CASE REPORT

CASE REPORT

Recalcitrant Infections Successfully Treated With Vaginal Acidification

Anjali Aggarwal, BSc, MD, R. Michael Shier, BSc, MD, FRCSC
Department of Obstetrics and Gynaecology, University of Toronto, Toronto ON

Abstract
Background: Recalcitrant vaginal trichomoniasis is extremely distressing for patients and frustrating for physicians because there are no current guidelines for treatment. Numerous studies have shown that an increase in vaginal pH creates a better environment for the growth of Trichomonas vaginalis. We describe two patients with recalcitrant trichomoniasis who were successfully treated using vaginal acidification. Cases: The first patient with trichomoniasis had a severe reaction to metronidazole, but the infection subsequently resolved after treatment with a combination of boric acid and clotrimazole. The second patient with resistant trichomoniasis had been treated unsuccessfully with multiple courses of metronidazole but was treated successfully with vaginal acidification using boric acid. Conclusion: A process of vaginal acidification resulted in resolution of recalcitrant Trichomonas vaginalis in two patients.

INTRODUCTION

Rsum
Contexte : La trichomonase vaginale rcalcitrante est extrmement troublante pour les patientes et frustrante pour les mdecins, puisque aucune directive clinique actuelle ne sest penche sur sa prise en charge. De nombreuses tudes ont indiqu quune hausse du pH vaginal cre un meilleur environnement pour la prolifration de Trichomonas vaginalis. Nous dcrivons le cas de deux patientes prsentant une trichomonase rcalcitrante qui ont t traites avec succs au moyen dune acidification vaginale. Cas : Bien que la premire patiente prsentant une trichomonase ait connu une grave raction au mtronidazole, linfection a subsquemment t rsolue par la mise en uvre dun traitement faisant appel une combinaison dacide borique et de clotrimazole. La deuxime patiente prsentant une trichomonase rsistante avait t traite, sans succs, au moyen de multiples traitements au mtronidazole; toutefois, la mise en uvre dune acidification vaginale au moyen dacide borique a men la rsolution de linfection. Conclusion : La mise en uvre dun processus dacidification vaginale a entran la rsolution dune infection rcalcitrante Trichomonas vaginalis chez deux patientes. J Obstet Gynaecol Can 2008;30(1):5558

richomoniasis is a sexually transmitted infection caused by the parasitic protozoan Trichomonas vaginalis. The World Health Organization estimates that 180 million new cases of trichomoniasis occur each year.1 This is more than the incidence rates of gonorrhea, chlamydia, and syphilis combined. Trichomoniasis accounts for 4% to 35% of vaginitis diagnosed in symptomatic women in a primary care setting in the United States.2 The symptoms of trichomoniasis in women range from none at all to a severe acute inflammatory state. Classic signs and symptoms include a purulent, malodorous vaginal discharge with associated pruritus, burning, dysuria and dyspareunia. Physical examination in affected women shows vaginitis and vulvitis, with a frothy, yellow-green mucupurulent discharge. Colpitis macularis (strawberry cervix) may be seen colposcopically.3 Trichomoniasis is a risk factor for post-hysterectomy cellulitis, tubal infertility, cervical neoplasia, premature rupture of membranes, and preterm labour.47 It has also been associated with an increased risk of HIV transmission (likely due to genital inflammation),8 and appropriate treatment is therefore imperative.

Key Words: Trichomonas vaginalis, trichomoniasis, recalcitrant, resistant, treatment Competing Interests: None declared. Received on May 11, 2007 Accepted on August 3, 2007

Currently, the mainstay of treatment for infection with Trichomonas vaginalis is oral metronidazole. Metronidazole is a 5-nitroimidazole derived from the Streptomyces antibiotic azomycin. It was developed in 1959 and approved for the treatment of trichomoniasis in the early 1960s. Metronidazole was the first drug to have a cure rate in trichomoniasis that approached 100% with systemic treatment.9 At present, metronidazole is prescribed either as a single 2 g oral dose or as a seven-day course of 500 mg twice daily for the treatment of trichomoniasis. A strain of metronidazole-resistant Trichomonas vaginalis was first isolated in 1978,10 although there were prior reports of treatment failures.11 Data published by the Centers for Disease Control (CDC) indicate that 5% of trichomoniasis showed some resistance to metronidazole, although 80% of cases
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responded to an increase in dose or duration.12 The current CDC guidelines for the treatment of refractory cases recommend the use of tinidazole (in a single 2 g oral dose) or an increased dose of metronidazole (2 g daily for 5 days).13 Most cases of refractory trichomoniasis are treated with metronidazole given in increased doses, increased duration of treatment, or multiple courses of treatment. Resistance appears to be relative, so an increased dose of metronidazole can overcome resistance but will also lead to an increase in the occurrence of side effects. Concurrent use of alcohol must be avoided, because reactions similar to those occurring with disulfiram can occur at any metronidazole dose level. Nuisance adverse effects are mostly gastrointestinal symptoms; however, because high dose metronidazole has been associated with irreversible peripheral neurotoxicity, this therapy is not without significant complications. Several alternatives to the standard dosing of metronidazole have been reported. A combination of oral and vaginal courses of treatment or an increase in dose and duration have been shown to be effective.14,15 Tinidazole, another nitro-imidazole, has been shown to achieve cure in cases of metronidazole failure; one study reported cure rates as high as 92% (in a special access program, as tinidazole was not commercially available).15,16 Topical treatments have also been studied, both in combination with oral metronidazole and alone, but they have shown much lower efficacy. Paromycin cream was the first to be used with any success, but it was associated with side-effects ranging from mild to severe, including vaginal and vulvar ulceration.17,18 Normal saline douching and pessaries containing acetarsol, clotrimazole, and provodine-iodine have all been used in cases of recalcitrant trichomoniasis with differing results.11,1926 A recent study cited a cure rate of 90% when combining clotrimazole pessaries with oral tinidazole in cases of metronidazole-resistant Trichomonas vaginalis.27 A combination of metronidazole with nonoxynol-9 intravaginal spermicide resulted in a cure rate of 90%, while nonoxynol-9 alone resulted in cure rates of 17.6% to 40%.28,29 Zinc sulphate douching has also been used in combination with metronidazole; one study found that lower doses of metronidazole were required in patients who also douched with zinc sulphate.30 Numerous studies have shown that an increase in pH creates a better environment for the growth of Trichomonas vaginalis, but to date there have been no case reports on the use of vaginal acidification for the treatment of trichomoniasis.3133 We describe here two patients with recalcitrant trichomoniasis who were successfully treated using vaginal acidification.
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CASE ONE

A 58-year-old woman with symptomatic vaginitis was shown to have a diamond media culture-positive Trichomonas vaginalis infection. She and her partner were both treated with a single 2 g oral dose of metronidazole. Her infection persisted. She was prescribed a second course of metronidazole, but she developed severe urticaria and acute respiratory suppression. She received resuscitative therapy, and the metronidazole was discontinued. It was concluded that she had developed an allergy to metronidazole, and various other therapies were then instituted; these included saline douches, iodine (Betadine) douches, and vaginal clotrimazole, both with and without vaginal conjugated equine estrogen cream.11,19,2326 The infection persisted despite these treatments. The patient was then treated with paromycin topical cream, but she developed severe vestibular sloughing, and this treatment was discontinued.17,18 The patient was referred to the colposcopy unit. She was no longer sexually active, and she remained severely symptomatic with wet preparation and cultures positive for Trichomonas vaginalis. Treatment was begun using vaginal conjugated equine estrogen cream 1g nightly alternating with vaginal clotrimazole cream. The patient was reevaluated two weeks later, and Trichomonas vaginalis was found to be still present. A 4% acetic acid vaginal douche/ debridement was applied, and a routine began of using vaginal clotrimazole alternating nightly with vaginal boric acid 600 mg in gelatin capsules to acidify the vagina. After six weeks, this regimen was stopped, and the vaginal symptoms with culture positive Trichomonas vaginalis returned within two weeks. The patient had not been sexually active during this time. The previous routine using boric acid alternating with clotrimazole was reintroduced and continued for a further five months. The patient has remained asymptomatic and culture negative for more than five years.
CASE TWO

A 40-year-old gravida 2, para 2 woman with symptomatic vaginitis was found to have a diamond media culturepositive and wet preparation positive Trichomonas vaginalis infection. She was not sexually active. She was treated initially with a single 2 g dose of oral metronidazole, but the infection persisted. She was then treated with metronidazole 250 mg three times daily for seven days, 2 g daily for five days, and 2 g daily for seven days, but all of these regimens failed to clear the infection. The patient was referred to the colposcopy unit. She remained severely symptomatic, with wet preparation and cultures positive for Trichomonas vaginalis. A 4% acetic acid

Recalcitrant Trichomonas Vaginalis Infections Successfully Treated With Vaginal Acidification

vaginal douche/debridement was applied, and a routine of using vaginal clotrimazole in the morning alternating with vaginal boric acid 600 mg in gelatin capsules at bedtime was begun. The patient was given a further single dose of oral metronidazole followed by 250 mg three times daily for seven days. She then underwent a further vaginal douche/acidification with 4% acetic acid, followed by continuing vaginal clotrimazole in the morning and boric acid in the evening for a further two weeks. When this regimen was stopped, symptomatic Trichomonas infection returned within two weeks. The patient remained not sexually active. The previous regimen of vaginal treatment was resumed. She then developed a culture positive yeast infection, treated successfully with oral fluconazole and intravaginal gentian violet. Following this, she was treated with vaginal 600 mg boric acid capsules twice daily and had intravaginal gentian violet applied once weekly on a continuing basis for one month. She has subsequently remained free of Trichomonas vaginalis for more than four months.
DISCUSSION

side effects. The most common concern when a patient is using boric acid intravaginally is an increase in vaginal discharge. Compared with the severe reactions patients may have with high dose metronidazole, having an increase in vaginal discharge seems trivial. Women with recalcitrant Trichomonas vaginalis infection may be required to have metronidazole sensitivity testing; creating a curative regimen that does not require metronidazole can eliminates an extra expense. On the basis of these cases, we recommend use of boric acid for vaginal acidification in cases of recalcitrant Trichomonas vaginalis.
ACKNOWLEDGEMENTS

The women whose stories are told in this case report have provided signed permission for its publication.
REFERENCES
1. WHO: Trichomoniasis. Available at: http://www.who.int. Accessed October 29, 2007. 2. Anderson MR, Klink K, Cohrssen A. Evaluation of vaginal complaints. JAMA 2004; 291:136879. 3. Cudmore SL, Delgaty KL, Hayward-McClelland SF, Petrin DP, Garber GE. Treatment of infections caused by metronidazole-resistant Trichomonas vaginalis. Clin Microbiol Rev 2004;17(4):78393. 4. Soper DE, Bump RC, Hurt WG. Bacterial vaginosis and trichomoniasis vaginitis are risk factors for cuff cellulitis after abdominal hysterectomy. Am J Obstet Gynecol 1990;163: 1016. 5. Grodstein F, Goldman MB, Cramer DW. Relation of tubal infertility to history of sexually transmitted diseases. Am J Epidemiol 1993;137:577. 6. Zhang ZF, Begg CB. Is Trichomonas vaginalis a cause of cervical neoplasia? Results from a combined analysis of 24 studies. Int J Epidemiol 1994;23:682. 7. Cotch MF, Pastorek JG 2nd, Nugent RP, Hillier SL, Gibbs RS, Martin DH, et al. Trichomonas vaginalis associated with low birth weight and preterm delivery. The Vaginal Infections and Prematurity Study Group. Sex Transm Dis 1997;24:353. 8. Cameron DE, Padian NS. Sexual transmission of HIV and the epidemiology of other sexually transmitted diseases. AIDS 1990;4(Suppl. 1):S99103. 9. Cosar C, Julou L. Activity of 1-(2-hydroxylethyl)-2-methyl-5-nitroimidazole (8823 RP) against experimental Trichomonas vaginalis infection. Ann Inst Pasteur 1959;96:23841. 10. Thurner J, Meingassner JG. Isolation of Trichomonas vaginalis resistant to metronidazole. Lancet 1978;ii:738. 11. Waters LJ, Dave SS, Deayton JR, French PD. Recalcitrant Trichomonas vaginalis infectiona case series. Int J STD AIDS 2005;16:5059. 12. Lossick JG. Chemotherapy of nitro-imidazole resistant vaginal trichomoniasis. Acta Univ Carol Biol 1991;30:53345. 13. Sexually Transmitted Diseases Treatment Guidelines, 2006. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/std/treatment/2006/vaginal-discharge.htm#vagdis3. Accessed October 30, 2007. 14. Lossick JG. Treatment of sexually transmitted vaginosis/vaginitis. [Review] Rev of Infect Dis 1990;12(Suppl):S66581. 15. Sobel JD, Nyirjesy P, Brown W. Tinidazole therapy for metronidazole-resistant vaginal trichomoniasis. Clin Infect Dis 2001;33:13416.

Although Trichomonas vaginalis is the worlds most common non-viral sexually transmitted infection and has been well studied, the exact mechanism of its pathogenesis is not clearly understood. Many mechanisms are thought to be involved, including cell-to-cell adhesion, hemolysis, and the secretion of proteinases in addition to the cell-detaching factor (CDF).34 Trichomoniasis is characterized by a rise in the pH of the vagina from 4 to as high as 7. This change in pH is associated with the loss of acid-producing Lactobacillus, which is usually a part of the normal vaginal flora. The increase in pH creates a better environment for the growth of the Trichomonas parasite.3 An acidic environment also inactivates factors contributing to the pathogenicity of Trichomonas, such as CDF.34 The need for an alkaline environment for the proliferation of Trichomonas vaginalis explains why this disease often worsens with menstruation. By using a process of vaginal acidification, we were able to resolve recalcitrant Trichomonas vaginalis infection in two patients As described in these cases, one patient was treated with a combination of gentian violet, vaginal acidification with boric acid, and clotrimazole, while the other used acidification and clotrimazole. Clotrimazole was used in these regimens because of evidence that it helps to reduce symptoms in patients with recalcitrant trichomoniasis and also reduces the risk of a superimposed yeast infection, but the process of vaginal acidification appears to have resulted in the final cure.23 Boric acid (applied in a gelatin capsule containing 600 mg boric acid) is inexpensive and has minimal

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16. Hager WD. Treatment of metronidazole-resistant Trichomonas vaginalis with tinidazole. Sex Transm Dis 2004;31(6):34345. 17. Njirjesy P, Sobel JD, Weitz MV, et al. Difficult to treat trichomoniasis: results with paromycin cream. Clin Infect Dis 1998;26:9868. 18. Poppe WA. Nitro-imidazole resistant vaginal trichomoniasis treated with paromycin. Eur J Obstet Gynaecol Reprod Biol 2001;96:11920. 19. Ratzan JJ. Monoilial and trichomonal vaginitistopical treatment with povidone-iodine preparations. Calif Med 1969;110:247. 20. Walker PP, Hall RE, Wilson JD. Arsenical pessaries in the treatment of metronidazole-resistant Trichomonas vaginalis. Int J STD AIDS 1997;8:4734. 21. Chen MY, Smith NA, Fox EF, Bingham JS, Barlow D. Acetarsol pessaries in the treatment of metronidazole resistant Trichomonas vaginalis. Int J STD AIDS 1999;10:27780. 22. Watson PG, Pattman RS. Arsenical pessaries in the successful elimination of metronidazole-resistant Trichomonas vaginalis. Int J STD AIDS 1996;7:2967. 23. DuBouchet L, Spence MR, Rein MF, Danzig MR, McCormack, WM. Multicenter comparison clotrimazole vaginal tablets, oral metronidazole, and vaginal suppositories containing sulphanilamide, aminacrine hydrochloride, and allantoin in the treatment of symptomatic trichomoniasis. Sex Transm Dis 1997;24:15660. 24. Schnell JD. The incidence of vaginal candida and trichomonal infections and the treatment of Trichomonas vaginitis with clotrimazole. Postgrad Med J 1974;50:813S. 25. Yu H, Tak-Yin M. The efficacy of povidone-iodine pessaries in a short, low-dose treatment regimen on candidal, trichomonal and non-specific vaginitis. Postgrad Med J 1993;69:55861.

26. Wong CA, Wilson PD, Chear TA. Povidone-iodine in the treatment of metronidazole-resistant Trichomonas vaginalis. Austr N Z J Obstet Gynaecol 1990;30:16971. 27. Mammen-Tobin A, Wilson JD. Management of metronidazole-resistant Trichomonas vaginalisa new approach. Int J STD AIDS 2005;16(7):48890. 28. Bassiouni SO, Riad RM. Nonoxynol 9 as an additive therapy in metronidazole-resistant cases of vaginal trichomoniasis. J Egypt Soc Paras 2005;35(2):55162. 29. Antonelli NM, Diehl SJ, Wright J. A randomized trial of intra-vaginal nonoxynol-9 versus oral metronidazole in the treatment of vaginal trichomoniasis. Am J Obstet Gynecol 2000;182:100810. 30. Houang ET, Ahmet Z, Lawrence AG. Successful treatment of four patients with recalcitrant vaginal trichomoniasis with a combination of zinc sulphate douche and metronidazole therapy. Sex Transm Dis 1997;24(2):1169. 31. Fiori PL, Rappelli P, Addis MF, et al. Trichomonas vaginalis haemolysis: pH regulates a contact-independent mechanism based on pore-forming proteins. Microb Pathog 1996;20(2):10918. 32. Meysick KC, Garber GE. Interactions between Trichomonas vaginalis and vaginal flora in a mouse model. J Parasitol 1992;78(1):15760. 33. Hanna NF, Taylor-Robinson D, Kalodiki-Karamanoli M, Harris JR, McFayden IR. The relation between vaginal pH and the microbiological status in vaginitis. BJOG 1985;92(12):126771. 34. Petrin D, Delgaty K, Bhatt R, Garber G. Clinical and microbiological aspects of Trichomonas vaginalis. Clin Microbiol Rev 1998;11(2):30017.

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