Salvage treatment

The characteristics that are important for successful salvage treatment are not known. One approach may be to use oral systemic fungicidal therapy in combination with topical therapy to penetrate into vaginal epithelia. It should be acknowledged that there are no established breakpoints for most of the topical antifungal agents. Moreover, accepted antifungal susceptibility breakpoints applied to drugs intended for systemic use cannot necessarily be applied to those agents when used topically as much higher local concentrations of the drugs may be achieved using topical treatment or at vaginal pH.9 Supplementary table 2 shows the susceptibility data for the 35 C glabrata isolates from vaginal swabs referred to the MRL during 2011 compared with the 204 C albicans isolates and as you can see the MIC₅₀ results (ie, the MIC at which 50% of the isolates are inhibited) obtained for the azole drugs are often considerably higher for C glabrata than those for C albicans which usually remain easier to treat with azole therapy.

Our clinical experience tells us that although relapses are common with inadequate treatment, once finally eradicated the organism rarely returns (although attacks with other species may still occur). Species identification is therefore essential for any further attacks to reassure the patient that their condition has not recurred. Certain symptoms, particularly vulval soreness, may take time to resolve and cure should be based on the results of swabs taken at least a week after treatment. If swabs are negative but symptoms persist then patients should be reassured that they will probably, in the absence of any other vulvovaginal condition, settle with the use of local emollients (recommended for all patients) and the judicious use of local steroids. Our suggestion is to use aqueous cream applied to dry skin as a soap substitute and a greasy preparation, for example, Diprobase as a skin ‘waterproofer’.

Step 1 The best evidence for first-line salvage treatment centres on the use of intravaginal flucytosine (5FC) for 2–3 weeks.2–5 ,7 Based on the susceptibility profiles of C glabrata (see supplementary table 2) and the possibility of potential synergies between the two agents a product was formulated in the UK using 5FC in combination with amphotericin. Although 5FC is fungicidal, emergent resistance is quite common when it is used as monotherapy and primary resistance is seen with some species but it is uncommon with isolates of C glabrata. Whether this justifies initial susceptibility testing is a matter of debate. Polyene antifungals (particularly amphotericin) have been shown to be synergistic in their effect with regards to C glabrata and also with other fungi, for example, Cryptococcus.10 The reported series with amphotericin and 5FC in lubricating jelly have suggested 100%3 ,7 success but we have had personal experience of failure and have been contacted for advice about apparent failures. There have recently been problems with the supply of pure amphotericin powder, so the preparation has been reformulated with the substitution of nystatin (also a polyene) in place of amphotericin, and is available from the University of North Staffordshire Manufacturing Pharmacy.

Step 2 Following the failure of 5FC/nystatin the next logical agent to choose is intravaginal boric acid 600 mg for 2–3 weeks. This is available from Martindale Pharma, Brentwood, Essex. Series suggest a cure rate of 64–72%.4 ,6 Boric acid is safe when used for short courses, although long-term data are lacking.11

Step 3 If the condition fails to respond despite the use of these treatments the next step is unclear and clinical reporting is lacking. If the organism remains susceptible and there was a temporary response to treatment then it might be worth trying a prolonged course, that is, 4 weeks of either 5FC/nystatin or boric acid but there are currently no reports to support this.

Step 4 If the patient still has persistent infection the next step may depend on the susceptibility profile of the isolate. C glabrata will usually remain susceptible to 5FC and moderately susceptible to azoles. For C glabrata, miconazole is the most active in vitro of the vaginal preparations but it is unclear whether resistance profiles are truly helpful in defining therapy. Assuming the organism remains 5FC susceptible then it seems logical that this should be used intravaginally in any further treatment. If there is 5FC resistance it then makes sense to use either boric acid or vaginal pessaries, for example, clotrimazole 500 mg or miconazole nitrate (Gyno-Daktarin) 1200 mg on alternate days alongside intensive oral treatment. If azole therapy must be revisited then there remains a question as to whether this should be with voriconazole, posaconazole or high-dose fluconazole. Recent literature on the use of fluconazole 1200 mg in AIDS-related cryptococcal meningitis suggests that there is synergism with other agents and an improved rate of sterilisation with high doses, although that may reflect penetration into the cerebral spinal fluid so is not necessarily relevant to mucosal tissue infections.12 The unpredictable bioavailability, high cost and unique side-effect profile of voriconazole limit its use in this setting (the first two points also apply to posaconazole). Again the length of course is unclear but in practical terms this may be dictated by the patient's ability to tolerate the drug.

Step 5 If the patient remains infected then they may be effectively incurable. Suppressive vaginal boric acid may be a useful option here (although this will become very expensive, see table 1). Some patients have reported making their own preparations by putting boric acid into gelatine capsules but safety concerns preclude any recommendation to this course of action.