TRICHOMONIASIS AFFECTS AN estimated 5 million women annually in the United States and nearly 180 million worldwide. 1 Trichomonas vaginalis is sexually transmitted, so men are also affected, although many remain asymptomatic. Recent evidence has linked T. vaginalis infection as a cofactor to a variety of complications among both women and men, including preterm labor; the development of pelvic inflammatory disease, infections after gynecologic surgery, and cervical intraepithelial neoplasia among women; development of nongonococcal urethritis in men; and as a risk factor for the transmission and acquisition of HIV infection in both sexes. 2–5
Oral metronidazole has been the gold standard for treatment of trichomoniasis for over 30 years. When first introduced in the United States, the dosing regimen for trichomoniasis was 250 mg 3 times a day for 7 days. However, we have previously shown that a single 2-g dose is equally effective as a 7-day course of therapy. 6 A recent report has suggested that cases of metronidazole-resistant trichomoniasis could be increasing. 7 Although oral metronidazole therapy is highly effective in treating trichomoniasis, clinical failures have been observed and clinical resistance has been reported throughout the United States. 8 Although currently, no formal reporting system for monitoring metronidazole-resistant cases exists, the Centers for Disease Control and Prevention (CDC) does offer consultation for managing cases of laboratory-confirmed infections not responding to multiple courses of metronidazole therapy, 9 and the CDC collects data on the resistant isolates sent to them for testing. Generally, treatment of such cases consists of higher and more prolonged doses of metronidazole therapy. 9 Despite such measures, some patients continue to be infected. In addition, patient tolerance of high-dose metronidazole is often a limiting factor in achieving cure. In the United States, no alternatives to metronidazole are available for the treatment of trichomoniasis. Tinidazole, a second-generation nitroimidazole available outside the United States, has been used successfully in cases of metronidazole-resistant T. vaginalis. Several U.S. publications have demonstrated that tinidazole has >90% efficacy in treating metronidazole-resistant cases. 10,11 In a case series published by Sobel et al., 10 tinidazole was given at high dose (2–3 g per day orally with 1–1.5 g intravaginally for 14 days). It is unclear as to what the dosing regimen should be, because lower doses of tinidazole have been reported to be successful in individual case reports. 12–14 I report my experiences using a lower total dose of tinidazole in treating 3 T. vaginalis patients in whom repeated metronidazole treatment regimens were unsuccessful. Tinidazole (sold as Fasigyn) was obtained from the University of Kentucky Pharmacy for the treatment of these 3 patients.
Case No. 1
A 33-year-old gravida 2, para 2 white woman weighing 164 lbs presented with vaginal discharge, pruritus, and burning of 4 months’ duration. Tests for chlamydia, gonorrhea, syphilis, and HIV infection were all negative. Vaginal pH was 4.5, and KOH wet mount and “whiff test” were negative. The patient had motile trichomonads and the presence of white blood cells on wet mount examination. Diagnosis of T. vaginalis was confirmed by subsequent culture on modified Diamond’s medium. Previous treatment had been administered by other physicians as follows: intravaginal metronidazole gel daily for 5 days, 2 g oral metronidazole in a single dose, and 500 mg metronidazole twice a day for 7 days. All regimens resulted in clinical failure and persistence of symptoms. It was therefore determined that the patient had clinically resistant trichomoniasis. After signing informed consent, treatment with 500 mg oral tinidazole 3 times a day for 10 days was initiated. The patient’s sexual partner (who was asymptomatic) was treated by another physician with 500 mg metronidazole twice a day for 7 days. At follow-up examination 14 days after therapy, wet prep examination revealed an absence of trichomonads and white blood cells and the patient was completely symptom-free. There was no evidence of T. vaginalis at a 1-month follow-up visit.
Case No. 2
A 38-year-old, gravida 3, para 2 white woman weighing 137 lbs presented with vaginal discharge and persistent pruritus of 6 months’ duration. Tests for chlamydia, gonorrhea, syphilis, and HIV infection were all negative. Motile trichomonads were observed on wet prep examination. The vaginal pH was 5.0 with a negative KOH wet mount and negative “whiff test.” Culture with modified Diamond’s medium confirmed a diagnosis of trichomoniasis. Previous treatment included a 2-g single dose of metronidazole, 500 mg metronidazole twice a day for 7 days, and 500 mg metronidazole twice a day for 7 days along with 500-mg intravaginal metronidazole suppositories twice a day for 7 days. No improvement was seen with any of these regimens and the patient was considered to have clinically resistant trichomoniasis. Informed consent was signed and 500 mg tinidazole 3 times a day oral treatment was initiated for 7 days, and her only sexual partner was treated by another physician with 500 mg metronidazole twice a day for 7 days with instructions to use condoms during intercourse. He was asymptomatic throughout this time. At follow-up examination 14 days after therapy, the patient had resolution of all symptoms and negative wet prep findings for trichomoniasis. Again, there was no recurrence at 1-month posttreatment.
Case No. 3
A 42-year-old gravida 1, para 1 black woman weighing 176 lbs presented with vaginal discharge, pruritus, and dysuria of 41/2 months’ duration. Tests for chlamydia, gonorrhea, syphilis, and HIV infection were all negative. Motile trichomonads were observed on wet prep examination, vaginal pH was 5, and KOH wet mount and “whiff test” were negative. Culture confirmed a diagnosis of trichomoniasis. Previous courses of metronidazole therapy administered by other physicians were as follows: a 2-g single dose of 500 mg oral metronidazole; 500 mg of oral metronidazole 3 times a day for 5 days and 500 mg metronidazole vaginal suppositories twice a day for 7 days. The patient failed to have any improvement in either symptoms or clinical findings after these regimens. Tinidazole given as 500 mg orally 3 times a day for 7 days was therefore initiated after informed consent was signed. Because the patient’s sexual partner was symptomatic with dysuria, he was also treated with 7 days of 500 mg tinidazole orally twice a day after signing informed consent and instructed to use condoms after sexual intercourse resumed. He was evaluated for chlamydia, gonorrhea, and HIV with all tests negative. At follow up 10 days and 30 days after therapy, the patient had resolution of all symptoms and was T. vaginalis-negative by wet prep with no recurrences. Her partner also became asymptomatic.
Clinically metronidazole-resistant trichomoniasis has been reported throughout the United States, with reports coming from 38 states, according to the CDC. 15
There is no formal surveillance system for reporting trichomoniasis, including metronidazole-resistant cases, so the true burden of disease in the United States is not known. Although metronidazole-resistant trichomoniasis is thought to be an infrequent occurrence, patients with resistant organisms are left without an alternative treatment. For over 25 years, tinidazole has been available outside the United States for the treatment of trichomoniasis, as well as for the treatment of many other infections involving parasites or anaerobic bacteria. In over 35 published clinical trials of tinidazole treatment of trichomoniasis, the efficacy and safety of the drug have been clearly established. 16 Tinidazole appears to offer several advantages over metronidazole, including greater in vitro potency against parasites and most anaerobic bacteria; a longer half-life (12–14 hours vs. 6–7 hours for metronidazole), producing a longer duration of action; improved tolerability with fewer side effects; and greater clinical efficacy in cases of metronidazole-resistant trichomoniasis. 16
Currently, the Centers for Disease Control and Prevention performs minimal lethal concentration (MLC) testing to both metronidazole and tinidazole of patient isolates whose infections have not been cured by previous courses of metronidazole therapy. In 3 published reports from the CDC, when comparing the in vitro activity of tinidazole with metronidazole against metronidazole-resistant T. vaginalis, the aerobic MLCs are consistently 2- to 4-fold lower for tinidazole versus metronidazole 17–19 (Table 1). In the most recent report, 17 MLC data on a total of 104 clinically metronidazole-resistant isolates sent to the CDC between 1995 and 2001 from practitioners across the country demonstrated lower MLCs for tinidazole versus metronidazole. Although increased metronidazole resistance was correlated with decreased sensitivity to tinidazole, the authors concluded that the increased sensitivity for trichomonads to tinidazole observed in this paper suggests clinical applicability for tinidazole in treating resistant trichomoniasis. All 3 of our patients had failed at least 3 regimens of metronidazole therapy, necessitating the use of tinidazole. Because, in the reported literature, tinidazole is associated with fewer adverse effects and better patient tolerance than metronidazole, I chose to use it rather than the very high doses of metronidazole that are often used to treat resistant trichomoniasis. The positive efficacy results reported by Sobel et al. 10 with high-dose tinidazole, along with good patient tolerance, encouraged me to use it in the patients reported here but with lower doses. Tinidazole is currently awaiting approval in the United States and is available through a compassionate-use program (Presutti Laboratories, personal communication, November 2002). In the 3 patients with metronidazole-resistant T. vaginalis reported here, a lower total dose and duration of tinidazole than was recently reported in the literature 10 was used to achieve successful clinical cure in all 3 patients. In 2 patients, we used a total dose of 10.5 g tinidazole given over 7 days, with the third patient receiving a total tinidazole dose of 15 g given over 10 days. This compares with a total tinidazole dose (given both orally and intravaginally) ranging from 42 to 63 g given over 14 days in the 2001 report by Sobel et al. 10 Case reports from the literature have varied in the tinidazole dosing regimen used to treat metronidazole-resistant trichomoniasis, ranging from a single 2-g dose up to a total dose of 63 g. Single tinidazole doses of 2 g for 1 to 2 days have been largely ineffective in metronidazole-resistant trichomoniasis. Other published reports using 1.5 to 4.5 g a day for 7 to 14 days have resulted in cure rates ranging from 80% to 100%. 11–14
Our case series has several limitations: 1) we did not perform cultures for test of cure after tinidazole therapy. Cultures are more sensitive for the detection of trichomoniasis than wet mount preparation, so it is possible that our patients were still infected posttherapy. However, all 3 of our patients had very abnormal wet mounts at entry with negative wet mounts posttherapy and remained symptom-free at 6 months, so I believe that all 3 patients were treatment successes. 2) I did not send our initial patient cultures to the CDC for MLC testing to both metronidazole and tinidazole. In the future, I would recommend that cultures be sent to the CDC for this testing, because it would provide useful information on the level of metronidazole resistance for each clinical isolate and would also allow for monitoring overall metronidazole resistance that exists in the United States. 3) I did not perform clinical examination or testing on 2 of the partners of these patients who were seen by other physicians, and no cultures were obtained from any partner to confirm infection with T. vaginalis in the males. If it is possible to see the partners, I would suggest that all male partners of infected patients be tested not only for trichomoniasis, but for other pathogens as well (ie, chlamydia, gonorrhea) and if positive, receive appropriate treatment.
Only 1 of the 3 partners in this report was symptomatic. He was treated with tinidazole rather than metronidazole, which was used by the other providers to treat the 2 asymptomatic partners. In the future, it would be advisable to treat all partners of patients with metronidazole-resistant trichomoniasis with tinidazole, because it could be assumed that the resistant isolate is being transmitted back and forth between the patient and her sexual partner. Hence, metronidazole treatment of the male partner in these instances could result in subsequent failure, although this did not occur with these women.
With regard to side effects, the only side effect reported by all 3 tinidazole-treated patients was a metallic taste, and 1 patient (case no. 1) reported mild nausea. These patients all reported metallic taste after previous courses of metronidazole therapy, and 1 patient also experienced nausea and vomiting after metronidazole. More importantly, 1 of my patients (case no. 3) reported tingling in her fingers during metronidazole treatment when administered as combined oral and vaginal therapy. This patient, when rechallenged with 500 mg tinidazole 3 times daily for 7 days did not experience this adverse event. Although side effect data were not provided in all the previously published reports of tinidazole used in metronidazole-resistant T. vaginalis, in those who did comment on side effects, tinidazole was well tolerated. In the report by Sobel, patient tolerance with tinidazole therapy was good, with none of the 26 patients treated with these very high doses (up to 63 g) discontinuing therapy as a result of gastrointestinal disturbances. This contrasts to the authors’ experiences with previous high-dose metronidazole treatment, in which patient tolerance was often a limiting factor in treatment. Peripheral neuropathy has been reported with metronidazole therapy and is of concern when attempting to eradicate resistant T. vaginalis, because high, prolonged doses of metronidazole are often necessary. Tinidazole could well offer a significant advantage in this regard by offering patients an alternative to high-dose metronidazole. It is our opinion that tinidazole is a very effective therapy for metronidazole-resistant trichomoniasis. Additional studies to determine the lowest effective dose in such patients are warranted.
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