The Association Between Human Immunodeficiency Virus and Bacterial Vaginosis and Metronidazole Treatment Failure for Trichomonas vaginalis.

BACKGROUND: Trichomonas vaginalis (TV) is a common sexually transmitted infection. High rates of repeated infections have been observed, particularly among women living with human immunodeficiency virus (HIV). Trichomonas vaginalis frequently cooccurs with bacterial vaginosis (BV). The purpose of this study was to determine if coinfections with TV, BV, and HIV could lead to differential treatment failure outcomes. METHODS: Data were pooled from 2 prior randomized control trials comparing 2 g oral single-dose versus 500-mg twice daily oral 7-day dose metronidazole for the treatment of TV in HIV infected and HIV uninfected women. Trichomonas vaginalis rates 1-month postcompletion of treatment were compared by arm, HIV and BV status after removing those who had sexual reexposure, and/or did not complete their treatment. RESULTS: Data for 795 subjects were included in the study, of which 76 (9.6%) experienced treatment failure. In the final multivariable model, which included treatment dose, HIV status, and BV status, odds of treatment failure infection in the 7-day dose group were lower than the odds in the single dose group (odds ratio, 040; 95% confidence interval, 0.23-0.68). Treatment failure was lower in the multidose arm compared with single dose for both HIV-infected (4.0% vs 10.3%; P = 0.0568) and HIV-uninfected (7.3% vs 15.4%; P = 0.0037). Neither HIV nor BV was associated with higher treatment failure. CONCLUSIONS: Human immunodeficiency virus infection and BV status did not significantly alter the rate of repeat infection for either single dose or 7-day dose metronidazole. Among all women, 7-day metronidazole lowered the odds of treatment failure.

Infectious Vaginitis, Cervicitis, and Pelvic Inflammatory Disease.

Vaginal symptoms are one of the most common reasons women consult with physicians and can significantly impact quality of life. The differential diagnosis of vaginal discharge includes physiologic discharge, vaginitis, cervicitis, and pelvic inflammatory disease (PID). Vaginitis is inflammation of the vagina, most commonly caused by bacterial vaginosis (BV), vulvovaginal candidiasis, and trichomoniasis infections. Cervicitis is an inflammation of the cervix and typically caused by Chlamydia trachomatis and Neisseria gonorrhoeae. PID is infection of the female upper genital tract, involving the uterus, fallopian tubes, ovaries, and/or pelvic peritoneum and usually caused by Chlamydia trachomatis, Neisseria gonorrhoeae, and bacterial vaginosis-associated pathogens. A pelvic exam should be performed for any woman presenting with vaginal discharge to confirm the diagnosis and rule out an upper tract infection. BV and vulvovaginal candidal infections only require treatment if symptomatic and do not require partner therapy, whereas treatment and partner therapy is recommended for sexually transmitted illnesses, such as trichomoniasis, chlamydia and gonorrhea. Vaginitis may be uncomfortable, but rarely leads to serious long-term consequence, but pelvic inflammatory disease can lead to serious long-term sequelae, including increased risk for ectopic pregnancy, infertility, and chronic pelvic pain.

Diagnosis and Management of Trichomonas vaginalis: Summary of Evidence Reviewed for the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines.

Trichomonas vaginalis is likely the most prevalent nonviral sexually transmitted infection, affecting an estimated 3.7 million women and men in the United States. Health disparities are prominent in the epidemiology of trichomoniasis, as African Americans are >4 times more likely to be infected than persons of other races. Since publication of the 2015 Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines, additional data have bolstered the importance of T. vaginalis infection sequelae in women, including increased risk of human immunodeficiency virus (HIV) acquisition, cervical cancer, preterm birth, and other adverse pregnancy outcomes. Less is known about the clinical significance of infection in men. Newly available diagnostic methods, including point-of-care assays and multiple nucleic acid amplification tests, can be performed on a variety of genital specimens in women and men, including urine, allowing more accurate and convenient testing and screening of those at risk for infection. Repeat and persistent infections are common in women; thus, rescreening at 3 months after treatment is recommended. In vitro antibiotic resistance to 5-nitroimidazole in T. vaginalis remains low (4.3%) but should be monitored. High rates of T. vaginalis among sexual partners of infected persons suggest a role for expedited partner treatment. A randomized controlled trial in HIV-uninfected women demonstrated that multidose metronidazole 500 mg twice daily for 7 days reduced the proportion of women with Trichomonas infection at 1 month test of cure compared with women receiving single-dose therapy (2 g). The 2-g single-dose oral metronidazole regimen remains the preferred treatment in men.

Diagnosis and Treatment of Sexually Transmitted Infections: A Review.

Importance: Approximately 1 in 5 adults in the US had a sexually transmitted infection (STI) in 2018. This review provides an update on the epidemiology, diagnosis, and treatment of gonorrhea, chlamydia, syphilis, Mycoplasma genitalium, trichomoniasis, and genital herpes. Observations: From 2015 to 2019, the rates of gonorrhea, chlamydia, and syphilis increased in the US; from 1999 to 2016, while the rates of herpes simplex virus type 1 (HSV-1) and HSV-2 declined. Populations with higher rates of STIs include people younger than 25 years, sexual and gender minorities such as men and transgender women who have sex with men, and racial and ethnic minorities such as Black and Latinx people. Approximately 70% of infections with HSV and trichomoniasis and 53% to 100% of extragenital gonorrhea and chlamydia infections are asymptomatic or associated with few symptoms. STIs are associated with HIV acquisition and transmission and are the leading cause of tubal factor infertility in women. Nucleic acid amplification tests have high sensitivities (86.1%-100%) and specificities (97.1%-100%) for the diagnosis of gonorrhea, chlamydia, M genitalium, trichomoniasis, and symptomatic HSV-1 and HSV-2. Serology remains the recommended method to diagnose syphilis, typically using sequential testing to detect treponemal and nontreponemal (antiphospholipid) antibodies. Ceftriaxone, doxycycline, penicillin, moxifloxacin, and the nitroimidazoles, such as metronidazole, are effective treatments for gonorrhea, chlamydia, syphilis, M genitalium, and trichomoniasis, respectively, but antimicrobial resistance limits oral treatment options for gonorrhea and M genitalium. No cure is available for genital herpes. Effective STI prevention interventions include screening, contact tracing of sexual partners, and promoting effective barrier contraception. Conclusions and Relevance: Approximately 1 in 5 adults in the US had an STI in 2018. Rates of gonorrhea, chlamydia, and syphilis in the US have increased, while rates of HSV-1 and HSV-2 have declined. Ceftriaxone, doxycycline, penicillin, moxifloxacin, and the nitroimidazoles are effective treatments for gonorrhea, chlamydia, syphilis, Mycoplasma genitalium, and trichomoniasis, respectively, but antimicrobial resistance limits oral therapies for gonorrhea and Mycoplasma genitalium, and no cure is available for genital herpes.

Trichomonas vaginalis infection impairs anion secretion in vaginal epithelium.

Trichomonas vaginalis is a common protozoan parasite, which causes trichomoniasis associated with severe adverse reproductive outcomes. However, the underlying pathogenesis has not been fully understood. As the first line of defense against invading pathogens, the vaginal epithelial cells are highly responsive to environmental stimuli and contribute to the formation of the optimal luminal fluid microenvironment. The cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel widely distributed at the apical membrane of epithelial cells, plays a crucial role in mediating the secretion of Cl- and HCO3-. In this study, we investigated the effect of T. vaginalis on vaginal epithelial ion transport elicited by prostaglandin E2 (PGE2), a major prostaglandin in the semen. Luminal administration of PGE2 triggered a remarkable and sustained increase of short-circuit current (ISC) in rat vaginal epithelium, which was mainly due to Cl- and HCO3- secretion mediated by the cAMP-activated CFTR. However, T. vaginalis infection significantly abrogated the ISC response evoked by PGE2, indicating impaired transepithelial anion transport via CFTR. Using a primary cell culture system of rat vaginal epithelium and a human vaginal epithelial cell line, we demonstrated that the expression of CFTR was significantly down-regulated after T. vaginalis infection. In addition, defective Cl- transport function of CFTR was observed in T. vaginalis-infected cells by measuring intracellular Cl- signals. Conclusively, T. vaginalis restrained exogenous PGE2-induced anion secretion through down-regulation of CFTR in vaginal epithelium. These results provide novel insights into the intervention of reproductive complications associated with T. vaginalis infection such as infertility and disequilibrium in vaginal fluid microenvironment.

Anti-trichomonad activities of different compounds from foods, marine products, and medicinal plants: a review.

Human trichomoniasis, caused by the pathogenic parasitic protozoan Trichomonas vaginalis, is the most common non-viral sexually transmitted disease that contributes to reproductive morbidity in affected women and possibly to prostate cancer in men. Tritrichomonas foetus strains cause the disease trichomoniasis in farm animals (cattle, bulls, pigs) and diarrhea in domestic animals (cats and dogs). Because some T. vaginalis strains have become resistant to the widely used drug metronidazole, there is a need to develop alternative treatments, based on safe natural products that have the potential to replace and/or enhance the activity of lower doses of metronidazole. To help meet this need, this overview collates and interprets worldwide reported studies on the efficacy of structurally different classes of food, marine, and medicinal plant extracts and some of their bioactive pure compounds against T. vaginalis and T. foetus in vitro and in infected mice and women. Active food extracts include potato peels and their glycoalkaloids α-chaconine and α-solanine, caffeic and chlorogenic acids, and quercetin; the tomato glycoalkaloid α-tomatine; theaflavin-rich black tea extracts and bioactive theaflavins; plant essential oils and their compounds (+)-α-bisabolol and eugenol; the grape skin compound resveratrol; the kidney bean lectin, marine extracts from algae, seaweeds, and fungi and compounds that are derived from fungi; medicinal extracts and about 30 isolated pure compounds. Also covered are the inactivation of drug-resistant T. vaginalis and T. foetus strains by sensitized light; anti-trichomonad effects in mice and women; beneficial effects of probiotics in women; and mechanisms that govern cell death. The summarized findings will hopefully stimulate additional research, including molecular-mechanism-guided inactivations and human clinical studies, that will help ameliorate adverse effects of pathogenic protozoa.

Call to action for health systems integration of point-of-care testing to mitigate the transmission and burden of sexually transmitted infections.

OBJECTIVES: In 2016, WHO estimated 376 million new cases of the four main curable STIs: gonorrhoea, chlamydia, trichomoniasis and syphilis. Further, an estimated 290 million women are infected with human papillomavirus. STIs may lead to severe reproductive health sequelae. Low-income and middle-income countries carry the highest global burden of STIs. A large proportion of urogenital and the vast majority of extragenital non-viral STI cases are asymptomatic. Screening key populations and early and accurate diagnosis are important to provide correct treatment and to control the spread of STIs. This article paints a picture of the state of technology of STI point-of-care testing (POCT) and its implications for health system integration. METHODS: The material for the STI POCT landscape was gathered from publicly available information, published and unpublished reports and prospectuses, and interviews with developers and manufacturers. RESULTS: The development of STI POCT is moving rapidly, and there are much more tests in the pipeline than in 2014, when the first STI POCT landscape analysis was published on the website of WHO. Several of the available tests need to be evaluated independently both in the laboratory and, of particular importance, in different points of care. CONCLUSION: This article reiterates the importance of accurate, rapid and affordable POCT to reach universal health coverage. While highlighting the rapid technical advances in this area, we argue that insufficient attention is being paid to health systems capacity and conditions to ensure the swift and rapid integration of current and future STI POCT. Unless the complexity of health systems, including context, institutions, adoption systems and problem perception, are recognised and mapped, simplistic approaches to policy design and programme implementation will result in poor realisation of intended outcomes and impact.

Diagnosis, Treatment, Follow-up, and Persistence of Trichomonas vaginalis in Women 45 Years and Older According to HIV Status: A 10-Year Retrospective Cohort.

BACKGROUND: Trichomonas vaginalis is a common treatable sexually transmitted infection among older women. Persistent T. vaginalis infection after treatment is common among women with human immunodeficiency virus (HIV). We sought to determine if HIV-negative women were as likely as women with HIV to have persistent T. vaginalis infection. METHODS: We performed a retrospective cohort study of women 45 years or older with T. vaginalis infection. We evaluated differences in persistent T. vaginalis infection according to HIV status using χ analysis. We performed regression analyses to describe factors associated with persistent and recurrent infection in older women. RESULTS: Over a 10-year study period, we identified 282 women with T. vaginalis, 46 with HIV. Most women (240, 86%) were treated in accordance with 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases treatment guidelines. Half of the women (144, 53%) had a repeat T. vaginalis test 90 to 365 days after treatment, and one third had persistent infection (39/125, 31%). Persistent infection was similar between women with HIV and HIV-negative women treated according to Centers for Disease Control recommendations (17% vs 33%, P = 0.3). When adjusting for age and incidental diagnosis, tobacco use was associated with an increased risk of more than 1 or recurrent T. vaginalis infection during the study period (adjusted odds ratio, 2.8; 95% confidence interval, 1.5-4.9). CONCLUSIONS: The HIV status did not affect persistent T. vaginalis infection in women 45 years or older. Given over one third of women have a positive test within a year after the recommended treatment, our data support repeat testing in women 45 years and older treated for T. vaginalis.

20S Proteasome as a Drug Target in Trichomonas vaginalis.

Trichomoniasis is a sexually transmitted disease with hundreds of millions of annual cases worldwide. Approved treatment options are limited to two related nitro-heterocyclic compounds, yet resistance to these drugs is an increasing concern. New antimicrobials against the causative agent, Trichomonas vaginalis, are urgently needed. We show here that clinically approved anticancer drugs that inhibit the proteasome, a large protease complex with a critical role in degrading intracellular proteins in eukaryotes, have submicromolar activity against the parasite in vitro and on-target activity against the enriched T. vaginalis proteasome in cell-free assays. Proteomic analysis confirmed that the parasite has all seven α and seven ß subunits of the eukaryotic proteasome although they have only modest sequence identities, ranging from 28 to 52%, relative to the respective human proteasome subunits. A screen of proteasome inhibitors derived from a marine natural product, carmaphycin, revealed one derivative, carmaphycin-17, with greater activity against T. vaginalis than the reference drug metronidazole, the ability to overcome metronidazole resistance, and reduced human cytotoxicity compared to that of the anticancer proteasome inhibitors. The increased selectivity of carmaphycin-17 for T. vaginalis was related to its >5-fold greater potency against the ß1 and ß5 catalytic subunits of the T. vaginalis proteasome than against the human proteasome subunits. In a murine model of vaginal trichomonad infection, proteasome inhibitors eliminated or significantly reduced parasite burden upon topical treatment without any apparent adverse effects. Together, these findings validate the proteasome of T. vaginalis as a therapeutic target for development of a novel class of trichomonacidal agents.

Sexually Transmitted Diseases in the Emergency Department.

Sexually transmitted diseases (STDs) continue to be underrecognized leading to devastating health and economic consequences. Emergency clinicians play an important role in diagnosing and managing STDs and in improving health care outcomes for both the patient and their partners. In addition, antibiotic resistance and emerging infections continue to challenge providers in clinical practice. This review focuses on the cause, history, physical examination, diagnostic studies, and treatment strategies for bacterial vaginosis, chlamydia, genital herpes, gonorrhea, human papillomavirus, granuloma inguinale, Lymphogranuloma Venereum, Mycoplasma genitalium, syphilis, and trichomoniasis.

Chemotherapeutic options for the treatment of human trichomoniasis.

Trichomonas vaginalis is the causative agent of the most common non-viral sexually transmitted disease worldwide. The infection may be associated with severe complications, including infertility, preterm labour, cancer and an increased risk of human immunodeficiency virus (HIV) transmission. Treatment remains almost exclusively based on 5-nitroimidazoles, but resistance is on the rise. This article provides an overview of clinically evaluated systemic and topical treatment options for human trichomoniasis and summarises the current state of knowledge on various herbal, semisynthetic and synthetic compounds evaluated for their anti-Trichomonas efficacy in vitro.

Transmission electron microscopy revealing the mechanism of action of photodynamic therapy on Trichomonas vaginalis.

Trichomonas vaginalis is an amitochondrial parasite that causes human trichomoniasis. Despite metronidazole effectiveness, resistant cases are becoming more frequent. This scenario reveals the need to develop new therapeutic options. Photodynamic Therapy (PDT) is an experimental treatment that involves the activation of photosensitive substances and the generation of cytotoxic oxygen species and free radicals to promote the selective destruction of target tissues. In previous work, we identified an excellent in vitro PDT activity using methylene blue and light emitting diode against metronidazole sensitive and resistant strains of T. vaginalis. Here, we evaluated the efficacy of PDT in vivo and its high trichomonicidal activity was assessed through transmission electron microscopy. Female Balb/c mice were infected intravaginally with T. vaginalis trophozoites. On the third day of infection, methylene blue was introduced into the vaginal canal, which then received 68.1 J/cm2 of radiation for 35.6 s. Twenty-four hours after treatment the vaginal canal of the animals was scraped and the samples processed by the immunocytochemistry technique. Besides that, in vitro photodynamic treatment was performed and T. vaginalis trophozoites were processed by transmission electron microscopy. PDT significantly reduced infection in animals treated, compared to control groups, being as efficient as metronidazole. Morphological changes observed have suggested that PDT activity on T. vaginalis was due to necrosis. These results, added to the high trichomonicidal activity of PDT confirm its feasibility for trichomoniasis treatment.

Anti-Trichomonas vaginalis activity of ursolic acid derivative: a promising alternative.

Trichomonas vaginalis is an extracellular parasite that binds to the epithelium of the human urogenital tract and causes the sexually transmitted infection, trichomoniasis. In view of increased resistance to drugs belonging to the 5-nitroimidazole class, new treatment alternatives are urgently needed. In this study, eight semisynthetized triterpene derivatives were evaluated for in vitro anti-T. vaginalis activity. Ursolic acid and its derivative, 3-oxime-urs-12-en-28-oic-ursolic acid (9), presented the best anti-T. vaginalis activity when compared to other derivatives, with minimum inhibitory concentration (MIC) at 25 µM. Moreover, 9 was active against several T. vaginalis fresh clinical isolates. Hemolysis assay demonstrated that 9 presented a low hemolytic effect. Importantly, 25 µM 9 was not cytotoxic against the Vero cell lineage. Finally, we demonstrated that compound 9 acts synergistically with metronidazole against a T. vaginalis metronidazole-resistant isolate. This report reveals the high potential of the triterpenoid derivative 9 as trichomonicidal agent.

Intravenous metronidazole, liquid tinidazole, and intra-vaginal boric acid to cure trichomonas in a patient with gastric bypass surgery.

This study presents a case report of a female patient with symptomatic refractory Trichomonas vaginalis infection who was not able to clear her infection with high-dose oral metronidazole, oral tinidazole, intra-vaginal zinc sulfate, intra-vaginal metronidazole, intra-vaginal tinidazole, and intra-vaginal boric acid. She was unable to tolerate intra-vaginal paromomycin. A combination of intravenous metronidazole, oral tinidazole liquid suspension, and intra-vaginal boric acid for 14 days subsequently achieved a complete symptomatic and laboratory cure.

The genetic diversity of metronidazole susceptibility in Trichomonas vaginalis clinical isolates in an Egyptian population.

Trichomoniasis is the most common curable sexually transmitted disease worldwide. Resistance to metronidazole in treating trichomoniasis is a problematic health issue. We aimed to determine the minimum lethal concentration (MLC) of metronidazole for Trichomonas vaginalis isolates detected in Mansoura, Egypt and studied the genotypic profile of these isolates. Vaginal swab specimens were obtained from 320 symptomatic and 100 asymptomatic females, for whom clinical examination, vaginal discharge wet mount, Giemsa stain, and culture in modified Diamond's media were performed. Metronidazole susceptibility testing by an aerobic tube assay was performed. Both sensitive and resistant isolates were examined by PCR amplification followed by restriction fragment length polymorphism (RFLP). Trichomonas vaginalis was identified in 49/420 (11.7%) using either culture or PCR, while wet mount and Giemsa stain detected the parasite in 8.1 and 7.6% of participants, respectively. After 48 h incubation, most isolates were sensitive to metronidazole with a minimal lethal concentration (MLC) of 1 µg/ml. Mild resistance was observed in two isolates with MLCs of 64 µg\ml and mild to moderate resistance was observed in an additional two isolates with MLCs of 128 µg/ml. The four isolates that demonstrated low to moderate metronidazole resistance displayed a unique genotype band pattern by RFLP compared to the other 45 samples that were metronidazole sensitive. Our results highlight the presence of in vitro metronidazole tolerance in a few T. vaginalis isolates in Mansoura, Egypt that may lead to the development of drug resistance as well as the possibility of an identifying RFLP pattern in the isolates.

The anti-Trichomonas vaginalis phloroglucinol derivative isoaustrobrasilol B modulates extracellular nucleotide hydrolysis.

Trichomonas vaginalis causes trichomoniasis, a neglected sexually transmitted disease. Due to severe health consequences and treatment failure, new therapeutic alternatives are crucial. Phloroglucinols from southern Brazilian Hypericum species demonstrated anti-T. vaginalis and anti-Leishmania amazonensis activities. The modulation of biochemical pathways involved in the control of inflammatory response by ectonucleotidases, NTPDase, and ecto-5'-nucleotidase represents new targets for combating protozoa. This study investigated the activity of phloroglucinol derivatives of Hypericum species from southern Brazil against T. vaginalis as well as its ability on modulating parasite ectonucleotidases and, consequently, immune parameters through ATP and adenosine effects. Phloroglucinol derivatives screening revealed activity for isoaustrobrasilol B (IC50 38 µm) with no hemolytic activity. Although the most active compound induced cytotoxicity against a mammalian cell lineage, the in vivo model evidenced absence of toxicity. Isoaustrobrasilol B significantly inhibited NTPDase and ecto-5'-nucleotidase activities, and the immune modulation attributed to extracellular nucleotide accumulation was evaluated. The production of ROS and IL-6 by T. vaginalis-stimulated neutrophils was not affected by the treatment. Conversely, IL-8 levels were significantly enhanced. The associative mechanism of trophozoites death and ectonucleotidases modulation by isoaustrobrasilol B may increase the susceptibility of T. vaginalis to host innate immune cell like neutrophils consequently, contributing to parasite clearance.

Potential of bisbenzimidazole-analogs toward metronidazole-resistant Trichomonas vaginalis isolates.

A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH2 to C10 H20 ) containing a meta- (m) or para (p)-benzimidazole linkage to the phenylene ring was tested for ability to inhibit the growth of metronidazole-susceptible (C1) and metronidazole-refractory (085) Trichomonas vaginalis isolates under aerobic and anaerobic conditions. Compound 3m, 2,2'-[α,ω-propanediylbis(oxy-1,3-phenylene)]bis-1H-benzimidazole, displayed a 5.5-fold lower minimum inhibitory concentration (MIC) toward T. vaginalis isolate 085 than metronidazole under aerobic growth conditions, (26 µm compared to 145 µm). A dose of 25 mg/kg per day for four days of compound 3m cured a subcutaneous mouse model infection using T. vaginalis isolates 286 (metronidazole susceptible) and 085 (metronidazole refractory). Compound 3m was weakly reduced by pyruvate:ferredoxin oxidoreductase, but unlike metronidazole was not dependent upon added ferredoxin. It is concluded from structure-activity relationships that there was no obvious trend based on the length of the central aliphatic chain, or the steric position of the bisbenzimidazole enabling prediction of biological activity. The compounds generally fulfill Lipinski's rile of five, indicating their potential as drug leads.

Sexually Transmitted Infections.

Sexually transmitted infections (STIs) remain a significant burden on public health in the United States. Primary prevention counseling with early diagnosis and treatment remain the best methods to decrease the incidence of STIs. Through significant public heath interventions, the incidence of gonorrhea, Chlamydia, and trichomoniasis is decreasing; however, the incidence of primary and secondary syphilis is increasing. Human papilloma virus remains the most common STI, but new vaccinations have the possibility of having a significant impact on this virus's disease potential. This review discusses the most common STIs in the United States, focusing on clinical presentation, diagnosis, and treatment.