2018 European (IUSTI/WHO) International Union against sexually transmitted infections (IUSTI) World Health Organisation (WHO) guideline on the management of vaginal discharge

Guidelines

2018 European (IUSTI/WHO)

International Union against sexually

transmitted infections (IUSTI) World

Health Organisation (WHO) guideline on

the management of vaginal discharge

Jackie Sherrard

, Janet Wilson

, Gilbert Donders

Werner Mendling

and Jørgen S Jensen

Abstract

Four common pathological conditions are associated with vaginal discharge: bacterial vaginosis, aerobic vaginitis, can-

didosis, and the sexually transmitted infection, trichomoniasis. Chlamydial or gonococcal cervical infection may result in

vaginal discharge. Vaginal discharge may be caused by a range of other physiological and pathological conditions including

atrophic vaginitis, desquamative inflammatory vaginitis, cervicitis, and mucoid ectopy. Psychosexual problems may pre-

sent with recurrent episodes of vaginal discharge and vulval burning. These need to be considered if tests for specific

infections are negative. Many of the symptoms and signs are non-specific and a number of women may have other

conditions such as vulval dermatoses or allergic and irritant reactions.

Keywords

Trichomoniasis (Trichomonas vaginalis), women, diagnosis, bacterial vaginosis, candida, aerobic vaginitis, vaginal discharge

Date received: 30 May 2018; accepted: 5 June 2018

Introduction

Four common pathological conditions are associated

with vaginal discharge: bacterial vaginosis (BV), aero-

bic vaginitis (AV), candidosis, and the sexually

transmitted infection, trichomoniasis. Chlamydial or

gonococcal cervical infection may result in vaginal dis-

charge. Vaginal discharge may be caused by a range of

other physiological and pathological conditions includ-

ing atrophic vaginitis, desquamative inﬂammatory

vaginitis (DIV), cervicitis, and mucoid ectopy.

Psychosexual problems may present with recurrent epi-

sodes of vaginal discharge and vulval burning. These

need to be considered if tests for speciﬁc infections are

negative. Many of the symptoms and signs are

non-speciﬁc and a number of women may have other

conditions such as vulval dermatoses or allergic and

irritant reactions.

Department of Genitourinary Medicine, Sexual Health Department,

Buckinghamshire Healthcare NHS Trust, Amersham, UK

Department of Genitourinary Medicine, Leeds Teaching Hospitals NHS

Trust, Leeds, UK

Department of Obstetrics and Gynecology, Regional Hospital H Hart

Tienen, University Hospital Antwerp

Infektionen in Gyn

€

akologie und Geburtshilfe, Wuppertal, Germany

Research Unit for Reproductive Microbiology, Statens Serum Institut,

Copenhagen, Denmark

Lead editor: Jørgen S Jensen

This guideline is an update of the European IUSTI vaginal discharge

guideline 2011.

Corresponding author:

Jackie Sherrard, Department of Genitourinary Medicine, Sexual Health

Department, Buckinghamshire Healthcare NHS Trust, Amersham, UK.

Email: [email protected]

International Journal of STD & AIDS

2018, Vol. 29(13) 1258–1272

! The Author(s) 2018

Article reuse guidelines:

sagepub.com/journals-permissions

DOI: 10.1177/0956462418785451

journals.sagepub.com/home/std

Aetiology and transmission

BV is the commonest cause of abnormal vaginal dis-

charge in woman of childbearing age but may also be

encountered in perimenopausal women.

1,2

Caucasian women the prevalence is 5–15%; in Black

women it is higher at 45–55%. Women who have s ex

with women (WSW) share similar lactobacillary types,

are more likely to have concordant vaginal microbiota

(ﬂora) patterns, and are at increased risk for BV.

BV is a dysbiosis of the vaginal microbiota. It is

characterised by an overgrowth of predominantly

anaerobic organisms (e.g. Gardnerella vaginalis,

Prevotella spp., Atopobium vaginae, Mycoplasma hom-

inis, Mobiluncus spp.) in the vagina leading to a

replacement of lactobacilli and an increase in vaginal

pH. Bacterial identiﬁcation using PCR has demonstrat-

ed that there are many different, previously unculti-

vated bacteria present in women with BV including

BV-associated bacterium 1, 2, and 3, and Sneathia spe-

cies.

Since these bacteria are difﬁcult to culture, the

antibiotic susceptibility of many is not known.

BV can arise and remit spontaneously and although

not strictly considered a sexually transmitted infection

(STI) it is associated with sexual activity. The exact

aetiology of BV is still unclear but current evidence

suggests that formation of a bioﬁlm with G. vaginalis

is important in the switch from normal vaginal ﬂora

to BV.

5,6

AV/DIV

AV presents with a purulent discharge, some degree of

atrophy, and vaginitis. Lactobacilli are decreased and

pH is elevated, but aerobic microorganisms, like

Escherichia coli, group B streptococci, and

Staphylococcus aureus predominate.

Mixed infections

are frequent. It is not known whether AV has an infec-

tious origin or whether it is an inﬂammatory process

followed by a dysbiosis. It can cause long-term symp-

toms with intermittent exacerbations, and recurrences

after treatment are common.

Atrophic vaginitis in lac-

tating women is probably a variant of AV. More severe

forms of AV and DIV are probably the same condition.

Candidosis

More than 60% of healthy premenopausal women are

colonised with candida, with higher rates in pregnancy,

and lower rates in children and postmenopausal

women without hormonal replacement therapy.

9,10

An estimated 75% of women will experience at least

one symptomatic episode during their lifetime and 6–

9% will experience chronic recurrent vulvovaginal can-

didosis (at least four episodes per year). Vulvovaginal

candidosis results from an overgrowth of Candida albi-

cans in 90% of women (remainder with other species,

e.g. Candida glabrata).

11,12

Precipitating factors include

antibiotic therapy, pregnancy, and endogenous or

exogenous immunosuppression (including diabetes

mellitus and immunosuppressive medication). In some

women, symptoms may occur with a low burden of

candida and it is thought this may be due to an allergic

or inﬂammatory response to the yeast.

Trichomoniasis

Trichomonas vaginalis (TV) is a ﬂagellated protozoon,

which is a parasite of the genital tract. In adults, it is

almost exclusively sexually transmitted. Due to site spe-

ciﬁcity, infection only follows intravaginal or intraure-

thral inoculation of the organism. In women urethral

infection is present in 90% of episodes, although the

urinary tract is the sole site of infection in <5% of

cases. The most obvious host response to infection is

a local increase in polymorphonuclear leucocytes.

Table 1. Symptoms and signs.

Bacterial vaginosis Aerobic vaginitis Candidosis Trichomoniasis

Approximately 50%

asymptomatic

10–20% asymptomatic Approx. 60% women colonised.

Minority develop symptoms

10–50% asymptomatic and

5–15% no abnormal signs

Thin white homogenous

discharge, coating walls

of vagina and vestibule

Purulent discharge Vaginal discharge may be curdy

(non-offensive)

Offensive vaginal discharge in up

to 70% – frothy and yellow in

10–30%

Offensive fishy odour Vulval burning or stinging Vulval soreness/itching

and erythema

Vulval itching/irritation

and erythema

Absence of vaginitis Superficial dyspareunia Vulval fissuring Dysuria

Vaginal er ythema and

oedema

Superficial dyspareunia Rarely low abdominal discomfort

Vaginal ulceration Satellite skin lesions Vaginitis

Vulval oedema Approx. 2% ‘strawberry’ cervix

visible to naked eye.

Sherrard et al. 1259

Clinical features

There are recognised symptoms and signs (Table 1).

The diagnosis of both BV and candidosis is syndromic,

i.e. based on clinical symptoms and signs supported by

laboratory test ﬁndings, which in themselves vary in

speciﬁcity and sensitivity. The classical features of TV

are frequently absent or non-speciﬁc.

13,14

Complications

Women with BV are at increased risk of acquiring

STIs. They have a two-fold increased risk of HIV

acquisition,

1.5–2-fold risk of Chlamydia

and gon-

orrhoea,

a nine-fold risk of TV,

and a two-fold risk

of herpes simplex virus type 2 (HSV-2)

compared to

women without BV. HIV-positive women with BV

have a three-fold risk of transmitting HIV.

Monthly

prophylaxis with metronidazole reduces the incidence

of STIs by almost 50%.

The BV-associated bacteria

are probably also implicated in the aetiology of pelvic

inﬂammatory disease (PID). A prospective study of

women with clinically-suspected PID reported

signiﬁcant correlations between the presence of

BV-associated bacteria and the presence of endometri-

tis and recurrent PID.

There is an association with BV and post-

hysterectomy vaginal cuff infection,

22,23

post-abortion

endometritis,

24,25

and an increased risk of spontaneous

miscarriage and preterm birth.

26,27

Symptomatic preg-

nant women with BV should be treated in the usual

way but the latest Cochrane review concludes there is

insufﬁcient evidence to recommend routine screening

and treating all pregnant women for asymptomatic

BV to prevent preterm birth.

Multiple reports support an epidemiological associ-

ation between HIV and trichomoniasis. There is grow-

ing evidence that trichomonal infection enhances HIV

transmission

29–32

and there may be an increased risk of

TV infection in those that are HIV-positive.

Trichomoniasis is associated with adverse pregnancy

outcomes.

34,35

The literature on metronidazole treat-

ment during pregnancy and preterm birth is not con-

clusive. The most recent Cochrane review found that

metronidazole is effective against trichomoniasis when

taken by women and their partners during pregnancy,

but it may harm the baby due to early birth.

Screening of asymptomatic individuals for TV infection

is therefore not currently recommended.

Although only recently described, moderate/severe

AV is associated with an increasing number of co-

infections and complications.

An increased risk of

preterm delivery and chorioamnionitis in women with

ﬁrst trimester AV has been described.

Several studies in the last decade have shown a

decrease in preterm birth, if vaginal candida colonisa-

tion or infection had been treated with clotrimazole.

In a study by Holzer et al.

women who were colonised

with candida spp. during the second trimester of preg-

nancy had higher rates of preterm birth and lower neo-

natal birthweight than those who were colonised

during the ﬁrst trimester of their pregnancy.

According to old studies the vaginal treatment of an

asymptomatic candida colonisation during the last six

weeks of pregnancy reduces the candida colonisation of

the newborn during vaginal delivery and thus reduces

oral thrush and napkin dermatitis of the baby during

the ﬁrst four weeks of life.

Modern studies are urgent-

ly needed to conﬁrm these ﬁndings.

Diagnosis

Women presenting with abnormal vulval or vaginal

symptoms should be tested to ensure that appropriate

treatment is given.

40,42–44

If this is not possible, then

examination and testing shoul d deﬁnitely be performed

in the following situations:

•

Severe or recurrent symptoms

•

Failure of vaginal discharge to respond to empiri-

cal treatment

•

Symptoms in pregnancy

•

Finding of TV on cervical cytology

•

Diagnosis of TV in sexual partner

Asymptomatic women do not require testing for BV,

AV, or candida. Testing asymptomatic women for TV

should be guided by local prevalence data.

The deﬁnitive diagnosis of each infection is based

upon clinical symptoms, examination, pH and micro-

scopic ﬁndings of the vaginal secretions, and for TV

additionally by laboratory tests. A sample of the dis-

charge is removed from the vaginal wall with a swab.

This can be performed by the clinician or be self-

collected by the woman.

The type of swab is not

important. An elevated pH (>4.5) is suggestive of BV

or trichomoniasis and is almost always normal in can-

dida infections. Direct microscopy should be done

immediately, if available.

Gram-stained microscopy is the reference method for

diagnosing BV.

A. Nugent score

– This is used as a gold standard for

studies and relies upon estimating the relative pro-

portions of bacterial morphotypes on a Gram-

stained vaginal smear to give a score between 0

1260 International Journal of STD & AIDS 29(13)

and 10. A score of <4 is normal, 4–6 is intermedi-

ate, and >6 is BV. However, it does not take bac-

terial morphotypes other than those associated with

BV into account. The clinical implications of ‘inter-

mediate ﬂora’ are unclear but they are associated

with complications.

B. Hay–Ison criteria

– These are also based on the

ﬁndings on a Gram-stained smear but are easier and

quicker to use in clinical practice and do include

non-BV-associated bacteria .

Grade 0: Not related to BV, epithelial cells only, no

lactobacilli, indicates recent antibiotics

Grade 1: (Normal): Lactobacillus morphotypes

predominate

Grade 2: (Intermediate): Mixed ﬂora with some lac-

tobacilli present, but Gardnerella or Mobiluncus mor-

photypes also present

Grade 3 (BV): Predominantly Gardnerella and/or

Mobiluncus morphotypes, clue cells. Few or absent

Lactobacilli.

Grade 4: Not related to BV, Gram-positive cocci

only, no lactobacilli (AV ﬂora)

Clinical criteria for diagnosis of BV (Amsel)

The presence of three of the four criteria is required;

as three are clinical criteria it is possible to make a

diagnosis of BV without microscopy or the use of a

microbiology laboratory. Compared to Gram-stained

microscopy, the presence of three of the four clinical

criteria has a sensitivity of 60–72% for the diagnosis

of BV.

50,51

1. Homogeneous grey-white discharge

2. pH of vaginal ﬂuid > 4.5 (measured using narrow

gauge pH paper)

3. Fishy odour (if not recognisable, use few drops of

10% KOH)

4. Clue cells present on wet mount microscopy (>20%

of all epithelial cells)

Other methods of diagnosing BV

Commercial tests for BV are also available. OSOM

BV Blue (Sekisui Diagnostics, Framingham, MA,

USA) is a point-of-care test which measures sialidase

levels and has sensitivity of 91.7% compared to micros-

copy.

The BD MAX

Vaginal Panel (Becton,

Dickinson and company, Franklin Lakes, NJ, USA)

is a microbiome-based, nucleic acid ampliﬁcation

assay that detects BV, TV, and several candida species.

The manufacturer insert quotes a sensitivity of 90.7%

for the diagnosis of BV.

The Guidelines Group recommends that the current

best test to diagnose BV in women is microscopy using

the Hay–Ison Criteria.

Strength of recommendation: Grade 1, quality of evi-

dence: Grade A.

Microscopy.

•

The gold standard for diagnosis is wet mount

microscopy.

The AV score combines information

about bacterial ﬂora, epithelial disruption, and

inﬂammation creating a score from 0 to 10: 0–2

(no AV), 3–4 (mild AV), 5–6 (moderate AV), or

7–10 (severe AV) (Table 2).

Cultures . Although most women with AV have positive

cultures for aerobic bacteria such as Streptococcus aga-

lactiae, S. aureus, E. coli, a positive vaginal culture does

not indicate the woman has AV and is not recom-

mended for diagnosis. However, culture with antimi-

crobial susceptibility testing may aid in treatment.

Molecular detection. Tests based on molecular biology

are being developed which correlate well with moder-

ate-to-severe AV compared with microscopy but need

conﬁrmation in larger trials assessing sensitivity and

speciﬁcity.

The Guidelines Group recommends that the current

best test to diagnose AV in women is mic roscopy.

Strength of recommendation: Grade 2, quality of evi-

dence: Grade B.

Table 2. Abbreviated template for assessing the aerobic vagi-

nitis score.

Enter score

Background flora

Unremarkable 0

Small coliforms 1

Cocci or chains 2

Lactobacillary grade

Predominant lactobacilli 0

Reduced lactobacilli 1

No lactobacilli 2

Number of leucocytes

<10/high-powered field 0

10/epithelial cells 1

>10/epithelial cells 2

Toxic leucocyte proportion

None or sporadic 0

50% leucocytes 1

>50% leucocytes 2

Parabasal cells proportion

None 0

10% epithelial cells 1

>10% epithelial cells 2

Sherrard et al. 1261

Candidosis

Microscopy.

•

Budding cells (and a positive candida culture) can

exist in asymptomatic, colonised women or in

women with candidosis. The diagnosis should be

based on a combination of the clinical signs and

microscopic ﬁndings. Pseudohyphae/mycelia are evi-

dence of candidosis.

55–58

•

Yeasts or pseudohyphae on wet mount microscopy

with either saline or 10–20% KOH solution (40–

60% sensitivity) of vaginal discharge.

•

Yeasts or pseudohyphae on Gram stain (up to 65%

sensitivity) of vaginal discharge.

Culture.

•

Vaginal culture positive for a candida species. If pos-

sible this should be delineated as C. albicans or non-

albicans. If directly inoculated on to a Sabouraud’s

plate results should be reported as light, medium, or

heavy growth as this correlates with speciﬁcity.

•

As a high number of women carry candida asymp-

tomatically, the signiﬁcance of light and medium

growths should be interpreted with caution.

•

Repeated culture of the same species of non-albicans

Candida (usually C. glabrata) indicates reduced anti-

fungal susceptibility to azoles.

The Guidelines Group recommends that the current best

test to diagnose candida in women is microscopy.

Strength of r ecommendation: Grade 1, quality of

evidence: Grade B.

Trichomoniasis

Microscopy. Direct observation of the organism by wet

mount microscopy (normal saline) or acridine orange-

stained slide from the posterior vaginal fornix. The wet

preparation should be read within 10 min of collection,

as the trichomonads quickly lose motility and will be

more difﬁcult to identify.

The sensitivity is highest in

women presenting with vaginal discharge. However,

the sensitivi ty is reported to be as low as 45–60%

60–62

so a negative result should be interpreted with caution.

The speciﬁcity with trained personnel is high.

Point-of-care tests. A number of point-of-care tests that

have the advantages of microscopy have been

described. The OSOM Trichomonas Rapid Test

(Sekisui Diagnostics, Framingham, MA, USA) has

demonstrated a sensitivity of 80–94% and a speciﬁcity

greater than 95%.

63,64

This test requires no instrumen-

tation and provides a result within 30 min and is a

suitable alternative to culture or molecular testing.

Although these tests are more sensitive than vaginal

wet mount microscopy, false positives might occur,

especially in populations with a low prevalence of

disease, so consideration should be given to conﬁrming

positives in that situation.

Culture. Culture of TV has a higher sensitivity com-

pared to microscopy but is not widely available.

A commercially available culture system (InPouch

TV; BioMed Diagnostics, White City, OR, USA),

offers many advantages over previous culture media

such as Diamond’s medium.

65–67

Once inocul ated the

pouches can be transferred to the laboratory for incu-

bation and the entire pouch read microscopically each

day for ﬁve days, negating the need to prepare wet

preparations every day that only sample a portion of

the culture medium.

Molecular detection. Nucleic acid ampliﬁcation tests

(NAATs) offer the highest sensitivity for the detection

of TV in comparison to both microscopy and cul-

ture.

68,69

They should be the test of choice where

resources allow. NAATs can detect TV in vaginal or

endocervical swabs and in urine samples from women

with sensitivities of 88–97% and speciﬁcities of 98–

99%, depending on the specimen and reference stan-

dard.

70–73

The Guidelines Group recommends that the current

best tests to diagnose TV in women are NAATs.

Strength of r ecommendation: Grade 1, quality of

evidence: Grade A.

Management

It should be explained that the cause is unclear and that

although there is increasing evidence of an association

with sexual activity, and of sexual transmissibility, it is

not yet proven to be a an STI.

Indications for treatment of BV:

•

Symptoms

•

Positive direct microscopy with/without symptoms

in some pregnant women (those with a history of

prior idiopathic preterm birth or second trimes-

ter loss)

•

BV in women undergoing gynaecological surgical or

invasive diagnostic procedures

Optional: positive direct microscopy in women with-

out symptoms. They may report a beneﬁcial change in

their discharge following treatment.

Recommended regimens for BV:

•

Metronidazole 400–500 mg orally twice daily for 5–7

days

1262 International Journal of STD & AIDS 29(13)

•

Intravaginal metronidazole gel (0.75%) once daily

for ﬁve days

•

Intravaginal clindamycin cream (2%) once daily for

seven days

Alternative regimens for BV:

•

Metronidazole 2 g orally in a single dose

•

Tinidazole 2 g orally in a single dose

•

Tinidazole 1 g orally for ﬁve days

•

Clindamycin 300 mg orally twice daily for seven days

•

Dequalinium chloride 10 mg vaginal tablet one daily

for six days

For BV, single dose therapies have lower cure rates

than prolonged treatment. Oral metronidazole for

seven days has a signiﬁcantly highe r cure rate

than single dose treatment (88% versus 54%

and

82% versus 62%

at 3–4 weeks after completion of

therapy). Fourteen days of oral metronidazole com-

pared with seven days showed improved cure initially

but there was no difference in cure rates 21 days after

completion of therapy.

A systematic review of trials

comparing clindamycin versus metronidazole conclud-

ed they have equal efﬁcacy, whether oral or vaginal

formulations, both after one week (combined RR

1.01, 95% CI 0.69–1.46) and after one month (com-

bined RR 0.91, 95% CI 0.70–1.18). Roughly, 58–88%

will be cured after ﬁve days treatment with metronida-

zole or clindamycin. However, in terms of side effects,

in most studies clindamycin tended to have fewer

adverse effects than metronidazole (RR 0.75, 95% CI

0.56–1.02). Combining seven days of oral metronida-

zole with vaginal clindamycin cream did not improve

the cure rate compared with seven days oral metroni-

dazole with placebo.

Vaginal dequalinium seems to

have similar cure rates to vaginal clindamycin cream.

The effectiveness of metronidazole and clindamycin is

the same, but the cost of oral metronidazole is signiﬁ-

cantly less than vaginal metronidazole which is cheaper

than clindamycin vaginal cream, with dequalinium

being the most expensive. Oral metronidazole has

more side effects than the other treatments but post-

treatment symptomatic candida is more common with

intravaginal treatments.

Clindamycin cream as well as metronidazole gel

contain mineral oils that are known to diminish the

strength of condoms. Therefore, use of barrier contra-

ception is not considered safe during the treatment with

any of these vaginal products.

The Guidelines Group recommends that 5–7 days of

topical or oral metronidazole or seven days of intravagi-

nal clindamycin can be considered ﬁrst line for uncom-

plicated BV in women depending on personal choice and

circumstances. Cost-effectiveness of the recommended

regimens should be considered when adapting the

guideline for local use.

Strength of recommendation: Grade 1, quality of

evidence: Grade A.

Recurrent BV

A longitudinal study of women, following treatment of

BV with oral metronidazole for seven days, reported

BV recurrence rates of 23% at one month, 43% at

three months, and 58% at 12 months.

BV is associ-

ated with smoking and vaginal douching

but there is

no evidence that stopping these reduces BV. Studies of

consistent condom use have shown a 50% reduction in

BV incidence; the combined oral contraceptive pill is

associated with a 16% reduction and progestogen

depot injections/implants are associated with a

19% reduction in BV incidence.

Small studies have

reported an increased incidence of BV with the copper

intrauterine contraceptive device but it is not known

what effect, if any, progestogen- containing levonorges-

trel intrauterine systems have on BV incidence.

Recurrence of BV is associated with a new or multiple

male partners and having had a female partner.

A number of trials have evaluated intravaginal and

oral therapies to reduce BV recurrences.

Intravaginal metronidazole. A placebo-controlled trial

using twice-weekly metronidazole vaginal gel or place-

bo for 16 weeks reported a signiﬁcant reduction in BV

recurrence. The relative risk at 16 and 28 weeks was

RR 0.43 (95% CI 0.25–0.73) and RR 0.68 (95% CI

0.49–0.93) with 70 and 39%, and 34 and 18% of

women being BV free at 16 weeks and 28 weeks, respec-

tively. Episodes of candidosis were more common with

metronidazole gel.

Another placebo-controlled trial

assessed vaginal pessaries containing metronidazole

750 mg plus miconazole 200 mg with matched placebo

for ﬁve nights per month for 12 months. The women

were evaluated every two months and the proportion of

visits with BV compared to placebo were 21.2 and

32.5%; RR 0.65 (95% CI 0.48–0.87). There was no

increase in candidosis with the intervention.

Oral metronidazole. A placebo-controlled trial assessed

the effect of monthly oral treatment (m etronidazole

2 g plus ﬂuconazole 150 mg) versus placebo for

12 months: the intervention reduced the incidence of

BV (hazard ratio 0.55 [95% CI 0.49–0.63]).

Sherrard et al. 1263

Intravaginal lactate gel. In a small placebo-controlled

trial of intravaginal lactate gel 5 ml used for three

days after menses for six months, 88% of women

using the lactate gel were BV free compared with

10% using placebo.

Probiotics. In a systematic review of probiotics for the

treatment of BV, the authors concluded that the results

do not provide sufﬁcient evidence for or against

recommending probiotics for the treatment of BV.

A subsequent meta-analysis concluded probiotic inter-

ventions were effective for treatment and prevention of

BV but the quality of the studies varied.

More good

quality research is needed to strengthen the body of

evidence needed for application by clinicians.

The Guidelines Group recommends that the current

best treatment for persistent and recurrent BV in

women is intravaginal metronidazole.

Strength of recommendation: Grade 2, quality of evi-

dence: Grade B.

AV/DIV

Indications for treatment of AV/DIV:

In one study, 5% of women presenting with vaginal

discharge had AV scores of 5 and over.

However,

these were a very heterogeneous group and speciﬁc

pathologies such as atrophic change, lichen planus,

and lichen sclerosus should be identiﬁed and treated

appropriately.

Recommended regimens for AV:

•

Two per cent clindamycin cream 5 g intravaginally

for 7–21 days

8,88

•

Combination use of intravaginal clindamycin and

intravaginal steroids,

e.g. hydrocortisone 300–

500 mg intravaginally for 7–21 days or Predfoam

enema applied intravaginally (off-label use) for

more severe cases

•

In cases with a signiﬁcant atrophy component, local

oestrogens can be add ed

Clindamycin is active against staphylococci and

streptococci as well as anaerobes. Other antimicrobials

which are used with success in AV include kanamycin

ovules or moxiﬂoxacin.

The Guidelines Group recommends that the current

best treatment for uncomplicated AV in women is clin-

damycin cream.

Strength of recommendation: Grade 2, quality of evi-

dence: Grade C.

Vaginal candidosis

Indications for therapy of candidosis:

•

Symptomatic women found to have candida on

either microscopy or culture.

Asymptomatic women do not require treatment

Asymptomatic male partners do not

require treatment

Recommended regimens for vaginal candidosis:

9,89,90

Oral preparations include

•

Fluconazole 150 mg as a single dose

•

Itraconazole 200 mg twice daily for one day

Intravaginal treatments include

•

Clotrimazole vaginal tablet 500 mg as single dose or

200 mg once daily for three days

•

Miconazole vaginal ovule 1200 mg as a single dose

or 400 mg once daily for three days

•

Econazole vaginal pessary 150 mg as a single dose

Treatment with azoles results in relief of symptoms

and negative cultures among 80–90% of patients after

treatment is completed, whether administered orally or

intravaginally. Only topical preparations should be used

during pregnancy. Overall, standard single-dose treat-

ments are as effective as longer courses. In a severely

symptomatic attack there is proven to be better symp-

tomatic beneﬁt in repeating ﬂuconazole 150 mg after

three days.

This does not affect relapse rates.

There are a number of other intravaginal preparat ions

available which are all either azoles, of limited availabil-

ity, e.g. nystatin, or unlicensed. There are limited data to

suggest that vulval treatment maybe of added beneﬁt to

intravaginal treatment.

Where itch is a signiﬁcant

symptom a hydrocortisone-containing topical prepara-

tion may provide more rapid symptomatic relief. Any

beneﬁt may be from the emollient effect. If oral antifun-

gals are used, then a moisturising cream is cheaper and

may be less likely to give an irritant reaction.

The Guidelines Group recommends that the current

best treatment for uncomplicated candida in women is

a single-dose azole (oral or vaginal).

Strength of r ecommendation: Grade 1, quality of

evidence: Grade A.

Recurrent candidosis

Deﬁned as four or more symptomatic episodes

per year

93,94

•

Document frequency, establish diagnosis and con-

ﬁrm by culture: all such women should have at

least one speciated culture.

1264 International Journal of STD & AIDS 29(13)

•

Exclude risk factors (e.g. diabetes, underlying immu-

nodeﬁciency, corticosteroid use, frequent antibiot-

ic use).

•

Consider other diagnoses – vulval dermatitis/

eczema/vestibulodynia are common either coexisting

or as a differential diagnosis.

Maintenance therapy needs to be given frequently

enough to prevent vaginal regrowth, but the optimal

dosing interval is not clear. There are differing opinions

on how aggressive maintenance therapy should be –

weekly or monthly treatments

93,95

and comparative

trials have not been undertaken. The long-term anti-

fungal regimen aims to prevent two essential pathoge-

netic mechanisms: increased risk of recolonisation and

increased risk of transformation to a symptomatic state

primarily as a function of pathologic host intolerance

of the candida.

Current recommendations are for an initial intensive

regimen of ﬂuconazole 150–200 mg daily for three days

to attempt mycologic remission before initiating a

maintenance regimen. Published maintenance regimens

include oral ﬂuconazole (i.e. 100, 150, or 200 mg dose)

weekly for six months

or 200 mg ﬂuconazole weekly

for two months, followed by 200 mg biweekly for four

months, and 200 mg monthly for six months, according

to the individual response to therapy.

If these regi-

mens are not feasible, topical treatments used intermit-

tently can also be considered.

Treatment of persistent vaginal yeast infection due

to species other than C. albicans is particularly

challenging.

General advice includes the use of a vulval moistur-

iser applied to dry skin and washed off as a soap sub-

stitute. Ovulation suppressing progesterone

contraception, e.g. medroxyprogesterone acetate

(Depo Provera), nomegestrol, or desogestrel, may

have some beneﬁts in particular women but the evi-

dence for this is poor.

The Guidelines Group recommends that the current

best treatment for persistent and recurrent candida in

women is a three-day induction course of an azole

followed by long-term maintenance suppressive regimen

for at least six months.

Strength of recommendation: Grade 2, quality of evi-

dence: Grade C.

As TV is a sexually transmitted organism, screening for

coexistent STIs should be undertaken. Sexual absti-

nence should be advised until treatment of all partners

is completed.

Indications for therapy of TV:

•

Positive test for TV regardless of symptoms

•

Epidemiological treatment of sexual partners

Recommended regimens fo r TV:

99–101

First choice:

•

Metronidazole 400–500 mg orally twice daily for 5–7

days

•

Metronidazole 2 g orally in a single dose

•

Tinidazole 2 g orally in a single dose

The nitroimidazoles are the only class of drugs

useful for the oral or parenteral therapy of trichomo-

niasis and most strains are highly susceptible. Due to

high rates of infection of the urethra and paraurethral

glands in women systemic chemotherapy should be

given to effect a cure. The use of metronidazole gel is

not recommended. Oral single dose treatment is asso-

ciated with more frequent side effects than longer treat-

ment and a recent meta-analysis

indicated higher

treatment failure for single-dose compared to multi-

dose. In patients with true metronidazole allergy,

desensitisation has been used.

102,103

Patients should be advised not to take alcohol for

the duration of treatment and for at least 48 h (72 h for

tinidazole) afterwards because of the possibility of a

disulﬁram-like (Antabuse

effect) CSL Biotherapies,

New Zealand reaction.

The Guidelines Group recommends that the current

best treatment for uncomplicated TV in women are nitro-

imidazoles (metronidazole or tinidazole).

Strength of recommendation: Grade 1, quality of evi-

dence: Grade A.

Persistent TV. Persistent or recurrent TV is due to inad-

equate therapy,

104

reinfection, or resistance. Check for

compliance and exclude vomiting of metronidazole and

exclude the possibility of reinfection from new or

untreated partners.

Treatment protocol for non-response to standard

TV therapy (having excluded reinfection and

non-adherence)

1. Repeat course of seven-day s tandard therapy

•

Metronidazole 400–500 mg twice daily for seven

days – in those who failed to respond to a ﬁrst

course of treatment, 40% responded to a repeat

course of standard treatment.

104

2. Higher-dose course of nitroimidazole

•

Metronidazole or tinidazole 2 g daily for 5–

7 days

105

Sherrard et al. 1265

•

Metronidazole 800 mg three times daily for seven

days – in those who failed to respond to a second

course of treatment, 70% responded to a higher-

dose course of metronidazole.

104

For those failing this regimen, resistance testing

should be performed if available as improved outcomes

were reported with a treatment protocol guided by the

results of a resistance test.

104

If resistance testing is not

available high-dose tinidazole regimens are recom-

mended as in the above study; 65% of women with

clinical treatment failure did not have tinidazole-

resistant isolates and 83% of those receiving the rec-

ommended high-dose treatment were cured compared

with 57% of women receiving a lower-than-recom-

mended dose.

105

Tinidazole has a longer serum half-

life, good tissue penetration, a better side effect proﬁle,

and lower levels of resistance than metronidazole so

should be used when infections have not responded

to metronidazole even though it is more expensive.

3. Very high-dose course of tinidazole

•

Tinidazole 1 g twice or three times daily, or 2 g

twice daily for 14 days  intravaginal tinidazole

500 mg twice daily for 14 days

105–107

–inthose

who had failed other treatments 92 and 90%

responded to a very high-dose course of tinidazole.

If very high-dose tinidazole has been unsuccessful it

is difﬁcult to recommend speciﬁc further treatment.

There are anecdotal reports of treatment success with

a number of other treatments. The reports are based on

success in one or two women who had usually received

a wide variety of prior treatments. Consequently, for

each successful anecdote there are a number of reports

of treatment failure.

The Guidelines Group recommends that the current

best treatment for persistent and recurrent TV in women

is repeated course of nitroimidazole at a higher dose.

Strength of recommendation: Grade B, quality of evi-

dence: Grade B.

Management during pregnancy and

breast feeding

A recent retrospective, case–control study found an

association between the use of a number of antibiotics

prescribed in the ﬁrst trimester of pregnancy and spon-

taneous abortion. Statistically signiﬁcant associations

were found with metronidazole. Clindamycin was not

tested in this study. Sexually transmitted genital infec-

tions themselves can cause pregnancy loss so failure to

treat them effectively may also result in spontaneous

abortion. The associations found might result from

women being prescribed the antibiotics for genital

infections with the increased risk of pregnancy loss

being due to the infections rat her than the antibiotics,

i.e. confounding by indication.

108

Meta-analyses have concluded that there is no evi-

dence of teratogenicity from the use of metronidazole

in women during the ﬁrst trimester of pregnancy.

109–112

Metronidazole can be used in all stages of pregnancy

and during breast feeding. Symptomatic women with

TV and BV shoul d be treated at diagnosis, although

some clinicians have preferred to defer treatment until

the second trimester. The British National Formulary

advises against high-dose regimens in pregnancy.

Metronidazole enters breast milk and may affect its

taste. The manufacturers recommend avoiding high

doses if breastfeeding or if using a single dose of met-

ronidazole, breastfeeding should be discontinued for

12–24 h to reduce infant exposure.

Tinidazole is pregnancy category C (animal studies

have demonstrated an adverse event, and no adequate,

well-controlled studies in pregnant women have been

conducted), and its safety in pregnant women has not

been well evaluated. The manufacturer states that the

use of tinidazole in the ﬁrst trimester is contraindicated.

Topical azoles can be used at any stage of pregnancy

for treatment of symptomatic candidosis. Oral ﬂucon-

azole is associated with early abortions and Fallot

tetralogy, if administered in the ﬁrst weeks of pregnan-

cy.

113,114

There appears to be less risk with oral prep-

arations after the ﬁrst trimester.

The Guidelines Group recommends that the current best

treatment for TV in pregnant women is metronidazole.

Strength of r ecommendation: Grade 1, quality of

evidence: Grade A.

The Guidelines Group recommends that the current

best treatment for BV in pregnant women is clindamycin.

Strength of r ecommendation: Grade 2, quality of

evidence: Grade C.

The Guidelines Group recommends that the current

best treatment for candida in pregnant women are

topical azole preparations.

Strength of recommendation: Grade 1, quality of evi-

dence: Grade B.

Management of sexual partners

A systematic review assessing the effectiveness of anti-

biotic treatment for male sexual partners of women

treated for BV concluded that antibiotic treatment

does not lead to a lower recurrence rate in the

women.

115

Routine screening and treatment of male

partners is therefore not indicated.

1266 International Journal of STD & AIDS 29(13)

In WSW, regular female partners frequently have

concordant vaginal microbiota so if one has BV the

partner is more likely to also have BV. It is thought

this is from sexual behaviours that transfer vaginal

secretions between them.

If a WSW is found to have

BV, and she has a regular female partner, it would be

reasonable to suggest that her partner be checked for

BV and be treated if positive although there is no evi-

dence that this will reduce BV recurrences.

The Guidelines Group recommends that the current

advice for women diagnosed with BV is that male

sexual partners do not require treatment. Female part-

ners may be treated if they have BV.

Strength of recommendation: Grade 2, quality of evi-

dence: Grade B.

Candidosis and AV

Routine screening and treatment of male partner(s) is

not indicated.

116,117

The Guidelines Group recommends that the current

advice for women diagnosed with candidosis or is that

sexual partners, do not require treatment.

Strength of recommendation: Grade 1, quality of evi-

dence: Grade B.

Trichomoniasis

Current sexual partners should be screened for STIs

and treated for TV regardless of the results of their

tests.

118,119

Patients should be instructed to avoid sex

until they and their sex partners are cured (i.e. when

therapy has been completed and patient and partner[s]

are asymptomatic).

The Guidelines Group recommends that the current

advice for women diagnosed with TV, is that their

sexual partners should be treated for TV.

Strength of recommendation: Grade 1, quality of evi-

dence: Grade A.

Follow-up

Only in women with persistent symptoms. If treatment

is prescribed in pregnancy to reduce the risk of preterm

birth, a repeat test should be made after one month and

further treatment offered if BV has recurred.

Women with persistent or recurrent symptoms.

Candida

Only in women with persistent or recurrent symptoms.

Consider other diagnoses, e.g. vulval dermatitis.

Trichomoniasis

Follow-up is unnecessary for men and women who

become asymptomatic after treatment or who are ini-

tially asymptomatic. Tests of cure are only recom-

mended if the patient remains symptomatic following

treatment or if symptoms recur.

Acknowledgements

The authors wish to acknowledge the following individuals

for their helpful comments:

Prof Harald Moi

Dr Raj Patel

Dr Keith Radcliffe

Prof Jonathan Ross

Dr Andy Winter

Composition of editorial board (see http://www.iusti.org/

regions/Europe/pdf/2017/EditorialBoardSept2017.pdf)

List of contributing organisations (see www.iusti.org/regions/

Europe/euroguidelines.htm)

Declaration of conflicting interests

The authors declared no potential conﬂicts of interest with

respect to the research, authorship, and/or publication of

this article.

Funding

The authors received no ﬁnancial support for the research,

authorship, and/or publication of this article.

Proposed review date: 2023

ORCID iD

Jackie Sherrard http://orcid.org/0000-0002-1310-0372

Jørgen S Jensen

http://orcid.org/0000-0002-7464-7435

References

1. Koumans EH, Sternberg M, Bruce C, et al. The preva-

lence of bacterial vaginosis in the United States, 2001–

2004; associations with symptoms, sexual behaviors,

and reproductive health. Sex Transm Dis 2007;

34: 864–869.

2. Lamont RF, Morgan DJ, Wilden SD, et al. Prevalence

of bacterial vaginosis in women attending one of three

general practices for routine cervical cytology. Int J

STD AIDS 2000; 11: 495–498.

3. Marrazo JM, Koutsky LA, Eschenbach DA, et al.

Characterization of vaginal ﬂora and bacterial vaginosis

in women who have sex with women. J Infect Dis 2002;

185: 1307–1313.

4. Fredricks DN, Fiedler TL and Marrazzo JM. Molecular

identiﬁcation of bacteria associated with bacterial vagi-

nosis. N Engl J Med 2005; 353: 1899–1911.

5. Schwebke JR, Muzny CA and Josey WE. Role of

Gardnerella vaginalis in the pathogenesis of bacterial

vaginosis: a conceptual model. J Infect Dis 2014;

10: 338–343.

Sherrard et al. 1267

6. Swidsinski A, Mendling W, Loening-Baucke V, et al.

Adherent bioﬁlms in bacterial vaginosis. Obstet

Gynecol 2005; 106: 1013–1023.

7. Donders GG. Deﬁnition of a type of abnormal vaginal

ﬂora that is distinct from bacterial vaginosis: aerobic

vaginitis. BJOG 2002; 109: 1–10.

8. Mason MJ and Winter AJ. How to diagnose and treat

aerobic and desquamative inﬂammatory vaginitis. Sex

Transm Infect 2017; 93: 8–10.

9. Lindner JG, Plantema FH and Hoogkamp K.

Quantitative studies of the vaginal ﬂora of healthy

women and of obstetric and gynaecological patients.

J Med Microbiol 1978; 11: 233–241.

10. Sobel JD. Pathogenesis and epidemiology of vulvova-

ginal candidosis. Ann N Y Acad Sci 1988;

544: 547–557.

11. Fidel PL Jr, Barousse M, Espinosa T, et al. An intra-

vaginal live Candida challenge in humans leads to new

hypotheses for the immunopathogenesis of vulvovaginal

candidiasis. Infect Immun 2004; 72: 2939–2946.

12. Holland J, Young ML, Lee O, et al. Vulvovaginal car-

riage of yeasts other than Candida albicans. Sex Transm

Infect 2003; 79: 249–250.

13. Wolner-Hanssen P, Kreiger JN, Stevens CE, et al.

Clinical manifestations of vaginal trichomoniasis.

JAMA 1989; 264: 571–576.

14. Fouts AC and Kraus SJ. Trichomonas vaginalis: re-

evaluation of its clinical presentation and laboratory

diagnosis. J Infect Dis 1980; 141: 137–143.

15. Atashili J, Poole C, Ndumbe PM, et al. Bacterial vagi-

nosis and HIV acquisition: a meta- analysis of published

studies. AIDS 2008; 22: 1493–1501.

16. Brotman RM, Klebanoff MA, Tonia R, et al. Bacterial

vaginosis assessed by gram stain and diminished coloni-

zation resistance to incident gonococcal, chlamydial,

and trichomonal genital infection. J Infect Dis 2010;

202: 1907–1915.

17. Rathod SD, Krupp K, Klausner JD, et al. Bacterial

vaginosis and risk for Trichomonas vaginalis infection:

a longitudinal analysis. Sex Transm Dis 2011;

38: 882–886.

18. Cherpes TL, Meyn LA, Krohn MA, et al. Association

between acquisition of herpes simplex virus type 2 in

women and bacterial vaginosis. Clin Infect Dis 2003;

37: 319–325.

19. Cohen CR, Lingappa JR, Baeten JM, et al. Bacterial

vaginosis associated with increased risk of female-to-

male HIV-1 transmission: a prospective cohort analysis

among African couples. PLoS Med 2012; 9: e1001251.

20. Balkus JE, Manhart LE, Lee J, et al. Periodic presump-

tive treatment for vaginal infections may reduce the

incidence of sexually transmitted bacterial infections.

J Infect Dis 2016; 213: 1932–1937.

21. Haggerty CL, Totten PA, Tang G, et al. Identiﬁcation

of novel microbes associated with pelvic inﬂammatory

disease and infertility. Sex Transm Infect 2016;

92: 441–446.

22. Persson E, Bergstrom M, Larsson PG, et al. Infections

after hysterectomy. A prospective nation-wide Swedish

study. The Study Group on Infectious Diseases. Acta

Obstet Gynecol Scand 1996; 75: 757–761.

23. Soper DE, Bump RC and Hurt WG. Bacterial vaginosis

and trichomoniasis vaginitis are risk factors for cuff cel-

lulitis after abdominal hysterectomy.

Am J Obstet

Gynecol 1990; 163: 1016–1021.

24. Charonis G and Larsson PG. Use of pH/whiff test or

QuickVue advanced pH and Amines test for the diag-

nosis of bacterial vaginosis and prevention of postabor-

tion pelvic inﬂammatory disease. Acta Obstet Gynecol

Scand 2006; 85: 837–843.

25. Miller L, Thomas K, Hughes JP, et al. Randomised

treatment trial of bacterial vaginosis to prevent post-

abortion complication. BJOG 2004; 111: 982–988.

26. Lamont RF, Nhan-Chang CL, Sobel JD, et al.

Treatment of abnormal vaginal ﬂora in early pregnancy

with clindamycin for the prevention of spontaneous pre-

term birth: a systematic review and metaanalysis. Am J

Obstet Gynecol 2011; 205: 177–190.

27. Leitich H, Bodner-Adler B, Brunbauer M, et al.

Bacterial vaginosis as a risk factor for preterm delivery:

a meta-analysis. Am J Obstet Gynecol 2003;

189: 139–147.

28. Brocklehurst P, Gordon A, Heatley E, Milan SJ.

Antibiotics for treating bacterial vaginosis in pregnancy.

Cochrane Database of Systematic Reviews 2013, Issue 1.

Art. No.: CD000262. DOI: 10.1002/14651858.

CD000262.pub4.

29. Sorvillo F and Kernott P. Trichomonas vaginalis and

ampliﬁcation of HIV-1 transmission. Lancet 1998;

351: 213–214.

30. Laga M, Manoka A, Kivuvu M, et al. Non ulcerative

sexually transmitted diseases as risk factors for HIV-1

transmission in women: results from a cohort study.

AIDS 1993; 7: 95–102.

31. McClelland RS, Sangere L, Hassan WM et al. Infection

with Trichomonas vaginalis increases the risk of HIV-1

acquisition. J Infect Dis 2007; 195: 698–702.

32. Tanton C, Weiss HA, Le Goff J et al. Correlates of

HIV-1 genital shedding in Tanzanian women. PLoS

One 2011; 6: e17480.

33. Mavedzenge SN, Pol BV, Cheng H et al.

Epidemiological synergy of Trichomonas vaginalis and

HIV in Zimbabwean and South African women. Sex

Transm Dis 2010; 37: 460–466.

34. Cotch MF, Pastorek JG, Nugent RP, et al. Trichomonas

vaginalis associated with low birth weight and preterm

delivery. Sex Transm Dis 1997; 24: 353–360.

35. French JI, McGregor JA, Draper D, et al. Gestational

bleeding, bacterial vaginosis, and common reproductive

tract infections: risk for preterm birth and beneﬁt of

treatment. Obstet Gynecol 1999; 93: 715–724.

36. Gu

lmezoglu AM and Azhar M. Interventions for

trichomoniasis in pregnancy. Cochrane Database Syst

Rev 2011; 5: CD000220.

37. Donders GGG, Bellen G, Grinceviciene S, et al. The

limited value of symptoms and signs in the diagnosis

of vaginal infections. Arch Intern Med 1990;

150: 1929–1933.

1268 International Journal of STD & AIDS 29(13)

38. Donders GG, Van CK, Bellen G, et al. Predictive value

for preterm birth of abnormal vaginal ﬂora, bacterial

vaginosis and aerobic vaginitis during the ﬁrst trimester

of pregnancy. BJOG 2009; 116: 1315–1324.

39. Roberts CL, Algert CS, Rickard KL, et al. Treatment of

vaginal candidiasis for the prevention of preterm birth: a

systematic review and meta-analysis. Syst Rev 2015;

4: 31.

40. Holzer I, Farr A, Hagmann M, et al. The colonization

with Candida species is more harmful in the second tri-

mester of pregnancy. Arch Gynecol Obstet 2017;

295: 891–895.

41. Abbott J. Clinical and microscopic diagnosis of vaginal

yeast infection: a prospective analysis. Ann Emerg Med

1995; 25: 587–591.

42. Eckert LO, Hawes SE, Stevens CE, et al. Vulvovaginal

candidosis: clinical manifestations, risk factors, manage-

ment algorithm. Obstet Gynecol 1998; 92: 757–765.

43. Sonnex C and Lefort W. Microscopic features of vagi-

nal candidosis and their relation to symptomatology.

Sex Transm Infect 1999; 75: 417–419.

44. Mendling W, Brasc h J , C ornely OA, et al. G uideline:

vulvovaginal candidosis (AWMF 015/072), S2k

(excluding mucocutaneous candidosis). Mycoses

2015; 58: 1–15.

45. van de Wigert J, Altini L, Jones H, et al. Two methods

of self-sampling compared to clinician sampling to

detect reproductive tract infections in Gugulethu,

South Africa. Sex Transm Dis 2006; 33: 516–523.

46. Nugent RP, Krohn MA and Hillier SL. Reliability of

diagnosing bacterial vaginosis is improved by a stan-

dardized method of gram stain interpretation. J Clin

Microbiol 1991; 29: 297–301.

47. Gue

dou FA, Van Damme L, Mirembe F, et al.

Intermediate vaginal ﬂora is associated with HIV

prevalence as strongly as bacterial vaginosis in a

cross-sectional study of participants screened for a rand-

omised controlled trial. Sex Transm Infect 2012;

88: 545–551.

48. Ison CA and Hay PE. Validation of a simpliﬁed grading

of gram stained vaginal smears for use in genitourinary

medicine clinics. Sex Transm Infect 2002; 78: 413–415.

49. Amsel R, Totten PA, Spiegel CA, et al. Nonspeciﬁc

vaginitis. Diagnostic criteria and microbial and epidemi-

ologic associations. Am J Med 1983; 74: 14–22.

50. Gallo MF, Jamieson DJ, Cu US, et al. Accuracy of

clinical diagnosis of bacterial vaginosis by human

immunodeﬁciency virus infection status. Sex Transm

Dis 2011; 38: 270–274.

51. Singh RH, Zenilman JM, Brown KM, et al. The role of

physical examination in diagnosing common causes of

vaginitis: a prospective study. Sex Transm Infect 2013;

89: 185–190.

52. Myziuk L, Romanowski B and Johnson SC. BVBlue

test for diagnosis of bacterial vaginosis. J Clin

Microbiol 2003; 41: 1925–1928.

53. Gaydos CA, Begaj S, Schwebke J et al. Clinical valida-

tion of a test for the diagnosis of vaginitis. Obstet

Gynecol 2017; 130: 181–189.

54. Donders GG, Vereecken A, Bosmans E, et al. Deﬁnition

of a type of abnormal vaginal ﬂora that is distinct from

bacterial vaginosis: aerobic vaginitis. BJOG 2002;

109: 34–43.

55. Rumyantseva TA, Bellen G, Savochkina YA, et al.

Diagnosis of aerobic vaginitis by quantitative real-time

PCR. Arch Gynecol Obstet

2016; 294: 109–114.

56. Hopwood V, Crowley T, Horrocks CT, et al. Vaginal

candidosis: relation between yeast counts and symptoms

and clinical signs in non-pregnant women. Genitourin

Med 1988; 64: 331–334.

57. Odds FC, Webster CE, Mayuranathan P, et al. Candida

concentrations in the vagina and their association with

signs and symptoms of vaginal candidosis. J Med Mycol

1988; 26: 277–283.

58. Priestley CJ, Jones BM, Dhar J, et al. What is normal

vaginal ﬂora? Genitourin Med 1997; 73: 23–28.

59. Kingston MA, Bansal D and Carlin EM. ‘Shelf life’ of

Trichomonas vaginalis. Int J STD AIDS 2003; 14: 28–29.

60. Bickley LS, Krisher KK, Punsalang A, et al.

Comparison of direct ﬂuorescent antibody, acridine

orange, wet mount and culture for detection of

Trichomonas vaginalis in women attending a public

sexually transmitted disease clinic. Sex Transm Dis

1989; 127–131.

61. Kreiger JN, Tam MR, Stevens CE, et al. Diagnosis of

trichomoniasis: comparison of conventional wet- mount

examination with cytological studies, cultures, and

monoclonal antibody staining of direct specimens.

JAMA 1988; 259: 1223–1227.

62. Nye MB, Schwebke JR and Body BA. Comparison of

APTIMA Trichomonas vaginalis transcription-mediated

ampliﬁcation to wet mount microscopy, culture, and

polymerase chain reaction for diagnosis of trichomoni-

asis in men and women. Am J Obstet Gynecol 2009; 200:

188.e181–188.e187.

63. Hegazy MM, El-Tantawy NL, Soliman MM, et al.

Performance of rapid immunochromatographic assay

in the diagnosis of Trichomoniasis vaginalis. Diagn

Microbiol Infect Dis 2012; 74: 49–53.

64. Campbell L, Woods V, Lloyd T, et al. Evaluation of the

OSOM Trichomonas rapid test versus wet preparation

examination for detection of Trichomonas vaginalis vag-

initis in specimens from women with a low prevalence of

infection. J Clin Microbiol 2008; 46: 3467–3469.

65. Borchardt KA, et al. A comparison of the sensitivity of

the InPouch TV, diamond’s and trichosel media for

detection of Trichomonas vaginalis. Genitourin Med

1997; 73: 297–298.

66. el Naga IF, Khalifa AM and el Azzouni MZ. In-pouch

TV culture system in diagnosis of Trichomonas vaginalis

infection. J Egypt Soc Parasitol 2001; 31: 647–656.

67. Levi MH, Torres J, Pina C, Klein RS. Comparison of

the InPouch TV culture system and diamond’s modiﬁed

medium for detection of Trichomonas vaginalis. J Clin

Microbiol 1997; 35: 3308–3310.

68. Van Der Shee C, van Belkum A, Zwiggers L et al.

Improved diagnosis of Trichomonas vaginalis infection

by PCR using vaginal swabs and urine specimens

Sherrard et al. 1269

compared to diagnosis by wet mount, culture and ﬂuo-

rescent staining. J Clin Microbiol 1999; 37: 4127–4130.

69. Radonjic IV, Dzamic AM, Mitrovic SM, et al.

Diagnosis of Trichomonas vaginalis: the sensitivities

and speciﬁcities of microscopy, culture and PCR

assay. Eur J Obstet Gynecol Reprod Biol 2006;

126: 116–120.

70. Hardick A, Hardwick J, Wood BJ, Gaydos C.

Comparison between the Gen-Probe transcription-

mediated ampliﬁcation Trichomonas vaginalis research

assay and real-time PCR for Trichomonas vaginalis

detection using a Roche LightCycler instrument with

female self-obtained vaginal swab samples and male

urine samples. J Clin Microbiol 2006; 44: 4197–4199.

71. Munson E, Napierala M, Olson R et al. Impact of

Trichomonas vaginalis transcription-mediated ampliﬁca-

tion-based analyte-speciﬁc reagent testing in a metropol-

itan setting of high sexually transmitted disease

prevalence. J Clin Microbiol 2008; 46: 3368–3374.

72. Schwebke JR, Hobbs MM, Taylor SN, et al. Molecular

testing for Trichomonas vaginalis in women: results from

a prospective U.S. clinical trial. J Clin Microbiol 2011;

49: 4106–4111.

73. Ginocchio CC, Chapin K, Smith JS, et al. Prevalence of

Trichomonas vaginalis and coinfection with Chlamydia

trachomatis and Neisseria gonorrhoeae in the United

States as determined by the Aptima Trichomonas vagi-

nalis nucleic acid ampliﬁcation assay. J Clin Microbiol

2012; 50: 2601–2608.

74. Larsson P-G. Treatment of bacterial vaginosis. Int J

STD AIDS 1992; 3: 239–247.

75. Joesoef MR and Schmid GP. Bacterial vaginosis: review

of treatment options and potential clinical indications

for therapy. Clin Infect Dis 1995; 20: S72–S79.

76. Schwebke JR and Desmond RA. A randomized trail of

the duration of therapy with metronidazole plus or

minus azithromycin for the treatment of symptomatic

bacterial vaginosis. Clin Infect Dis 2007; 44: 213–219.

77. Bradshaw CS, Pirotta M, De GD, et al. Efﬁcacy of oral

metronidazole with vaginal clindamycin or vaginal pro-

biotic for bacterial vaginosis: randomised placebo-

controlled double-blind trial. PLoS One 2012; 7: e34540.

78. Weissenbacher ER, Donders G, Unzeitig V, et al.

A comparison of dequalinium chloride vaginal tablets

(Fluomizin) and clindamycin vaginal cream in the treat-

ment of bacterial vaginosis: a single-blind, randomized

clinical trial of efﬁcacy and safety. Gynecol Obstet Invest

2012; 73: 8–15.

79. Bradshaw CS, Morton AN, Hocking J, et al. High

recurrence rates of bacterial vaginosis over the course

of 12 months after oral metronidazole therapy and fac-

tors associated with recurrence. J Infect Dis 2006;

193: 1478–1486.

80. Brotman RM, Klebanoff MA, Nansel TR et al. A lon-

gitudinal study of vaginal douching and bacterial vagi-

nosis – a marginal structural modeling analysis. Am J

Epidemiol 2008; 168: 188–196.

81. Bradshaw CS, Vodstrcil LA, Hocking JS et al.

Recurrence of bacterial vaginosis is signiﬁcantly

associated with posttreatment sexual activities and hor-

monal contraceptive use. Clin Infect Dis 2013;

56: 777–786.

82. Sobel JD, Ferris D, Schwebke J, et al. Suppressive anti-

bacterial therapy with 0.75% metronidazole vaginal gel

to prevent recurrent bacterial vaginosis. Am J Obstet

Gynecol 2006; 194: 1283–1289.

83. McClelland RS, Balkus JE, Lee J, et al. Randomised

trial of periodic presumptive treatment with high dose

intravaginal metronidazole and miconazole to prevent

vaginal infections in HIV-negative women. J Infect Dis

2015; 211: 1875–1882.

84. McClelland RS, Richardson BA, Hassan WM, et al.

Improvement of vaginal health for Kenyan women at

risk for acquisition of human immunodeﬁciency virus

type 1: results of a randomized trial. J Infect Dis 2008;

197: 1361–1368.

85. Andersch B, Lindell D, Dahlen I, et al. Bacterial vagi-

nosis and the effect of intermittent prophylactic treat-

ment with an acid lactate gel. Gynecol Invest 1990;

30: 114–119.

86. Senok AC, Verstraelen H, Temmerman M, et al.

Probiotics for the treatment of bacterial vaginosis.

Cochrane Database Syst Rev 2009; 4: CD006289.

87. Hanson L, VandeVusse L, Jerme M, et al. Probiotics for

treatment and prevention of urogenital infections in

women: a systematic review. J Midwifery Womens

Health 2016; 61: 339–355.

88. Sobel JD, Reichman J, Misra D, et al. Prognosis and

treatment of desquamative inﬂammatory vaginitis.

Obstet Gynecol 2011; 117: 850–855.

89. Watson MC, Grimshaw JM, Bond CM, et al. Oral

versus intra-vaginal imidazole and triazole anti-fungal

agents for the treatment of uncomplicated vulvovaginal

candidiasis (thrush): a systematic review. BJOG 2002;

109: 85–95.

90. Nurbhai M, Grimshaw J, Watson M, et al. Oral versus

intra-vaginal imidazole and triazole anti-fungal treatment

of uncomplicated vulvovaginal candidiasis (thrush).

Cochrane Database Syst Rev 2007; 4: CD002845.

91. Sobel JD, Kapernick PS, Zervos M, et al. Treatment of

complicated Candida vaginitis: comparison of single and

sequential doses of ﬂuconazole. Am J Obstet Gynecol

2001; 185: 363–369.

92. Mendling W and Schlegelmilch R. Three-day combina-

tion treatment for vulvovaginal candidosis with 200 mg

clotrimazole vaginal suppositories and clotrimazole

cream for the vulva is signiﬁcantly better than treatment

with vaginal suppositories alone – an earlier, multi-

centre, Placebo-Controlled Double Blind Study.

Geburtsh Frauenheilk 2014; 74: 355–360.

93. Sobel J, Wiesenfeld H, Martens M, et al. Maintenance

ﬂuconazole therapy for recurrent vulvovaginal candidi-

asis. N Engl J Med 2004; 351: 876–883.

94. Cooke G, Watson C, Smith J, et al. Treatment for recur-

rent vulvovaginal candidiasis (thrush). Cochrane

Database Syst Rev 2011; 5: CD009151.

95. Donders G, Bellen G, Byttebier G et al. Individualized

decreasing-dose maintenance ﬂuconazole regimen for

1270 International Journal of STD & AIDS 29(13)

recurrent vulvovaginal candidiasis (ReCiDiF trial). Am

J Obstet Gynecol 2008; 199: 613–619.

96. Rosa MI, Silva BR, Pires PS et al. Weekly ﬂuconazole

therapy for recurrent vulvovaginal candidiasis: a sys-

tematic review and meta-analysis. Eur J Obstet

Gynecol Reprod Biol 2013; 167: 132–136.

97. Nyirjesy P, ZhaoDavies S, Johnson E, et al. How to

treat persistent vaginal yeast infection due to species

other than Candida albicans. Sex Transm Infect 2013;

89: 165–166.

98. Dennerstein GJ. Depo-Provera in the treatment of

recurrent vulvovaginal candidiasis. J Reprod Med

1986; 31: 801–803.

99. Forna F and Gu

lmezoglu AM. Interventions for treat-

ing trichomoniasis in women. Cochrane Database Syst

Rev 2003; 2: CD000218.

100. Thin RN, Symonds MAE, Booker R, et al. Double-

blind comparison of a single dose and a ﬁve-day

course of metronidazole in the treatment of trichomoni-

asis. Br J Vener Dis 1979; 55: 354–356.

101. Howe K and Kissinger PJ. Single-dose compared with

multidose metronidazole for the treatment of trichomo-

niasis in women: a meta-analysis. Sex Transm Dis 2017;

44: 30–35.

102. Pearlman MD, Yashar C, Ernst S, et al. An incremental

dosing protocol for women with severe vaginal tricho-

moniasis and adverse reactions to metronidazole. Am J

Obstet Gynecol 1996; 174: 934–936.

103. Kurohara ML, Kwong FK, Lebherz TB, et al.

Metronidazole hypersensitivity and oral desensitization.

J Allergy Clin Immunol 1991; 88: 279–280.

104. Das S, Huengsberg M and Shahmanesh M. Treatment

failure of vaginal trichomoniasis in clinical practice. Int

J STD AIDS 2005; 16: 284–286.

105. Bosserman EA, Helms DJ, Mosure DJ, et al. Utility of

antimicrobial susceptibility testing in Trichomonas vagi-

nalis-infected women with clinical treatment failure. Sex

Transm Dis 2011; 38: 983–987.

106. Sobel JD, Nyirjesy P and Brown W. Tinidazole therapy

for metronidazole-resistant vaginal trichomoniasis. Clin

Infect Dis 2001; 33: 1341–1346.

107. Mammen-Tobin A and Wilson JD. Management of

metronidazole-resistant Trichomonas vaginalis – a new

approach. Int J STD AIDS 2005; 16: 488–490.

108. Muanda FT, Sheehy O and Be

rard A. Use of antibiotics

during pregnancy and risk of spontaneous abortion.

CMAJ 2017; 189: E625–E633.

109. Gu

lmezoglu AM and Azhar M. Interventions for

trichomoniasis in pregnancy. Cochrane Database Syst

Rev 2011; 5: CD000220.

110. Czeizel AE and Rockenbauer M. A population based

case-control teratologic study of oral metronidazole

treatment during pregnancy. BJOG 1998; 105: 322–327.

111. Burtin P, Taddio A, Ariburnu O, et al. Safety of met-

ronidazole in pregnancy: a meta-analysis. Am J Obstet

Gynecol 1995; 172: 525–529.

112. Caro-Paton T, Carvajal A, de Diego IM, et al. Is met-

ronidazole teratogenic: a meta-analysis. Br J Clin

Pharmacol 1997; 44: 179–182.

113. Molgaard-Nielsen D, Pasternak B and Hviid A. Use of

ﬂuconazole during pregnancy and risk of birth defects.

N Engl J Med 2013; 369: 830–839.

114. Mølgard-Nielsen D, Svanstr

€

om H, Melbye M, et al.

Association between use of oral ﬂuconazole during

pregnancy and risk of spontaneous abortion and still-

birth. JAMA 2016; 315: 58–67.

115. Amaya-Guio J, Viveros-Carre

no DA, Sierra-Barrios

EM, et al. Antibiotic treatment for the sexual partners

of women with bacterial vaginosis. Cochrane Database

Syst Rev 2016; 10: CD011701.

116. Bisschop MP, Merkus JM, Scheygrond H, et al. Co-treat-

ment of the male partner in vaginal candidosis: a double-

blind randomized control study. BJOG 1986; 93: 79–81.

117. Fong IW. The value of treating the sexual partners of

women with recurrent vaginal candidiasis with ketoco-

nazole. Genitourin Med 1992; 68: 174–176.

118. Lyng J and Christensen J. A double blind study of treat-

ment with a single dose tinidazole of partners to females

with trichomoniasis. Acta Obstet Gynecol Scand 1981;

60: 199–201.

119. Schwebke JR and Desmond RA. A randomized con-

trolled trial of partner notiﬁcation methods for preven-

tion of trichomoniasis in women. Sex Transm Dis 2010;

37: 392–396.

Appendix 1

Review of the literature

An extensive literature review was performed using

Medline for the years 2009–2017. MEDLINE search-

keywords: vulvovaginal candidosis, vaginal candidosis,

vaginal candida, Trichomonas vaginalis, trichomonia-

sis, Bacterial vaginosis, non-speciﬁc vaginitis, abnor-

mal vaginal ﬂora, vaginal dysbiosis. The resulting

articles were handsearched and sorted. Further refer-

ences were obtained from these articles.

The Cochrane Library was searched; search-

keywords were:

vulvovaginal candidosis, vaginal candidosis, vaginal

candida, Trichomonas vaginalis, in women, bacteri-

al vaginosis.

The 2015 US CDC guidelines for the treatment of

Sexually Transmitted Diseases and the related UK

national guidelines (www.bashh.org) were reviewed.

Tables of levels of evidence and grading of

recommendations:

(see http://www.iusti.org/regions/Europe/pdf/2017/

ProtocolForProduction2017.pdf).

Appendix 2. Declarations of interests

Jackie Sherrard: JS has received consultancy fees from

Becton Dickinson

Janet Wilson: JW has received speaker fees from BD

Diagnostics; unconditional research grants in the form

Sherrard et al. 1271

of diagnostic tests from Hologic; and remuneration for

contract research from Starpharma.

Gilbert Donders: received consultancy fees and /or

speakers fees from Medinova, Alfa-Wasserma n,

Bayer, Phacobel and GSK.

Werner Mendling: WM declares in the last three

years royalties by Aristo Pharma GmbH Berlin, Dr

August Wolff GmbH & Co. KG Arzneimittel

Bielefeld, Dr Kade Pharmazeutische Fabrik GmbH

Berlin, Pierre Fabre Pharma GmbH Freiburg,

SymbioPharm Herborn and Johnson & Johnson

GmbH Neuss (all Germany), and Medinova AG

Zurich/Switzerland

Jørgen S Jensen: JSJ has received speaker fees from

Hologic and SSI has received remuneration for con-

tract research from Hologic, SpeeDx, NYtor,

Diagenode, Nabriva, Angelini, GSK, and Osel

1272 International Journal of STD & AIDS 29(13)