Curr Infect Dis Rep (2015) 17:24

DOI 10.1007/s11908-015-0477-6

GENITOURINARY INFECTIONS (J SOBEL, SECTION EDITOR)

Selecting Anti-Microbial Treatment of Aerobic Vaginitis

# Springer Science+Business Media New York 2015

Abstract Aerobic vaginitis (AV) is a vaginal infectious con- treatment is still needed. Vaginal rinsing with povidone iodine
dition which is often confused with bacterial vaginosis (BV) can provide rapid relief of symptoms but does not provide
or with the intermediate microflora as diagnosed by Nugent’s long-term reduction of bacterial loads. Local antibiotics most
method to detect BV on Gram-stained specimens. However, suitable are preferably non-absorbed and broad spectrum, es-
although both conditions reflect a state of lactobacillary dis- pecially those covering enteric gram-positive and gram-
ruption in the vagina, leading to an increase in pH, BVand AV negative aerobes, like kanamycin. To achieve rapid and
differ profoundly. While BV is a noninflammatory condition short-term improvement of severe symptoms, oral therapy
composed of a multiplex array of different anaerobic bacteria with amoxyclav or moxifloxacin can be used, especially in
in high quantities, AV is rather sparely populated by one or deep dermal vulvitis and colpitis infections with group B
two enteric commensal flora bacteria, like Streptococcus streptococci or (methicillin resistant) Staphylococcus aureus.
agalactiae, Staphylocuccus aureus, or Escherichia coli. AV Since the latter colonizations are frequent, but seldom inflam-
is typically marked by either an increased inflammatory re- matory infections, we in general discourage the use of oral
sponse or by prominent signs of epithelial atrophy or both. antibiotics in women with AV. In cases with a severe atrophy
The latter condition, if severe, is also called desquamative component (more than 10 % of epithelial cells are of the
inflammatory vaginitis. As AV is per exclusionem diagnosed parabasal type), local estrogens can be used; and in postmen-
by wet mount microscopy, it is a mistake to treat just vaginal opausal or breast cancer patients with a contraindication for
culture results. Vaginal cultures only serve as follow-up data estrogens, even a combination of probiotics with an ultra-low
in clinical research projects and are at most used in clinical dose of local estriol may be considered.
practice to confirm the diagnosis or exclude Candida infec-
tion. AV requires treatment based on microscopy findings and
Keywords Aerobic vaginitis . Desquamative inflammatory
a combined local treatment with any of the following which
vaginitis . Bacterial vaginosis . Wet mount . Microscopy .
may yield the best results: antibiotic (infectious component),
Corticosteroids . Vaginal treatment . Metronidazole .
steroids (inflammatory component), and/or estrogen (atrophy
Clindamycin . Gynoflor . Probiotic . Local estrogen .
component). In cases with Candida present on microscopy or
Vaginal atrophy . Vaginal immunity . Group B streptococ .
culture, antifungals must be tried first in order to see if other
Kanamycin . Pregnancy complications . Vaginal
inflammation . Leucorrhea . Dyspareunia
This article is part of the Topical Collection on Genitourinary Infections
G. G. G. Donders : K. Ruban : G. Bellen
Femicare Clinical Research for Women, Tienen, Belgium Introduction
G. G. G. Donders
Health-care workers frequently taking care of women with
University Hospital Antwerp, Antwerp, Belgium
vulvovaginal complaints recognize that besides the common
G. G. G. Donders threesome, bacterial vaginosis (BV), Candida vaginitis (CV),
Regional Hospital H Hart, Tienen, Belgium and trichomoniasis (TV), other infectious and noninfectious
conditions can seriously affect vaginal health, cause
G. G. G. Donders (*)
Femicare vzw, Gasthuismolenstraat 31, 3300 Tienen, Belgium distressing symptoms, or endanger the course of pregnancy
e-mail: [email protected] [1, 2]. The most frequent and enigmatic cause is aerobic
24 Page 2 of 7 Curr Infect Dis Rep (2015) 17:24

vaginitis (AV), a term coined in a hallmark paper in 2002 to In studies of Briselden et al., hydrolytic bacterial enzymes
emphasize its difference from BV and the need to recognize known as sialidases are produced by BV-associated bacteria,
this condition as a separate entity requiring attention [3•]. such as Gardnerella vaginalis and Prevotella bivia [15].
Whereas in TV and CV, one specific microorganism or Sialidase degrades host defence molecules such as
pathogen is responsible for the symptomatic infection and immunoglobulin-A (IgA) against G. vaginalis hemolysin, which
hence specific antimicrobials effective against the responsible can be harmful to a healthy vaginal environment and may in high
specific pathogen are sufficient to treat the vaginitis; this is not concentrations be a risk factor for preterm birth [16–18].
the case for the multifactorial disturbances seen in BV or AV. Marconi C. et al. reported a more intense inflammatory
In both conditions, the lactobacillary microflora is disturbed, host response in AV than in BV and in women with normal
with no or sporadic visible remaining lactobacillary flora [19]. They detected, however, increased sialidase activity
morphotypes on microscopy specimens of vaginal fluid of in both AVand BV, indicating that both abnormal vaginal flora
affected women. This is associated with an increase in vaginal types could interfere with a healthy vaginal environment.
pH, which is usually between 4.5 and 5 in BV, but can be as Hence, it comes as no surprise that both clinical conditions
high as 6–8 in AV. BV is typically recognized by its with abnormal vaginal flora and reactive immune responses
polymicrobial, origin of the mainly anaerobic microorgan- are associated with several gynecological and obstetric com-
isms, which are not only 10-fold more diverse, but also a plications, such as pelvic inflammatory disease, increased risk
1000-fold more abundant than in normal flora. In AV, on the of sexually transmitted diseases (STD), and preterm birth.
other hand, one or a few single organisms of aerobic origin
overgrow the normal LB dominant flora, a picture which is
completely distinct from the granular BV flora and easy to Aim
recognize by microscopy of fresh or gram stained vaginal
specimens [1]. In some, but not all patients, infection elicits In this review, we aim to review the efficacy of treatment with
at times a dramatic immune response, as evidenced by in- antimicrobials for AV. We also reviewed the evidence of other
creased numbers of leucocytes in vaginal smears. In addition, types of treatment such as corticosteroids, estrogens, and
increased activity of the leukocytes in response to the patho- probiotics.
gens (toxic leukocytes) is often seen, which is typically absent
in BV patients. Finally, another major difference is thinning of
the vaginal epithelium in women with AV, as compared with Methods
BV, where the vaginal wall retains its full 10 to 12 epithelial
cell layer thickness. This vaginal thinning in AV is demon- A systematic search was performed in the Limo, PubMed,
strated in the vaginal smears by the appearance of increased Scopus databases in December 2014. The following search
numbers of intermediate and parabasal cells, indicating an term was applied to all published articles: [Baerobic^ and
increased turnover and desquamation of superficial epithelial (Bvaginitis^ Or Bvaginosis^) or Bdesquamative inflammatory
cell layers. In extreme cases, therefore, AV has a similar ap- vaginitis^] and Btreatment^ or Btherapy^ or Bantimicrobial^.
pearance as the so-called desquamative inflammatory vagini- The bibliographies of relevant articles were also hand-
tis (DIV), which was first described as a separate entity by searched in order to identify further potentially eligible studies.
Gardner [4] and later confirmed and recognized by others Any article reporting the prevalence of AV or aerobic path-
[5–8]. ogens in vaginal swabs among pregnant and nonpregnant
symptomatic women who were given treatment were
reviewed. Among studies reporting the prevalence of aerobic
Pathogenesis and Need for Treatment pathogens but not the prevalence of AV, only studies reporting
women with symptoms of vaginitis were considered eligible
Vaginal epithelial cells express on their surfaces receptors for for the review in order to avoid including women who were
microbial recognition, such as toll-like receptors (TLR). These only colonized but not infected with aerobic bacteria. Studies
receptors recognize molecular patterns present on the bacterial concerning children, prepubertal, or adolescent girls were not
surface and in response to induce production of protective pro- included in the review. Case reports and case series were not
inflammatory cytokines through nuclear factor kappa B acti- evaluated for inclusion in the review.
vation [9]. According to several studies, pathologic vaginal
flora activate the local immune response as evidenced by ele-
vation of cytokines level and interleukin (IL)-1b levels in bac- Treatment
terial vaginosis (BV) and aerobic vaginitis (AV) [3•, 9–14]. In
the same studies, however, the levels of IL-6 were elevated As the ethiopathogenesis of AV is not yet fully understood, it
only in AV. is not possible to dictate optimal treatment or prevention. One
Curr Infect Dis Rep (2015) 17:24 Page 3 of 7 24

study of Neng et al. from China (unpublished data) found a However, as the product rapidly disappears from the vagina
strong inverse relation with the consistent use of condoms after use, it is uncertain whether any prolonged effect can be
during sexual intercourse. Marconi et al. found an increased expected with this method in women with an already
prevalence of Chlamydia trachomatis in AV patients [20]. established vaginal aerobic infection, and whether the short
Although this may suggest a relevance for this as a sexually term improvement is not merely a consequence of the me-
transmitted microorganism, it may also indicate that unpro- chanical, cleaning effect of the rinsing rather that the antimi-
tected sexual intercourse may challenge or diminish the nor- crobial properties of the product itself. Although the regrowth
mal defensive lactobacillary microflora which is needed to of lactobacilli is rather swift in women with BV treated with
prevent the emergence of abnormal vaginal flora types such povidone iodine [27], we found no validated, controlled stud-
as BV and AV. Accordingly, providing directed antibiotic or ies documenting the usefulness of povidone iodine in women
probiotic therapy may exert a positive influence in the man- with AV.
agement of AV. Furthermore, the presence of intrauterine de- In the study of Mumtaz et al., a significant growth of aer-
vice, low estrogen dose contraception pills, or continuous use obic pathogens was seen in 76.6 % of patients with AV. Staph-
of progestins may have a serious impact in the development ylococcus aureus was the most prevalent vaginal pathogen in
and sustaining of AV, especially the type with prominent signs 31–40-year-old patients, followed by enteric gram-negative
of atrophy. Hence, the management of AV should be a global bacilli and other gram-positive cocci [28]. There were very
consideration of different approaches and not a single antibiotic few antibiotics among the conventionally available aminogly-
treatment, considering hormonal adjusments in selected cases. cosides, third-generation cephalosporins, penicillin, quino-
Accordingly, treatment of AV may include local estradiol lones, sulfonamides, and tetracyclines that possess potent ac-
or estriol administration, with or without probiotic lactobacilli tivity (more than 80 %) against the common aerobic vaginal
in cases where atrophy dominates (increased number of pathogens. The effective chemotherapeutics agents belong to
parabasal cells) [21, 22] or local application of a corticosteroid the groups of carbapenems and clavulanic-beta-lactam com-
when noninfectious inflammation predominates (>20 leuko- binations (amoxyclav) [28]. In a study of Fan et al. of 39
cytes per epithelial cell), but in cases with clear infectious patients with AV given one course of 400 mg for 6 days and
abnormalities (lactobacillary grade IIb or III with cocci, chains 21 received two courses of 400 mg for 12 days, cure rate
of cocci, heavy growth Escherichia coli, group A streptococci, 1 month after treatment was 90 % in the 6-day group and
staphylococci or group B streptococci), primary anti- 75 % in the 12-days group [29].
microbial treatment is indicated (Fig. 1). However, it is very unlikely that oral administration of the
As a result, trials with antiseptic and antibiotic drugs have above antibiotics will have a long-term positive effect on the
emerged, as recently described in an excellent review [23•]. vaginal milieu. Hence, they should only be considered for
The use of povidone iodine rinsings of the vagina may have initial use, with short courses, to control acute symptoms in
some logic as the product inhibits the growth of most major complicated and severe cases such as staphylococcal or mac-
groups of gram positive and gram negative enteric bacteria, ular streptococcal vaginitis, rare and specific subcategories of
possibly involved in the pathogenesis of AV. This technique severe AV [30–33].
has merit as a preoperative preventive measure to prevent Per definition, the use of metronidazole is unlikely to im-
postoperative infectious morbidity for women undergoing prove the condition AV, as the microbiota of AV are typically
in vitro fertilization, abortion or ceasarian section [24–26]. not composed of major amounts of multiple subtypes of an-
aerobic bacteria, as seen in BV, but rather a small limited
number of aerobic enteric bacterial microorganisms. Thus,
treatment failure of metronidazole in women with symptom-
atic vulvovaginitis is a common reason to suspect AV as an
underlying diagnosis.
Clindamycin, on the other hand, with its broader spectrum
also active against several aerobic gram-positive cocci species
[34], seems to have a much more profound effect on women
with a very severe form of AV (or DIV) [35].
Sobel first used clindamycin to treat DIV: 45 patients re-
ceived 2 % vaginal clindamycin during 14 days [35]. Of these
patients, 16 were postmenopausal and started hormone re-
placement therapy, and 17 were not cured and needed a sec-
Fig. 1 Aerobic vaginitis (AV) according to its major component as
diagnosed by fresh wet mount microscopy (AV score [3•]) and the
ond course of treatment. After this second course, still one
specific according treatment preferences. DIV desquamative third failed to attain a normal vaginal flora. A further six re-
inflammatory vaginitis (severe AV) fractory postmenopausal patients were cured by applying
24 Page 4 of 7 Curr Infect Dis Rep (2015) 17:24

estrogen. Therefore, with its activity of anti-gram-positive only methods, or in elderly women in their perimenopausal or
cocci, clindamycin turns out to be effective in DIV patients, untreated menopausal period. However, in women with con-
but some women may also require estrogen therapy, with or traindications for use of steroid hormones, such as breast can-
without the combination with clindamycin. In a later study, the cer patients, patients with previous thromboembolism, etc.,
same author studied the outcome of women with DIV treated this approach is not possible and other options have to be
with topical application of either 2 % clindamycin or 10 % explored. Recently, excellent treatment success was achieved
hydrocortisone [36]. However, as this was an open-label, non- with the use of a vaginal product combining a probotiotic (107
controlled observation study, not much can be concluded as to viable lactobacillus acidophilus) with an ultra-low dose of
whether one therapy is better than the other. In clinical prac- 30 μg estriol (E3) for the treatment of severe symptomatic
tice, therapy is decided upon the microscopic findings, leading vaginal atrophy in menopausal women [43] and in women
to the increased likelihood that women with predominant in- with hormone receptor positive breast cancer taking anti-
flammation are receiving hydrocortisone, the ones with low hormonal aromatase inhibitors [22, 44].
maturation index estrogens, and the more infectious types (as
evidenced by large numbers of cocci) of antibiotics. Hence,
comparing therapies in such heterogeneous groups is unlikely Treatment in Pregnancy
to produce any conclusion about which therapy is superior.
The only outcome that can be retained from this study is an AV is a notorious cause of complications in pregnancy. In the
early high failure rate (37 %) and a high recurrence rate of 32, original paper describing AV, it was shown that AV is associ-
43, and 74 % after 6 weeks, 6 months, and 1 year, respectively ated with massive concentrations of pro-inflammatory cyto-
[36], although continued therapy often resulted in control but kines, such as interleukin (IL)-1b, IL-6, and IL-8 in the vagina
not cure. [3•], and it is clear that these substances are widely prevalent
Clindamycin as first choice may have its shortcomings. in the vagina of women with abnormal vaginal flora, including
Infection control may be short lived and may not cover all pregnant women with AV [13, 45]. There is evidence that AV,
species involved in AV and, most disturbingly, is prone to and not only certain types of BV, may contribute to an in-
resistance development in patients treated repeatedly for re- creased risk of preterm delivery [46], intra-amniotic infection
current disease, especially with methicillin-resistant S. aureus [47], and chorioamnionitis [48]. The broad-spectrum effect of
(MRSA) and group B streptococci [37–39]. clindamycin versus the narrow anaerobic spectrum of metro-
Focusing on the gram-negative bacilli, rather than the nidazole is also seen as one of the explanations why
gram-positive cocci, Tempera et al. studied the use of local clindamycin is, but metronidazole is not, capable of stemming
51 mg meclocycline and 100 mg kanamycin to treat AV, as the complications of preterm delivery and PPROM in women
these drugs are not absorbed and, like quinolones, spare vag- with an abnormal vaginal flora pattern [49, 50]. Accordingly,
inal lactobacilli [40]. After 6 days of treatment, 80 % of the preterm delivery can be caused by abnormal vaginal flora,
meclocycline and 100 % of the kanamycin-treated patients both BV and AV or a combination thereof, but metronidazole
were cured after 7 days, while after 13–16 days, only the will only treat for BV, leaving the dangerous inflammatory
kanamycin-treated women remained in remission with normal cytokine producing condition AV untouched, while
vaginal pH and LBG1 lactobacilli [41••]. In a larger study, clindamycin is active against both. To date, four randomized
they ramdomized 81 patients with AV to intravaginal 6-day controlled studies have shown a substantial reduction in the
treatment with either 100 mg kanamycin ovules or 35 mg occurrence of preterm birth in women with AVF treated with
meclocycline. One to 2 days following completion of treat- clindamycin [51–54]. However, two other randomized studies
ment, they found a reduction in vaginal leukocytes, reduction could not find an improved outcome after clindamycin treat-
of isolation of Enterobacteriaceae (97 vs 76 %), and less vag- ment and concluded that some cases are refractory to treat-
inal mucosa burning and itching in the group treated with ment or cause frequent recurrences [55, 56], leading some
kanamycin as compared to the meclocycline-treated group authors to advise rescreening and retreatment of cases in
[42]. At the second follow-up, vaginal homeostasis (normali- whom no cure has been achieved with initial antimicrobial
zation of pH and presence of lactobacilli) was more evident in treatment [56, 57].
the kanamycin-treated group. In patients with proven intra-amniotic infection (IAS) due
In most women with a prominent atrophy component, as to ascending AV microorganisms, Curzik et al. were able to
diagnosed by an increased number of parabasal cells (more improve the pregnancy outcome of pregnant women, by
than 10 % of epithelial cells) by microscopy of the vaginal treating them with erythromycin, cefuroxime, and local tetra-
fluid, local, intravaginal application of estrogens (e.g., 0.1 % cycline [47]. The cervical swab became negative in 30 of 50
estradiol valerate) is very helpful in most cases. This is typi- patients with IAS, and in these women, perinatal loss was only
cally effective in young women in their postpartum period, or 6.7 %, while in cases with persistent infection loss was
when on low dose combined contraceptive pills, or progestin 55.0 %.
Curr Infect Dis Rep (2015) 17:24 Page 5 of 7 24

Donders et al. have emphasized that AV, with or without Compliance with Ethics Guidelines
the presence of concomitant bacterial vaginosis, may be a
Conflict of Interest Gert Bellen, Kateryna Ruban, and Gilbert Donders
better candidate than BV in causing pregnancy complications, have no relevant disclosures to report.
such as preterm delivery [49]. They, as well as Nenadic et al.,
claim that some patients with a common, mild to moderate Human and Animal Rights and Informed Consent This article does
form of AV are often misdiagnosed as BVor misclassified into not contain any studies with human or animal subjects performed by the
the group with Bintermediate^ findings [49, 58]. On the other author.
hand, in one recent study, only 5.2 % of cases with interme-
diate Nugent scores were so classified, and 3.7 % of the BV
positive cases was classified as moderate AV [59]. It is note- References
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preterm birth, unlike Donders’ series in which both BV and Papers of particular interest, published recently, have been
AV posed a risk for adverse pregnancy outcome [46]. highlighted as:
A randomized, controlled study was performed to compare • Of importance
the clinical and microbiological results between patients with •• Of major importance
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