The vagina of a normal healthy woman has a natural defense against pathogenic invasion. The normal flora grows on the mucosal surface of the vaginal wall through its own adhesion mechanism and binds to the receptors of the vaginal epithelium, participating in material metabolism and nutrient transformation; it acts as an antigen to stimulate the host to produce antibodies and enhance its immunity; its metabolites can form a biological barrier against foreign bacteria and play an important role in maintaining the stability of the vaginal environment. The metabolites of Lactobacillus are important in maintaining the stability of the vaginal environment. Lactobacillus is absolutely dominant, with normal pH, cleanliness and immune function. When these factors are altered for various reasons, the vaginal microecological balance becomes unbalanced and some pathogenic bacteria multiply abnormally, causing vaginal inflammation.
Vaginal inflammation accounts for about one-third of patients in gynecological clinics. The most common ones are trichomonalvaginitis (TV), vulvovaginal candidiasis (VVC), bacterial vaginosis (BV), and atrophic vaginitis (AVC). More than 50% of vaginitis is clinically a mixed infection. Currently, some vaginitis treatments are not effective, recurrence rates are high, and patient compliance is poor, so the ultimate goal is to standardize the treatment of vaginitis and choose a treatment plan that is effective, rapid, low recurrence, and safe.
Treatment of TV
Patients with TV often have trichomonas infection of the urethra, paraurethral glands, and vestibular glands, so systemic treatment is recommended.
I. Treatment of non-pregnancy TV
In 2006, the Centers for Disease Control (CDC) recommended the following treatment regimen: metronidazole 2 g as a single oral dose or tinidazole 2 g as a single oral dose. Alternative regimens: metronidazole 500 mg twice/d for 7 d. Cure rates are 90-95% for metronidazole and 86-100% for tinidazole. The cure rate can be improved if the sexual partners receive treatment at the same time. Those who cannot tolerate oral or systemic medication may choose to administer vaginal topical medication, but the CDC believes that vaginal application of metronidazole gel is less effective than oral medication, generally less than 50%. In one study, 34 patients with comprehensive data of suspected metronidazole allergy in TV were cured after 15 cases were treated with gradually increasing dosage of metronidazole desensitization therapy (7 intravenous and 8 oral), with a cure rate of 100% (15/15); 7 cases received standard treatment with metronidazole (metronidazole 2 g, single oral dose) and 6 cases were cured, with a cure rate of 85.7% (6/7); the remaining 12 cases were treated with alternative vaginal medication (no standard dose, duration of use). The remaining 12 cases were treated with alternative vaginal drugs (no standard dose, method and duration of treatment), among which 4 cases were treated with povidone iodine douche (vaginal douche tends to disrupt the vaginal ecological environment and is now not recommended), 4 cases with balomycin suppositories, 2 cases each with clotrimazole suppositories and furazolidone suppositories, and only 5 cases were cured (3 cases with povidone iodine douche, 1 case each with balomycin suppositories and clotrimazole suppositories), with a cure rate of only 41.7% (5/12). It is suggested that patients with allergy to nitroimidazoles can be treated with desensitization therapy, but more clinical studies are needed to confirm its feasibility.
Treatment of TV during pregnancy and lactation
In 2006, the CDC recommended a treatment regimen of metronidazole 2 g as a single oral dose. The U.S. Food and Drug Administration (FDA) has classified metronidazole as a Class B drug. Animal studies have confirmed that tinidazole can cause adverse effects, but its safety in pregnant women has not been evaluated, and the FDA classifies tinidazole as a Class C drug and therefore does not recommend it as treatment for TV during pregnancy. The FDA classifies tinidazole as a Class C drug, so it is not recommended for the treatment of TV during pregnancy. The Chinese Drug Manual still lists metronidazole as a prohibited drug during pregnancy, so informed consent should be obtained from patients and their families before application to avoid unnecessary medical disputes. Follow-up: The patient should be followed up until the symptoms disappear after treatment, and the patient should be reviewed 1 month after treatment if the symptoms persist. The majority of patients with symptoms after TV treatment are re-infected with trichomonas. Since metronidazole is rarely resistant, the dosage and course of treatment can be increased if the initial treatment fails. If the treatment is still ineffective, metronidazole 2 g, 1 time/d for 3-5 days or tinidazole 2 g, single oral dose may be used.
Treatment of VVC
Before treating VVC, it is necessary to classify it clinically and choose the appropriate treatment according to the clinical classification. There are two types of VVC: (1) Simple VVC: including disseminated or infrequent attacks, mild to moderate disease severity, Pseudomonas albicans as the causative agent, and normal immune function of the host. ② Complex VVC: including recurrent VVC (RVVC), disease clinical manifestations are severe, the pathogen is a non-Pseudomonas albicans, and the host has abnormal immune function, including: uncontrolled diabetes in the host, low immunity, application of immunosuppressive drugs and women during pregnancy.
Treatment principles
Treatment should be given to those with signs and symptoms and positive potassium hydroxide wet film tests; empiric treatment is also considered for those with signs and symptoms and negative cultures; positive cultures without signs and symptoms of vaginitis are not an indication for treatment.
Treatment of simple VVC
In 2006, the CDC recommended the following treatment regimens: (1) Vaginal: miconazole suppositories 1 200 mg single or 400 mg once/d for 3 d or 200 mg once/d for 7 d; clotrimazole suppositories 500 mg single or 100 mg once/d for 7 d; mycobacterial suppositories 100,000 U once/d for 14 d. (2) Systemic: itraconazole 200 mg twice/d for 3-5 d; fluconazole 150 mg in a single dose. Short-term topical agents (single dose or 1 to 3 d regimen) are effective in treating simple VVC. Azoles are more effective than mycoplasma, providing relief in 80% to 90% of patients. Partner therapy is not generally recommended for simple VVC.
Treatment of RVVC
Four or more episodes of symptomatic VVC within a year are called RVVC. Intensive therapy is given first, followed by maintenance therapy. (1) Intensive treatment: If the initial treatment is topical, extend the duration of treatment to 7-14 d. If the oral treatment is fluconazole 150 mg, add one dose on day 4 and one dose on day 7. ② Consolidation therapy: oral fluconazole 150 mg once/week for 6 months; miconazole suppository 400 mg once/d for 3-6 d/month for 6 months; clotrimazole suppository 500 mg once/week for 6 months. Treatment of VVC in pregnancy. In 2006, the CDC recommended topical treatment with azoles, with 7-day therapy being preferred. The FDA classifies clotrimazole suppositories and myclobutanil as Class B and miconazole suppositories as Class C in the classification of the risk of drugs to the fetus. Even if the drug is not harmful to the fetus and pregnant women, it may cause psychological burden to pregnant women or increase medical disputes, so it should not be used during pregnancy as much as possible. There is no optimal treatment for Pseudomonas albicans VVC. An azole other than fluconazole (oral or topical) and extended antifungal therapy (7-14 d) may be used as first-line agents. Boric acid capsules 600 mg placed deep in the vagina once/d for 14 d are recommended in case of relapse; similarly, Ray et al. study confirmed that boric acid is superior to fluconazole in the treatment of non-Pseudomonas albicans VVC.
Treatment of BV
I. Treatment of non-pregnant BV
The US CDC believes that symptomatic women should be treated. Treatment of asymptomatic women with BV is controversial and does not require routine treatment, but BV may increase the risk of post-surgical infection and should be treated in patients undergoing gynecologic procedures such as hysterectomy, adnexal resection, and curettage.
Recommended regimen: metronidazole 500 mg orally 2 times/d for 7 d; or 0.75% metronidazole gel 5 g/d vaginally 1 time/d for 5 d; or 2% clotrimazole cream 5 g/d vaginally 1 time nightly for 7 d. Alternative regimen: clotrimazole 300 mg orally 2 times/d for 7 d; or clotrimazole suppository 100 mg vaginally 1 time nightly for 3 d. The FDA has approved the use of metronidazole vaginal extended-release tablets (750 mg, 1 time/d, placed vaginally for 7 d) for the treatment of BV. Metronidazole 2 g is no longer recommended for the treatment of BV because of its poor effectiveness as a single dose. One study reported that metronidazole-resistant A. vaginalis novel pathogens were isolated from the vaginal secretions of 55% of BV patients, resulting in the ineffectiveness of metronidazole for some BV. The plasma half-life of tinidazole is twice that of metronidazole, and its adverse effects are lower than those of metronidazole, so it can be used for the treatment of metronidazole-resistant cases.
Treatment of BV in pregnancy
Treatment regimen: metronidazole 500 mg orally twice/d for 7 d; or metronidazole 250 mg orally three times/d for 7 d; or clotrimazole 300 mg orally twice/d for 7 d. All symptomatic pregnant women should be treated. The US CDC believes that screening and treatment should be considered for asymptomatic women with high-risk factors for BV (e.g., history of premature rupture of membranes, preterm delivery, miscarriage) and should be performed at the time of the first obstetric visit; the optimal regimen remains undetermined; whether treatment of asymptomatic women with low-risk factors for BV will reduce adverse pregnancy outcomes remains unclear. The U.S. Defense Agency does not believe that screening and treatment of all women with asymptomatic low-risk factor pregnancies is necessary.
Treatment of recurrent BV
Recurrent BV is defined as 3 or more recurrent episodes of BV within 1 year. Sobel et al. proposed consolidation therapy for recurrent BV with 0.75% metronidazole cream (5 g) administered vaginally once/d for 10 d and twice weekly for 16 weeks after symptom-free treatment, which significantly reduced the recurrence of BV, but secondary pseudomelanosis is common, so effective treatment options remain to be explored.
Treatment of atrophic vaginitis
Atrophic vaginitis, also known as senile vaginitis, occurs in postmenopausal women due to estrogen deficiency and has a high prevalence, with symptoms occurring in approximately 45% of postmenopausal women.
Hormone therapy
Estrogen supplementation is an effective treatment for postmenopausal urogenital tract atrophy. In recent years, the use of transvaginal estrogen supplementation has been increasing. Currently, there are various types of vaginal estrogens in the form of suppositories, tablets, creams and silicone ring extended-release systems. Commonly used are combined estrogen ointment (Premarin), micronized estradiol (E2) vaginal tablets (Vagifem), estriol (E3) ointment (Ovestin), low-dose E2 vaginal ring (Estring, 7.5 μg/d), and high-dose E2 vaginal ring (Femring, 50 μg/d or 100 μg/d).
In 2006, Suckling et al [10] conducted a systematic evaluation of the efficacy and safety of topical low-dose estrogen treatment for vaginal atrophy using the Cochrane database and showed that vaginal administration of low-dose estrogen significantly relieved the symptoms associated with vaginal atrophy compared with placebo and lubricant. However, in terms of ease of use, comfort and satisfaction, patients were more likely to accept the estrogen-release vaginal ring. The vaginal ring can be inserted and removed by the patients themselves, and each ring can be used for 3 months, which makes it convenient and comfortable to use and easy to accept by patients, and has a good application prospect. Randomized controlled trials have shown [11] that topical estrogen supplementation restores vaginal lactobacilli and lowers vaginal pH, helping to maintain ecological balance. It is difficult to answer the question of whether progestins should be routinely added to protect the endometrium when low-dose estrogens are administered vaginally for more than 6 months. The need, timing, dosage, and mode of adding progestin should be studied, and endometrial thickness should be monitored or endometrial biopsy should be performed when appropriate.
Antibiotic therapy
Bacterial cultures in atrophic vaginitis show bacterial growth in more than 90% of cases, with both aerobic and anaerobic bacteria, or pure aerobic bacteria such as Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, etc. Therefore, it is also advisable to use sensitive antibiotic vaginal suppositories or oral preparations locally before using estrogenic drugs.
Treatment of mixed vaginitis
Mixed vaginitis requires the presence of at least 2 pathogens, both of which can cause abnormal local conditions and symptoms, and both of which require treatment to completely eradicate the acute signs and symptoms. For example, the common types of mixed vaginitis are: BV+Trichomonas, BV+VVC, Trichomonas+VVC, Trichomonas+BV+VVC, all of the above + other genital pathogens (mycoplasma, chlamydia, etc.), and about 50% of vaginitis is clinically mixed.
In clinical practice, mixed vaginitis requires longer treatment time and is more prone to recurrence than simple infections, making it a difficult area of clinical treatment. In mixed infections, multiple pathogens and some conditionally pathogenic microorganisms can be isolated at the same time. For mixed infections with different pathogens, different effective antibiotics are selected for combination therapy. Ozyurt et al. reported that 42 cases of mixed vaginitis (11 BV+VVC, 28 BV+Trichomonas, and 3 BV+VVC+Trichomonas) were treated with Neo-Penotran (a mixture of metronidazole 500 mg and miconazole nitrate 100 mg) vaginal suppositories once in the morning and once in the evening for 7 d. Bacteriological evaluation at the end of 2 weeks of treatment showed a cure rate of 86% for mixed vaginal infections, including 73% for BV+VVC, 93% for BV+Trichomonas, and 93% for 3 BV+VVC. The bacteriological evaluation at the end of 2 weeks of treatment showed a cure rate of 86% for mixed vaginal infections, including 73% for BV+VVC and 93% for BV+Trichomonas.
Recently, the application of acid buffering bioadhesive vaginal gel (ABBV, containing clotrimazole 1 g, metronidazole 750 mg, Lactobacillus 500 mg and sodium citrate 200 mg) for the treatment of mixed vaginitis has been reported in the literature. In vitro studies have shown that ABBV has better antibacterial effects than the usual vaginal extended-release formulations, retaining the drug in the vagina for 12-13 h. However, more clinical studies are needed to verify its therapeutic effects. However, the vaginal mixture is sometimes underdosed and may be ineffective, or even resistant or resistant to the drug. Different routes of administration can also be used to treat mixed vaginitis at the same time. For mixed BV+Trichomonas infections, metronidazole can be given orally for 1 week or as a single oral dose with vaginal administration. For BV+VVC or Trichomonas+VVC infections, oral metronidazole and topical vaginal antifungal medication may be chosen. In addition, antibiotics should be chosen with Mycoplasma solani and Chlamydia trachomatis in mind because of their high rate of infection and the fact that most infections are mixed.
Lactobacillus is used to keep the vaginal pH below 4.5 in a slightly acidic environment to inhibit the growth of other pathogenic bacteria. The anti-microbial factors produced in the metabolism of Lactobacillus are effective in inhibiting the growth and reproduction of other bacteria. After the inhibition of Lactobacillus growth, the proliferation of Pseudomonas aeruginosa is an important reason for the occurrence and recurrence of VVC. In a randomized, double-blind controlled trial, Martinez et al. reported that 55 patients with VVC received a single oral dose of fluconazole 150 mg followed by two Lactobacillus probiotic capsules or placebo capsules every morning for 4 weeks and showed a significant reduction in symptoms in the Lactobacillus group (symptom The results showed a significant reduction in symptoms in the Lactobacillus group (10.3% vs. 34.6%; P = 0.03) and a significant reduction in positive fungal cultures (10.3% vs. 38.5%; P = 0.014).
However, the efficacy of Lactobacillus preparations for VVC is still controversial and more basic and clinical studies are needed to prove this. Anti-Pseudomonas vaccines have been successfully used to prevent VVC in rodents, but have not yet been reported in humans, and more studies are needed to confirm their feasibility. Dysbiosis of the vaginal microecology, especially the reduction of Lactobacillus, is an important factor in the development of BV. Current findings suggest that supplementation with Lactobacillus may treat BV and reduce its recurrence and complications. Petricevic et al. reported that 190 patients with BV were randomly divided into two groups after standardized treatment with clojibimycin, one as a control group and the other with vaginal capsules containing live 109 CFU of Lactobacillus rhamnosus (Lcr35) for 7 d and evaluated 4 weeks after discontinuation of the drug. Larsson et al. reported that 100 BV patients were randomized to two groups after standardized treatment with clojibimycin, one group was given lyophilized Lactobacillus vaginal capsules containing 109 CFU for 10 d and the other group was given the same placebo capsules for 10 d for 3 menstrual cycles. The results showed that the recurrence rate of BV was significantly reduced in the Lactobacillus group. However, the CDC concluded that there was no difference in the restoration of the vaginal flora with Lactobacillus as the dominant organism when Lactobacillus suppositories or placebo were administered 1 month after BV was cured, and that the quality of the currently available live bacterial preparations for BV is uncertain. In atrophic vaginitis, the vaginal microecological environment is imbalanced. Lactobacillus preparations directly replenish Lactobacillus in the vagina, regulating the vaginal flora, lowering the pH value of the vagina, and enhancing vaginal self-cleaning for therapeutic purposes.
Although antibiotic treatment for mixed vaginitis can solve the problem of symptoms, signs and pathogens, antibiotics do not help to restore the damaged vaginal micro-ecological environment caused by vaginitis, mainly because they cannot quickly restore the quantity and quality of Lactobacillus in the vagina, and therefore cannot solve the problem of vaginitis recurrence. Therefore, after antibiotic treatment for mixed vaginitis, timely application of microecological agents such as Lactobacillus to replenish Lactobacillus in the vagina can combine treatment and prevention into one, which can fundamentally restore the vaginal microecological balance and play an important role in consolidating treatment and preventing recurrence.
In conclusion, vaginitis is a common and frequent disease in women of all ages, and it is a difficult disease for women to cure because of its high recurrence rate. In addition to using antibiotics that are sensitive to the pathogens and highly effective, timely supplementation of Lactobacillus should be used to restore the vaginal micro-ecological balance, and a combination of antibiotics and Lactobacillus preparations is beneficial in curing various vaginal inflammatory diseases and preventing their recurrence. That’s why my vaginitis patients can use Lactobacillus capsules for a while after mycobacterial, trichomonas and bacterial treatment, which I affectionately call “vaginal yogurt tablets”.