Candidiasis is a fungal condition, also known as thrush or candidosis. The most common cause is a very common yeast called Candida albicans, although candidiasis can also be caused by related fungi such as C. krusei, C. tropicalis and Torulopsis glabrata (Bessarab 2004; Melo 2004).

These fungi are very common, but do not normally cause health problems because a fully functioning immune system can keep them suppressed. In people whose immune system is damaged, however, Candida can overgrow and cause symptoms. It can also flourish if the immune system is suppressed for other reasons, such as stress, other viral infections or conditions such as diabetes, or if other normal micro-organisms that live in the body are killed by a course of antibiotics.

There is some evidence that HIV may also play a direct role in candidiasis. Recent research has linked oral candidiasis in HIV-infected people to high viral load, regardless of CD4 count.

Very preliminary research using HIV-positive couples has suggested that in some cases, Candida strains can be transmitted from one person to another. As some strains can be resistant to anti-fungal treatment, this raises the possibility that drug-resistant strains could be passed on to people who have never received anti-fungal treatment themselves.

Diagnosis

Candida in the mouth can be presumptively diagnosed simply by examining it, but definitive diagnosis and diagnosis of Candida in other parts of the part requires a sample to be taken by biopsy or smear and examined under the microscope.

Tests for Candida itself or antibodies to it in the blood are not useful since they can be present even in healthy people, and do not prove that Candida is causing disease. People with oesophageal symptoms may be treated presumptively for Candida, since it is the commonest cause of throat infections among people with HIV.

Anti-fungal treatments

There are several anti-fungal drugs that are effective against candidiasis. Anti-fungals come as local treatments or systemic treatments, i.e. as a cream or pessaries, or in tablet form.

For Candida infection of the skin or nails, anti-fungal creams or powders may be tried. Anti-fungal creams or pessaries are also usually the initial treatment for vaginal candidiasis. These include clotrimazole (Canesten / Candiden / Abtrim), which is available over-the-counter.

For mild oral candidiasis, treatment options include topical agents that only affect the mouth, such as clotrimazole lozenges, nystatin syrup or mouthwash (Nystan / Nystamont) or amphotericin lozenges (Fungilin). The most effective topical agent appears to be fluconazole oral solution (Diflucan), which is swilled around the mouth before being swallowed. Itraconazole oral solution (Sporanox) is a promising new treatment.

Nystatin or gentian violet are recommended by the World Health Organization for the treatment of oral thrush. However, nystatin must be dosed five times a day due to rapid clearance by saliva, whilst gentian violet stains the mouth and saliva.

A buccal patch formulation of miconazole (Daktarin) has been developed for the treatment of oropharyngeal thrush. This is a tablet that sticks inside the mouth and is a low-cost treatment option that acts locally, in the saliva. This formulation limits the side-effects and drug interactions that can be a problem with anti-fungal drugs. A comparative study showed that the miconazole patch is as effective as systemic ketoconzole in treating oral thrush in people with advanced HIV disease (Van Roey 2004).

For more severe oral candidiasis and for oesophageal candidiasis, systemic therapy is required. Fluconazole or itraconazole tablets or solution may be prescribed. These drugs are of similar effectiveness. The new drug posaconazole has recently been shown to be as effective as fluconazole, but with a reduced risk of relapse (Vazquez 2006).

For severe candidiasis that has spread through the body, the liposomal form of amphotericin B is recommended. One study showed that it was as effective as conventional amphotericin B, but less toxic to the kidneys.

A new class of anti-fungal agents is the glucan synthesis inhibitors which block fungal cell wall synthesis. One class of glucan synthesis inhibitor is the echinocandins. Currently, three drugs belong to this class: caspofungin (Cancidas), micafungin (Mycamine) and anidulafungin.

Caspofungin is already approved in Europe and the United States for invasive aspergillosis in HIV-infected people, and it has shown equivalence to amphotericin B as a treatment for oropharyngeal and oesophageal candidiasis in a phase II study, while causing fewer side-effects (Arathoon 2002). It is also as effective as amphotericin B against azole-resistant invasive candidiasis (Kartsonis 2002; Mora-Duarte 2002; Garbino 2003; Smith 2003). Micafungin has shown efficacy against oral and oesophageal candidiasis, with similar efficacy to fluconazole (Pettengell 1999; de Wet 2004). However, micafungin is unlikely to be available in Europe until 2006.

Drug-resistant candidiasis

Anti-fungal drug resistance is common among people with advanced HIV, due in part to long-term prophylaxis or treatment. An American report claimed that 5 to 10% of oral candidiasis cases do not respond to fluconazole (White 1999). It is in these cases that alternatives to fluconazole, or possibly higher doses of fluconazole, are most likely to be used.

Experimental drugs, such as posaconazole may also be of benefit in fluconazole-resistant candidiasis. An observational trial of posaconazole found that 71% of 107 people with oral or oesophageal candidiasis resistant or unresponsive to fluconazole or intraconazole responded to the new drug, while 75% of 199 patients with advanced HIV disease showed a clinical response with the drug (Skiest 1999, 2004). A similar drug code named D0870 is also effective against fluconazole-resistant candidiasis (Cartledge 1998).

Complementary treatments

In milder candidiasis, some complementary therapists advise completely avoiding refined sugars, on which Candida feeds. This involves avoiding most sweet foods, as well as white flour and starch. People who choose this option you inform their doctor to ensure that they are getting enough calories in the diet.

Live, unpasteurised yoghurt can help, since Lactobacillus bacteria can compete with Candida. There is a very small risk that live yoghurt may contain tuberculosis, brucellosis, Listeria or Salmonella, so yoghurt from a 'certified herd' should be chosen, since it is carefully screened against these pathogens. The yoghurt is applied directly to the vagina or is eaten.

Tea tree oil is a herbal remedy that may be effective against various fungal infections including Candida, although some doctors dispute its benefits. See Tea tree oil in Drugs used by people with HIV: Herbal and naturopathic treatments for more information.

Prophylaxis

There is no agreed standard practice for providing primary prophylaxis to prevent the occurrence of a first episode of candidiasis. Some doctors offer their patients low dose fluconazole, but others are concerned that long-term use may encourage the development of Candida strains which are resistant to this drug.

After treating an episode of candidiasis, some doctors advocate staying on a low dose of ketoconazole (Nizoral), itraconazole or fluconazole to prevent Candida returning (i.e. as secondary prophylaxis). This may also help prevent cryptococcosis in the case of high dose fluconazole.

A recent study found that weekly intra-vaginal treatment with clotrimazole or Lactobacillus acidophilus reduces episodes of vaginal thrush in HIV-infected women (Williams 2001). There is also some preliminary evidence that for women with recurrent vaginal candidiasis, consuming live yoghurt every day can reduce the amount of Candida in the vagina.

Candidiasis in the age of highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) has reduced the prevalence of mouth infections such as candidiasis among people with AIDS (Ceballos-Salobreñ¡ ²000; Eyeson 2000; Sherson 2000; Tappuni 2000; Zakrewska 2000). However, this is not fully explained by immune reconstitution and researchers believe other mechanisms may play a part in reducing candidiasis among people taking anti-HIV treatment (Cauda 1999). The link between high viral load and oral Candida, regardless of CD4 count, suggests that HIV itself may play a part in HIV-related thrush.

There is evidence that protease inhibitors directly affect Candida growth by inhibiting a Candida protease enzyme called Sap. One study found that indinavir (Crixivan) and ritonavir (Norvir) reduced Sap activity by more than 90%, as well as reducing Candida growth in both laboratory tests and in women with vaginal candidiasis (Cassone 1999). Another in vitro study found that indinavir and saquinavir (Invirase / Fortovase) reduced the activity of Sap in both HIV-infected and non-HIV-infected individuals with candidiasis (Korting 1999). This may explain the dramatic impact of protease inhibitors on oral candidiasis.

Key research on epidemiology

Researchers from Guys, Kings and St Thomass Schools of Medicine and Dentistry, St Bartholemews and Royal London Hospital School of Medicine and Dentistry, and the Sydney United Dental Hospital in Sydney, Australia, presented studies at the recent Fourth International Workshop on Oral Manifestations of HIV Infection held in South Africa (Sherson; Eyeson; Tappuni; Zakrewska). Oral candidiasis was one of several oral infections which was less frequent among individuals on antiretroviral treatment. For example, Tappuni found oral candidiasis among 21% of untreated patients and among 11% of those treated.

Gottfredsson studied 83 HIV-infected people with no clinical evidence of thrush and no recent anti-fungal use. Yeast colonisation was significantly associated with high viral load but not with low CD4 count.

Dodd reported that oral candidiasis is the most common opportunistic infection among people with HIV. McCarthy found that one-third of HIV-positive people developed thrush prior to their AIDS diagnosis, and over 90% of people with AIDS develop thrush at some point. Dueer found that rates of vaginal candidiasis were similar among HIV-negative women and HIV-positive women with normal CD4 counts, but the risks of vaginal colonization by Candida albicans and symptomatic vulvovaginitis were increased approximately threefold and fourfold respectively, in HIV-positive women with CD4 counts below 200 compared with either immunocompetent HIV-positive women or HIV-negative women.

Martins reported that among 70 individuals who switched their antiretroviral therapy from nucleoside monotherapy or dual therapy to triple therapy with a protease inhibitor, the incidence of Candida albicans culture positivity fell from 61% to 38%, the incidence of oropharyngeal candidiasis fell from 49% to 11%, and the incidence of fluconazole-resistant candidiasis fell from 19% to 11%.

Boerlin reported that Candida albicans strain identity, assessed using MEE typing and Ca3 typing, was found in at least 5 of 19 groups of HIV-positive partners, suggesting a possible high frequency of transmission between HIV-positive people. No association between transmission and present or previous oropharyngeal candidiasis could be found.

Dromer reported that 10 HIV-infected couples tended to share genetically indistinguishable clones of Candida albicans, suggesting that they are transmitted between partners.

Nittayananta reported that although smoking is a recognised risk factor for oral candidiasis among the general population, in a cohort of 94 HIV-positive individuals smokers were at no greater risk of developing clinical candidiasis than non-smokers. However, Candida species could be isolated in the mouths of a significantly higher proportion of smokers than non-smokers (88.7% versus 65.6%).

Research into HAART and candidiasis

Cauda enrolled 93 people with recurrent oral candidiasis (OC) into a prospective, observational study of protease inhibitors in the treatment of OC. 30 people were on PIs and 63 were not. Participants were matched for age, CD4 count, sex, and stage of HIV infection. During the 1-year follow-up, OC occurred in 2 people on PIs (7%) and 23 people not on PIs (36%). 14 people (50%) on RTIs but not PIs developed OC. Researchers tested for Candida specific immune response: 41% had a lymphoproliferative response to Candida but none had a skin hypersensitivity reaction to Candida. This suggests factors other than immune reconstitution are reducing the incidence of oral candidiasis in people on PIs.

Cassone and Korting (1999) have suggested that HIV protease inhibitors appear to have a direct effect on one of the key virulence factors of C. albicans - the secreted aspartic proteinases (Saps). This suggests that the lower incidence of candidiasis among HIV-positive patients taking HAART might not be solely the result of improved immunological status but could also be due to the HAART treatment directly inhibiting Candida protease.

Cassone (2002) compared PI- and NNRTI-based HAART in 30 treatment-naive patients and 30 treatment-experienced patients. PIs had an inhibitory effect on secretory aspartyl proteinase (Sap), a virulence trait for mucosal candidiasis. The anti-Sap effect of PI-HAART was associated with clinical resolution of oral candidiasis although this was not due to superior immunological recovery. In the treatment-naive PI group, the number of episodes of oral candidiasis declined (from 7 at baseline to 1 at 30 days) and oral Candida carriage was progressively reduced. In contrast, oral Candida carriage was not significantly affected by 180 days of treatment with NNRTI-HAART

Treating oral candidiasis

Cartledge (1998) evaluated 26 people with HIV-related fluconazole-resistant oro-oesophageal candidiasis. At day 7, 16 showed partial improvement and nine showed no improvement. One person had full recovery although testing showed this person did not have fluconazole resistance. Poor response to treatment was associated with low blood levels of D0870.

Pons (1993) conducted a 14 day comparative study of fluconazole (100 mg by mouth every day) versus clotrimazole (10 mg by mouth five times a day) in 258 people with oral thrush, reporting comparable clinical response in both groups. However, fluconazole was judged more effective in eliminating Candida (with more rapid remission of symptoms) and maintaining a disease-free state.

Pons (1997) treated 167 people with oral candidiasis with either fluconazole liquid suspension(100 mg/day) or topical liquid oral nystatin (500,000 units 4 times daily) for 14 days. At day 14, 87% of the fluconazole-treated group were clinically cured, as opposed to 52% in the nystatin-treated group (p<0.001). Fluconazole eradicated Candida organisms from the oral flora in 60% vs a 6% eradication rate with nystatin (p<0.001). The fluconazole group had fewer relapses at day 28 (18% vs 44%; p<0.001). This relapse difference no longer existed by day 42.

De Wit (1993) randomly treated 51 people with oral candidiasis with either single-dose fluconazole (150 mg) or seven days of fluconazole (50 mg/day). Clinical cure was observed at day 7 in 21/24 (85%) people treated with single-dose of fluconazole and 26/27 (96%) treated for 7 days (difference not significant).

Frechette treated 244 people with oral candidiasis with either itraconazole oral solution (100 mg twice daily for either 7 or 14 days) or fluconazole (100 mg/day tablet). All three groups were found to be equivalent (cure or marked improvement in 84%-91%).

Graybill treated 190 people (179 evaluable, with a mean CD4 count of 94) with oropharyngeal candidiasis with either itraconazole oral solution (200 mg/day for either 7 or 14 days) or fluconazole (200 mg/day on day 1 then 100 mg/day for 7 days). There was no difference in efficacy between the arms, with clinical success seen in 83%, 97% and 87% respectively. Mycological cure was seen in 60%, 76% and 68% respectively.

Darouiche compared the efficacy of a 14 day course of itraconazole solution versus clotrimazole troches (10 mg five times daily for 14 days) in 149 people with oral candidiasis, 83% of whom were HIV-positive. There was no statistically significant difference in the proportions achieving a clinical response (77% of the itraconazole group versus 66% of the clotrimazole group), although itraconazole was more effective in decreasing fungal colony counts and culture positivity.

Nandwani reported that terbinafine proved ineffective against oral candidiasis in a pilot study.

Treating oesophageal, oropharyngeal and systemic candidiasis

de Wet (2004) randomised 245 HIV-positive patients with oesophageal candidiasis that was not fluconazole resistant to receive fluconazole 200mg daily, or micafungin 50, 100 or 150mg daily by intravenous infusion for 14-21 days. Intent-to-treat analysis showed that 87% of the fluconazole group and 69%, 77% and 90% of the micafungin groups respectively showed clearance of Candida, assessed by endoscopy. Improvement was dose-related. Side-effects were similar in all groups, although renal effects were more common in the micafungin groups (4% vs. 0%). No interaction with efavirenz or nevirapine was detected.

Van Roey (2003) compared the effectiveness of the slow-release mucoadhesive tablet containing miconazole with systemic ketoconazole therapy in a randomised study involving 306 HIV-infected individuals in Uganda. All the patients had oropharyngeal candidiasis. The median CD4 cell count was 36 cells/mm³. At day seven, 92.8% of patients treated with miconazole and 96.4% of ketoconazole-treated patients had responded to treatment (not statistically significant). End-of-treatment (day 14) response rates were also similar (93% and 96% respectively). Relapse rate was 30.8% for the miconazole group and 23% for the ketoconazole group. The difference was not statistically significant. By day 14 only 1% of both study arms still had pain on swallowing. The incidence of the most frequently reported adverse events, such as fever and headache was comparable between the two arms of the study. However, the incidence of vomiting was only 1% in the miconazole group versus 8% in the ketoconazole group. Although the miconazole tablet was mucoadhesive, attaching to the gum, the investigators found no signs of local irritation.

Mora-Duarte (2002) conducted a randomised, double-blind study of caspofungin versus amphotericin B for invasive candidiasis in 224 people (HIV status not mentioned). Successful outcome occurred in 73% of the caspofungin group and 62% of the amphotericin group (non-significant). This study demonstrated that caspofungin was at least as effective as amphotericin B for the treatment of systemic candidiasis.

Arathoon conducted a double-blind, dose-ranging study of caspofungin for oropharyngeal and/or oesophageal candidiasis. 140 patients were enrolled in the study; 63% had oesophageal involvement and most had advanced HIV infection (98% HIV-infected, median CD4 count of 30). Participants were randomised to either caspofungin acetate (35, 50, or 70 mg) or amphotericin B (0.5 mg/kg of body weight) intravenously once daily for 7-14 days. Complete resolution of symptoms and quantifiable improvement of mucosal lesions 3 to 4 days after discontinuation of treatment was deemed to be a positive response. By intent-to-treat analysis, 74-91% of the caspofungin groups had a favourable response compared to a 63% response rate among amphotericin B recipients (63%), but there was considerable overlap in the 95% confidence intervals surrounding these estimates. Fewer side-effects occurred among people taking caspofungin compared to patients taking amphotericin B (p<0.01).

Bessarab (2003) reported candidiasis of the nasal cavity or paranasal sinuses in 68 HIV-infected people. Various types of Candida were detected in the nasal canals: C. albicans (51), C. tropicalis (7), C. krusei (4), C. parapsilosis (2). Candida-bacterial coinfection occurred in more than half of the cases

(S. aureus, S. haemolyticus, S. agalacticae, S. anginosus and others). Antifungal and antibiotic treatment based on sensitivity testing was effective.

Pettengell treated 74 people with the experimental anti-fungal drug FK463 of the echinocandin class. Doses of 50, 25 and 12.5 mg/day were given as a daily infusion for 12 days. Clinical response occurred in 100% of the 50mg group, 90% of the 25 mg group and 81% of the 12.5mg group. Response was more complete and quicker for the high dose group. Three people discontinued FK463 due to adverse events and one due to non-response. One serious adverse event (diarrhoea and dehydration) occurred.

De Wit (1989) conducted a randomized, double-blind study of fluconazole and ketoconazole. 37 HIV-infected people with oropharyngeal candidiasis were treated with either fluconazole (50 mg by mouth every day) or ketoconazole (200 mg by mouth every day) for 28 days. Clinical remission was achieved at the end of therapy in all fluconazole-treated cases and 75% of ketoconazole-treated cases.

Barbaro randomised 2213 people experiencing their first episode of oesophageal candidiasis to receive two weeks treatment with either itraconazole (100 mg twice daily) or fluconazole (100 mg twice daily). Mean CD4 count at baseline was approximately 65. At two weeks, 65.5% of itraconazole recipients and 81.2% of fluconazole recipients had no evidence of candidiasis on endoscopy. 75.2% and 81.5% experienced clinical cure respectively.

De Repentigny conducted a multicentre, prospective, double-blind, randomized trial comparing itraconazole and ketoconazole in the treatment of oropharyngeal and/or oesophageal candidiasis and the rate of post-treatment relapse. 98 patients had oropharyngeal candidiasis and 31 oesophageal infection. Oropharyngeal infection was cleared clinically at 21 days in 71% of patients receiving itraconazole and 60% receiving ketoconazole, and oesophageal candidiasis was cleared at 41 days in 100% of patients receiving itraconazole and 91% receiving ketoconazole. Differences between itraconazole and ketoconazole in clearing of infection were barely significant (p=0.0614 oropharyngeal and p=0.0781 oesophageal). Mean rates of infection relapse were not statistically different in the two treatment groups.

Smith (1991) enrolled 106 evaluable people with oesophageal candidiasis in a randomised trial comparing itraconazole (200 mg/day) with ketoconazole (200 mg by mouth twice a day) for 28 days. After 1 week, 75% and 82% of the itraconazole and ketoconazole groups respectively had responded clinically. After 4 weeks of treatment response was 93% in each group. 1 participant discontinued itraconazole because of rash; 5 discontinued ketoconazole (2 nausea, 2 hepatotoxicity, and 1 rash). Relapse rates were identical with 80% having a further episode of candidiasis within 3 months.

Laine conducted a randomised, double-blind study of fluconazole (100 mg every day) and ketoconazole (200 mg every day). 169 HIV-positive people with oesophageal candidiasis were treated for up to 8 weeks. Endoscopic cure occurred in 58/64 (91%) participants treated with fluconazole and 34/65 (52%) treated with ketoconazole. Clinical symptoms resolved in 61/72 (85%) fluconazole-treated participants and 46/71 (65%) in ketoconazole-treated participants. The authors speculate that the superior efficacy of fluconazole may be explained by its more consistent gastric absorption.

Moskowitz enrolled 110 people with oesophageal candidiasis in a study comparing itraconazole solution (100-200 mg daily) versus fluconazole (100-200 mg daily). Treatment was continued for two weeks beyond symptom resolution, with a minimum of three weeks and maximum of eight weeks duration. 91% of the itraconazole recipients and 86% of the fluconazole recipients were symptom-free at the end of treatment (difference not significant). Endoscopy-determined cure had occurred in 90% versus 80% respectively (p=0.44), and the proportions achieving mycological eradication were 92% and 78% respectively (p=0.002). During four weeks of follow-up, relapse occurred in 18% and 27% respectively.

Anaissie treated 231 people who had severe systemic candidiasis with amphotericin B lipid complex (ABLC) (5 mg/kg/day) or conventional amphotericin B (AMB) (0.6 to 1.0 mg/kg/day). The median duration of therapy was 14 days for both groups. Response rates were 63% for ABLC and 68% for AMB. The frequency of adverse events was similar between the two treatment groups except for nephrotoxicity which was more common in patients receiving AMB. Baseline serum creatinine doubled in 28% of ABLC patients and in 47% of AMB patients and the median number of days to doubling of serum creatinine was 82 days for ABLC, and 19 days for AMB. At 3-month follow-up, there were no significant differences in relapse or survival.

Treating anti-fungal resistant candidiasis

Skiest (2004) treated 199 patients with advanced HIV disease (median CD4 cell count 12 cells/mm³) and fluconazole- or intraconazole-resistant oral or oesophageal candidiasis. 75% were cured or improved.

Garbino (2003) and Smith (2003) have both reported case studies of HIV-infected people with -azole resistant candidiasis who responded to treatment with caspofungin.

Saag conducted an open-label study of itraconazole solution in 74 HIV-infected people who failed fluconazole treatment. 100mg was administered twice daily for 14 or 28 days. 41(55%) responded to treatment by day 28. Of the 22 people who discontinued treatment after a response, all relapsed within 6 weeks. HAART was not available when the study was conducted.

Skiest treated 107 individuals with candidiasis that was resistant or unresponsive to either fluconazole or itraconazole or both to a new azole called SCH 56592 or posaconazole. Half had in vitro evidence of resistance. Dose was 400 mg twice daily for 3 days and then 400 mg daily to complete 28 days. Non-responders could increase the dose to 400mg twice daily at day 10. 71% (76 of 107) responded to treatment. Half of responders had complete clearance of lesions.

Pfaller presented in vitro data on BMS-207147, Sch 56592 and voriconazole against a range of candida species. The 3 agents were all more active against C. albicans, C. parapsilosis, C. tropicalis and C. krusei than itraconazole and fluconazole. There was evidence of activity against itraconazole and fluconazole-resistant species.

Cartledge (1999) reported that non-albicans species of candidiasis are associated with fluconazole resistance both in vitro and clinically. A culture test therefore may be used to guide treatment.

Chavanet reported that systematic use of fluconazole as prophylaxis against candidiasis does not increase the incidence of resistance. During two months in 1993 and 1994, oral swabs were taken from 154 and 142 consecutive people with HIV, respectively, for routine mycologic analysis. During the first time period, fluconazole prophylaxis was used routinely, but since then no prophylaxis had been given. There was no significant difference in the proportion of samples that were resistant to fluconazole (9% and 12.9% respectively).

Fichtenbaum enrolled 846 people with CD4 counts below 100 in ACTG 816, and obtained oral cultures every six months in a subset of 250 patients whose median CD4 count was 23. Fluconazole failure, defined as persistent candidiasis despite 14 days treatment with fluconazole at a dose of at least 200 mg/day, occurred at a rate of 3.9% with 682 patient years of follow-up. All patients experiencing fluconazole failure had resistant isolates, and failure was more common among those treated with fluconazole during the previous six months.

Fichtenbaum (2000) further reported on a study of amphotericin B oral suspension for the treatment of fluconazole-resistant oral candidiasis in 54 patients. Treatment was 100 mg/ml, 5 ml swish and swallow, four times daily for 14 days, with an additional 14 days of treatment for incomplete or non-responders. Responders received maintenance amphotericin B twice daily for up to 6 months. 23 people (42.6%) were classified as responders after 28 days while 5 (9%) stopped treatment due to toxicity. Relapse occurred in 16 responders (70%).

Katsonis conducted a retrospective analysis of the efficacy of caspofungin in adults with endoscopically documented oesophagitis from four Phase II and III studies using two definitions of resistance to fluconazole: clinically refractory infection based on failure of oesophageal symptoms to improve despite at least 1 week of >or=200 mg/d of fluconazole; or microbiologically resistant infection with either susceptible dose-dependent or resistant isolates based on MICs of 16 to 32 and >or=64 microg fluconazole/mL, respectively. A favourable response required resolution of all symptoms and substantial improvement in endoscopic findings. Seven of 11 patients (64%) who had been clinically refractory to fluconazole had favourable responses to caspofungin. Eleven of 14 patients (79%) whose isolates had decreased susceptibility to fluconazole had favourable responses to caspofungin, including 5 (83%) of 6 patients infected by isolates with MICs of >or=64 microg fluconazole/mL. Caspofungin appeared to be efficacious therapy for some patients with oesophageal candidiasis who were clinically refractory to fluconazole or infected by with reduced susceptibility to fluconazole in vitro.

Revankar (1998a) treated 57 people with a median CD4 count below 50 who had recurrent oropharyngeal candidiasis with escalating doses of fluconazole in a longitudinal study. Participants were started on 100 mg/day, and told to double the dose up to 800 mg/day at the end of the week until a response was seen. At the 100 mg dose, resolution occurred in 76 of 102 episodes with fluconazole-susceptible cultures, and 18/53 with confirmed fluconazole resistance. Candidiasis resolved in all cases where yeasts were susceptible vs 44 (92%) of 48 episodes with resistant or dose-dependent susceptible strains (p=0.008). Patients with fluconazole-resistant yeasts required longer courses of therapy and higher doses of fluconazole for response.

Revanker (1998b) conducted a prospective, randomized study of 68 people who, after the initial period of treatment for oropharyngeal candidiasis, received either continuous fluconazole (200mg/day) or intermittent fluconazole at the time of relapse. During a mean follow-up of 11 months, median annual relapse rates were lower in patients on continuous therapy (0 episodes/year) than in patients on intermittent therapy (4.1 episodes/year; p<0.001). There was no significant difference in the rate of fluconazole resistance between the two groups (56% vs 46; p=0.75). 42 of 44 patients responded to fluconazole in doses up to 800 mg/day.

Fessel treated 78 people with oral candidiasis who had failed despite at least 14 days' prior fluconazole therapy with itraconazole solution (100 mg twice daily for 14 days). Participants with an incomplete response were treated for a further 14 days. Resolution was seen in 41/75 participants (55%), and clinical improvement in 70% by day 14 or 28. Mean severity of soreness/burning and erythema, and mean extent of lesions was significantly reduced.

Cartledge (1994b) reported a response to itraconazole solution in 16 out of 25 people with oral candidiasis that had previously failed to respond to fluconazole.

Prophylaxis and maintenance

Williams enrolled 164 women in a randomised, placebo controlled study of prophylaxis for candidiasis. Women were randomised to weekly intravaginal application of lactobacillus acidophilus gelatin capsules or clotrimazole tablets or placebo. After a median follow-up time of 21 months, 34 cases of candidiasis occurred. Relative risk of an episode of candidiasis was 0.4 in the clotrimazole arm and 0.5 in the lactobacillus arm versus placebo. Time to first episode of candidiasis was significantly longer in the clotrimazole arm (p<0.03) and in the lactobacillus (p<0.06). Both interventions reduced the number of episodes by half.

Powderly compared the effectiveness of fluconazole (200 mg/day) or clotrimazole troches (10 mg five times daily) as primary prophylaxis against fungal infections in 428 people with advanced HIV infection who were taking part in a trial of PCP prophylaxis. After a median follow-up of 35 months, invasive fungal infections had developed in 4.1% of the fluconazole group and 10.9% of the clotrimazole group. Of the 32 invasive fungal infections, 17 were cryptococcosis (2 in the fluconazole group and 15 in the clotrimazole group). The benefit of fluconazole was greater for people with CD4 counts below 50. Fluconazole was also effective in preventing oesophageal and oropharyngeal candidiasis (5.7 versus 38.1 cases per 100 person-years. Survival was similar in the two groups.

Schuman enrolled 323 HIV-positive women with CD4 counts below 300 or CD4 percentages less than 20% in a placebo-controlled study of fluconazole (200 mg/week) for the prevention of mucosal candidiasis. After a median follow-up of 29 months, fluconazole reduced the risk of oropharyngeal and vaginal candidiasis by 50% and 36% respectively. There was no significant difference in the risk of oesophageal candidiasis. There was no increase in serious adverse events or resistance to fluconazole in the treated group.

Just-Nubling conducted a randomized, open-label study of fluconazole as prophylaxis for recurrent oral candidiasis in HIV-positive people with CD4 counts below 100. 58 evaluable participants received fluconazole either 50 or 100 mg daily (observation time 137-215 days). Compared to untreated controls, fluconazole prophylaxis significantly reduced the frequency of candidiasis relapse. The two fluconazole doses were equally effective. Other studies have shown (Esposito; Stevens) that fluconazole (50-100 mg daily) appears to be effective in preventing recurrence of oral candidiasis in the short term (3-6 months).

Smith (1994) randomised 44 people who had had an episode of oral and/or oesophageal candidiasis successfully treated with itraconazole to receive either maintenance therapy with itraconazole (200 mg/day) or placebo. After 6 months follow-up 68% of the itraconazole recipients remained free of Candida, versus 13% of the placebo group. 2/16 itraconazole recipients discontinued because of possible hepatotoxicity which may not have been drug-related.

Marriott enrolled 84 people in a double-blind, placebo-controlled study of fluconazole as secondary prophylaxis for oral candidiasis. After two to four weeks of therapy with fluconazole, participants were randomized to receive fluconazole (150 mg weekly) or placebo. Of the 73 evaluable participants, the median time to relapse was more than168 days for the fluconazole group and 37 days for the placebo group.

Parente assigned people with AIDS whose oesophageal candidiasis had resolved following treatment either to receive maintenance therapy with fluconazole (50 mg/day) or ketoconazole (200 mg/day) or placebo. During 12 months follow-up, 84% of the placebo group experienced relapses, compared with a cumulative total of 38% of the treatment arms. No significant differences between fluconazole and ketoconazole were observed.

Gripshover reported that there were no recurrences of candidiasis during a median of five months follow-up in 18 out of 20 patients receiving azole maintenance therapy who discontinued after experiencing a mean 134 cell increase in CD4 count during HAART therapy.

Hilton conducted a crossover trial with women with verified episodes of candida vaginitis who were evaluated for 6 months without yoghurt ingestion and for six subsequent months with daily Lactobacillus acidophilus-yoghurt ingestion. 33 women with recurrent candida vaginitis were recruited, but 12 were eliminated for protocol violations, and of the remaining 21, eight who were assigned to the yoghurt arm initially refused to enter the control phase six months later. Thirteen patients completed the protocol. A threefold decrease in infections was seen when patients consumed yoghurt containing Lactobacillus acidophilus. The mean number of infections per 6 months was 2.54 in the control arm and 0.38 in the yoghurt arm. Candida colonisation decreased from a mean of 3.23 per 6 months in the control arm to 0.84 per 6 months in the yoghurt arm.

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