SINCE ITS INTRODUCTION, metronidazole has been an effective agent in the treatment of Trichomonas vaginalis infection. Recalcitrant infection is fortunately uncommon, but causes physical discomfort and handicaps the patient in personal relationships. A variety of therapeutic regimens have been tried and reported, although there seems to be no certain cure.1 Krieger and Rein reported that trichomonads were rapidly killed by zinc salts at physiologic concentrations.2 We report here our experience of an empirical combination regimen of zinc sulfate douching and metronidazole at a moderate dosage in the successful treatment of four patients with longstanding recalcitrant Trichomonas infection.
Materials and Methods
The Combination Therapy
Zinc sulfate 10% solution was prepared with zinc sulfate (Thornton & Ross, Huddersfield, UK) and sterile distilled water in the Pharmacy Department at Queen Charlotte's and Chelsea Hospital. This was dispensed in bottles of 800 ml together with a plastic douche can. The patient was instructed to put in 25 ml of zinc sulfate solution and fill the can (250 ml) with freshly drawn warm water from the tap to the mark on the can to achieve the concentration of 1%, a concentration present in Zinc Sulphate Lotion, which has been used externally as an astringent for indolent ulcers. The patient was advised to sit in the bath before inserting the nostril deep into the vagina gently. She was instructed to withdraw the nostril a little before squeezing the can to release the solution. The douche can should be kept squeezed until it is completely removed from the body, to avoid sucking back. Two canfuls were used for each application. After douching, a metronidazole suppository (500 mg) was inserted into the vagina.
Patients selected for this treatment had documented evidence of recurrent symptomatic trichomoniasis that had not responded to repeated courses of conventional therapy with metronidazole given orally and topically. For selection, there should also be evidence that this chronic recurrence was not due to reinfection from an infected partner.
At each visit, a high vaginal swab was taken with the aid of Cuscoe's speculum. The swab in Stuart's transport medium was sent to the laboratory and examined within 2 hours in the routine manner. The presence of T. vaginalis was determined by microscopic examination of wet preparations of the swab before and after 48 hours' incubation at 35 °C in a cysteine‐peton‐liver‐maltose complete medium (Oxoid; Unipath, Basingstoke, UK). The presence of yeasts, Gardnerella vaginalis, and other potential pathogens was sought by methods as described.3
Between 1985 and 1990, the Pharmacy record showed the combination therapy was used on six patients. Because the case notes of two patients were missing, we report only four here. All patients found the douching procedure acceptable. The solution caused slight irritation (Cases 2 and 3) when there was vaginal inflammation at the beginning of therapy. The irritation was not severe enough for the patient to require diluting the zinc sulfate concentration further. It disappeared by the second or third day of douching. Three of the four patients (Case 1, 2, and 3), although symptom free, used the combination therapy for 2 to 4 days from the last day of menstruation as prophylaxis for 2 to 9 months after their initial therapy. They found the regimen acceptable.
The patient (AB), aged 32 years, was a tertiary referral in February, 1987 with a 3‐year history of recurrent trichomoniasis with greenish vaginal discharge. Numerous courses of metronidazole, sometimes with tetracycline or ampicillin, vaginal application of 1% gentian violet, or povidone‐iodine pessaries gave temporary relief of 2 to 3 weeks only. She did not have a partner and had had no sexual relationship for the previous year. During the first 3 months after referral, she responded to a 10‐day course of oral metronidazole tablets 200 mg three times a day (TDS) and suppository 500 mg per vaginale twice daily, but she relapsed 3 to 4 weeks afterwards, 1 week after menstruation, with severe, culture‐positive Trichomonas vaginitis. Having taken multiple courses of metronidazole, the patient identified the side effects of the drug to be “furred tongue” and “loose stool.” The cervical cytology smear showed a severe inflammatory response. She was then prescribed the combination regimen to be used nightly plus oral metronidazole 200 mg TDS for 10 days (the therapeutic phase). When seen at the end of therapy, her symptoms and signs of vaginitis had much improved and no T. vaginalis was cultured. She was asked to use the combination therapy for 3 nights after menstruation (the prophylactic phase) for next two cycles, at the end of which she was reviewed. She had remained asymptomatic and did not suffer from the mild side effects of the drug with the prophylactic course. The monthly course was reduced to 2 nights after menstruation. Some symptoms recurred, however, 1 month later immediately after menstruation. T. vaginalis was not seen on the wet preparation of vaginal secretion, but cultured. She was advised to use the combination therapy for 7 days, and the course was repeated for 3 nights after menstruation for the next three cycles. She remained asymptomatic and culture negative. The monthly course was reduced to 2 nights, but she relapsed again after the second month. Despite these two relapses, the patient was relatively happy because she had enjoyed being symptom free for a much longer period than with previous therapeutic regimens. It was therefore decided to try a more rigorous course of therapy. She used the combination twice a day for 1 week and then once a day for 2 weeks. She then used only the zinc sulfate douching without the metronidazole suppository on alternate nights. For 3 nights after menstruation, she used the combination therapy again. She remained asymptomatic and culture negative for the next 3 months. The douching was then reduced to twice a week but the combination therapy remained for 3 nights after menstruation for the next 2 months. She then used only the monthly combination therapy for 3 nights for another 2 months. This was reduced to 2 nights after menstruation for two cycles before all therapy was discontinued. She remained asymptomatic for the following 5 months, at the end of which she was reviewed. No clinical, hematologic, or microbiologic abnormality was found, and the cytology smear was negative. She was then discharged from our clinic.
The case histories of the other three patients are summarized in Table 1. At their last review, all patients had remained symptom free with normal clinical examination results and negative microbiologic culture results for T. vaginalis and other vaginal pathogens.
Recalcitrant vaginal trichomoniasis is uncommon. The British Co‐operative Clinical Group (BCCG) in 1989 reported 24 cases from genitourinary clinics throughout the United Kingdom, most of which presented between 1987 and 1989. This figure is likely to be an underestimate.1 Our cases were not included in the BCCG survey, because they were seen as gynecology outpatients in the then Chelsea Hospital for Women (later Queen Charlotte's and Chelsea Hospital). Reinfection by the sexual partner and patient noncompliance should always be considered first as causes of treatment failure. Similar to the experience reported in the BCCG survey, our patients were highly motivated, and we were able to form a close doctor‐patient relationship throughout their period of treatment. We were therefore confident of excluding reinfection and of their compliance with therapy.
T. vaginalis strains resistant in vitro to metronidazole have been described as an important cause of treatment failure.4 Because of lack of expertise, we did not attempt to examine the minimal lethal concentrations of metronidazole for our patients' strains. All of our patients experienced improvement, lasting for days or weeks, together with a negative high vaginal swab culture result immediately after a course of metronidazole therapy. This supports the contention by Lossick et al that resistance to metronidazole was relative and not absolute.5 Some isolates were clinically more resistant than others with similar minimal lethal concentration values. The cure of vaginal trichomoniasis may not simply be a result of a direct relation between the metronidazole susceptibility of the organism and drug dosage, but probably depends on a complex interaction of several factors.5 One limiting factor in the treatment of such cases is the amount of drug that the patient can safely tolerate.5,6 For example, it would not have been ethical to increase the dose of metronidazole for two of our patients (Cases 1 and 4) when they had already experienced side effects, although tolerable, from courses of the drug given before their referral to us.
The exact role of zinc sulfate douching in the successful outcome for our patients is uncertain. The douching per se would reduce the trichomonad population in the vagina and thereby present a smaller inoculum to the antitrichomonal activity of the topical metronidazole applied immediately afterwards. Zinc has been found to have an antitrichomonal activity. Krieger and Rein measured the in vitro zinc sensitivity of 15 clinical isolates of T. vaginalis obtained from different symptomatic women.4 They found the minimal inhibitory concentrations of ZnSO4 and ZnCl2 in the Feinberg‐Whittington medium of 14 isolates were 1.6 mmol/l or 0.027% (Wt/V) (± one twofold dilution), a level below the physiologic concentrations in the prostatic secretions of normal men. They suggested that the zinc present in seminal plasma passing through the anterior urethra could be important in the spontaneous resolution of trichomonal urethritis. The minimal inhibitory concentration of the remaining isolate, described as zinc resistant, was 6.4 mmol/l or 0.11% (Wt/V), a level well below that of the 1% solution used by our patients. Zinc in equimolar concentration enhanced the activity of bacitracin against T. vaginalis by 5 to 10 times.7 Experiments would be necessary to determine whether zinc also enhances the antitrichomonal activity of metronidazole.
We made no attempt to determine the optimal concentration of zinc sulfate solution and the minimal douching regimen required to cure our patients. The schedules used should not be regarded as optimal. Our experience indicates that the combination therapy should be used twice daily during the treatment phase, but the final successful schedule for the first patient might have been unnecessarily rigorous. Nevertheless, after the initial successful treatment, the subsequent monthly treatment after menstruation may be important for the final eradication of the organism. The third patient, who did not have prophylactic combination therapy, experienced a relapse two menstruation cycles later after an apparent cure. But the fourth patient, with a much shorter history, was cured without prophylaxis. The authors speculate that in patients with a chronic history, the initial combination therapy suppresses or damages the trichomonads sufficiently to bring about an apparent clinical and laboratory cure. The milieu in the vagina after menstruation, however, may be particularly favorable for their recovery and multiplication. The repeat courses after menstruation therefore help to ensure the final eradication of the organism.
An association between a low plasma zinc concentration and recalcitrant trichomoniasis has been reported.8 The BCCG report cautioned the use of oral zinc replacement therapy.1 Malabsorption of metronidazole may be a cause of refractoriness to the treatment. Intravenous metronidazole has been used in some cases successfully,1 but not for our patient (Case 2). Potential metronidazole inactivation by other vaginal organisms was proposed as a possible cause of treatment failure.9,10 The combination of metronidazole and antibiotics such as ampicillin, tetracycline, or erythromycin was unsuccessful in our patients, a finding similar to that described by the BCCG.1 Anecdotal experience of success with a variety of other therapies has been reported in the literature, including the use of intravaginal nonoxynol‐9 on one patient5 and povidone‐iodine douche on one patient in each report,1,11 and the use of inactivated Lactobacillus acidophilus vaccination (Gynatren; Cabot, Bucks, UK) on three patients.1 Because of the empirical nature of our therapeutic trials and lack of laboratory data on the metronidazole susceptibility of the isolates, we did not attempt to publish our experience until now. So far, for recalcitrant vaginal trichomoniasis, there seems to be no certain cure. Although we are not certain of the exact role of zinc sulfate douching, the combination therapy apparently achieved a cure in our patients, using only a moderate dose (1.6–2.2 g/day) of oral and per vaginale metronidazole, a dosage that had failed before when used alone. We therefore believe that our combination regimen merits further independent evaluation.
1. British Co-operative Clinical Group. An investigation, by questionnaire, of cases of recalcitrant vaginal trichomoniasis seen in genitourinary medicine clinics in the United Kingdom. Int J STD AIDS 1992; 3:24–27.
2. Krieger JN, Rein MF. Zinc sensitivity of Trichomonas vaginalis:
In vitro studies and clinical implications. J Infect Dis 1982; 146:341–345.
3. Smith JW, Barlett MS. Diagnostic parasitology. In: Balows A, Hausler WJ, Herrmann KL, et al, eds. Manual of Clinical Microbiology. Washington, DC: American Society for Microbiology 1991:701–716.
4. Muller M, Lossick JG, Gorrell TE. In vitro susceptibility of Trichomonas vaginalis
to metronidazole and treatment outcome in vaginal trichomoniasis. Sex Transm Dis 1988; 15:17–24.
5. Lossick JG, Muller M, Gorrell TE. In vitro drug susceptibility and doses of metronidazole required for cure in cases of refractory vaginal trichomoniasis. J Infect Dis 1986; 153:948–954.
6. Livengood CH III, Lossick JG. Resolution of resistant vaginal trichomoniasis associated with the use of intravaginal nonoxynol-9. Obstet Gynecol 1991; 78:954–956.
7. Andrews BJ, Mylvaganam H, Yule A. Sensitivity of Trichomonas vaginalis, Tritrichomonas foetus
and Giardia intestinalis
to bacitracin and its zinc salt in vitro. Trans R Soc Trop Med Hyg 1994; 88:704–706.
8. Willmott F, Say J, Downey D, Hookham A. Zinc and recalcitrant trichomoniasis. Lancet 1983; 1:1053.
9. Edwards DI, Thompson EJ, Tomusange J. Inactivation of metronidazole by aerobic organisms. J Antimicrob Chemother 1978; 6:315–316.
10. Ralph ED, Clarke DA. Inactivation of metronidazole by anaerobic and aerobic bacteria. Antimicrob Agents Chemother 1978; 14:377–387.
11. Wong CA, Don Wilson, Chew TA. Povidone-iodine in the treatment of metronidazole-resistant Trichomonas vaginalis.
Aust N Z J Obstet Gynaecol 1990; 30:169–171.