C.glabrata infections.pdf

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Sex Transm Inf 2001; 77 :212–213

Case

report

Combined topical ﬂucytosine and amphotericin B

for refractory vaginal Candida glabrata infections

D J White, A R Habib, A Vanthuyne, S Langford, M Symonds

Patients with vaginitis due to highly azole resistant Candida glabrata can be particularly di Y cult

to treat. We describe three cases of longstanding vaginal candidiasis due to C glabrata . These had

failed to respond to local and systemic antifungals. Flucytosine (1 g) and amphotericin B (100

mg) formulated in lubricating jelly base in a total 8 g delivered dose, was used per vagina once

daily for 14 days with signiﬁcant improvement, both clinically and microbiologically.

( Sex Transm Inf 2001; 77 :212–213)

Keywords: amphotericin; ﬂucytosine; Candida glabrata

Introduction

Candida glabrata is the second most common

yeast recovered from the genital tract of women

with vaginitis and accounts for about 5% of

vaginal infections. 1 A substantial minority of C

glabrata isolates are azole resistant 23 and

further resistance may be selected out by non-

curative treatment. Although infections with

this organism are not always associated with

symptoms and clinical signs 4 some a V ected

women have discharge and/or vulvitis and a

poor response to antifungal therapy. 56

We describe three cases of persistent vaginal

candidiasis due to C glabrata , unresponsive to

conventional antifungal therapy including

boric acid. Flucytosine tablets 500 mg (Center

Specialites Pharmaceutiques Cournon Cedex,

France) and amphotericin B BP1998 1 mg =

859IU (Bufa BV Uitgeest Holland) were com-

bined in lubricating jelly, Aquagel (Adams

Healthcare, UK). This was used per vagina

with clinical and microbiological cure. Treat-

ment was delivered by a unit dose vaginal

applicator containing amphotericin 100 mg +

ﬂucytosine 1 g based in Aquagel in a total 8 g

delivered dose. This preparation has an un-

known shelf life and is obtainable from the

pharmacy manufacturing unit, North Sta

days combined with clotrimazole 500 mg vagi-

nal pessaries for 7 nights, intravaginal painting

with gentian violet 0.5% aqueous solution for 3

days, and boric acid 600 mg in gelatine

capsules once daily for 14 nights.

Intravaginal amphotericin B and ﬂucytosine

in lubricating jelly was given at night for 14

days. Her symptoms improved and Gram stain

and cultures were negative 2 and 5 weeks

following treatment.

Department of Sexual

Medicine,

Birmingham

Heartlands Hospital,

Birmingham B9 5SS,

D J White

A R Habib

A Vanthuyne

ord-

shire Hospital, Stoke on Trent ST4 6QG (tel

01782 552 289; fax 01782 552 916). The

preparation was compounded no more than 48

hours before treatment began.

Case 2

A 63 year old woman presented witha6year

history of intermittent vulvo-vaginitis and per-

sistent isolation of C glabrata on Gram stain

and culture. This had failed to respond to a

variety of di V ering types and lengths of azole

therapy. She had had a hysterectomy 5 years

before presentation following which she com-

menced subcutaneous oestrogen hormone

replacement implants. One year after the

hysterectomy her symptoms of vaginal dis-

charge and vulval soreness became continuous.

She had had some minor symptomatic im-

provement to dydrogesterone and intravaginal

boric acid.

She was treated with itraconazole 100 mg

daily combined with nystatin pessaries for 4

weeks followed by intravaginal boric acid for 2

weeks. Despite this, Gram stain and cultures

remained positive for C glabrata. This was fully

sensitive to antifungals in vitro (table 1).

Amphotericin B and ﬂucytosine in lubricat-

ing jelly was given once daily for 14 days. She

improved symptomatically and follow up swabs

were negative by Gram stain microscopy and

culture 3, 4, and 8 weeks afterwards. Seven

ordshire

Hospital, Stoke on

Trent ST4 6QG, UK

S Langford

Department of

Pharmacy,

Birmingham

Heartlands Hospital,

Birmingham

M Symonds

Case 1

A 42 year old woman presented with “recur-

rent vaginal thrush” since the age of 19. At

referral she had had several recent swabs show-

ing heavy growths of candida species in Gram

stain microscopy despite 3 months’ treatment

with itraconazole 100 mg twice daily for 2 days

every week, two Depo-provera (Pharmacia &

Upjohn) injections, and a number of other

unspeciﬁed antifungal treatments including

courses of nystatin pessaries. None of these

produced any symptomatic response.

Vaginal swabs were positive by Gram stain

and culture for C glabrata which persisted

despite itraconazole 200 mg once daily for 14

Table 1 Antifungal sensitivities (NCCLS method Bristol

PHLS mycology reference laboratory) before treatment with

intravaginal ﬂucytosine/amphotericin B in lubricating gel

Correspondence to:

D J White, Department of

Sexual Medicine, Hawthorn

House, Heartlands Hospital,

Birmingham B9 5SS, UK

dwhite@hawthorn.co.uk

or A R Habib

ahabib@hawthorn.co.uk

Case 1 Case 2 Case 3

Amphotericin B

—

Flucytosine

—

Fluconazole

Itraconazole

Miconazole

—

Nystatin

—

Accepted for publication

22 March 2001

S = sensitive, R = resistant.

www.sextransinf.com

Pharmacy

Manufacturing Unit,

North Sta

Combined topical ﬂucytosine and amphotericin B for refractory vaginal C glabrata

213

months later she presented witha4week

history of discharge. Microscopy of a Gram

stained slide was positive for spores and a non-

albicans yeast (not further speciated) was

isolated in culture. She responded symptomati-

cally and microbiologically to nystatin pessa-

ries at night for 14 nights.

there has previously been no further treatment

available. Intravaginal amphotericin/

ﬂucytosine o V ers a possible treatment for such

patients.

Topical ﬂucytosine has been used for vaginal

infections caused by both C albicans 9 and anti-

fungal resistant non- albicans candidiasis 10 11 but

a suitable formulation has not been available in

the United Kingdom. Although it is the only

available fungicidal agent, 1 there are reserva-

tions about its topical use because of the

potential development of ﬂucytosine resist-

ance, which occurs by mutation of a single

gene. The risk of such resistance developing is

thought to be reduced by combination with

polyene antifungals such as amphotericin B

with which ﬂucytosine is synergistic in vitro. 19

Our three cases demonstrate that ﬂucytosine

and amphotericin in lubricating jelly may be

e V ective in chronic vaginal C glabrata infection

where all other available agents have failed.

This treatment was well tolerated in all patients

with no or minimal side e V ects.

Case 3

A 42 year old woman presented with intracta-

ble symptoms of “vaginal thrush” which had

started since a hysterectomy 1 year earlier, fol-

lowing which she had started unopposed

oestrogen hormone replacement therapy.

Microscopy of a Gram stained vaginal slide

showed spores and C glabrata was isolated

which persisted despite dydrogesterone 10 mg

daily for 28 days combined with nystatin

pessaries at night for 14 days, combined nysta-

tin pessaries and itraconazole 400 mg daily for

7 days, and vaginal boric acid 600 mg daily for

14 days.

Intravaginal amphotericin B and ﬂucytosine

in lubricating jelly was given at night for 14

days. Her symptoms improved and microscopy

and cultures were negative 2 and 5 weeks

following treatment.

We would like to thank Professor Frank Odds for his initial

advice and Dr Elizabeth Johnson for help with the results of the

antifungal sensitivity tests.

Contributors: DJW, ARH, and AV collected the patients and

wrote the paper; DJW had the idea of using ﬂucytosine and

amphotericin intravaginally; MS and SL developed the formu-

lation of amphotericin and ﬂucytosine in lubricating jelly.

Discussion

By comparison with C albicans , C glabrata is

intrinsically less sensitive to azole antifungals

and, because this organism is haploid (unlike C

albicans which is diploid) selection of drug

resistant strains may occur. 7 Persistent vaginal

C glabrata is more likely to be found in patients

who are clinically not or partially responsive to

azole antifungals, older patients, diabetics, and

women who have had hysterectomies. 4 Symp-

toms are, however, not a reliable guide to the

causative organism. It is therefore important to

speciate isolates from patients presenting with

problem vaginal candidosis. 4 Because of the

relatively small numbers of patients presenting

with this condition, treatment of persistent C

glabrata vaginitis is not evidence based but

remains largely anecdotal. Most clinicians

would start treatment with intravaginal nysta-

tin (the only licensed alternative to azoles in the

United Kingdom) and then proceed to either

high dose oral itraconazole together with high

dose intravaginal azole pessaries or nystatin.

Following this with intravaginal boric acid 600

mg at night for 14 days. 8

If this fails however

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8 Bingham JS. What to do with the patient with recurrent vul-

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