In 1836, Donne described the protozoan Trichomonas vaginalis. In 1936 Hohne demonstrated the relationship between the presence of Trichomonas vaginalis in the vagina and symptoms localized to the vagina, such as increased vaginal discharge. In 1940, Trussell and Plass inoculated the vaginas of healthy volunteers with pure cultures of Trichomonas vaginalis and established acute symptomatic vaginitis. This fulfilled Koch’s postulates. In 1947, Trussell published a monograph on Trichomonas vaginalis describing infection of the lower genital tract. Subsequent to the work of Trussell, Trichomonas vaginalis has been the subject of intense study because of the suspected related infectious complications associated with vaginal trichomoniasis, including premature labor, premature rupture of amniotic membranes (PRAM), postoperative pelvic infections, and salpingitis.
Although effective antimicrobial therapy (metronidazole) has been available in the United States since 1963, urogenital trichomoniasis continues to be one of the world’s most prevalent sexually transmitted diseases (STD). This is because the patients can have either asymptomatic infection or the presence of persistent and chronic recurring infection. In rare instances, the patient may be allergic to metronidazole. The absence of effective alternatives to be used in these patients can result in the failure to eradicate the trichomonads. Finally, the emergence of Trichomonas vaginalis strains resistant to metronidazole, although rare, has been documented. Trichomonads that parasitize humans are unique because each species occupies a specific anatomical site in the host. Each species also has a distinct structure, function, and relationship with its host. Trichomonas vaginalis adapted to the vaginal environment of pregnant women, and infection during pregnancy is associated with an increase in the severity of symptoms, but the reason for this increase in symptomatic infection has not been defined. Trichomonas vaginalis has been recognized for decades as a significant vaginal pathogen and continues to be a perplexing problem. The lifecycle of this organism has not been delineated, while the pathophysiology of symptomatic and asymptomatic infection is not understood. A significant area yet to be elucidated is the interaction of Trichomonas vaginalis with endogenous microbes of the lower genital tract. Is there a relationship between Trichomonas vaginalis and other microbes with regard to infections of the lower and upper genital tract? Does Trichomonas vaginalis play a role in pelvic inflammatory disease (PID), infertility, PRAM, premature labor, or postoperative pelvic infections? While vaginitis and vaginosis are the most common problems the gynecologist addresses in the ambulatory setting, the incidence of trichomoniasis appears to have decreased in the United States and Scandinavia. In 1995, the World Health Organization estimated that there were 170 million cases of trichomoniasis in the world.
The standard treatment for uncomplicated Trichomonas vaginalis vaginitis is oral metronidazole. Oral, or in rare instances parenteral, metronidazole is preferred to intravaginally administered metronidazole because the trichomonads commonly infect other sites in the lower genital tract. Successful treatment of the infected woman also depends upon removing her exposure to a contaminated or infected partner. Therefore the sexual partner, male or female, must also be treated. Prevention of transmission is accomplished by prohibiting infected penile or vaginal discharge from coming in contact with the partner’s genitalia.
Management of the sexual partner is of paramount importance if the patient under treatment is to be cured of her infection. All people who have come into contact with the infected patient should be treated, and if possible treatment should occur simultaneously among all potentially infected individuals. If this cannot be accomplished, the patient in question should refrain from sexual intercourse until her partner or partners can be treated. If the woman’s partner takes metronidazole and the woman is shown to be cured of her infection, but subsequent to having sexual intercourse becomes infected, then it can be assumed that her partner may have a prostate infection. Of course, this is based on the following: (1) she has not had sexual intercourse with a different partner; (2) he has not had sexual intercourse with a different partner; and (3) he has taken a full course of therapy. Males who develop trichomoniasis of the prostate gland require a prolonged course of metronidazole treatment. Prostate infection with Trichomonas vaginalis was first demonstrated in 1936 in expressed prostatic fluid obtained from husbands of women infected with Trichomonas vaginalis. Isolation of trichomonads from men who have had sexual intercourse with women infected with Trichomonas vaginalis ranges from 9 to 10%. Interestingly, in males diagnosed with urethritis but failing to respond to several courses of antibiotics not active against Trichomonas vaginalis, 85% were subsequently found to be infected with the protozoan. However, one difficulty with these studies was that the patients were not evaluated for the presence of N. gonorrhoeae, C. trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, or HSV.
It may be that infection in the male tends to be asymptomatic and it is often difficult to document the presence of a protozoan. Several studies have demonstrated the presence of Trichomonas vaginalis in asymptomatic husbands and the sexual partners of infected women. In one investigation, 30 husbands of infected women were cultured; 60% of the husbands were found to be positive for Trichomonas vaginalis and 61 % of the males were asymptomatic. The percentage of male sexual contacts of infected women who subsequently develop symptomatic urethritis and are found to be positive for Trichomonas vaginalis ranges from 16 to 83%.
Sexual partners treated simultaneously may not respond in a similar manner. The trichomonads present in all infected tissue may not all be killed, and adequate levels of metronidazole may not be achieved in sufficient concentration in all infected tissues. The male infected with Trichomonas vaginalis possesses significant problems, for example, treating the infected prostate gland is often difficult and requires prolonged administration of metronidazole. Infection in the male may involve various sites, like the epididymis, posthitis (infection of the foreskin), balanitis (infection of the glans penis), and may result in draining sinus of the median raphe. Infection in males also appears to occur easily. In 1963 Weston and Nicol examined male sexual partners 2 days after being exposed to infected females and recovered Trichomonas vaginalis from 70% of the males. Interestingly, increasing the time between sampling of the male and exposure correlated with a decrease in recovery rate of the protozoan. Only 30% of the exposed males had positive Trichomonas vaginalis cultures when sampled 14 days after exposure to an infected female. Thirty days following exposure, only 23% of the males remained positive and subsequent examination failed to recover trichomonads. Trichomonas vaginalis in males can be summarized thus:
(1) symptomatic infection is common;
(2) males exposed to infected females should be considered colonized, whether symptomatic or asymptomatic;
(3) symptomatic male infection is typically diagnosed as urethritis and these individuals typically have a purulent discharge; and
(4) prostatitis is uncommon.
Thus, a physician responsible for the health of women should remember that all women with documented vaginal trichomoniasis should be considered a vector for the transmission of Trichomonas vaginalis. Finally, when treating a woman for vaginal trichomoniasis it is imperative that her sexual partners be treated, whether they are symptomatic or not.
The only anti-trichomonal agent approved for use in the United States is metronidazole, which was approved for use in 1963. An azomycin, a nitroimidazole drug, isolated from a species of Streptomjces lead to the discovery of synthetic agents that have activity against Trichomonas vaginalis. Metronidazole was one of these agents and it was subsequently found to have activity against Giardia lamblia, and can also be used in the treatment of amebiasis. Theanaerobic activity of metronidazole was discovered accidentally: a woman was treated with metronidazole for vaginal trichomoniasis and she was also known to have acute ulcerative gingivitis that simultaneously responded to the treatment for vaginal trichomoniasis. Davis and co-workers confirmed that metronidazole was effective in the treatment of Vincent’s stomatitis and the drug inhibited Fusobacterium necrophorum.
Nitroimidazole available in countries other than the United States are: nimorazole (Nagogin), tinidazole (Fasigyn), ornidazole, secnidazole, carnidazole, and misonidazole. Tinidazole is similar to metronidazole in its spectrum of activity against parasites and obligate anaerobic bacteria. The minimum trichomonicidal concentration is lower than that for metronidazole. Trichomonas vaginalis resistant to metronidazole are usually resistant to tinidazole, but there have been reports of strains resistant to the former agent but sensitive to tinidazole.
Metronidazole, when taken orally, is almost completely absorbed by the gastrointestinal tract and approximately 95% of this antimicrobial agent is bioavailable. The serum half-life is approximately 8.5 h. Peak serum levels are reached 1 — 3 h after oral administration. If metronidazole is taken after a meal, absorption is delayed and peak serum levels are not reached for 3 h. Metronidazole is metabolized by the liver into at least five different metabolites. Approximately 20% of the daily dose is excreted in the urine and feces. Studies have demonstrated small amounts of mutagenic derivatives and an acetamide have been found in the urine of patients receiving metronidazole. When metronidazole is administered vaginally as a cream or suppository, absorption occurs with peak levels of 0.2 ng/ml within 12 — 24 h of a S00 mg dose. Absorption is greater when metronidazole is in cream form as opposed to a suppository. Adverse effects associated with metronidazole are listed in the Table Adverse effects of metronidazole:
|1. Nausea||6. Dizziness|
|2. Vomiting||7. Seizures|
|3. Gastric distress||8. Peripheral neuropathy|
|4. Metallic taste||9. Ataxia|
|5. Headache||10. Disulfram-like reaction|
Patients receiving metronidazole therapy should be strongly advised not to imbibe alcoholic beverages, or take medication containing alcohol, because they may develop severe abdominal pain (a disulfiram-like reaction). Individuals taking anticonvulsant medication or warfarin should be warned that metronidazole could enhance the action of these medications.
The standard regimens for trichomoniasis treatment are based on the assumption that the organism is likely to infect the vagina, urethra, bladder, Skene’s glands, and Bartholin’s glands; therefore, metronidazole should be administered via a route that will achieve adequate serum and tissue levels. The most expedient and inexpensive route is oral. The standard dosing regimens are 2 g administered as a single dose; 2S0 mg three times a day or S00 mg twice a day for 7 days. Some physicians favor the 2-g single oral dose regimen because it can be taken once so compliance is greater. However, this can cause considerable gastric distress. When trichomoniasis is diagnosed accidentally, perhaps by Pap smear, the patient should be examined and the diagnosis confirmed. If the patient is not treated, she may serve as a vector for Trichomonas vaginalis transmission and is likely to experience acute exacerbations of infection. She is also likely to develop an abnormal Pap smear in the future. If she is treated but does not have trichomoniasis, she is being unnecessarily exposed to an antibiotic. If the exposed male is left untreated, he may infect approximately 24% of the women with whom he has had sexual contact.
Metronidazole has been effective in the treatment of Trichomonas vaginalis and most strains are sensitive to concentrations of less than 1 — 16 µg/ ml. Under normal anaerobic concentrations most strains of Trichomonas vaginalis are sensitive to metronidazole at a concentration of 3 µg/ml or less, and under aerobic conditions sensitivity occurs at a concentration of 25 µg/ml or less
Although Trichomonas vaginalis has remained relatively sensitive to metronidazole, resistance to this antimicrobial agent has been reported. In one study, vaginal fluid was obtained from 911 women; Trichomonas vaginalis was detected in 82 (9%), and two isolates were found to have a low-level resistance to metronidazole. Some investigators have found patients infected with resistant strains but were able to treat these patients successfully by increasing the dose of metronidazole. Patients who appear to have intractable or resistant trichomoniasis should be managed by first having the organism isolated and its sensitivity or resistance to metronidazole determined. Isolates that have an aerobic minimal lethal dose (MLD) greater than 50 µg/ml but lower than 200 µg/ml will be moderately sensitive; those with an MLD over 200 µg/ml will be resistant. Thus, patients with moderate sensitivity to metronidazole may be successfully treated with a total daily dose of 2 — 3.5 g per day for 7 — 14 days. Oral and vaginal administration of metronidazole can be combined for treatment. In cases where higher doses of oral metronidazole cannot be tolerated, the drug can be given intravenously. Metronidazole doses exceeding 2 g per day can induce nausea, vomiting, gastrointestinal discomfort, headache, peripheral neuropathy, and seizures that usually appear within 72 h of beginning treatment (Table Recommended treatment regimens).
Table Recommended treatment regimens
|Metronidazole 2 g orally administered as a single dose|
|Metronidazole 500 mg administered twice daily for 7 days|
|Pregnant patients: metronidazole 2 g in a single dose|
Patients who continue to demonstrate a failure to respond to metronidazole, even at higher doses, can be treated with tinidazole.
Although tinidazole is not currently available in the United States, it can be obtained in Canada; however, it is expected that tinidazole will become available in the United States in the near future. Sobel and co-workers reported that tinidazole therapy was successful treatment for refractory trichomoniasis in 22 of 24 patients.
Metronidazole and tinidazole are not themselves active or cytocidal against Trichomonas vaginalis, but their metabolic products are active agents. Metronidazole enters the protozoan through diffusion and is activated in the hydrogenosomes of the organism. The nitro group is reduced anaerobically by the enzyme pyruvate-ferredoxin oxidoreductase. This reaction yields cytotoxic nitro radicalion intermediates that break DNA strands of the protozoan. In Fitrostudies have demonstrated also that the effect of metronidazole on Trichomonas vaginalisis rapid, causing cessation of cell division and motility within 1 h, while cell death occurs within 8 h of exposure to the drug.
Treatment in the pregnant patient
Some investigators have attempted to demonstrate an association between Trichomonas vaginalis vaginitis, PRAM, and premature delivery. However, other investigators failed to show any association between Trichomonas vaginalis vaginitis and poor pregnancy outcome. Thus, the significance of Trichomonas vaginalis vaginitis in pregnant and non-pregnant women, especially those who are to have pelvic surgery, most likely rests in the fact that these women have an altered vaginal microflora. Whether or not Trichomonas vaginalis vaginitis has an adverse effect on pregnancy outcome will most likely remain unresolved because this protozoan infection is associated with, and probably is responsible for, the alteration in vaginal flora. The shift in vaginal flora can be skewed towards a Gram-positive, Gram-negative facultative, or obligate anaerobic bacteriology. Significant increases in the pathogenic vaginal endogenous flora can, and does, result in an increased risk for postpartum endometritis and post-hysterectomy pelvic cellulitis and abscess formation. Screening symptomatic pregnant patients by either wet mount or culture is beneficial, whereas when asymptomatic patients were screened, culture (94.5%) proved to be better than wet mount (70%). These investigators also found that in the inner-city population in Denver, Colorado, 9.4% of 1175 pregnant women had Trichomonas vaginalis vaginitis. Approximately 18.2% of the 110 infected women complained of symptoms consistent with vaginitis. Both pregnant and non-pregnant women complaining of symptoms associated with vaginitis should be thoroughly evaluated. However, at the individual’s first prenatal visit, in an attempt to enhance the patient’s ability to maintain the pregnancy, it is in the patient’s best interest to evaluate the vaginal ecosystem. This can be easily done by the physician determining the vaginal pH. If the pH is 4.5 or higher, a wet prep should be obtained and examined microscopically. The presence of WBC (> 5/hpf) should be an indication to determine if Trichomonas vaginalis infection is present. Cervical specimens for the detection of C. trachomatis and N. gonorrhoeae should also be obtained.
Treatment of the pregnant patient with Trichomonas vaginalis vaginitis is no different than treatment of the non-pregnant patient. Struthers published a review of metronidazole use in pregnancy over approximately four decades and found that the drug did not have a teratogenic effect, no matter in which trimester it was taken.
One of the studies reviewed by Struthers was by Rosa and co-workers, who used a database of 104 339 pregnant women who delivered normal babies and 6564 infants with anomalies. Among these women, 1083 received metronidazole in the first trimester. Of these, 1020 were normal and 63 had some anomaly. The relative risk of an abnormality being associated with metronidazole was 0.92.
Pregnant women can be treated safely for trichomoniasis with metronidazole in the first, second, and third trimesters. However, when administering any therapeutic agent to a pregnant woman the risk-benefit ratio must be determined. An asymptomatic pregnant woman who’s Pap smear indicates the presence of Trichomonas vaginalis should be evaluated to determine if she indeed has vaginal trichomoniasis. If the patient is proven to harbor Trichomonas vaginalis, but is asymptomatic, one may elect to hold off on therapy until the second trimester, but consideration must be given to the possibility of an increased risk of abortion.
Selections from the book: “Vaginitis: Differential Diagnosis and Management” (2003).