Aerobic Vaginitis Caused by Enterococcus Faecalis - Clinical Features and Treatment

Abstract

Bckground:

Aerobic vaginitis is an imbalance of the vaginal flora and the main characteristic is an abnormal vaginal flora that contains aerobic and intestinal pathogens with varying degrees of vaginal inflammation. The frequency of AV varies from 12% to 23.7% in symptomatic women who are not pregnant and 4 to 8% during pregnancy and has an increased risk for sexually transmitted diseases (STI). The causative agents of AV are: Enterococcus faecalis (E. faecalis), Esherichia coli, group B streptococcus and Staphylococcus aureus.

Objective:

The aim of this review was to present the most important features of aerobic vaginitis regarding description of this frequent clinical problems within population in Bosnia and Herzegovina and also worlfwide.

Methods:

Author analized aerobic vaginitis based on scientific literature by searching published papers in important indexed databases.

Results and Discussion:

The most frequently isolated AV pathogen is E. faecalis in about 31%. New works indicate the presence of the HPV 16 gene and genome in E. faecalis in the biopsied material of cervical cancer, as well as the ability that HPV 16 genes can be translated and transcribed in these bacteria, and that the HPV gene can form viral particles in these bacteria leads to certain connection that can be a risk factor in the progression of cervical lesions to cancer. A decrease in the number of lactobacilli in the vaginal secretion reduces the defense ability and changes the pH value of the vaginal environment, which favors the development of bacterial inflammation. AV positive for E. faecalis leads to a change in the pH value of the vaginal environment above 5, and the increased pH value of the vaginal environment in HPV positive women can be an association for cervical intraepithelial lesion (CIN). A dominant pathogen in AV such as E. faecalis can reduce the protective effect of lactobacilli by causing inflammation, as well as an increase in IL-6, IL-8 and TNF, increasing the risk of HPV 16 infection resulting in CIN and cervical cancer. In cervical cancer research, the presence of genes and genomes (except E1) of human papillomavirus (HPV) type 16 was found in bacteria such as: E. faecalis and Staphylococcus aureus from cervical cancer biopsies. Intensive treatment of AV could be a very important factor in preventing the onset of precancerous lesions and cervical cancer. The recommended treatment of AV includes a combination of therapy such as: antibacterial (antiseptic and antibiotic), hormonal, non-steroidal anti-inflammatory and/or probiotics, which can be prescribed in the form of local or systemic therapy.

Conclusion:

There is no generally accepted clinical strategy for the treatment of AV caused by E. faecalis. Most authors suggest that therapy be based on microscopic or microbiological findings using a topical antibiotic for the infectious agent, a topical steroid to reduce inflammation, and estrogen to treat atrophy.

1. AEROBIC VAGINITIS CAUSED BY ENTEROCOCCUS FAECALIS

Vaginitis is an acute inflammation of the vagina characterized by increased vaginal secretion in which leukocytes are present in large numbers along with vulvar pruritus (itching) and irritation (1).

Aerobic vaginitis (AV) is an imbalance of the vaginal flora and was first mentioned in 2002 by Donders and others (1). The main characteristic is an abnormal vaginal flora that contains aerobic and intestinal pathogens and different degrees of vaginal inflammation (2) .

The frequency of AV varies from 12% to 23.7% in symptomatic women who are not pregnant and 4 to 8% during pregnancy (1) and has an increased risk for sexually transmitted diseases (STI) (3). The causative agents of AV are: Enterococcus faecalis (E. faecalis), Esherichia coli, group B streptococcus and Staphylococcus aureus (2, 4, 5). The most frequently isolated AV pathogen is E. faecalis in about 31% (6).

The pathogenic effect of E. faecalis shows that it is the cause of spontaneous abortion, premature birth, puerperal sepsis, abscess and infection of the urinary system (7).

New articles indicate the presence of the HPV 16 gene and genome in E. faecalis in the biopsied material of cervical cancer, as well as the ability that HPV 16 genes can be translated and transcribed in these bacteria, and that the HPV gene can form viral particles in these bacteria leads to certain connection that can be a risk factor in the progression of cervical lesions to cancer (9).

AV positive for E.faecalis is very often unrecognized or ignored and may be the reason for neglected diagnosis. If this AV is not diagnosed or neglected in HPV-positive women, there is a justified possibility of long-term infection due to the presence of HPV in E. faecalis. The presence of HPV in this bacterium can lead to persistent HPV infection and the occurrence of high-grade CIN as well as progression to cervical cancer (9, 10).

Colonization of the vaginal mucosa with E. faecalis is made possible by the reduction or disappearance of lactobacilli, natural colonizers of the vaginal mucosa (11, 12). The use of broad-spectrum antibiotics or spermicidal ointments leads to a reduction in the number or destruction of lactobacilli and thus enables the overgrowth of the vaginal mucosa with E. faecalis and/or other bacteria (13). Colonization of the mucous membrane with E. faecalis is conditioned by its natural as well as acquired resistance to various antibiotics and disinfectants (14). Therapy with drugs that have a limited effect on E. faecalis is one of the main predisposing factors for colonization and infection with these conditionally pathogenic bacteria. Therapy with metronidazole and cephalosporins to which E. faecalis is resistant causes overgrowth and, in extreme cases, bacteremia and infection with this agent (10, 15).

E. faecalis produces cytolysin (hemolysin) which facilitates infection with its cytolytic effect on cells (11). It hemolyzes erythrocytes of humans, sheep, rabbits and cattle. Hemolysin also lyses some gram positive microorganisms (16). The aggregative substance participates in the adhesion of E. faecalis to cells of the urogenital apparatus and renal epithelium (17).

Different strains of E. faecalis differ from each other in virulence factors (11). Those strains isolated from patients with endocarditis, sepsis, or urogenital infections usually have all, or almost all, of the listed virulence factors (hemolysin/cytolysin, aggregating substance, gelatinase), while strains isolated from the intestine usually do not have them (12). This indicates that some mechanisms present in the host organism also play a role in enhancing the virulence of E. faecalis (12). A large number of strains of E. faecalis produce hydrogen superoxide. By comparing strains isolated from bacteremia and those that are normal commensals in human intestines, it was found that strains isolated from blood produce superoxide much more often (60%) (13). The produced hydrogen superoxide can injure the vaginal epithelium, cause its inflammation and lead to AV (16).

Virulent properties of E. faecalis include adherence to host tissue, ability to invade and form abscesses, resistance to antibacterial agents, modulation of host defenses, and secretion of cytolysin and other toxic products (11).

Propagation of E. faecalis from the mucous membrane of the vagina to the uterus, fallopian tubes and ovaries can lead to inflammation of these organs. This microorganism can cause pelvic abscesses and bacteremia as complications after caesarean section, endometritis or salpingitis. Also, E. faecalis can spread to the urethra and ascend to inflammation of the urethra, bladder and renal pelvis (1). It can be artificially transferred from the vaginal mucosa into the systemic circulation and cause serious diseases (6). Long-term vaginitis caused by E. faecalis in HPV 16 positive women, if not treated, can persist for a very long time and thus provide the conditions for persistent HPV infection, which is one of the prerequisites for the development of precancerous lesions of the cervix (18–20). In recent times, it has been increasingly written about its frequent presence in cervical cancer, oral cavity cancer and colon cancer (21, 22).

A decrease in the number of lactobacilli in the vaginal secretion reduces the defense ability and changes the pH value of the vaginal environment, which favors the development of bacterial inflammation (23, 24). AV positive for E. faecalis leads to a change in the pH value of the vaginal environment above 5, and an increased pH value of the vaginal environment in HPV positive women can be an association for cervical intraepithelial lesion (CIN) (2, 25).

2. CLINICAL PRESENTATION OF AEROBIC VAGINITIS

AV is a form of vaginal dysbiosis characterized by purulent vaginal secretion, significant inflammation and peeling of epithelial cells. AV is the transition between a healthy and lactobacilli-rich vaginal environment to a disturbed vaginal flora marked by inflammation, vaginal redness, burning and sticky yellow vaginal discharge with dyspareunia (1). A typical vaginal secretion is described as homogeneous or purulent, yellow or yellow-green in color with an unpleasant smell of rot (8). Symptoms can last for a long time with fluctuations in the degree of inflammation. When examined under a speculum, the severity of inflammation and the redness of the walls of the vagina varies depending on the degree of inflammation. Bleeding and erosion of the vaginal mucosa may be present (25).

Severe forms of AV cannot be distinguished from desquamative vaginitis because both are chronic forms with purulent vaginal secretion, vaginal irritation and erythema lasting 12 months or longer (26).

3. ENTEROCOCCUS FAECALIS POSITIVE AEROBIC VAGINITIS AND HPV IN VAGINAL FLORA

Persistent infection with human papillomavirus (HPV) is a necessary factor for the development of cervical precancerous lesions and cervical cancer (22), and the presence of inflammation increases the risk of cancer (22, 27). In recent years, an increasing number of studies indicate that abnormal vaginal flora play an important role in the development of CIN. Very little is known about the role of AV positive for E. faecalis and precancerous lesions. In 2021, Plisko investigated the connection between abnormal vaginal flora including AV and the histological finding of CIN and found that AV was significantly more common in subjects with a high degree of lesion (CIN II) compared to a low degree of lesion (CIN I) (2). She also states that in women with cervical pathology, the pH value of the vaginal environment is significantly higher, which is associated with CIN changes, as well as the association of a severe form of AV with an HPV-induced lesion (19). A decrease in the number of lactobacilli in the vaginal secretion reduces the defense capacity and changes the pH value of the vaginal environment, which favors the development of bacterial inflammation. AV positive for E. faecalis leads to a change in the pH value of the vaginal environment above 5, and an increased pH value of the vaginal environment in HPV positive women can be an association for cervical intraepithelial lesion (CIN) (22, 28).

In a letter to the author, Donders and Viera Bapista (28) comment on the work of Jucar Mario (29) on the strong association between bacterial vaginosis and HPV infection and find that AV is a greater predictor of CIN lesions in 889 Portuguese women than BV. AV has an increased pH of the vaginal environment and a reduced number of lactobacilli, which are key promoters of HPV reproduction in the cervix. Biochemical methods have proven that in AV there is a decrease in the vaginal content of succinate and an increase in interleukin-6, the opposite of the situation in developed bacterial vaginosis (6).

Vieira-Baptista also found a connection between abnormal vaginal flora of the AV type and cervical precancerous lesions, where he stated a significantly greater association between AV but not bacterial vaginosis with abnormal Pap test cytological findings compared to normal cervical cytology (18, 26). Severe forms of AV with HPV-induced precancerous lesions of the cervix could have a common and crucial role in the progression of the lesion to invasive cancer. Indeed, one of the critical mechanisms of HPV carcinogenesis is inflammation, which shows an increase in inflammatory interleukins in the progression of CIN (28).

A dominant pathogen in AV such as E. faecalis can reduce the protective effect of lactobacilli by causing inflammation, as well as an increase in IL-6, IL-8 and TNF, increasing the risk of HPV 16 infection resulting in CIN and cervical cancer (21). In research on cervical cancer, the presence of genes and genomes (except E1) of human papillomavirus (HPV) type 16 was found in bacteria such as: E. faecalis and Staphylococcus aureus from cervical cancer biopsies (30). Usually, high-risk HPV DNA is integrated in high-grade cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (20). DNA a charming role. In essence, this could mean several steps to establish this balance that depend on several factors. Some of them are: type of cause of inflammation, degree of inflammatory changes, duration of inflammation, hormonal status, immune status of the woman and stress component. the integration profile of the virus is different in cervical cancer depending on the type of virus; for HPV 16, episomal and integrated forms can coexist in cancer cells (9). The main oncogenic proteins of HPV E6 and E7 are involved in cervical cancer transformation, immortalization and malignancy.

It is unknown why some women develop persistent cervical HPV infection. So far, it has been shown that the reduction of lactobacilli combined with the diversity of the vaginal microflora is associated with HPV persistence (19). HPV infection leads to the loss of lactobacilli, destroying the biologic barrier of the local vaginal immune microenvironment, promoting abnormal adhesion of HPV in the vagina, causing local microecological imbalance in the vagina and destroying the local immune functions of the cervix while simultaneously increasing adhesion, invasion and colonization of abnormal flora. This leads to a vicious circle in the vaginal environment and the further development of HPV infection that causes cervical lesions. Whether long-term infection with E. faecalis can be a risk factor supporting persistent HPV16 infection (E. faecalis can contain HPV 16 in an episomal form) is still an open question with indicators supporting this observation. Modulation of the microflora in terms of intensive treatment of AV could promote the elimination of E. faecalis and thereby: the removal of HPV and the normalization of lactobacilli and reverse the natural history of HPV infection. According to various studies, the vaginal microflora plays a crucial role in the prevention of HPV infection and accelerates HPV clearance (29). An understanding of the functional properties of AV positive for E.faecalis and HPV is needed to supplement what we already know about their interaction and its impact on the development of CIN.

4. MODERN TREATMENT OF AEROBIC VAGINITIS POSITIVE FOR ENTEROCOCCUS FAECALIS

Intensive treatment of AV could be a very important factor in preventing of precancerous lesions and cervical cancer. The recommended treatment of AV includes a combination of therapy such as: antibacterial (antiseptic and antibiotic), hormonal, non-steroidal anti-inflammatory and/or probiotics, which can be prescribed in the form of local or systemic therapy (1).

There is no generally accepted clinical strategy for the treatment of AV caused by E. faecalis. Han et al suggested that therapy should be based on microscopic or microbiological findings using a topical antibiotic for the infectious agent, a topical steroid to reduce inflammation, and estrogen to treat atrophy (25).

AV caused by E. faecalis can be treated with ampicillin, a combination of ampicillin and aminoglycosides such as gentamicin or spectinomycin (15). In his work on the treatment of bacterial vaginitis caused by E. faecalis and E coli, Jahić in 2009 found successful elimination of symptoms and causative agents in 72%, using nitrofurantoin 500 mg once a day for 6 days of vaginal application (10), while in a randomized short study treatment with 500 mg nifuratel intravaginally for 10 days showed good clinical efficacy for AV and bacterial vaginosis in 43% (1).

Sangeetha et al (2015) found about 40% of isolated Enterococci resistant to penicillin and ampicillin, while only 10% showed resistance to aminoglycosides (8).

It is very important to know that AV cannot be treated with metronidazole, as bacterial vaginosis is treated, because it will not be cured but will lead to increased infection, due to the natural resistance of E. faecalis to this drug. If it is a question of pregnancy, it is better to opt for clindamycin (7). Fluoroquinolones such as ciprofloxacin and ofloxacin can be used in AV therapy because they have little effect on the normal vaginal flora, leading to rapid recovery from AV (15). Wang investigated the therapeutic efficacy of oral moxifloxacin therapy for AV and found that oral administration of moxifloxacin 400 mg once daily for 6 days led to a cure in 65.7% of women, and after 2 treatments in 85.3%. The author suggests that two treatments should be used only in the case of elevated vaginal pH above 5 (pH>5) before the treatment (31).

In a large number of women with pronounced atrophy (microscopic examination of a large number of parabasal cells - more than 10%), the local application of estrogen is very useful in women who are premenopausal or postmenopausal (32).

It has recently been noticed that a probiotic (Lactobacilus acidophilus) can improve the condition after targeted antibiotic therapy of AV (3). Also some studies state that vaginal probiotics can be valuable for preserving and establishing the vaginal microflora. The direct use of vaginal probiotics such as Lactobacillus can influence the reduction of the rate of HPV infection and thereby contribute to a new approach to establishing the homeostasis of the vaginal mucosa (33).

Local application of corticosteroids can be used when inflammation prevails (over 20 leukocytes per epithelial cell) with antibiotic therapy according to the isolated microorganism (1).

Essential treatment should result in the establishment of homeostasis of the vaginal environment where Lactobacilli play a role a charming role. In essence, this could mean several steps to establish this balance that depend on several factors. Some of them are: type of cause of inflammation, degree of inflammatory changes, duration of inflammation, hormonal status, immune status of the woman and stress component.

5. CONCLUSION

Aerobic vaginitis is an imbalance of the vaginal flora and the main characteristic is an abnormal vaginal flora that contains aerobic and intestinal pathogens with varying degrees of vaginal inflammation. Essential treatment should result in the establishment of homeostasis of the vaginal environment where Lactobacilli play a role a charming role. In essence, this could mean several steps to establish this balance that depend on several factors. The author suggests that two treatments should be used only in the case of elevated vaginal pH above 5 (pH>5) before the treatment. In a large number of women with pronounced atrophy (microscopic examination of a large number of parabasal cells - more than 10%), the local application of estrogen is very useful in women who are premenopausal or postmenopausal.

Author’s Contribution:

The author was involved in all steps of preparation this article including final proofreading.

Conflicts of interest:

There are no conflicts of interest.

Financial support and sponsorship:

None.