regard to efficacy and in contrast to the 2010 study of HIV-infected women, the 2018 study did not find a statistically significant difference in cure rates based on BV presence or absence in either treatment group [20,48]. It is possible that the 2018 study did not have enough power to detect a difference by BV status; however, the relative risks by BV status did not indicate a trend, so it is unlikely that a larger sample size would have led to a different conclusion [20].

The overall efficacy of a single 2-g oral dose of SEC for women with trichomoniasis in the recent US-based trial was 92.2%. For the nine HIV-positive women in this study, cure rates were 100% (4/4) for SEC and 0% (0/5) for placebo [31]. For the 79 women co-infected with BV at baseline (defined as meeting ≥3 Amsel criteria), cure rates were 97.7% (42/43) for SEC and 0% (0/36) for placebo (unpublished data).

No US-based studies have been conducted using the TDZ 2-g oral dose for the treatment of trichomoniasis in women and men. Approval for TDZ was based on nine studies [50–58] conducted outside of the US that were considered by the FDA to be of poor quality due to methods of randomization and blinding, lack of clarity on withdrawals and dropouts, and statistical analyses that may have falsely elevated efficacy rates [59]. Four studies [50,52,56,58] submitted to support the TDZ label used wet mount for T. vaginalis diagnosis at TOC, which has a low sensitivity of 44–68% [60]. Reported T. vaginalis cure rates for these studies ranged from 80% (8/10) to 100% (16/16). Four additional studies [51,53,54,57] used culture at TOC at time points post-treatment ranging from 1 week to 1 month. Reported cure rates ranged from 92% (37/40) to 100% (65/65). The single oral 2-g TDZ dose also was assessed in four open-label trials in men (one comparative to MTZ and 3 single-arm studies) [59,61–63]. Parasitological evaluation of urine (by culture or other unspecified methods) was performed both pre- and post-treatment, and reported cure rates ranged from 83% (25/30) to 100% (80/80).

The most common adverse events in these studies were gastrointestinal complaints. In the 2010 MTZ trial [48], the most common adverse events reported for the single- and multi-dose MTZ groups were nausea and upset stomach (22.4% and 28.5%), headache (7.2% and 10%), dizziness (8% and 9.2%), and vomiting (4% and 5.4%). In the 2018 MTZ trial, the most common adverse events reported in the single- and multi-dose MTZ groups were nausea (22.6% and 23.3%), vomiting (2.2% and 4.8%), and headache (5.6% and 8.5%) [20]. In the TDZ trials [50–58], combined adverse events for single- and multi-dose regimens were metallic/bitter taste (3.7% and 6.3%) and nausea (3.2% and 4.5%). Adverse events reported in the SEC trial were nausea (2.7%) and vulvovaginal candidiasis (2.7%) [31]. Table 4 compares the characteristics of SEC, MTZ, and TDZ for the treatment of trichomoniasis.

Table 4. Characteristics of secnidazole, metronidazole, and tinidazole

	Secnidazole [64]	Metronidazole [65]	Tinidazole [66]
Drug family	5-nitroimidazole	5-nitroimidazole	5-nitroimidazole
Formula	C7H11N3O3	C6H9N3O3	C8H13N3O4S
Molecular mass	185.18	171.15	247.27
Dose	2 g	500 mg	2 g
Treatment course for T. vaginalis	Single dose	BID x 7 days	Single dose
Route of administration	Oral granules	Oral	Oral
Half-life (t1/2) in women	17–19 h	7.3 h	11.7 ± 1 h
Half-life (t1/2) in men	20.2 ± 3.1 h [43]	7.3 h [43]	13.6 ± 1.2 h [43]
Time to peak concentration (Tmax)	4 h	1–2 h	1.6 ± 0.7 h
Peak concentration (Cmax)	45.4 mcg/mL	12 mcg/mL	47.7 ± 7.5 mcg/mL
Minimum lethal concentration	5.9 ± 13.2 μg/mL	13.5 ± 26.9 μg/mL	0.8 μg/mL
Contraindications	Hypersensitivity to SEC or other nitroimidazole derivatives Cockayne syndrome*: severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of MTZ [64].	Hypersensitivity to MTZ or other nitroimidazole derivatives Psychotic reaction with disulfiram: in alcoholic patients using disulfiram concurrently; MTZ should not be administered to patients who have taken disulfiram within the last 2 weeks. Interaction with alcohol: MTZ associated with disulfiram-like reaction to alcohol; discontinue consumption of alcohol or products containing propylene glycol during and for ≥3 days after MTZ. Cockayne syndrome*: severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported [65].	Hypersensitivity: to TDZ Cockayne syndrome*: severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of MTZ [67].
Alcohol Interaction	In vitro studies showed that secnidazole had no effect on aldehyde dehydrogenase activity [64]. Alcoholic beverages and preparations containing ethanol or propylene glycol should be avoided during therapy and for 2 days after treatment is stopped. (post-marketing) [64]. Updated data suggest that refraining from alcohol use while taking 5-nitroimidazoles is unnecessary [2,68].	Associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Alcohol or products containing propylene glycol should be discontinued during and for ≥3 days after treatment is stopped [65]. Updated data suggest that refraining from alcohol use while taking 5-nitroimidazoles is unnecessary [2,68].	Alcoholic beverages and preparations containing ethanol or propylene glycol should be avoided during tinidazole therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. Updated data suggest that refraining from alcohol use while taking 5-nitroimidazoles is unnecessary [2,68].
Pregnancy	Limited available data on use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. No evidence of adverse developmental outcomes in animal studies [64,69].	No adequate studies in pregnant women. However, no evidence of teratogenicity or mutagenic effects among infants has been reported in multiple cross-sectional, case-control, and cohort studies of pregnant women. No evidence of harm to the fetus in animal studies [70–72]. Updated data indicate that MTZ poses a low risk to the developing fetus. No evidence of teratogenicity or mutagenic effects in infants has been found in multiple studies of pregnant women taking single- or multiple-dose MTZ regimens [2].	Available published data from a case-control study [73] and case report with TDZ use [74] in pregnant women are insufficient to identify a risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, additional preclinical data indicate that TDZ poses a moderate risk. Thus, TDZ should be avoided for pregnant women [2].
Breastfeeding	No data on the presence of SEC in human milk, the effects on the breast- fed child, or the effects on milk production. Breastfeeding is not recommended during treatment and for 96 hours after administration [64].	Present in human milk. Decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother. Clinicians sometimes advise deferring breastfeeding for 12–24 hours after maternal treatment with MTZ.	No reports of adverse effects in breastfed infants and no information on effects on milk production. Due to the potential for serious adverse reactions, including tumorigenicity, breastfeeding is not recommended during therapy and for 3 days after the last dose [66]. Breastfeeding should be deferred for 72 hours after a single 2-g oral dose of tinidazole [2].

*Cockayne syndrome: is an inherited form of dwarfism diagnosed according to the presence of (1) growth retardation (ie, short stature), abnormal sensitivity to light, and prematurely aged appearance (progeria).

7. Regulatory status of secnidazole

On 18 September 2017, the FDA approved SEC (2-g oral granules) for the treatment of BV in adult women. On 30 June 2021, the FDA approved SEC (2-g oral granules) for the treatment of T. vaginalis in adult women and men. SEC also is approved for the treatment of BV and trichomoniasis in France and is used in other countries to treat various bacterial and parasitic infections including amoebiasis and giardiasis.

8. Conclusion

Cure rates for single-dose oral SEC 2-g in treating trichomoniasis in women (including women with HIV or BV coinfection) and men are high (92.2–100%). These rates are comparable or even slightly numerically better to multi-dose MTZ, which has recently become the recommended regimen for the treatment of T. vaginalis in all women. SEC has a longer half-life compared with MTZ and TDZ. It also has a lower MLC and similar MIC and MTC compared to MTZ. SEC has a favorable safety profile and is the only FDA-approved single-dose oral treatment for both trichomoniasis and BV.

9. Expert opinion

SEC is a newly FDA-approved treatment for trichomoniasis in women and men that was found to have comparable efficacy to multi-dose MTZ and a favorable safety profile. MTZ has been used to treat bacterial and parasitic infections since the 1960s. As previously mentioned, until recently, the recommended dosing regimen for the treatment of trichomoniasis in both women and men was a single 2-g dose of MTZ. Recently updated 2020 ACOG guidelines [9] and 2021 CDC STI treatment guidelines [2] now recommend MTZ 500 mg orally twice daily for 7 days in all T. vaginalis−infected women based on a meta-analysis [19] and updated clinical trial data [20], or alternatively, TDZ 2-g single dose [2,9]. In men, the CDC continues to recommend MTZ 2-g single dose (as a rigorous head-to-head comparison of single- and multi-dose oral MTZ has not been conducted for men), or alternatively, TDZ 2-g single dose [2].

Thus, for the first time, recommended treatment of a STI (with MTZ) is different based on gender. This presents some unique challenges for the management of sexual partnerships infected with T. vaginalis. For example, if a T. vaginalis-infected woman is treated with the multi-dose MTZ regimen but her male partner(s) is/are treated with the single-dose MTZ regimen, there could be a conflict in the timing of abstinence from sex, which could put the couple at risk for re-exposure to T. vaginalis [21]. Use of single-dose 2-g oral SEC (or TDZ) in both T. vaginalis-infected women and their male sexual partner(s) eliminates any confusion that may occur when using different MTZ dosing regimens. Although single-dose TDZ 2 g is an alternative recommended treatment for T. vaginalis in both women and men, it is important to note that that single-dose TDZ is not a recommended treatment in the setting of BV coinfection [2]. Both the updated 2020 ACOG [9] and 2021 CDC guidelines [2] were published before FDA approval of SEC for trichomoniasis. Although SEC is not yet included in national treatment guidelines, we believe SEC to be a valuable additional treatment option for trichomoniasis based on its efficacy, excellent safety profile, and the same one-time dosing regimen in both women and men. In addition, SEC is the only oral, single-dose treatment option for both BV and trichomoniasis in women.

Given the serious consequences and increased risk for transmission and acquisition of HIV and other STIs associated with BV and trichomoniasis, treatment adherence is critical. Poor treatment adherence to multi-dose treatment regimens may be a potential cause of recurrent or persistent T. vaginalis infection. Studies have shown that adherence to multi-dose antibiotics is low [75,76]. One study reported adherence rates of only 50–63% for patients taking multi-dose MTZ for BV [77]. Duration of therapy can be a barrier and adherence can worsen as the length of therapy increases [78]. Although a head-to-head study has not been conducted to evaluate single-dose SEC compared with multi-dose MTZ for women with trichomoniasis, adherence is likely to be improved with a single-dose treatment option (i.e. single-dose SEC) compared to a multi-dose treatment option (i.e. 14 pills over 7 days for oral MTZ). Improved adherence may lead to better patient outcomes by reducing the partner-to-partner cycle of reinfections.

While there are some benefits to single-dose oral SEC, there are some drawbacks. It is in the same class of 5-nitroimidazoles as MTZ and TDZ. This makes it susceptible to drug class issues such as hypersensitivity reactions and potentially drug resistance. Nevertheless, resistance to 5-nitroimidazoles in trichomoniasis has been found to be relative and not absolute (as discussed above), dating back to 1986 [25]. Thus, there is a role for treating through drug resistance, particularly low-level resistance or in the setting of clinical treatment failure, with higher doses of 5-nitroimidazoles for longer periods of time, as is currently recommended in the 2021 CDC STI Treatment Guidelines [2]. Although SEC is not explicitly discussed in the trichomonas section of these guidelines, in our expert opinion, its use can be considered in T. vaginalis-infected patients in the presence of known MTZ drug resistance or clinical treatment failure. Although susceptibility breakpoints are not yet clearly defined for SEC, susceptibility testing can provide useful information, particularly in the setting of a favorable MLC of one 5-nitroimidazole over another.

In developed countries like the US, cost of medications is complex and should be taken into account when considering use of SEC or other 5-nitroimidazoles for the treatment of trichomoniasis. To our knowledge, there are no published cost-effectiveness or real-world compliance studies comparing all three 5-nitroimidazoles which should be an area of future research. Thus, whether the additional direct cost of SEC is countered by an overall reduction in health-care costs, particularly compliance-related therapeutic failure, is unknown. Patient-specific factors, including cost, preferences, insurance coverage, assistance programs, pharmacy availability, and compliance considerations should guide decisions regarding the selection of therapy. In developing countries, the cost of SEC therapy or product availability may be overriding factors, with limited resources and patient assistance opportunities.

Article highlights

• In the United States, trichomoniasis affects 2.1% of women and 0.5% of men aged 18–59 years and disproportionately affects African Americans [1].

• Trichomoniasis is associated with significant adverse outcomes if not treated promptly and appropriately. In women, trichomoniasis can cause vaginitis, cervicitis, pelvic inflammatory disease [2-4], cervical cancer [5], infertility [6], and adverse birth outcomes, including preterm birth, premature rupture of membranes, and low birth weight [7,8]. In men, trichomoniasis can result in non-gonococcal urethritis, epididymitis, prostatitis, and infertility [1,9]. Infection can increase the risk for human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs; chlamydia, gonorrhea, herpes simplex virus, and syphilis) in both sexes [1].

• Coexistence of bacterial vaginosis (BV) and T. vaginalis is very common, with coinfection rates of 60–80% [10]. The risk of acquiring trichomoniasis is two-fold higher among women with BV compared to women without BV [11].

• The Centers for Disease Control and Prevention (CDC) recommend diagnostic testing for T. vaginalis for all women seeking care for vaginal discharge. Screening is recommended annually for HIV-infected women and can be considered for persons receiving care in high-prevalence settings (e.g. STD clinics and correctional facilities) and for asymptomatic women at high risk for infection (e.g. multiple sexual partners, transactional sex, drug misuse, and/or a history of STIs or incarceration) [1].

• Updated guidelines now recommend multi-dose metronidazole (MTZ) 500 mg orally twice daily for 7 days for the treatment of all women with T. vaginalis, although a single 2-g dose of oral MTZ remains the recommended treatment for men. This is the first time recommended treatment regimens for a STI differ based on gender, which may present unique challenges.

• Updated guidelines have removed the recommendation to refrain from alcohol use while taking 5-nitroimidazoles due to lack of data on disulfiram-like reaction [1].

• Retest all sexually active T. vaginalis-infected women within 3 months of treatment due to high rates of recurrence. If retesting at 3 months is not possible, providers can retest whenever women next seek medical care [1].

A single 2-g dose of secnidazole is newly approved by the U.S. Food and Drug Administration for the treatment of trichomoniasis in adult women and men and is the only single-dose oral treatment option for both BV and trichomoniasis.

Declaration of interest

C Muzny has received research grant support from Lupin Pharmaceuticals, Gilead Sciences, Inc, and Abbott Molecular, is a consultant for Lupin Pharmaceuticals, PhagoMed, and BioFire Diagnostics, and has received honoraria from Elsevier, Abbott Molecular, Cepheid, Becton Dickinson, Roche Diagnostics, and Lupin. O Van Gerwen has received research grant support from Gilead Sciences, Inc and Abbott Molecular. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Scientific accuracy review

Lupin Pharmaceuticals provided a scientific accuracy review at the request of the journal editor.

Acknowledgments

Elizabeth Sarkar, Jespersen & Associates, LLC for communications with authors, coordination of reference retrieval and illustration of molecular structures.

Additional information

Funding

Medical writing assistance was provided by Linda Goldstein, PhD, CMPP, of The Write Source MSC, LLC and funded by Lupin Pharmaceuticals. Lupin Pharmaceuticals had no other role in the design and development of the content, writing, or reviewing of this manuscript. The opinions in this article are solely those of the authors.