Dan, Michael MD*†; Sobel, Jack D. MD‡
From the *Infectious Diseases Unit, E Wolfson Hospital, Holon, Israel; †Tel Aviv University School of Medicine, Tel Aviv, Israel; and ‡Division of Infectious Diseases, Harper Hospital, Detroit Medical Center, and Wayne State University School of Medicine, Detroit
Correspondence: Michael Dan, MD, E. Wolfson Hospital, Holon 58100, Israel. E-mail: firstname.lastname@example.org.
Received for publication November 27, 2006, and accepted March 13, 2007.
NITAZOXANIDE IS A NEW nitrothiazolide antiparasitic agent that shows excellent in vitro activity against a wide variety of protozoa and helminths by blocking anaerobic metabolism in eukaryocytes.1 Like metronidazole, nitazoxanide is a nitro-derivative, but nitazoxanide has a nitrothiazolyl ring instead of the nitroimidazole ring of metronidazole, which could enhance its efficacy and decrease its toxicity.2 The drug is given by the oral route with good bioavailability, and is well tolerated with primarily mild gastrointestinal side effects.1 At present, there are no documented drug interactions. Nitazoxanide has been licensed for the treatment of Giardia intestinalis and Cryptosporidum infections for which the routine adult regimen is 500 mg bid for 3 days (Alinia package insert). The in vitro activity of nitazoxanide against Trichomonas vaginalis was recently reported.2 These properties of nitazoxanide, together with increasing need to expand the arsenal of antitrichomonal drugs, motivated us to use this agent in selected cases of trichomoniasis.
We performed a retrospective review of charts of patients treated with nitazoxanide for trichomoniasis at the Vaginitis Clinics in the Detroit Medical Center and Wolfson Hospital (Holon, Israel). “Metronidazole-resistant trichomoniasis” was defined clinically as failure to respond to conventional therapy with oral metronidazole, 500 mg bid for 7 days (total dose 7 g). “Failure to respond” was defined as persistence or recurrence (within 28 days) of symptoms and signs of vaginitis together with the following confirmatory laboratory features of vaginal trichomoniasis: high vaginal pH, increased numbers of polymorphonuclear leukocytes, and a visualization of motile trichomonads using microscopy. In vitro Trichomonas cultures of individual specimens were performed using Diamond’s Medium Modified (Remel) or the InPouch TV culture system (Biomed Diagnostics). In total, 3 patients were treated with nitazoxanide for trichomoniasis at our clinics.
A 43-year-old woman was referred because of chronic refractory, metronidazole-resistant trichomoniasis. She further failed high-dose, prolonged tinidazole therapy including 2 total dose regimens of 42–60 g of tinidazole administered orally and vaginally. She similarly failed a course of topical intravaginal paromomycin. She subsequently failed successive courses with thiobendazole and albendazole, atovaquone, zinc bacitracin, furazolidone-nifuratel, all in combination with tinidazole including prolonged courses lasting a few weeks. In vitro tests under aerobic and anaerobic conditions indicated a MIC of 60 μg/mL metronidazole and 30 μg/mL tinidazole with control organism MIC 6.25 μg/mL. A nitazoxanide MIC of 1.56 μg/mL was observed and nitazoxanide was obtained from the company on a compassionate basis before its FDA approval and commercial availability. She was treated with nitazoxanide orally 2.0 g bid for 14 days without clinical or microbiologic benefit. The drug was poorly tolerated with significant nausea. A repeat course of intravaginal nitazoxanide gel 1.0 g bid together with oral tinidazole similarly failed to eradicate the motile microorganisms. The patient has remained trichomonas positive but with minimal symptoms for the last 5 years.
A 61-year-old female presented with a 3-month history of malodorous vaginal discharge, accompanied by local burning and irritation. Physical examination revealed mild inflammation and minimally purulent vaginal discharge. Vaginal pH was increased at 6.0 with 4+ polymorphonuclear leukocytes, absent clue cells and although no trichomonads were seen on wet mount microscopy, culture in Diamond’s medium was positive for T. vaginalis. The patient reported developing severe urticaria upon receiving oral metronidazole some 10 years previously. Accordingly, she was prescribed nitazoxanide orally 1.0 g bid for 7 days. She returned 3 weeks later reporting no improvement. Physical examination revealed more severe inflammation with a copious, malodorous discharge, this time with 4+ motile trichomonads visualized. She underwent oral tinidazole desensitization and treated with oral tinidazole 500 mg bid for 7 days. Follow up examinations on 1 and 4 weeks after completing therapy were completely normal in an asymptomatic patient with negative trichomonas culture.
A 35-year-old woman complained of a copious malodorous vaginal discharge and vulvar soreness. Her symptoms started 3 months earlier following unprotected sexual intercourse. Her medical history included epilepsy from the age of 10 years, for which she was treated with valproic acid. Trichomoniasis was diagnosed on microscopy; however, 2 standard courses of tinidazole (2.0 g single dose) failed to alleviate symptoms and to eradicate the parasite. On examination in the vaginitis clinic the vulva and vagina were erythematous and there was a profuse frothy yellow vaginal discharge with a pH of 5.5 and a positive amine test. On microscopy there were increased numbers of polymorphonuclear leukocytes and trichomonads were observed. The presence of T. vaginalis was confirmed by culture. Treatment with a 7-day course of oral metronidazole 500 mg bid was initiated. On follow-up visit 2 weeks after completion of treatment, the patient complained of persisting symptoms, and trichomonade were seen again on microscopy; she insisted on having maintained sexual abstinence. The patient experienced a seizure while on metronidazole, 2 days after she stopped taking her anticonvulsive drug; she nevertheless completed the full course of metronidazole as prescribed. Accordingly, we were reluctant to treat her with a high dose of a nitroimidazole and nitazoxanide 1.0 g bid for 7 days was recommended. Compliance was verified by daily phone calls and inspection of the returned empty drug package. Two days after completing the treatment, the patient reported symptomatic improvement. On examination, however, the findings remained practically unchanged with purulent discharge and trichomonads detected on microscopy and culture. No adverse events were noted other than yellow discoloration of secretions. The patient denied any sexual activity during the entire period. She was finally cured with high-dose tinidazole (1.0 g orally 3 times daily and 0.5 g intravaginally 3 times daily, for 14 days)3 after adequate serum levels of her anticonvulsant drug was achieved.
Our limited experience with nitazoxanide in the treatment of trichomoniasis was disappointing: although we have treated only 3 patients with nitazoxanide, none showed even a temporary response to the regimens administered. Two of the patients (Cases 1 and 3) had metronidazole-resistant infections, although in Case 3 the trichomonas infection was finally cured with high divided dose tinidazole therapy.
We have no explanation for the failure of nitazoxanide in our patients. Cedillo-Rivera et al.2 have found that while the 50% inhibitory concentration (IC50) values of nitazoxanide and metronidazole were similar (0.034 and 0.037 μg/mL, respectively), based on the IC90 values metronidazole exhibited more potent trichomonicidal activity than did nitazoxanide (0.169 and 2.046 μg/mL, respectively). Another factor that may interfere with the response of trichomoniasis to nitazoxanide is the possibility of inadequate drug concentrations in the urethral and vaginal mucosa. With the conventional dose, the Cmax of the active metabolite of nitazoxanide in plasma is around 1.1–2.5 mg/mL; however, plasma concentrations increase linearly with the dose from 1 to 4 g, and a trend to increased bioavailability was observed at 4 g.4 The drug is excreted mainly in feces and probably in the intestine (66.2% of the dose on average), explaining its high efficacy against intestinal parasites, while 31.2% of the dose on average is eliminated in the urine.5 We have found no data on the concentrations of the active metabolite of nitazoxanide in vaginal and urethral mucosa. Yet, with the MIC of nitazoxanide documented (1.56 μg/mL) and the very high dose (total dose, 56 g) including intravaginal application used in Case 1, we would have expected a better therapeutic result.
Although the dosages of nitazoxanide that we have used (total dose, 14–56 g) were markedly higher than the recommended standard dosage (total dose, 3 g), a significant adverse reaction (poorly tolerated nausea) was observed only with the very high dose (total dose, 56 g).
Despite the discouraging preliminary results, more pharmacological and clinical data should be gathered before determining the role of nitazoxanide in the treatment of trichomoniasis. Alternative drugs for patients with trichomoniasis unable to receive a nitroimidazole because of intolerance, allergy, or drug resistance are needed.
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