MIXED VAGINAL INFECTIONS

Introduction

The vagina offers a unique environment for bacterial colonization. It undergoes several developmental, hormonal and microbiological changes over the course of a lifetime. At birth, it is lined by stratified squamous epithelium, which regresses as the influence of maternal estrogen wanes. In childhood, the vaginal flora contains skin commensals and bowel organisms. At menarche, the pH falls from neutral to approximately 4, and lactobacilli dominate the flora, which also includes many other organisms in lower concentrations, such as anaerobic and facultative anaerobic bacteria and Candidaspp. The hormonal environment alters every month, and the ecosystem is further disturbed by menstruation, washing, and hygiene. Sexual activity can introduce a number of new species and pathogens, as well as alter the pH. The hormonal balance undergoes further fluctuations during pregnancy and lactation. At menopause, the vaginal epithelium gradually atrophies, the pH rises, and a flora more similar to that of skin may become re-established.¹

Vaginal infections (vaginitis) comprise over 95% of lower female genital tract infections, and are the most common reason for patient visits to obstetrician-gynecologists.²

These infections affect 75% of the woman worldwide, and are encountered by almost every woman during some period in her life, and cause considerable impairment in the quality of life.³

Symptoms of vaginal infection

Most common symptoms of vaginal infections are:³

• Increase in vaginal discharge
• Changes in color and consistency
• Unpleasant odor
• Vaginal and vulvar itching, burning, irritation and discomfort
• Painful micturition
• Dyspareunia

Other less common forms of vaginal symptoms include^4,5

• Atrophic vaginitis
• Chemical irritation
• Lichen planus
• Allergic vaginitis
• Desquamative vaginitis
• Foreign body

Types of vaginal infections

Vaginal symptoms are usually related to one of following types of vaginal infections:⁴

• Bacterial vaginosis (BV)
• Vulvovaginal candidiasis (VC)
• Trichomoniasis
• Mixed vaginal infections

The common causes, symptoms and signs of the different types of vaginitis are shown in Table 1.^6,7

Bacterial vaginosis

Bacterial vaginosis (BV) is the most prevalent cause of vaginal discharge or malodor, occurring in up to 30% of women.⁸   A substantial number of women are asymptomatic, and there are no features of vaginal inflammation (e.g., presence of excess leukocytes in the discharge or vaginal wall erythema).⁹

As already mentioned, the normal vaginal flora during the reproductive years mostly comprises lactobacilli. These lactobacilli produce bacteriocins, hydrogen peroxide and lactic acid, all of which lower the vaginal pH. The low pH prevents colonization by bacteria other than lactobacilli. In BV, the normal lactobacilli in the vagina are reduced, resulting in an increase in pH and consequent overgrowth of anaerobic and facultative bacteria, such as Gardnerella vaginalis, Mycoplasma hominus and Ureaplasma urealyticum. Other anaerobes, such as Prevotella, Mobiluncus, Bacteroides, and Peptostreptococcus, have also been identified as flora associated with BV.¹⁰

Bacterial vaginosis, even when asymptomatic, is associated with a high incidence of endometritis and pelvic inflammatory disease following abortion and gynecologic procedures in the general population. It is also associated with late miscarriages, premature rupture of membranes, and preterm birth.¹¹   Both symptomatic and asymptomatic bacterial vaginosis have been strongly linked with an increased risk of human immunodeficiency virus (HIV)-1 transmission.

The risk factors associated with BV are shown in Table 2.

In clinical practice, bacterial vaginosis is diagnosed by the presence of three out of four Amsel criteria:¹²

• Thin, homogenous vaginal discharge
• Vaginal pH > 4.5
• Positive whiff test (fishy amine odor when 10% potassium hydroxide solution is added)
• At least 20% clue cells (vaginal epithelial cells with borders obscured by adherent coccobacilli on wet-mount preparation or Gram stain; Fig. 1).

Trichomoniasis

Trichomoniasis is the most common nonviral sexually transmitted infection, caused by a protozoan, Trichomonas vaginalis.¹³   Infection with this organism is easily transmitted sexually and is associated with an increased risk of acquiring HIV.^13,14

The pathophysiology involves an increase in the vaginal secretions of CD4+ cells, which serve as target cells for the HIV virus.¹⁵     There may also be coinfection with other sexually transmitted infections.¹⁴

The disease is asymptomatic in 50-75% of patients.¹⁴   The most common symptoms are vulvar itching and copious foul smelling vaginal discharge, which is yellow-green in color.¹³   Other symptoms may include petechiae on the cervix and erythema of the vagina.

Since these symptoms are non-specific, diagnosis is made mostly on the basis of microscopic features, which include:¹⁶

• Presence of trichomonads on saline preparation
• Preponderance of leukocytes over epithelial cells
• Positive whiff test
• Vaginal pH > 5.4

In addition, a wet-mount preparation is an inexpensive and quick test with variable sensitivity of 58-82% (Fig. 2).¹⁷   Examination of the spun urine specimen can increase the detection rate of Trichomonas vaginalis from 73% to 85%.¹⁸

Vulvovaginal candidiasis

Vulvovaginal candidiasis (VC) is the most common cause of infectious vaginitis, found in 40-50% of all cases. It may cause genital discomfort, loss of productivity, reduced sexual pleasure, psychological problems, and may involve high medical expenses.¹⁹   An estimated 75% of women in the reproductive age group will have at least one episode of VC in their lifetime, and 40-45% will have two or more episodes.^4,20

VC is most commonly caused by Candida albicans, which is a normal inhabitant of the vagina. Changes in the host vaginal environment precipitate and induce pathologic effects in the organism.²¹   Other organisms that can cause the disease are C glabrataand C tropicalis. The latter two types are often more resistant to treatment.¹³

Risk factors for VC include:^4,22

• Positive HIV status
• Diabetes
• Recent IV drug use
• Recent antibiotic use

Due to non-specificity of symptoms, diagnosis is made by microscopic examination of vaginal secretions with a 10% potassium hydroxide solution (Fig. 3). Vaginal pH is usually normal (4.0 to 4.5). Vaginal culture should be considered in recurrently symptomatic women with negative microscopy and a normal pH. Among other investigations, a rapid yeast detection test is much less expensive than yeast culture,¹⁵   but the most sensitive method is the polymerase chain reaction.²³

Mixed vaginal infections

Approximately 30% of all cases of vaginitis are caused by simultaneous infections with at least two or more pathogens (e.g., bacterial vaginosis in patients of vulvovaginal candidiasis). Vaginal infections can be diagnosed by clinical examination, pH measurement and microscopic examination of vaginal discharge. The pH of vaginal secretion is elevated (> 4.5) in case of bacterial vaginosis and trichomoniasis.²⁴

In a study²⁵   conducted on pregnant women in a developing community where mixed cervico-vaginal infections were common, the prevalence of mixed vaginal infections (BV and trichomoniasis) was 14%. As many as 71% of asymptomatic women showed microbiological evidence of a lower genital tract infection. A total of 46% of women studied had poor pregnancy outcome as measured by obstetrical complications, pregnancy loss and/or neonatal morbidity.

Complications of vaginal infections²⁶  

Without treatment, vaginal infections can lead to further complications, especially in pregnant women.

Complications of bacterial vaginosis

• Premature delivery
• Miscarriage
• Low birth weight infant
• Postpartum infections
• Pelvic inflammatory disease, e.g., postpartum endometritis
• Postsurgical complications (after abortion, hysterectomy, cesarian section)
• Increased vulnerability to HIV infection
• Infertility

Complications of trichomoniasis   

• Increased likelihood of acquiring HIV

Complications causing daily discomfort

• Persistent discomfort
• Superficial skin infection (from scratching)
• Complications of the causative condition (such as gonorrhea and candida infection)

Treatment of mixed vaginal infections

Combination therapy

Since 90% of vaginal infections are mixed infections, their treatment also requires more than one drug to combat the multiplicity of pathogens. Combination therapy may provide immediate and effective treatment for vaginal infections, irrespective of single or multiple types or even when the diagnosis is not precisely accurate.²⁴

The combination of a broad spectrum antibiotic with an antifungal agent, e.g., clindamycin + clotrimazole, is particularly effective in treating mixed infections. Benefits of the dual combination regimen are:

• Wider coverage against mixed infections
• Complete elimination of vaginal infections within 7 days. This is particularly useful as a prophylactic measure before gynecological or IVF procedures, in which a pathogen-free vagina is required. In such situations, a 7-day course of the combination is better and more effective than a 3-day course.
• Decreased relapse rate
• No secondary infection

Efficacy of clindamycin in vaginal infection

Recommended antimicrobial treatments for nonpregnant women often include oral or intravaginal therapy with clindamycin. While both oral and intravaginal administrations are effective, intravaginal medications carry the advantage of causing better treatment satisfaction and less adverse effects than oral therapy.²⁷

A prospective, randomized, double-blind, placebo-controlled, tricenter study²⁸   evaluated the efficacy of a vaginal preparation of clindamycin to treat bacterial vaginosis (BV) in pregnancy. For this purpose, 404 women with BV were randomized to receive either clindamycin or placebo. The outcome was assessed using an intention to treat analysis at 3 weeks and 6 weeks post-treatment according to three different diagnostic methods based on five criteria (Gram stain and all four elements of clinical composite criteria: vaginal discharge, abnormal vaginal pH, clue cells, amine odor), three criteria (vaginal pH, clue cells, amine odor) or two criteria (clue cells and amine odor) to reflect stringency of diagnosis, historical precedence and government agency recommendations respectively.

The results obtained, according to the various criteria used, are depicted in Table 3.

Thus, clindamycin appeared to be well tolerated by the mother and was statistically significantly more efficacious than placebo in the treatment of BV during the second trimester of pregnancy.

In another study,²⁹   the same authors evaluated the efficacy of clindamycin in reducing the incidence of preterm birth in women with abnormal genital tract flora in the second trimester of pregnancy.

In this randomized, double-blind, placebo-controlled, tricenter study, 409 women with abnormal genital tract flora at 13-20 weeks’ gestation were randomized to receive a course of clindamycin or placebo.

A statistically significant reduction of 60% in the incidence of preterm birth was noticed in the clindamycin group (4%) compared with the placebo group (10%). This also reduced the need for neonatal intensive care.

A meta-analysis³⁰   of 5 trials comprising 2346 women led to similar findings. The results showed that clindamycin administered at <22 weeks of gestation to women with abnormal vaginal flora was associated with a significantly reduced risk of preterm birth at <37 weeks of gestation and late miscarriage.

Clindamycin vs metronidazole

A study by Nyirjesy and colleagues³¹   evaluated the effects of clindamycin and metronidazole on vaginal Mobiluncus morphotypes in 55 patients of BV. Both drugs demonstrated significant reductions in the Mobiluncus score. However, the Mobiluncus score at test-of-cure was lower with clindamycin than with metronidazole. The rates of microbiologic, clinical, and therapeutic cure were greater in the clindamycin group as compared to the metronidazole group (Fig. 4).

Thus, clindamycin was found to reduce vaginal Mobiluncus morphotypes to a greater extent than metronidazole, leading to a higher BV cure rate.

In another comparison³²   between intravaginal clindamycin and metronidazole in the treatment of BV, the cure rate with metronidazole was found to be 87.5% while that with clindamycin was 90.3%. In addition, the new formulation of clindamycin vaginal tablet did not irritate the vaginal mucosa and was easy to dissolve in the vagina. There was no discontinuation of treatment because of side-effects.

Efficacy of clotrimazole in vaginal infection

A study by Singh et al ³³   found clotrimazole to be the most active azole in the treatment of vaginal fungal infections caused by C. krusei, which is resistant to fluconazole. The MIC90   of clotrimazole was 0.25 microg/mL.

Clotrimazole vs polyherbal pessary

A randomized trial³⁴   was conducted at PGI, Chandigarh, India, to compare a polyherbal pessary with one containing clotrimazole. The latter was found to be 100% effective in treating bacterial vaginosis, and was less irritant to the vagina than the herbal preparation.

Intravaginal clotrimazole vs oral fluconazole

In a study by Mendling et al³⁵   intravaginal clotrimazole was found to be as effective as oral fluconazole. The drug was safe and well-tolerated and the number of patients experiencing adverse events was low.

Safety profile of clotrimazole

A study by Czeizel et al ³⁶   found that clotrimazole use did not have any teratogenic effects and was not clearly associated with an increase in the total (fetal + birth) prevalence of any congenital abnormality. In fact, there was a suggestion that clotrimazole use might be associated with a decrease in the prevalence of undescended testis.

Mucoadhesive vaginal drug delivery systems – a new breakthrough in vaginal drug delivery

Vaginal delivery is an important route of drug administration for both local and systemic diseases. The vaginal route has some advantages due to its large surface area, rich blood supply, avoidance of the first-pass effect, relatively high permeability to many drugs and facility of self-insertion. The problem with traditional commercial preparations, such as creams, foams, gels, irrigations and tablets, is their poor retention and failure to spread uniformly in the vaginal cavity owing to the self-cleaning action of the vaginal tract, and the need of multiple daily doses to ensure the desired therapeutic effect. Besides, they may leak and prove to be messy. This adversely affects compliance and clinical outcome.³⁷

In an attempt to circumvent the drawbacks of traditional vaginal drug delivery while maintaining and even improving safety profiles, a new form of vaginal drug delivery was developed – the bioadhesive drug delivery system. This unique delivery system prolongs the drug’s stay in the vaginal cavity, and has both bioadhesive and sustained release properties.³⁸

The vaginal route appears to be highly appropriate for bioadhesive drug delivery systems in order to retain drugs for treating largely local conditions, or for use in contraception, and also to provide protection from sexually-transmitted diseases. The bioadhesive therapeutic systems have been developed in the form of semi-solid and solid dosage forms.³⁷

The bio-compatible muco-adhesive polymers swell, spread and adhere uniformly all around the vaginal mucosa, increasing the availability of drugs at the site of infection, i.e., the vaginal mucosa. Thus, the residence time of drugs at the target membrane is extended, and the duration of effectiveness is prolonged.

Bioadhesive polymers can hold the drug delivery systems in the vaginal tube by interacting with vaginal mucosa and thereby increase patient compliance as well as delivery system efficiency.²⁴

In a study by Chang et al,³⁹   the efficacy of treatment for vaginal candidasis was sought to be enhanced by formulating clotrimazole in mucoadhesive thermosensitive gels (MTG). As a result, the in vivo antifungal activity of the drug was significantly prolonged after vaginal delivery using MTG. Moreover, the treatment also enhanced the viability of epithelial cells without affecting the morphology of the vaginal mucosa. These results indicated that clotrimazole-containing vaginal MTG might be further developed for safe, convenient, and effective treatment of vaginal candidasis with reduced dosing interval.

The combination of clindamycin and clotrimazole is available as a mucoadhesive vaginal drug delivery system, and thus is effective in completely eliminating the pathogens, leaving nothing to chance.

Conclusion

Vaginal infections are of four types: bacterial vaginosis, vulvovaginal candidiasis, trichomoniasis and mixed infections, the last named accounting for almost 90% of all vaginal infections. These infections can be diagnosed by clinical examination, pH measurement and microscopic examination of vaginal discharge. Mixed vaginal infections are best treated with combination therapy, such as that of clindamycin and clotrimazole. The advent of mucoadhesive vaginal drug delivery systems has revolutionized the treatment of vaginal infections, leading to enhanced retention time and better compliance.

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