Trichomonas vaginalis (Trichomoniasis)

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PARASITOLOGY

Trichomonas vaginalisis a flagellated protozoan organism which commonly causes sexually transmitted illness in humans. Discovered in 1836 (12), but only determined to be a human pathogen in the middle of the last century (23, 29), T. vaginalisis now known to cause more than simply urethritis and vaginitis.

ClINICAL MANIFESTATIONS

In men, T. vaginalisis primarily responsible for urethritis, colonization by the organism resulting in an uncomfortable, inflammatory urethral discharge (25). However, sites other than the urethra may be involved (e.g., seminal vesicles), prolonged asymptomatic carriage is common, and spontaneous resolution of urethral colonization may occur in up to a third of infected individuals (26). Rarely, infection may be more parenchymal in location, as in trichomoniasis of the median raphe of the penis (49). It is asymptomatic carriage, obviously, which predisposes to ongoing sexual transmission, since the lack of symptoms precludes the seeking of medical care.

Trichomoniasis in women is primarily thought of as an inflammatory vaginitis, although up to half of women harboring the organism may be asymptomatic (42). Characteristic clinical findings include yellow vaginal discharge, vulvar pruritis, vulvar erythema, and vaginal erythema (55). In pregnant women, trichomoniasis is significantly associated with a yellow, green or bloody vaginal or cervical discharge, abnormal odor after the addition of KOH (positive "whiff test"), vaginal pH of over 5.0, and friability of the cervix (39). In addition, trichomoniasis during pregnancy has been associated with low birth weight and prematurity (8, 20, 24), as well as respiratory disease and vaginitis in the neonate born to a gravida colonized with Trichomonas (9, 33).

Besides prematurity and neonatal infection, trichomoniasis has been shown to increase the intrauterine transmission of cytomegalovirus (17). Further, infection with T. vaginalishas been found to increase the risk of transmission of human immunodeficiency virus (27). Indeed, other species of Trichomonas have also been implicated in illness in immunocompromised individuals (47). Obviously, human trichomoniasis has been recognized in the last decade of the twentieth century as being more important a disease than previously thought.

LABORATORY DIAGNOSIS

Although Trichomonas vaginalis may be cultured in vitro in a number of culture media, most notably Diamond’s medium, the diagnosis is usually made by microscopy of a wet preparation of vaginal secretions or urethral discharge, as culture is more expensive and time-limited. Clinical specimens should be examined mixed with 0.9% normal saline, as well as separately mixed with 10% KOH, to differentiate between and among T. vaginalis, bacterial vaginosis, and vaginal candidiasis ((5). Trichomonas may be evident as a motile protozoan, somewhat larger than a polymorphonuclear leukocyte, with characteristic flagellae. In cases of question as to diagnosis, or possible antimicrobial resistance, cultures should be taken for more extensive testing.

Clinical examination of the patient and the various clinical specimens is a must for the appropriate treatment of trichomoniasis and other types of vaginitis and urethritis. The patient whose practitioner is tempted to "treat over the phone" is doomed to suffer misdiagnosis and ineffective therapy. The telephone has been proven to be an ineffective tool for the diagnosis and treatment of these types of complaints, most notably vulvovaginitis, yielding very poor agreement between practitioners’ diagnoses and microbiologic and microscopic data (1). Patient’s who treat themselves for a yeast infection with over-the-counter antifungals likewise misdiagnose themselves, at the rate of approximately 66% (16).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Trichomonas vaginalis is not susceptible to many of the usual antibiotic medications, as one would expect of a protozoan (46). However, the nitroimidazole family of drugs, which are active against a number of bacterial, protozoal, and helminthic organisms, offers many compounds which are useful now, or show promise for the future, in the treatment of human trichomoniasis (28).

The mechanism of action of the nitroimidazoles compounds against trichomonads depends upon the anaerobic metabolism of the organism. Initially, the parent compound passively diffuses into the cell. Then, the drug is reduced at the nitro group by anaerobic cellular metabolism. In the presence of molecular oxygen, this reduction would be reversed, since oxygen is a ready electron acceptor. Thus, in order to have significant cell damage, anaerobic metabolism must be in force. The reduced nitro group produces damage to DNA causing strand breakage and cell death, disrupts of electron flow, and increases in the gradient of unreduced drug, thus facilitating more passive diffusion of the compound into the cell (14).

Metronidazole

The standard nitroimidazole agent used for trichomoniasis for many years has been metronidazole.Susceptibility of Trichomonasto metronidazole can be determined under aerobicor anaerobic conditions. Generally, the presence of oxygen causes higher minimum lethal concentrations (MLCs), since the presence of oxygen prevents the reduced nitro group from causing cellular damage. In fact, one suspected mechanism of resistance of the organism to the nitroimidazoles is tolerance to oxygen, i.e., allowing higher concentrations of oxygen within the cell, providing more electron sinks to prevent reduction of the parent drug (15). Thus, one measure of clinically significant metronidazole resistance is an elevated aerobic MLC, or more specifically an elevated aerobic/anaerobic MLC ratio (31, 35).

Most strains of Trichomonas vaginalisare clinically susceptible with MLCs in the range of 0.5-32 µg/ ml, based upon aerobictesting conditions (10).However, since 1962, metronidazole resistance has been demonstrated among trichomonads (43). In the U.S., the rate of metronidazole-resistance T. vaginalishas been consistently less than 5%, with most isolates only exhibiting low level resistance (44).

Based upon in vitrotesting under aerobicconditions, the resistance of Trichomonasto metronidazole has been stratified as follows (32):

susceptible MLC < 50 µg/ml
marginal resistance MLC = 50 µg/ml
mild resistance MLC = 100 µg/ml
moderate resistance MLC = 200 µg/ml
severe resistance MLC > 200 µg/ml

One caveat, however, is that these measured MLCs, based upon aerobic in vitrotesting, are not indicative of the necessary blood or tissue levels of drug necessary for clinical efficacy, as is generally understood for usual bacterial minimum inhibitory concentrations (MICs) in determining dosing of an antibiotic. Often, laboratory resistance does not correlate with clinical antibiotic susceptibility (44). Therefore, much of the dosing knowledge of metronidazole has been determined empirically, accumulated as the collected wisdom of the medical community experienced in the treatment of human trichomoniasis.

Other Drugs

Other nitroimidazole compounds have been shown to be active against Trichomonas vaginalis. Tinidazole appears to be about as active, with sensitive aerobicMLCs<25 µg/ml. Metronidazole resistant strains are generally resistant to tinidazole as well, with MLCs>50 µg/ml (36), though some metronidazole-resistant strains will respond clinically to tinidazole (22, 48).Ornidazole, a nitroimidazole with pharmacokinetic parameters lending themselves to single (1.5 gm oral) dose administration, has been shown to be effective in human trichomoniasis (18), as has been (4.0 gm in divided doses of) nimorazole (6). Other compounds with activity similar to metronidazole are under investigation (13).

Older imidazole drugs, which have been developed in topical form for such maladies as vaginal candidiasis, have some activity against trichomonads, though the MLCs are somewhat higher than that of metronidazole. Interestingly, however, the topical application of such drugs as clotrimazole has been used to augment the activity of systemic metronidazole, in order to achieve synergistic activity against metronidazole-resistant strains (10).

Some alternative chemical species have been investigated for trichomoniasis, especially in view of the presence of resistant organisms. The nitrofuran drug furazolidone has been shown to be active against Trichomonas vaginalis, with MLCs in the range of 0.8 µg/ml-3.1 µg/ml, even for organisms with metronidazole and tinidazole MLCs in excess of 200 mg/ml (36).Another drug, purpuromycin, a naphtharazin-isocoumarin compound, as well as some of its semi-synthetic derivatives, has been shown to be active (MLC<25 µg/ml) in vitroagainst Trichomonas vaginalis (19).Clinical efficacy has been demonstrated with the aminocyclitol paromomycin, given as a vaginal cream, in a case of nitroimidazole-resistant trichomoniasis, although side effects are somewhat disconcerting.And a rather archaic therapy, arsenic, has been used successfully to treat resistant trichomoniasis (37, 41). Arsenicals were used for Trichomonasinfection before the availability of the nitroimidazole drugs. Thus, it is not surprising that arsenical pessaries would be ef cacious in the therapy of vaginitis due to highly nitroimidazole-resistant Trichomonas(54).

It is interesting to note that not only does Trichomonasvaginalis develop resistance to the various antiprotozoal compounds by becoming more tolerant to oxygen, hence less anaerobic and less sensitive to the nitroimidazole drugs, but the organism, being motile, may actually run away from toxic chemicals. Trichomonasdisplays chemorepulsion activity very shortly after exposure to various toxic agents, allowing the organism to avoid cidal concentrations of drug (52). In fact, the more toxic the compound, the more evasive chemotaxis exhibited by the protozoan. This would explain the inability of topical preparations (e.g., clotrimazole vaginal cream) to cause much more than symptomatic relief in patients with trichomonal vaginitis. It would also explain the poor efficacy observed when topical metronidazole is compared to systemic administration of the drug (53).

Work is still being done on vaginal therapies, including a promising metronidazole/ miconazole vaginal pessary for multiple vaginitis organisms (38). Less-than-promising, however, was a study of women with documented motile trichomonads found on a wet preparation randomly assigned to either a single oral dose of 2 g metronidazole or a single 150-mg nonoxynol-9 suppository placed intravaginally for 3 consecutive nights (2). The study was terminated prematurely because of the poor efficacy of the nonoxynol-9 suppositories. Patients treated with nonoxynol-9 and negative wet preparation results at retest demonstrated a 17.6% cure rate, while all 16 patients treated with metronidazole had negative wet preparation results (100% cure rate). All women with nonoxynol-9 failures who were evaluated after treatment with 2 gm metronidazole had negative wet preparation results.

ANTIPARASITIC THERAPY Guided Medline Search Smart search

Metronidazole remains the drug of choice for the treatment of human trichomoniasis. It is the only antitrichomonal medication available in the United States, though other nitroimidazoles, such as tinidazole, are available in Canada and Europe.Metronidazole has excellent bioavailability when given orally, essentially 100%, and it is readily distributed throughout most of the body.The major toxicity of metronidazole is its disulfuram-like effect, consisting of tachycardia, flushing, nausea and vomiting, when taken with ethanol. As well, metronidazole and disulfuram taken together may induce an acute psychosis. At higher dosages, such as those over 2 gm/day used when treating nitroimidazole-resistant strains of T. vaginalis, metronidazole may cause gastrointestinal upset, metallic taste in the mouth, and peripheral neuropathy. The urine may also become darkly colored (45).

Several metronidazole dosing regimens are recommended for the treatment of uncomplicated trichomoniasis caused by metronidazole-sensitive organisms. The current recommendations by the Centers for Disease Control (5) include:

metronidazole 2 g orally in a single dose

-RECOMMENDED
metronidazole 500 mg orally twice daily for 7 days

-ALTERNATE

An older, slightly different regimen, metronidazole 250 mg orally thrice daily for 7 days, has also been used, with efficacy similar to the single dose regimen (21). The U.S. Food and Drug Administration has approved a 375 mg twice daily dose of metronidazole for seven days of treatment, based on the pharmacologic equivalence of this and the 250 mg thrice daily dose. No clinical study has demonstrated the equivalence, however (5). The lowest effective single dose of metronidazole has been shown to be 1.5 gm orally, given once (51).

In any case, patients being treated for trichomoniasis should be instructed to avoid sexual intercourse until they and their partners are cured (5), although such barrier methods as the female condom have been shown to prevent transmission of the organism (50). Simultaneous treatment of the partner is recommended to prevent reinfection (5). If this is accomplished, all of these regimens are said to be 85-95% effective.

Treatment with vaginal metronidazole gel, while effective for the therapy of bacterial vaginosis, is not recommended for trichomoniasis (5, 53).Investigators continue to search for an effective topical therapy, however. A Turkish study investigated the efficacy of vaginal pessaries containing metronidazole 500 mg and miconazole nitrate 100 mg, for the treatment of candidiasis, bacterial vaginosis and trichomoniasis and in mixed vaginal infections (38). Clinical cure was obtained in 91% of the 74 patients evaluated, with improvement in another 7%. Microbiological cure rates were 97.3% for trichomoniasis, 86.6% for bacterial vaginosis and 81% for candidiasis. Recurrence rates were 2.7, 3.8 and 16.1%, in the respective groups. Overall microbiological cure rate for mixed infections was 86%, with 93% for trichomoniasis plus bacterial vaginosis, and 73% for bacterial vaginosis plus candidal vaginitis. In two out of three cases with all three conditions, the microorganisms were eradicated completely.

Special Considerations

Metronidazole-Resistance:Should the practitioner suspect metronidazole resistance or tolerance, there are several metronidazole dosing alterations which can be utilized. The CDC recommends metronidazole at an oral dose of 2 gm daily for 3-5 days (5). One alternative, which attempts to achieve higher blood and tissue levels than oral administration, is intravenous metronidazole given as a 2 gm loading dose and one gram intravenously every six hours for 24 hours, followed by an increase to 2 gm orally every six hours for 36 hours. In the patient treated by this protocol, a serum level of 110 µg/ ml was reached, significantly higher than the 40 µg/ ml attained by an oral 2 gm dose (11). The shortcoming of this strategy is the adverse symptoms attendant to high blood levels of drug (although this patient failed to demonstrate any adverse event save mild nausea).

Other therapeutic strategies include simultaneous use of oral and vaginal metronidazole, use of an imidazole cream vaginally along with oral metronidazole, or the use of another of the nitroimidazole medications (e.g., tinidazole), though none of these strategies are well studied, and no other drugs have been approved in the United States for the treatment of trichomoniasis.

One recent US study reported a cure rate of 22 (92%) of 24 patients with refractory trichomoniasis treated with high doses of oral and vaginal tinidazole (48). This series included 15 cases with increased in vitro MLC values of metronidazole. Tinidazole, despite the high doses used, was extremely well tolerated, with few side effects.

Topical paromomycin as been found to be modestly effective in patients with resistant trichomoniasis, but frequent and occasionally severe local vulvovaginal adverse reactions preclude extensive use (41, 48).

Metronidazole Allergy:If a patient with trichomoniasis is allergic to metronidazole, the CDC offers no alternative therapy (5). Other appropriate drugs would be hard to find, since true allergy to any one of the nitroimidazoles would probably mean a high degree of cross-allergenicity (e.g., to tinidazole). However, there has been at least one attempt at desensitizing patients with metronidazole allergy which shows promise. Women were treated with graduated, increasing doses in the microgram range over a period of several hours, followed by increasing doses of oral tablets culminating in a 2 gm dose. No ill effects were noted, and the patients were cured of their infestation (40).

Pregnancy:Since pregnancy can be adversely affected by trichomoniasis, the general trend in recent years has been treatment of trichomoniasis during pregnancy when ever it is discovered. The theoretic drawback to the use of metronidazole during pregnancy has been the threat of teratogenicity, since metronidazole has been shown to be mutagenic in bacterial experimental systems and carcinogenic and tumorigenic when given to rats and mice at high doses. However, this has not been found to be a problem in humans (45). Meta-analysis confirms that the entire human experience with metronidazole in pregnancy has been relatively uneventful (4).

Previously, the CDC recommended withholding metronidazole during the first trimester, to obviate the need even to worry about possible effects on the infant. Current recommendations do not mention this caveat (5). However, the CDC currently notes that treatment of trichomoniasis with metronidazole during pregnancy is only indicated for symptomatic relief, not for the prevention of adverse pregnancy outcome due to the infection (5).

Although it is apparent that trichomoniasis is associated with preterm delivery (8, 30), a recent randomized trial (24) assigned 617 women with asymptomatic trichomoniasis who were 16 to 23 weeks pregnant to receive two 2-g doses of metronidazole (320 women) or placebo (297 women) 48 hours apart, with retreatment with the same two-dose regimen at 24 to 29 weeks of gestation. Trichomoniasis resolved in 249 of 269 women for whom follow-up cultures were available in the metronidazole group (92.6 percent) and 92 of 260 women with follow-up cultures in the placebo group (35.4 percent). Interestingly, delivery occurred prematurely (before 37 weeks of gestation) in 60 women in the metronidazole group (19.0 percent) and 31 women in the placebo group (10.7 percent), attributable primarily to an increase in preterm delivery resulting from spontaneous preterm labor. Therefore, treatment of pregnant women with at least asymptomatic trichomoniasis does not prevent preterm delivery. Routine screening and treatment of asymptomatic pregnant women for this condition could not be recommended by the investigators, although treatment of symptomatic illness would still be pursued. The story is yet unfolding.

HIV Infection:Patients infected with HIV are recommended to the same therapeutic regimens as those who are HIV-negative (5).

ENDPOINTS FOR MONITORING THERAPY Guided Medline Search

According to the CDC, patients who become asymptomatic following treatment need no follow up. However, if symptoms persist, or there is any other reason to suspect relapse or reinfection, reexamination is recommended and retreated with the 7 day regimen. The practitioner should be wary, however, of the possibility of a metronidazole-resistant or tolerant strain of Trichomonas. In fact, in cases such as this, the CDC recommends consultation with an expert, and metronidazole susceptibility studies should be performed (5).

VACCINES Guided Medline Search

There are no vaccines available against trichomoniasis in humans. However, a bovine model of trichomoniasis has been developed for study of mechanisms of immunoprophylaxis (7). Systemic and local immunization with an immunoaffinity purified antigen cleared the genital tract of trichomonads of infected cows significantly earlier than non-immunized controls. Investigators found that predominantly IgA responses or predominantly IgG responses in uterine and vaginal secretions were essentially equally protective, and uterine and vaginal IgA responses could be induced by systemic priming and local boosting via either the vaginal or nasal mucosa. In either case, lymphoid aggregates were formed in the uterine and vaginal mucosa which were not present in the genital mucosa of uninfected and unexposed animals. The researchers concluded that systemic immunization or systemic priming with local boosting protects against bovine trichomoniasis via IgG or IgA antibodies (respectively) to a major trichomonal surface antigen, and immunization of the genital mucosa results in formation of inductive sites for a local IgA response.

PREVENTION Guided Medline Search Smart search

Trichomoniasis is an important human disease, affecting over 170 million people. Importantly, infection with Trichomonas vaginalismay increase the spread of HIV infection (26). Computer modeling has demonstrated that treating only those with symptoms of disease had minimal effect upon the endemic prevalence of disease even at high levels of coverage, while identification of individuals with both symptomatic and asymptomatic infection is the most efficient method of control, but was sensitive to the screening interval (3). The control of trichomoniasis is probably a success in developed countries because of the regular access to health care, whereas trichomoniasis has remained endemic in many developing countries because control may only be possible by less regular symptomatic treatment. A large investment in services may be necessary for success in controlling trichomoniasis.

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