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. 2012 Feb 20;2012:1304.

Candidiasis (oropharyngeal)

Caroline L Pankhurst 1
PMCID: PMC4429411  PMID: 22348417

Abstract

Introduction

Candida is a fungus present in the mouths of up to 60% of healthy people, but overt infection is associated with immunosuppression, diabetes, broad-spectrum antibiotics, and corticosteroid use. In most people, untreated candidiasis persists for months or years unless associated risk factors are treated or eliminated. In neonates, spontaneous cure of oropharyngeal candidiasis usually occurs after 3 to 8 weeks.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent and treat oropharyngeal candidiasis in: adults having treatment causing immunosuppression; infants and children; people with diabetes; people with dentures; and people with HIV infection? Which treatments reduce the risk of acquiring resistance to antifungal drugs? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 51 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: antifungals (absorbed or partially absorbed, and topical absorbed/partially absorbed/non-absorbed: e.g., amphotericin B, clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole, nystatin, posaconazole) used for intermittent or continuous prophylaxis or treatment, and denture hygiene.

Key Points

Opportunistic infection with the fungus Candida albicans causes painful red or white lesions of the oropharynx, which can affect taste, speech, and eating.

  • Candida is present in the mouth of up to 60% of healthy people, but overt infection is associated with immunosuppression, diabetes, broad-spectrum antibiotics, corticosteroid use, haematinic deficiencies, and denture wear.

In people with immunosuppression following cancer treatment, absorbed (ketoconazole, itraconazole, or fluconazole) or partially absorbed antifungal drugs (miconazole, clotrimazole) prevent oropharyngeal candidiasis compared with placebo or non-absorbed antifungal drugs. We don't know whether antifungal treatment is effective in this group.

  • Non-absorbed antifungal drugs (nystatin or amphotericin B) may be no more effective than placebo at preventing candidiasis.

  • We don't know whether antifungal prophylaxis is effective in adults having tissue transplants, as we found few studies.

  • We don't know whether antifungals are effective in preventing or treating oropharyngeal candidiasis in people with diabetes mellitus.

Prophylaxis with fluconazole is more effective than oral nystatin or amphotericin B at preventing candidiasis in immunocompromised infants and children, while treatment with fluconazole and miconazole increases cure rates compared with nystatin in both immunocompromised and immunocompetent infants and children.

Antifungal drugs may increase clinical improvement or cure in people with oropharyngeal candidiasis caused by wearing dentures.

  • We don't know whether denture hygiene or removing dentures at night reduces the risk of developing oropharyngeal candidiasis.

Daily or weekly prophylaxis with fluconazole or itraconazole reduces the incidence of candidiasis in people with HIV infection. Prophylaxis with nystatin may not be effective.

  • Topical treatments with clotrimazole lozenges and miconazole buccal slow-release tablets may be as effective as oral tablets/suspensions of oral antifungals (fluconazole/itraconazole) at reducing symptoms of candidiasis in people with HIV infection.

  • A single dose of fluconazole (750 mg) may be as effective as a 14-day course of fluconazole in reducing symptoms of candidiasis in people with HIV infection.

Continuous prophylaxis with antifungal agents may not increase the risk of developing antifungal resistance compared with intermittent prophylaxis, but it may be no more effective at reducing the number of attacks in people with HIV infection the majority of whom were receiving highly active antiretroviral treatment (HAART).

About this condition

Definition

Oropharyngeal candidiasis is an opportunistic mucosal infection caused, in most cases, by the fungus Candida albicans, but it can be caused by other species such as C glabrata, C tropicalis, and C krusei. The 4 main types of oropharyngeal candidiasis are: (1) pseudomembranous (thrush), consisting of white, curd-like, discrete plaques on an erythematous background, which is exposed after the removal of the plaque, and found on the buccal mucosa, throat, tongue, or gingivae; (2) erythematous, consisting of smooth red patches on the hard or soft palate, dorsum of tongue, or buccal mucosa; (3) hyperplastic, consisting of white, firmly adherent patches or plaques that cannot be removed, usually bilaterally distributed on the buccal mucosa, tongue, or palate; and (4) denture-induced stomatitis, presenting as either a smooth or a granular erythema confined to the denture-bearing area of the hard palate and often associated with an angular cheilitis, which occurs as red, fissured lesions in the corners of the mouth. Symptoms vary, ranging from none to a sore and painful mouth with a burning tongue and altered taste. Oropharyngeal candidiasis can impair speech, nutritional intake, and quality of life. Oropharyngeal candidiasis is the most common oral manifestation of HIV infection. HIV-seropositive people with recurrent oropharyngeal candidiasis have overall lower levels of oral health as measured by a higher decayed, missing, and filled-teeth index; dry mouth; and taste problems.

Incidence/ Prevalence

Candida species are commensals in the gastrointestinal tract. Most infections are endogenously acquired, although infections in neonates can be primary infections. Transmission can also occur directly from infected people or on fomites (objects that can harbour pathogenic organisms). Candida is found in the mouth of 18% to 60% of healthy people in high- and middle-income countries. One cross-sectional study in China (77 HIV-seropositive outpatients and 217 HIV-negative students) found no significant difference in the rates of asymptomatic Candida carriage reported in healthy and HIV-seropositive people (18% of healthy people v 29% of HIV-seropositive people; P = 0.07). Denture stomatitis associated with Candida is prevalent in 65% of denture wearers. Oropharyngeal candidiasis affects between 15% and 60% of people with haematological or oncological malignancies during periods of immunosuppression. The prevalence of oral candidiasis during head and neck radiation therapy is similar to that during chemotherapy. Oropharyngeal candidiasis occurs in 7% to 48% of people with HIV infection and in >90% of those with advanced disease. In severely immunosuppressed people, relapse rates are high (30–50%) and relapse usually occurs within 14 days of stopping treatment.

Aetiology/ Risk factors

Risk factors associated with symptomatic oropharyngeal candidiasis include: local or systemic immunosuppression; haematological disorders; broad-spectrum antibiotic use; inhaled or systemic corticosteroids; xerostomia; diabetes; wearing dentures, obturators, or orthodontic appliances; and smoking. Smoking predisposes to oral carriage of Candida. In one study of 2499 men with HIV and a baseline CD4+ cell count >200 cells/microlitre, smoking increased the risk of pseudomembranous candidiasis by 40% (P less than or equal to 0.01). However, another study (139 people with HIV infection) suggested that smoking was not a risk factor for those with a baseline CD4+ cell count <200 cells/microlitre. The exact mechanism of action by which smoking predisposes to Candida is not known, but it may involve the impairment of local immunity by inducing cytokine changes and reducing epithelial cell-mediated anticandidal activity. The same Candida strain may persist for months or years in the absence of infection. In people with HIV infection, there is no direct correlation between the number of organisms and the presence of clinical disease. Candidal strains causing disease in people with HIV infection seem to be the same as those colonising HIV-negative people, and in most people do not change over time. Symptomatic oropharyngeal candidiasis associated with in-vitro resistance to fluconazole occurs in 5% of people with advanced HIV disease. Resistance to azole antifungal drugs is associated with severe immunosuppression (CD4+ cell count 50 cells/microlitre or less), more episodes treated with antifungal drugs, and longer median duration of systemic azole treatment.

Prognosis

In most people, untreated candidiasis persists for months or years unless associated risk factors are treated or eliminated. In neonates, spontaneous cure of oropharyngeal candidiasis usually occurs after 3 to 8 weeks. Protease inhibitors used in highly active antiretroviral treatment (HAART) regimens in HIV-seropositive people have been shown to directly attenuate the adherence of Candida albicans to epithelial cells in vitro by inhibiting the action of Candida virulence factors.

Aims of intervention

To resolve signs and symptoms of oropharyngeal candidiasis; to prevent or delay relapse in immunocompromised people; to minimise drug-induced resistance, with minimum adverse effects.

Outcomes

Prevention of oral candidiasis: rate of occurrence or recurrence on the basis of scoring of signs and symptoms. Treatment success: cure; clinical cure; resolution of signs and symptoms of oral candidiasis. Many RCTs report the results of mycological culture but, whenever possible, this review does not use these intermediate outcomes because the relation between the clinical and mycological culture findings is uncertain. Adverse effects. For the question on which treatments reduce the risk of acquiring resistance to antifungal drugs, the previously listed outcomes plus mortality and drug-induced resistance to treatment.

Methods

Clinical Evidence search and appraisal August 2011. The following databases were used to identify studies for this systematic review: Medline 1966 to August 2011, Embase 1980 to August 2011, and The Cochrane Database of Systematic Reviews, 2011, Issue 3 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, including open studies, and containing >25 individuals of whom >80% were followed up. We included studies of candidiasis in people with HIV infection no matter what proportion were followed up. There was no minimum length of follow-up required to include studies. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Candidiasis (oropharyngeal).

Important outcomes Drug-induced resistance to treatment, Mortality, Prevention of oral candidiasis, Treatment success
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of interventions to prevent and treat oropharyngeal candidiasis in adults having treatment causing immunosuppression?
7 (1153) Prevention of oral candidiasis Absorbed antifungal drugs versus placebo or no treatment 4 0 0 0 +1 High Effect-size point added for RR <0.5
4 (292) Prevention of oral candidiasis Partially absorbed antifungal drugs versus placebo or no treatment 4 0 0 0 +2 High Effect-size points added for RR <0.2
8 (382) Prevention of oral candidiasis Non-absorbed antifungal drugs versus placebo or no treatment 4 0 –1 –1 0 Low Consistency point deducted for statistical heterogeneity between RCTs. Directness point deducted for use of co-interventions
9 (2120) Prevention of oral candidiasis Absorbed versus non-absorbed antifungal drugs 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (177) Prevention of oral candidiasis Antifungal prophylaxis in people having liver transplant 4 –2 0 –1 0 Very low Quality points deduced for sparse data and incomplete reporting of results. Directness point deducted for small number of comparators
3 (177) Prevention of oral candidiasis Antifungal prophylaxis in people having bone marrow transplant 4 –2 0 –1 0 Very low Quality points deduced for sparse data and incomplete reporting of results. Directness point deducted for poor compliance in 1 RCT
1 (56) Treatment success Antifungal drugs versus placebo 4 –1 0 –1 +1 Moderate Quality point deducted for sparse data. Directness point deducted for unclear definition of outcome. Effect-size point added for RR >2
2 (334) Treatment success Different doses of the same antifungal drug 4 –1 0 –1 0 Low Quality point deducted for methodological weaknesses in some trials (inadequate blinding and allocation concealment). Directness point deducted for unclear definition of outcome
3 (267) Treatment success Absorbed antifungal drugs versus each other 4 0 0 –2 0 Low Directness points deducted for unclear definition of outcome and small number of comparators
3 (207) Treatment success Absorbed versus non-absorbed antifungal drugs 4 0 –1 –1 0 Low Consistency point deducted for heterogeneity among studies. Directness point deducted for inclusion of data from children
What are the effects of interventions to prevent and treat oropharyngeal candidiasis in infants and children?
2 (502) Prevention of oral candidiasis Fluconazole versus oral nystatin or amphotericin B 4 0 0 –2 0 Low Directness points deducted for inclusion of pretreated children in 1 RCT and open label
3 (325) Treatment success Antifungals versus placebo or each other in immunocompetent children 4 0 0 –1 0 Moderate Directness point deducted for low rate of follow-up in 1 RCT
1 (182) Treatment success Antifungals versus placebo or each other in immunocompromised children 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for small number of comparators
What are the effects of interventions to prevent and treat oropharyngeal candidiasis in people with dentures?
3 (120) Treatment success Antifungal treatment versus placebo in people with denture stomatitis 4 –1 0 –2 0 Very low Quality point deducted for sparse data. Directness points deducted for outcomes not defined in 1 RCT, composite in 1 RCT, and proxy outcome in 1 RCT
4 (455) Treatment success Different antifungal treatments versus each other 4 –1 0 –2 0 Very low Quality point deducted for incomplete reporting of results. Directness points deducted for inclusion of non-denture-wearing population, use of non-clinical outcomes, and use of subjective outcomes
2 (74) Treatment success Different modes of administration of antifungal drugs 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for unclear and proxy outcome (palatal erythema)
4 (215) Treatment success Denture hygiene for treating oropharyngeal candidiasis 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for use of co-intervention (nystatin), and non-clinical outcomes in 1 RCT
What are the effects of interventions to prevent and treat oropharyngeal candidiasis in people with HIV infection?
at least 5 (at least 599) Prevention of oral candidiasis Fluconazole versus placebo or no treatment 4 0 0 0 0 High
4 (842) Prevention of oral candidiasis Itraconazole versus placebo 4 –1 0 0 0 Moderate Quality point deducted for early termination of 1 RCT
1 (128) Prevention of oral candidiasis Nystatin versus placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and combination of 2 different doses in same group in analysis
1 (75) Prevention of oral candidiasis Chlorhexidine versus saline 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (428) Prevention of oral candidiasis Fluconazole versus clotrimazole 4 0 0 –1 0 Moderate Directness point deducted for small numbers of comparators
7 (1184) Treatment success Topical antifungal treatment versus oral antifungal treatment 4 0 0 –1 0 Moderate Directness point deducted for inclusion of composite outcome (also including mycological cure)
3 (818) Treatment success Different topical antifungal drugs versus each other 4 0 0 –2 0 Low Directness points deducted for lack of comparators and use of composite outcome in 1 RCT
4 (749) Treatment success Different oral antifungals versus each other 4 0 0 –1 0 Moderate Directness point deducted for composite outcome in 1 RCT
2 (276) Treatment success Different doses of the same oral antifungal drug 4 –1 0 –1 0 Low Quality point deducted for lack of blinding in 1 RCT. Directness point deducted for highly selected population (>35% using HAART in the largest RCT)
Which treatments reduce the risk of acquiring resistance to antifungal drugs?
1 (829) Mortality Intermittent antifungal treatment versus continuous antifungal prophylaxis 4 0 0 –2 0 Low Directness points deducted for highly selected population (majority of people receiving HAART) and low rates of treatment completion
2 (897) Drug-induced resistance to treatment Intermittent antifungal treatment versus continuous antifungal prophylaxis 4 0 0 –2 0 Low Directness points deducted for highly selected population (majority of people receiving HAART) and low rates of treatment completion
2 (891) Prevention of oral candidiasis Intermittent antifungal treatment versus continuous antifungal prophylaxis 4 0 –1 –2 0 Very low Consistency point deducted for heterogeneity between RCTs. Directness points deducted for highly selected population (majority of people receiving HAART) and low rates of treatment completion
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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Highly active antiretroviral treatment (HAART)

Combination drug treatment used to achieve maximal suppression of HIV replication.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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BMJ Clin Evid. 2012 Feb 20;2012:1304.

Antifungal prophylaxis in adults having chemotherapy or radiotherapy

Summary

In people with immunosuppression following cancer treatment, absorbed (ketoconazole, itraconazole, or fluconazole) or partially absorbed antifungal drugs (miconazole, clotrimazole) prevent oropharyngeal candidiasis compared with placebo or non-absorbed antifungal drugs.

Non-absorbed antifungal drugs (nystatin or amphotericin B) may be no more effective than placebo at preventing candidiasis.

Benefits and harms

Absorbed antifungal drugs versus placebo or no treatment:

We found one systematic review (search date 2009, 28 RCTs, 4226 people), which grouped antifungal drugs according to gastrointestinal absorption characteristics into: absorbed drugs (ketoconazole, itraconazole, or fluconazole), partially absorbed drugs (miconazole, clotrimazole), and non-absorbed drugs (nystatin, amphotericin B).

Prevention of oral candidiasis

Compared with placebo or no treatment Absorbed antifungal drugs (ketoconazole, itraconazole, fluconazole) are more effective at reducing the proportion of people who develop oral candidiasis at 2 to 10 weeks in people having chemotherapy or radiotherapy for cancer (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oral candidiasis

Systematic review		 1153 people having chemotherapy or radiotherapy for cancer
7 RCTs in this analysis		 Oral candidiasis 2 to 10 weeks
39/575 (7%) with absorbed antifungal drugs (ketoconazole, itraconazole, or fluconazole)
81/578 (14%) with placebo
RR 0.47
95% CI 0.29 to 0.78 		Moderate effect size absorbed antifungal drugs (ketoconazole, itraconazole, or fluconazole)
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 871 people having chemotherapy or radiotherapy for cancer
3 RCTs in this analysis		 Adverse effects
62/437 (14%) with absorbed antifungal drugs (ketoconazole, itraconazole, or fluconazole)
52/434 (12%) with placebo
RR 1.18
95% CI 0.84 to 1.67 		Not significant
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Partially absorbed antifungal drugs versus placebo or no treatment:

We found one systematic review (search date 2009, 28 RCTs, 4226 people having chemotherapy or radiotherapy for cancer).

Prevention of oral candidiasis

Compared with placebo or no treatment Partially absorbed antifungal drugs (miconazole, clotrimazole) are more effective at reducing the proportion of people who develop oral candidiasis at 3 to 8 weeks in people having chemotherapy or radiotherapy for cancer (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oral candidiasis

Systematic review		 292 people having chemotherapy or radiotherapy for cancer
4 RCTs in this analysis		 Oral candidiasis 3 to 8 weeks
7/147 (5%) with partially absorbed antifungal drugs (miconazole or clotrimazole)
53/145 (37%) with placebo or no treatment
RR 0.13
95% CI 0.06 to 0.46 		Large effect size partially absorbed antifungal drugs (miconazole or clotrimazole)
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Adverse effects

No data from the following reference on this outcome.

Non-absorbed antifungal drugs versus placebo or no treatment:

We found one systematic review (search date 2009, 28 RCTs, 4226 people having chemotherapy or radiotherapy for cancer).

Prevention of oral candidiasis

Compared with placebo or no treatment We don't know whether non-absorbed antifungal drugs are more effective at reducing the proportion of people who develop oral candidiasis at 3 to 52 weeks in people having chemotherapy or radiotherapy for cancer (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oral candidiasis

Systematic review		 382 people having chemotherapy or radiotherapy for cancer
8 RCTs in this analysis		 Oral candidiasis 3 to 52 weeks
85/216 (39%) with non-absorbed antifungal drugs
101/166 (61%) with placebo or no treatment
RR 0.68
95% CI 0.46 to 1.02 		Not significant
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Absorbed versus non-absorbed antifungal drugs:

We found one systematic review (search date 2009, 28 RCTs, 4226 people having chemotherapy or radiotherapy for cancer), comparing absorbed antifungal drugs (ketoconazole, itraconazole, or fluconazole) versus non-absorbed antifungal drugs (nystatin alone, amphotericin B alone, or amphotericin B plus nystatin), and one subsequent RCT (106 adults with haematological malignancies and neutropenia), comparing itraconazole solution (5 mg/kg twice daily) versus non-absorbed amphotericin B solution (1000 mg 3 times daily).

Prevention of oral candidiasis

Absorbed compared with non-absorbed antifungal drugs Absorbed antifungal drugs (ketoconazole, itraconazole, fluconazole) seem more effective than non-absorbed antifungal drugs (nystatin, amphotericin B, amphotericin B plus nystatin) at reducing the proportion of people who develop oral candidiasis at 3 to 12 weeks (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oral candidiasis

Systematic review		 2014 people having chemotherapy or radiotherapy for cancer
8 RCTs in this analysis		 Oral candidiasis 3 to 12 weeks
30/1059 (3%) with absorbed antifungal drugs (ketoconazole, itraconazole, or fluconazole)
81/1044 (8%) with non-absorbed antifungal drugs (nystatin alone, amphotericin B alone, or amphotericin B plus nystatin)
RR 0.40
95% CI 0.21 to 0.76
Significant statistical heterogeneity among RCTs; see further information on studies for full details 		Moderate effect size absorbed antifungal drugs (ketoconazole, itraconazole, or fluconazole)

RCT		 106 adults with haematological malignancies and neutropenia Candida colonisation rate in the oropharynx treatments given until neutropenia had resolved
20% with itraconazole solution (5 mg/kg twice daily)
41% with non-absorbed amphotericin B solution (1000 mg 3 times daily)
Absolute numbers not reported
P <0.05 		Effect size not calculated itraconazole solution

RCT		 106 adults with haematological malignancies and neutropenia Clinical oropharyngeal candidiasis with positive cultures treatments given until neutropenia had resolved
2% with itraconazole solution (5 mg/kg twice daily)
8% with non-absorbed amphotericin B solution (1000 mg 3 times daily)
Absolute numbers not reported
Significance not assessed
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 2018 people having chemotherapy or radiotherapy for cancer
6 RCTs in this analysis		 Adverse effects
67/1011 (6.6%) with absorbed antifungal drugs (ketoconazole, itraconazole, or fluconazole)
67/1007 (6.7%) with non-absorbed antifungal drugs (nystatin alone, amphotericin B alone, or amphotericin B plus nystatin)
RR 0.88
95% CI 0.33 to 2.30 		Not significant
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No data from the following reference on this outcome.

Further information on studies

For the comparison of non-absorbed antifungal drugs versus placebo or no treatment, the review found significant heterogeneity in the included RCTs (P <0.001) because of the wide range of drugs and combinations assessed. For all comparisons, adverse effects were documented in 13 of the 28 trials in the review, and ranged from 0% to 18%. However, few data were reported by the RCTs on the nature and severity of the adverse effects. None of the RCTs included in the review gave information on general wellbeing or quality of life in people having antifungal prophylaxis. For the comparison of partially absorbed antifungal drugs versus placebo or no treatment, two of the RCTs identified by the review (60 people) reported no treatment-related adverse effects. For the comparison of non-absorbed antifungal drugs versus placebo or no treatment, the RCTs identified by the review gave no information on harms.

The RCT comparing itraconazole solution versus non-absorbed amphotericin B solution reported that a power calculation suggested that 80 people would be needed in each group. However, the RCT did not meet this recruitment target.

Comment

Topical preparations of amphotericin B are no longer available in the UK.

Substantive changes

Antifungal prophylaxis in adults having chemotherapy or radiotherapy One systematic review updated, no new data added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2012 Feb 20;2012:1304.

Antifungal prophylaxis in adults having tissue transplants

Summary

We don't know whether antifungal prophylaxis is effective in adults having tissue transplants, as we found few studies.

Benefits and harms

Antifungal prophylaxis in people having liver transplant:

We found no systematic review of antifungal prophylaxis specifically for the prevention or treatment of oropharyngeal candidiasis in people having liver transplants. We found two small RCTs in people having liver transplants, comparing the abilities of different antifungal drugs to prevent oropharyngeal candidiasis.

Prevention of oral candidiasis

Different types of antifungal prophylaxis compared with placebo or each other in people having liver transplant We don't know whether different regimens of antifungal prophylaxis differ in their effectiveness at preventing oral candidiasis in people having liver transplants (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oral candidiasis

RCT		 143 people having liver transplants Oropharyngeal candidiasis 28 days
8/76 (11%) with fluconazole
14/67 (21%) with nystatin
Significance not assessed
The RCT may have lacked power to detect a clinically important difference between groups

RCT		 34 people having liver transplants Oropharyngeal candidiasis during hospital stay after transplantation
1/17 (6%) with clotrimazole
1/17 (6%) with nystatin
Significance not assessed
The RCT may have lacked power to detect a clinically important difference between groups
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Adverse effects

No data from the following reference on this outcome.

Antifungal prophylaxis in people having bone marrow transplant:

We found no systematic review. We found three RCTs in people with neutropenia who had received bone marrow transplants.

Prevention of oral candidiasis

Different types of antifungal prophylaxis compared with placebo or each other in people having bone marrow transplant Chlorhexidine may be more effective than placebo at reducing the proportion of people with oral candidiasis at 60 days in people with neutropenia who received bone marrow transplants, but we don't know if different regimens of antifungal prophylaxis differ in their effectiveness at preventing oral candidiasis (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oropharyngeal candidiasis

RCT		 51 people with neutropenia who had received bone marrow transplants Oropharyngeal candidiasis 60 days
2/24 (8%) with chlorhexidine
15/27 (56%) with placebo
ARR 47%
95% CI 24% to 54%
RR 0.15
95% CI 0.03 to 0.57
NNT 2
95% CI 2 to 4 		Large effect size chlorhexidine

RCT
4-armed trial 		86 adults with leukaemia and bone marrow transplant Oropharyngeal candidiasis
with rinse containing saline alone
with rinse containing chlorhexidine
with rinse containing nystatin alone
with rinse containing nystatin plus chlorhexidine
Absolute results not reported
Significance not assessed
The RCT was not powered to detect a clinically important difference between groups

RCT		 40 people with a variety of malignancies including lymphoma, breast cancer, multiple myeloma, and testicular cancer, who had neutropenia and who had received bone marrow transplants Clinical signs of oropharyngeal candidiasis
4/20 (20%) with adding topical amphotericin B 500 mg suspension
8/19 (42%) with adding nystatin suspension 400,000 IU four times daily
P = 0.18
Results may have been affected by compliance: see further information on studies 		Not significant

RCT		 40 people with a variety of malignancies including lymphoma, breast cancer, multiple myeloma, and testicular cancer, who had neutropenia and who had received bone marrow transplants Oral colonisation by Candida species
4/20 (20%) with adding topical amphotericin B 500 mg suspension
5/19 (26%) with adding nystatin suspension 400,000 IU four times daily
P = 0.72
Results may have been affected by compliance: see further information on studies 		Not significant
Open in a new tab

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 40 people with a variety of malignancies including lymphoma, breast cancer, multiple myeloma, and testicular cancer, who had neutropenia and who had received bone marrow transplants Nausea
16/20 (80%) with adding topical amphotericin B 500 mg suspension
17/20 (85%) with adding nystatin suspension 400,000 IU four times daily
P = 1.00 		Not significant

RCT		 40 people with a variety of malignancies including lymphoma, breast cancer, multiple myeloma, and testicular cancer, who had neutropenia and who had received bone marrow transplants Vomiting
13/20 (65%) with adding topical amphotericin B 500 mg suspension
11/20 (55%) with adding nystatin suspension 400,000 IU four times daily
P = 0.75 		Not significant

RCT		 40 people with a variety of malignancies including lymphoma, breast cancer, multiple myeloma, and testicular cancer, who had neutropenia and who had received bone marrow transplants Diarrhoea
6/20 (30%) with adding topical amphotericin B 500 mg suspension
5/20 (25%) with adding nystatin suspension 400,000 IU four times daily
P = 1.00 		Not significant
Open in a new tab

No data from the following reference on this outcome.

Further information on studies

Antifungal prophylaxis in people having liver transplant The RCT found no increased hepatotoxicity, ciclosporin interaction, or emergence of clinically relevant resistant strains reported in people taking antifungal prophylaxis after liver transplantation. However, again, the RCT may have lacked power to detect clinically important increases in adverse effects.

Antifungal prophylaxis in people having bone marrow transplant In the third RCT, significantly fewer people taking amphotericin B than nystatin completed the trial (3/20 [15%] with amphotericin B v 10/20 [50%] with nystatin; P = 0.04). The difference in trial completion was primarily because of lack of patient compliance with amphotericin B, which was related to its texture (viscosity) and taste.

Comment

Antifungal prophylaxis in people having liver transplant:

We found one systematic review (search date 2004, 6 RCTs, including 1 RCT described in the benefits section above) comparing systemic antifungal prophylaxis versus control (placebo, no treatment, or oral non-absorbable antifungal treatments such as nystatin) in people having a liver transplant. The systematic review did not distinguish between superficial oral infections and superficial infections at other sites (skin, vagina, gastrointestinal tract, or urinary tract), or distinguish between different types of fungal infection. It found that antifungal prophylaxis reduced superficial fungal infections compared with control (5 RCTs, 679 people; AR: 5.2% with antifungal prophylaxis v 19.1% with control; RR 0.27, 95% CI 0.16 to 0.45). It is not clear whether this result is generalisable to oropharyngeal candidiasis.

Substantive changes

No new evidence

BMJ Clin Evid. 2012 Feb 20;2012:1304.

Antifungal treatment in adults having chemotherapy or radiotherapy

Summary

We don't know whether antifungal treatment is effective in people with immunosuppression following cancer treatment.

Benefits and harms

Antifungal drugs versus placebo:

We found one systematic review (search date 2010, 10 RCTs, 940 people with cancer having chemotherapy, radiotherapy, or both).

Treatment success

Antifungal drugs compared with placebo Ketoconazole seems more effective at reducing the proportion of people with oral candidiasis at 14 days in people who have had chemotherapy, radiotherapy, or both for cancer (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Eradication of oral candidiasis

Systematic review		 56 people with cancer having chemotherapy, radiotherapy, or both
Data from 1 RCT		 Proportion of people with eradication of oral candidiasis 14 days
26/36 (72%) with ketoconazole
4/20 (20%) with placebo
RR 3.61
95% CI 1.47 to 8.88
P = 0.0052 		Moderate effect size ketoconazole
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Different doses of the same antifungal drug:

We found one systematic review (search date 2010, 10 RCTs, 940 people with cancer having chemotherapy, radiotherapy, or both).

Treatment success

Different doses of the same antifungal drug compared with each other We don't know whether different doses of clotrimazole differ in their effectiveness at increasing clinical cure rates in people who have had chemotherapy, radiotherapy, or both for cancer. A lower-dose mucoadhesive buccal tablet of the partially absorbed drug miconazole may be as effective as a higher dose of miconazole gel (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Persistence of oral candidiasis

Systematic review		 52 people with cancer having chemotherapy, radiotherapy, or both
Data from 1 RCT		 Proportion of people with persistence of oral candidiasis
1/26 (4%) with clotrimazole 50 mg lozenge
1/26 (4%) with clotrimazole 10 mg lozenge
RR 1.00
95% CI 0.07 to 15.15 		Not significant

Systematic review		 282 people with head and neck cancer having chemotherapy or radiotherapy
Data from 1 RCT		 Proportion of people with persistence of oral candidiasis
74/141 (52%) with miconazole mucoadhesive buccal tablets (50 mg)
64/141 (45%) with miconazole gel (125 mg applied 4 times daily)
RR 1.16
95% CI 0.91 to 1.47 		Not significant
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Absorbed antifungal drugs versus each other:

We found one systematic review (search date 2010, 10 RCTs, 940 people with cancer having chemotherapy, radiotherapy, or both).

Treatment success

Absorbed antifungal drugs compared with each other We don't know whether fluconazole, ketoconazole, and itraconazole differ in their effectiveness at increasing clinical cure rates in people who have had chemotherapy, radiotherapy, or both for cancer (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Clinically assessed cure

Systematic review		 293 people with cancer having chemotherapy, radiotherapy, or both
2 RCTs in this analysis		 Clinically assessed cure 6 weeks
118/149 (79%) with fluconazole
100/144 (69%) with itraconazole
RR 1.13
95% CI 1.00 to 1.28 		Not significant

Systematic review		 267 people with cancer having chemotherapy, radiotherapy, or both
Data from 1 RCT		 Clinically assessed cure 4 to 27 days
15/19 (79%) with fluconazole
14/18 (78%) with ketoconazole
RR 1.02
95% CI 0.72 to 1.42 		Not significant
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Absorbed versus non-absorbed antifungal drugs:

We found one systematic review (search date 2010, 10 RCTs, 940 people with cancer having chemotherapy, radiotherapy, or both). The review identified three RCTs comparing absorbed and non-absorbed antifungal drugs. The review reported significant heterogeneity among the RCTs. The first RCT identified by the review (186 people) assessed immunocompromised children and is not reported individually here (see antifungal treatment in immunocompetent or immunocompromised infants and children). However, this RCT is included in the meta-analysis performed by the review.

Treatment success

Absorbed antifungal drugs compared with non-absorbed antifungal drugs Antifungal drugs absorbed from the GI tract may be more effective at increasing clinical cure rates in people who have had chemotherapy, radiotherapy, or both for cancer (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Clinically assessed cure rates

Systematic review		 207 people (including children)
3 RCTs in this analysis		 Proportion of people with eradication of oral candidiasis
89/105 (85%) with absorbed drugs (fluconazole/ketoconazole)
67/102 (66%) with non-absorbed drugs (amphotericin/nystatin)
RR 1.29
95% CI 1.09 to 1.52
P = 0.0026 		Small effect size absorbed drugs (fluconazole/ketoconazole)
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Further information on studies

Given the heterogeneity of the three RCTs included in the meta-analysis of absorbed versus non-absorbed antifungal drugs, the results may not be robust. The review reported inadequate blinding and allocation concealment in most of the included trials.

Comment

In assessing outcomes, the review noted that few RCTs described the clinical criteria used. The review concluded that there were insufficient trials to make strong recommendations for patient care, and that further well-designed, placebo-controlled trials were needed to assess the effectiveness of old and new interventions for treating oral candidiasis.

Substantive changes

Antifungal treatment in adults having chemotherapy or radiotherapy One systematic review updated. New data added. Categorisation unchanged (Unknown effectiveness), as there remains insufficient evidence to judge the effectiveness of this intervention.

BMJ Clin Evid. 2012 Feb 20;2012:1304.

Antifungal prophylaxis in immunocompromised infants and children

Summary

Prophylaxis with fluconazole is more effective than oral nystatin or amphotericin B at preventing candidiasis in immunocompromised infants and children.

Benefits and harms

Fluconazole versus oral nystatin or amphotericin B:

We found no systematic review. We found no placebo-controlled RCTs, but found two RCTs comparing antifungal drugs with each other for prevention of oropharyngeal candidiasis.

Prevention of oral candidiasis

Different antifungal regimens compared with each other Antifungal prophylaxis with fluconazole may be more effective than oral polyenes (nystatin, oral amphotericin B, or both) at preventing candidiasis in immunocompromised infants and children aged 6 months to 17 years, about to have initial or repeat courses of chemotherapy or radiotherapy for haematological or oncological malignancies (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Incidence of oropharyngeal candidiasis

RCT		 502 immunocompromised infants and children aged 6 months to 17 years, about to have initial or repeat courses of chemotherapy or radiotherapy for haematological or oncological malignancies Incidence of oropharyngeal candidiasis
3/236 (1%) with fluconazole
15/249 (6%) with oral polyenes (nystatin, oral amphotericin B, or both)
RR 0.21
95% CI 0.06 to 0.72
NNT 21
95% CI 18 to 58 		Moderate effect size fluconazole

RCT		 50 immunocompromised children
Subgroup analysis		 Incidence of oropharyngeal candidiasis
2/25 (8%) with fluconazole
3/25 (12%) with nystatin
P = 0.63 		Not significant
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Adverse effects

No data from the following reference on this outcome.

Further information on studies

In the RCT, adverse events caused 8/245 (3%) children on fluconazole to withdraw compared with 3/257 (1%) on oral polyenes.

Eighteen of the children from one multicentre RCT were enrolled in this small RCT. The inclusion of pretreated children may have biased results, and the study may have lacked power to detect clinically important differences. In the second RCT, no children were withdrawn from the study, but three children treated with fluconazole reported nausea and abdominal discomfort and one reported pruritus.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2012 Feb 20;2012:1304.

Antifungal treatment in immunocompetent or immunocompromised infants and children

Summary

Treatment with fluconazole and miconazole increases cure rates compared with nystatin in both immunocompromised and immunocompetent infants and children.

Benefits and harms

Antifungals versus placebo or each other in immunocompetent children:

We found no systematic review or placebo-controlled RCTs. We found two RCTs in immunocompetent infants with oropharyngeal candidiasis comparing miconazole gel, nystatin suspension, and nystatin gel. We found one RCT comparing fluconazole versus nystatin.

Treatment success

Antifungal treatments compared with placebo or each other in immunocompetent infants and children Both miconazole and fluconazole seem more effective than nystatin at increasing rates of clinical cure of oral candidiasis in immunocompetent infants (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Cure of oral candidiasis

RCT		 183 infants aged <1 year with signs of oropharyngeal candidiasis Cure rate 5 days
83/98 (85%) with miconazole gel (25 mg 4 times daily)
18/85 (21%) with nystatin (100,000 units 4 times daily)
P <0.0001 		Effect size not calculated miconazole gel (25 mg 4 times daily)

RCT		 183 infants aged <1 year with signs of oropharyngeal candidiasis Cure rate 12 days
97/98 (99%) with miconazole gel (25 mg 4 times daily)
46/85 (54%) with nystatin (100,000 units 4 times daily)
P <0.0001 		Effect size not calculated miconazole gel (25 mg 4 times daily)

RCT		 95 infants, mean age 5 months, range 2 to 17 months, with clinical oral thrush Clinical cure 14 days
with miconazole gel
with nystatin gel preparation
Absolute results not reported
P = 0.0032
Miconazole gel also significantly improved cure rate versus another brand of nystatin gel (P = 0.00068) 		Effect size not calculated miconazole gel

RCT		 47 infants, aged 1 to 12 months, with clinical signs of oral candidiasis and culture positive for Candida species Clinical cure
15/15 (100%) with fluconazole (suspension 3 mg/kg once daily for 7 days)
6/19 (32%) with nystatin (oral suspension 100,000 IU/mL 4 times daily for 10 days)
Absolute results not reported
P <0.0001 		Effect size not calculated fluconazole (suspension 3 mg/kg once daily for 7 days)
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Adverse effects

No data from the following reference on this outcome.

Antifungals versus placebo or each other in immunocompromised children:

We found no systematic review or placebo-controlled RCTs. We found one multicentre RCT (32 centres, 182 immunocompromised infants and children, aged 5 months to 14 years) comparing fluconazole suspension 3 mg/kg versus nystatin 400,000 units 4 times daily for 14 days.

Treatment success

Antifungal treatments compared with placebo or each other in immunocompromised infants and children Fluconazole may be more effective than nystatin at increasing rates of clinical cure in immunocompromised infants and children aged 5 months to 14 years (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Cure of oral candidiasis

RCT		 182 immunocompromised infants and children, aged 5 months to 14 years Clinical cure rate 14 days
78/86 (91%) with fluconazole suspension 3 mg/kg for 14 days
37/73 (51%) with nystatin 400,000 units 4 times daily for 14 days
RR 1.8
95% CI 1.6 to 1.9
NNT 2
95% CI 2 to 3 		Small effect size fluconazole suspension 3 mg/kg

RCT		 64 children with HIV infection
Subgroup analysis		 Clinical cure rate 14 days
28/35 (80%) with fluconazole suspension 3 mg/kg for 14 days
6/29 (21%) with nystatin 400,000 units 4 times daily for 14 days
P <0.001 		Effect size not calculated fluconazole suspension 3 mg/kg

RCT		 92 children with malignancy
Subgroup analysis		 Clinical cure rate 14 days
49/50 (98%) with fluconazole suspension 3 mg/kg for 14 days
30/42 (71%) with nystatin 400,000 units 4 times daily for 14 days
P = 0.001 		Effect size not calculated fluconazole suspension 3 mg/kg

RCT		 182 immunocompromised infants and children, aged 5 months to 14 years Clinical relapse rate 14 days after clinical cure
18% with fluconazole suspension 3 mg/kg for 14 days
24% with nystatin 400,000 units 4 times daily for 14 days
Absolute numbers not reported
Significance not assessed
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Adverse effects

No data from the following reference on this outcome.

Further information on studies

Immunocompromised infants and children Adverse events caused 2/94 (2%) children on fluconazole to withdraw compared with 0/88 (0%) children on nystatin (P = 0.04).

Immunocompetent infants and children The most common adverse events with both miconazole and nystatin were vomiting and, more rarely, diarrhoea, affecting <4.5% of infants.

Immunocompetent infants and children As above, the most common adverse events with both miconazole and nystatin were vomiting and, more rarely, diarrhoea, affecting <4.5% of infants.

Comment

Immunocompetent infants and children:

The RCTs were not blinded or placebo-controlled. There is potential for observer bias, but the clinical results were corroborated by mycological findings, which were blinded. The larger RCT was carried out in 26 general practices, and so it is representative of the context in which most otherwise healthy infants with oropharyngeal candidiasis would be treated, especially regarding adherence and cure rate.

Immunocompromised infants and children:

Participants included in the RCT were immunocompromised for different reasons: 64 had HIV infection, 92 had a malignancy, and 26 were taking immunosuppressive treatment.

Substantive changes

No new evidence

BMJ Clin Evid. 2012 Feb 20;2012:1304.

Antifungal prophylaxis or treatment in people with diabetes mellitus

Summary

We don't know whether antifungals are effective in preventing or treating oropharyngeal candidiasis in people with diabetes mellitus as we found no trials.

Benefits and harms

Antifungal prophylaxis:

We found no systematic review or RCTs assessing the prevention or treatment of oropharyngeal candidiasis in people with diabetes.

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2012 Feb 20;2012:1304.

Antifungal prophylaxis or treatment in people with dentures

Summary

Antifungal drugs may increase clinical improvement or cure in people with oropharyngeal candidiasis caused by wearing dentures.

We found no clinically important results from RCTs about antifungal prophylaxis in people with dentures.

Benefits and harms

Antifungal prophylaxis in people with dentures:

We found no systematic review or RCTs.

Antifungal treatment versus placebo in people with denture stomatitis:

We found no systematic review. We found three small RCTs comparing topical antifungal drugs versus placebo for the treatment of denture stomatitis.

Treatment success

Antifungal treatment compared with placebo Topical fluconazole may be more effective than placebo at increasing the proportion of people with the composite outcome of clinical improvement or cure at 2 and 4 weeks, and topical nystatin and amphotericin B may be more effective than placebo at increasing clinical cure of denture stomatitis (outcome not further defined) in people with denture stomatitis. We don't know whether miconazole dental lacquer (applied to the denture) is more effective than placebo lacquer at improving palatal symptoms (not further defined) at 14 days in people with denture stomatitis (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Treatment success

RCT		 46 people with denture stomatitis Clinical cure of denture stomatitis after 4 weeks' treatment
with nystatin
with placebo
Absolute results not reported
P less than or equal to 0.05 		Effect size not calculated nystatin

RCT		 46 people with denture stomatitis Clinical cure of denture stomatitis after 4 weeks' treatment
with amphotericin B
with placebo
Absolute results not reported
P less than or equal to 0.01 		Effect size not calculated amphotericin B

RCT		 36 people with denture stomatitis Resolution of palatal symptoms 14 days
54% with miconazole dental lacquer (applied to the fit surface of an upper denture as a single application)
23% with placebo lacquer
Absolute numbers not reported
RR 2.40
95% CI 0.89 to 3.80 		Not significant

RCT		 38 people with denture stomatitis Clinical improvement or cure rates 2 weeks
10/19 (53%) with fluconazole
0/18 (0%) with placebo
P <0.001 		Effect size not calculated fluconazole

RCT		 38 people with denture stomatitis Clinical improvement or cure rates 4 weeks
5/19 (26%) with fluconazole
0/19 (0%) with placebo
P <0.02 		Effect size not calculated fluconazole
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Adverse effects

No data from the following reference on this outcome.

Different antifungal treatments versus each other:

We found no systematic review. We found 4 RCTs.

Treatment success

Different antifungal treatments compared with each other We don't know whether antifungal treatments differ in their effectiveness at improving cure rates, clinical response rates, or signs and symptoms (including mycological clearance rates) in people with dentures (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Treatment success

RCT		 29 people with denture stomatitis Clinical cure rate
84% with fluconazole 50 mg daily for 14 days
90% with amphotericin B lozenges plus denture cream for 28 days
Absolute numbers not reported
Significance not assessed

RCT		 305 older people with oropharyngeal candidiasis, 176 with dentures Clinical cure
with fluconazole 50 mg
with amphotericin B 0.5 g
Absolute results not reported
Significance not assessed

RCT
3-armed trial 		61 people with oral candidiasis associated with denture stomatitis Candida albicans counts in saliva 14 days
with fluconazole capsules 50 mg once daily
with hexetidine used as a denture rinse 0.1% twice daily
with combination of fluconazole capsules 50 mg once daily plus hexetidine denture rinse 0.1% twice daily
Absolute results not reported
P = 0.60 for among-group comparison 		Not significant

RCT
3-armed trial 		61 people with oral candidiasis associated with denture stomatitis Proportion of people with no C albicans detected in lesion swab 14 days
17/21 (81%) with fluconazole capsules 50 mg once daily
13/18 (72%) with hexetidine used as a denture rinse 0.1% twice daily
14/22 (64%) with combination of fluconazole capsules 50 mg once daily plus hexetidine denture rinse 0.1% twice daily
P = 0.44 for among-group comparison 		Not significant

RCT
3-armed trial 		61 people with oral candidiasis associated with denture stomatitis Proportion of people with no C albicans detected in denture swab 14 days
15/21 (71%) with fluconazole capsules 50 mg once daily
13/18 (72%) with hexetidine used as a denture rinse 0.1% twice daily
18/22 (82%) with combination of fluconazole capsules 50 mg once daily plus hexetidine denture rinse 0.1% twice daily
P = 0.68 for among-group comparison 		Not significant

RCT		 60 people with dentures and mycologically confirmed oropharyngeal candidiasis The proportion of people with "satisfactory" or "regular" clinical response (measured on a 3-point scale of "satisfactory", "regular", or "unsatisfactory") 15 days
27/30 (90%) with miconazole gel applied 3 times daily
21/30 (70%) with a gel extract of pomegranate (Punica granatum Linné) applied 3 times daily
P <0.01 		Effect size not calculated miconazole
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 305 older people with oropharyngeal candidiasis, 176 with dentures Adverse events (including diarrhoea, buccal bitterness, aggravation of pre-existing renal dysfunction, and increased liver transaminases)
6/150 (4%) with fluconazole 50 mg
0/155 (0%) with amphotericin B 0.5 g
Significance not assessed
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No data from the following reference on this outcome.

Different modes of administration of antifungal drugs:

We found no systematic review. Two RCTs (41 people and 33 people) compared a single application of miconazole dental lacquer versus miconazole gel 2% applied to the denture 4 times daily.

Treatment success

Different modes of administration of antifungal drugs compared with each other We don't know whether miconazole dental lacquer applied to the denture is more effective than miconazole gel applied to the denture at improving palatal erythema (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Treatment success

RCT		 41 people Palatal erythema 14 days after treatment
13/20 (65%) with single application of miconazole dental lacquer
16/21 (76%) with miconazole gel 2% applied to the denture 4 times daily
RR 0.85
95% CI 0.42 to 1.20 		Not significant

RCT		 33 older people Palatal erythema
with single application of miconazole dental lacquer
with miconazole gel 2% applied to the denture 4 times daily
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
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Adverse effects

No data from the following reference on this outcome.

Further information on studies

The RCT, which exclusively enrolled people with dentures, was not large enough to report reliably on adverse effects.

The RCT, which exclusively enrolled people with dentures, was not large enough to report reliably on adverse effects.

The RCT, which exclusively enrolled people with dentures, was not large enough to report reliably on adverse effects.

Clinical relapse was common in both groups (fluconazole 50 mg daily for 14 days and amphotericin B lozenges plus denture cream for 28 days) at 12 weeks. The RCT, which exclusively enrolled people with dentures, was not large enough to report reliably on adverse effects.

Wearing dentures did not affect the response to antifungal treatment (fluconazole 50 mg or amphotericin B 0.5 g) (clinical cure rate: 151/176 [86%] of denture wearers v 102/124 [82%] of non-denture wearers; P value not reported). One person had aggravation of pre-existing renal dysfunction, and withdrew from the RCT. One person had increased liver transaminases, but was not withdrawn from the RCT.

The RCT, which exclusively enrolled people with dentures, was not large enough to report reliably on adverse effects.

The RCT comparing miconazole versus extract of pomegranate found that all people receiving miconazole reported adverse effects (most commonly nausea and gastric disorders), whereas there were no adverse effects of treatment with pomegranate extract. The RCT was not large enough to report reliably on adverse effects.

The RCT, which exclusively enrolled people with dentures, was not large enough to report reliably on adverse effects.

The RCT, which exclusively enrolled people with dentures, was not large enough to report reliably on adverse effects.

Comment

Co-interventions included professional cleaning of the dentures at the start of the study, combined with advice on denture hygiene and advice not to wear the dentures while asleep at night. Because the fit surface of the denture may act as a reservoir of primary and recurrent infection, this cleaning and advice may explain the high clinical cure rate in the placebo groups. The RCTs comparing different antifungal drugs were not sufficiently powered to detect clinically important differences between treatments.

Substantive changes

No new evidence

BMJ Clin Evid. 2012 Feb 20;2012:1304.

Denture hygiene

Summary

We found limited evidence that mouth rinsing three times daily plus denture soaking once daily using an antimicrobial mouth rinse (not specified) may be more effective than the same procedure using a control mouth rinse (not specified) at reducing symptoms of denture stomatitis (outcome not further defined) in people with mild to moderate denture stomatitis.

We don't know whether denture hygiene or removing dentures at night reduces the risk of developing oropharyngeal candidiasis.

Benefits and harms

Denture hygiene for preventing oropharyngeal candidiasis:

We found one systematic review assessing interventions for cleaning dentures in adults, which included 6 RCTs; however, none of the interventions used prevention or treatment of oropharyngeal candidiasis as an outcome measure.

Denture hygiene for treating oropharyngeal candidiasis:

We found no systematic review, but found 4 RCTs.

Treatment success

Denture hygiene regimens for treating oral candidiasis compared with placebo or each other Mouth rinsing three times daily plus denture soaking once daily using an antimicrobial mouth rinse (not specified) may be more effective than the same procedure using a control mouth rinse (not specified) at reducing symptoms of denture stomatitis (outcome not further defined) in people with mild to moderate denture stomatitis; we found insufficient evidence on other regimens compared with placebo or each other (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Treatment success

RCT		 43 people, aged 35 to 73 years with denture stomatitis Stomatitis 4 weeks
with daily soaking of dentures in disinfectant (potassium persulphate 1%)
with daily soaking of dentures in placebo (water, peppermint, or dye)
Absolute results not reported
Significance not assessed

RCT
3-armed trial 		78 people with mild to moderate denture stomatitis Symptoms of denture stomatitis 4 weeks
with mouth rinsing 3 times daily plus denture soaking once daily using an antimicrobial mouth rinse
with mouth rinsing 3 times daily plus denture soaking once daily using a control mouth rinse
Absolute results not reported
P <0.01 for antimicrobial mouth rinse v control mouth rinse 		Effect size not calculated antimicrobial mouth rinse

RCT		 34 people in long-term care with acrylic dentures and a positive test for Candida albicans Rates of dentures recolonised with C albicans 3 months
with microwave treatment (dentures scrubbed with antibacterial soap and water and then microwaved individually for 1 minute at 850 W on days 1, 5, and 10)
with control treatment (dentures soaked in 0.2% chlorhexidine solution overnight for 14 days and scrubbed with antibacterial soap and water on days 1, 5, and 10)
Absolute results not reported
RR 0.64
95% CI 0.38 to 1.06
The RCT may have lacked power to detect a clinically important difference between groups in this outcome 		Not significant

RCT		 34 people in long-term care with acrylic dentures and a positive test for C albicans Proportion of people with infection of the oral mucosa on cytological smear 3 months
with microwave treatment (dentures scrubbed with antibacterial soap and water and then microwaved individually for 1 minute at 850 W on days 1, 5, and 10)
with control treatment (dentures soaked in 0.2% chlorhexidine solution overnight for 14 days and scrubbed with antibacterial soap and water on days 1, 5, and 10)
Absolute results not reported
RR 0.25
95% CI 0.06 to 0.59 		Moderate effect size microwave treatment

RCT
4-armed trial 		60 people with maxillary complete acrylic dentures and a positive test for C albicans and denture stomatitis Inflammation severity on Newton scale of 0 to 1 30 and 90 days
with microwave treatment (650 W for 6 minutes) 3 times weekly for 30 days
with microwave treatment plus topical miconazole gel 3 times daily for 30 days
with topical miconazole gel 3 times daily for 30 days
with routine dental care (control)
P <0.001 for both microwave-treatment arms v non-microwave treatment arms
The RCT may have lacked power to detect a clinically important difference between groups in this outcome 		Effect size not calculated microwave treatment
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Adverse effects

No data from the following reference on this outcome.

Further information on studies

In this RCT, exposure time to microwaves was decided arbitrarily. Exposure to microwaves at 850 W for 90 seconds seemed to damage the denture material. The RCT noted that microwave treatment may damage complete dentures that have been relined, repaired, or both, by producing a bubble (pocketing) in the acrylic material; and porcelain teeth with metal retaining pins may cause the microwave to spark and scorch the denture material. It noted that microwave treatment was not suitable for all dentures and should be used with caution. Microwave treatment cannot be used for chrome dentures or dentures with metal clasps.

Comment

Two observational studies found a correlation between the prevalence of denture stomatitis and an unhealthy lifestyle (a global measure including dietary habits, physical activity, alcohol consumption, and smoking), wearing dentures at night, and poor oral hygiene.

Substantive changes

Denture hygiene New evidence added. Categorisation unchanged (Unknown effectiveness), as there remains insufficient evidence to judge the effectiveness of this intervention.

BMJ Clin Evid. 2012 Feb 20;2012:1304.

Antifungal prophylaxis in people with HIV infection

Summary

Daily or weekly prophylaxis with fluconazole or itraconazole reduces the incidence of candidiasis in people with HIV infection. Prophylaxis with nystatin may not be effective.

Benefits and harms

Fluconazole versus placebo or no treatment:

We found one systematic review (search date 2009, 33 RCTs, 3445 people), which identified RCTs that enrolled people with AIDS, AIDS-related complex, or CD4+ cell counts of 300 cells/microlitre or less.

Prevention of oral candidiasis

Compared with placebo or no treatment Fluconazole is more effective at reducing the proportion of people with oral candidiasis at 1 to 24 weeks compared with placebo, and is more effective at reducing the proportion of people with oral candidiasis at 20 to 30 weeks compared with no treatment in people with AIDS, AIDS-related complex, or CD4+ cell counts of 300 cells/microlitre or less (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oral candidiasis

Systematic review		 599 people
5 RCTs in this analysis		 Rate of relapse 1 to 24 weeks
100/301 (33%) with fluconazole (either once weekly or once daily)
170/298 (57%) with placebo
RR 0.61
95% CI 0.50 to 0.74 		Small effect size fluconazole

Systematic review		 65 people
2 RCTs in this analysis		 Rate of relapse 20 to 30 weeks
6/43 (14%) with fluconazole (either once weekly or once daily)
20/22 (91%) with no treatment
RR 0.16
95% CI 0.08 to 0.34 		Large effect size fluconazole
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 25 people
In review 		Adverse effects
10/12 (83%) with fluconazole
9/13 (69%) with placebo
P = 0.6 		Not significant

RCT		 138 people
In review 		Rate of microbial resistance 37 months
8/67 (12%) with fluconazole
4/71 (6%) with placebo
P = 0.20 		Not significant
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Itraconazole versus placebo:

The systematic review identified one RCT, and we found three additional RCTs.

Prevention of oral candidiasis

Compared with placebo Itraconazole seems more effective at decreasing the proportion of people with oral candidiasis at up to 1 year and at increasing the time to development of oral candidiasis in people with HIV infection, but we don't know whether it is more effective at 32 months (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oral candidiasis

Systematic review		 295 people
Data from 1 RCT		 Rate of recurrence 32 months
17/149 (11%) with itraconazole
15/146 (10%) with placebo
RR 0.90
95% CI 0.47 to 1.73 		Not significant

RCT		 44 men with HIV, successfully treated for oral candidiasis Relapse rate 24 weeks
5/24 (21%) with daily itraconazole 200 mg for 24 weeks
14/20 (70%) with placebo
ARR 49%
95% CI 19% to 64%
NNT 2
95% CI 2 to 5 		Effect size not calculated itraconazole

RCT		 44 men with HIV, successfully treated for oral candidiasis Median increase in time to relapse
10.4 weeks with daily itraconazole 200 mg for 24 weeks
8.0 weeks with placebo
P = 0.001 		Effect size not calculated itraconazole

RCT		 374 people Incidence of oral candidiasis 386 days
25% with itraconazole 200 mg daily
48% with placebo
Absolute numbers not reported
RR 0.33
CI not reported
P <0.001 		Moderate effect size itraconazole

RCT		 374 people Time to development of oral candidiasis
508 days with itraconazole 200 mg daily for a mean duration of 448 days
413 days with placebo for a mean duration of 386 days
P <0.001, log-rank test 		Effect size not calculated itraconazole

RCT		 129 people Two or more episodes of oral candidiasis follow-up 6 to 104 weeks in the itraconazole group and 5 to 104 weeks in the placebo group
6/63 (10%) with itraconazole 200 mg daily
15/66 (23%) with placebo
P = 0.04 		Effect size not calculated itraconazole
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

Systematic review		 262 people
Data from 1 RCT		 Skin rash
15/149 (10%) with itraconazole
3/113 (2%) with placebo
P = 0.02 		Effect size not calculated itraconazole

RCT		 129 people
In review 		Skin rash
16/63 (25%) with itraconazole 200 mg daily
15/66 (23%) with placebo
P >0.05 		Not significant

RCT		 129 people
In review 		Mild anaemia
4/63 (6%) with itraconazole 200 mg daily
5/66 (8%) with placebo
P >0.05 		Not significant

RCT		 129 people
In review 		Diarrhoea
3/63 (5%) with itraconazole 200 mg daily
5/66 (8%) with placebo
P >0.05 		Not significant
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No data from the following reference on this outcome.

Nystatin versus placebo:

The systematic review identified one RCT (128 men) comparing higher-dose nystatin (400,000 units) and lower-dose nystatin (200,000 units) versus placebo.

Prevention of oral candidiasis

Compared with placebo Nystatin may be no more effective at decreasing the proportion of people with oral candidiasis at 20 weeks in people with AIDS, AIDS-related complex, or CD4+ cell counts of 300 cells/microlitre or less (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oral candidiasis

Systematic review		 70 people with recent infection from an RCT of 128 men
Data from 1 RCT
Subgroup analysis		 Rate of recurrence of oral candidiasis 20 weeks
33/47 (70%) with both doses of nystatin (higher-dose nystatin [400,000 units] and lower-dose nystatin [200,000 units])
20/23 (87%) with placebo
RR 0.82
95% CI 0.65 to 1.04 		Not significant

Systematic review		 48 people with no infection in the preceding year from an RCT of 128 men
Data from 1 RCT
Subgroup analysis		 Rate of recurrence of oral candidiasis 20 weeks
19/38 (50%) with both doses of nystatin (higher-dose nystatin [400,000 units] and lower-dose nystatin [200,000 units])
10/20 (50%) with placebo
RR 0.99
95% CI 0.52 to 1.89 		Not significant
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Adverse effects

No data from the following reference on this outcome.

Chlorhexidine versus saline:

The systematic review identified one RCT comparing chlorhexidine with normal saline.

Prevention of oral candidiasis

Compared with saline Chlorhexidine may be no more effective at decreasing episodes of oral candidiasis in people with HIV infection (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Rate of recurrence

RCT		 75 people
In review 		Rate of recurrence of oropharyngeal candidiasis measured every 2 weeks until recurrence noted
with chlorhexidine 0.12%
with 0.9% normal saline
Absolute numbers not reported
P >0.05 		Not significant
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Adverse effects

No data from the following reference on this outcome.

Fluconazole versus clotrimazole:

We found one additional RCT (428 people from 29 sites) that compared fluconazole 200 mg daily versus clotrimazole 10 mg five times daily over 35 months.

Prevention of oral candidiasis

Fluconazole compared with clotrimazole Fluconazole seems more effective than clotrimazole at decreasing episodes of oral candidiasis in people with HIV infection (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oral candidiasis

Systematic review		 428 people from 29 sites
Data from 1 RCT		 Rate of recurrence of oropharyngeal candidiasis 35 months
6 episodes/100 person-years with fluconazole 200 mg daily over 35 months
38 episodes/100 person-years with clotrimazole 10 mg five times daily over 35 months
P <0.001 		Effect size not calculated fluconazole
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Adverse effects

No data from the following reference on this outcome.

Further information on studies

Itraconazole versus placebo In one RCT identified by the review, two people who received itraconazole developed Stevens–Johnson syndrome, one of whom was also taking trimethoprim–sulfamethoxazole. Other adverse effects reported included diarrhoea, nausea, vomiting, and elevated liver enzyme levels.

The RCT found that itraconazole was associated with a widespread itchy rash in 5 people; the rate with placebo was not reported. Concomitant medication and severe underlying disease may have confounded attribution of adverse events.

The study was terminated because of inadequate power.

One person discontinued treatment with itraconazole because of a skin rash, and concerns about hepatotoxicity resulted in treatment being discontinued in two people (1 with itraconazole, 1 with placebo). There was one case of Stevens–Johnson syndrome in a person taking trimethoprim–sulfamethoxazole as well as itraconazole. Concomitant medication and severe underlying disease may have confounded attribution of adverse events.

The RCT reported that more people discontinued fluconazole due to adverse effects than with clotrimazole, although the difference was not significant (13 with fluconazole v 6 with clotrimazole; P = 0.11). Rashes and hepatotoxicity were reported in both groups. Concomitant medication and severe underlying disease may have confounded attribution of adverse events.

Comment

Clinical guide:

Many of the RCTs were small and not blinded, and most did not adjust for confounding factors such as antiretroviral treatment or other established risk factors for oropharyngeal candidiasis. Chlorhexidine and normal saline rinses may have a beneficial mechanical cleaning effect, but without a placebo control this could not be established. No RCTs used quality-of-life scores. The optimal dosage schedule and frequency of administration of preventive treatment have not been established. We found no RCTs comparing weekly versus daily regimens of antifungal drugs. We found one RCT that compared two different doses of fluconazole. It found no significant difference between fluconazole 50 mg and 100 mg daily (oropharyngeal candidiasis: 2/18 [11%] with fluconazole 50 mg v 4/19 [21%] with fluconazole 100 mg; RR 0.53, 95% CI 0.09 to 2.09). Subgroup analysis in the RCT comparing fluconazole versus placebo found that people with a history of oropharyngeal candidiasis had an absolute benefit of treatment with weekly fluconazole that was higher than in those with no history of infection (ARR: 25.6/100 person-years for those with previous infection v 11.2/100 person-years for those with no history of infection).Chlorhexidine mouth wash should not be used in conjunction with nystatin owing to the formation of a low-solubility chlorhexidine-nystatin salt that renders the drug complex virtually ineffective as an antifungal agent.

Substantive changes

Antifungal prophylaxis in people with HIV infection One systematic review updated. New data added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2012 Feb 20;2012:1304.

Antifungal treatment in people with HIV infection

Summary

Clotrimazole lozenges and miconazole buccal slow-release tablets may be as effective as oral tablets/suspensions of oral antifungals (fluconazole/itraconazole) at reducing symptoms of candidiasis in people with HIV infection.

Gentian violet mouth wash may be more effective than nystatin mouth wash at increasing clinical cure in people with HIV infection.

Fluconazole, ketoconazole, and posaconazole may be equally effective at increasing cure rates for candidiasis in people with HIV infection, but we don’t know whether posaconazole oral suspension is more effective than fluconazole oral suspension.

A single dose of fluconazole (750 mg) may be as effective as a 14-day course of fluconazole in reducing symptoms of candidiasis in people with HIV infection.

Benefits and harms

Topical antifungal treatment versus placebo:

We found no systematic review or RCTs.

Oral antifungal treatment versus placebo:

We found no systematic review or RCTs.

Topical antifungal treatment versus oral antifungal treatment:

We found one systematic review (search date 2009, 22 RCTs, 1389 people) assessing topical antifungal treatment in people with HIV infection. The review was not restricted to topical treatments and included topical, parenteral, and intravenous formulations of antifungals, plus gentian violet, lemon grass, lemon juice, melaleuca, and tea tree oil. The data were pooled for the meta-analysis by type of antifungal, and did not distinguish by method of administration. For most comparisons, the review found only one RCT.

Treatment success

Topical antifungal treatment compared with oral antifungal treatment Fluconazole suspension (directly swallowed) seems more effective than nystatin suspension (used with swish-and-swallow technique) at increasing clinical cure at 14 days, and oral ketoconazole seems more effective than nystatin mouth wash at increasing clinical cure rates in people with HIV infection. Oral fluconazole tablets and clotrimazole lozenges seem equally effective at increasing clinical cure at 14 days, and itraconazole oral solution and clotrimazole lozenges seem equally effective at increasing clinical or mycological cure rates at 7 to 14 days. Oral ketoconazole and topical miconazole slow-release buccal tablets seem equally effective at increasing clinical cure at 14 days (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Treatment success

Systematic review		 167 people
Data from 1 RCT		 Clinical cure 14 days
60/83 (72%) with fluconazole suspension (directly swallowed) 100 mg daily
36/84 (43%) with nystatin suspension (used with swish-and-swallow technique)
RR 1.69
95% CI 1.27 to 2.23 		Small effect size fluconazole

Systematic review		 150 people with oral candidiasis and HIV
Data from 1 RCT		 Clinical cure
10/45 (22%) with ketoconazole
2/47 (4%) with nystatin mouth wash
RR 5.22
95% CI 1.21 to 22.53 		Large effect size ketoconazole

Systematic review		 358 people
2 RCTs in this analysis		 Clinical cure 14 days
151/189 (80%) with oral fluconazole tablets
124/169 (73%) with clotrimazole lozenges
RR 1.14
95% CI 0.92 to 1.42 		Not significant

Systematic review		 152 people
2 RCTs in this analysis		 Clinical or mycological cure rates 7 to 14 days
43/75 (57%) with itraconazole oral solution
28/77 (36%) with clotrimazole lozenges
RR 1.34
95% CI 0.56 to 3.20 		Not significant

Systematic review		 357 people
Data from 1 RCT		 Clinical cure 14 days
159/179 (89%) with oral ketoconazole
155/178 (87%) with topical miconazole nitrate (10 mg once-daily slow-release mucoadhesive buccal tablet)
RR 1.02
95% CI 0.94 to 1.10 		Not significant
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 Number of people not reported Adverse effects
with oral antifungals
with topical antifungals
Absolute numbers not reported
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Different topical antifungal drugs versus each other:

We found one systematic review (search date 2009, 22 RCTs, 1389 people) assessing topical antifungal treatment in people with HIV infection, and one subsequent RCT comparing once-daily bucco-adhesive miconazole tablet with 5 times daily clotrimazole lozenges. For most comparisons, the review found only one RCT.

Treatment success

Different topical antifungal drugs compared with each other Gentian violet mouth wash may be more effective than nystatin mouth wash at increasing clinical cure in people with HIV infection. A once-daily bucco-adhesive miconazole tablet may be as effective as clotrimazole lozenges 5 times daily. We don't know how lemon juice, lemon grass, and gentian violet compare with each other at increasing cure rates (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Treatment success

RCT		 578 people with oral candidiasis and HIV Proportion of people with clinical cure 14 days
164/240 (68%) with once-daily miconazole 50 mg bucco-adhesive tablet
175/236 (74%) with 10 mg clotrimazole lozenges 5 times daily
Treatment difference –0.059
95% CI –0.140 to +0.022 		Not significant

Systematic review		 150 people with oral candidiasis and HIV
Data from 1 RCT		 Clinical cure
11/49 (22%) with gentian violet
2/47 (4%) with nystatin mouth wash
RR 5.28
95% CI 1.23 to 22.55 		Large effect size gentian violet

RCT
3-armed trial 		90 people
In review 		Proportion of people with clinical cure
16/30 (53%) with lemon juice
9/30 (30%) with gentian violet 0.5%
RR 1.78
95% CI 0.94 to 3.37 		Not significant

RCT
3-armed trial 		90 people
In review 		Proportion of people with clinical cure
15/30 (50%) with lemon grass
9/30 (30%) with gentian violet 0.5%
RR 1.67
95% CI 0.87 to 3.20 		Not significant

RCT
3-armed trial 		90 people
In review 		Proportion of people with clinical cure
16/30 (53%) with lemon juice
15/30 (50%) with lemon grass
RR 1.07
95% CI 0.65 to 1.04 		Not significant
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT
3-armed trial 		90 people
In review 		Adverse effects
with lemon juice
with lemon grass
with lemon juice
Significance not assessed

RCT		 578 people with oral candidiasis and HIV Proportion of people with at least 1 adverse event
161/290 (56%) with once-daily miconazole 50 mg bucco-adhesive tablet
152/287 (53%) with 10 mg clotrimazole 5 times daily
P value not reported
Reported as not significant 		Not significant
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Different oral antifungals versus each other:

We found one systematic review (search date 2009) assessing oral antifungal treatments versus each other in people with HIV infection; and different doses of fluconazole versus each other.

Treatment success

Different oral antifungals compared with each other Itraconazole (suspension used in a swish-and-swallow mode) and oral fluconazole tablets seem equally effective at increasing clinical cure at 14 days in people with HIV infection, but we don’t know whether posaconazole oral suspension is more effective than fluconazole oral suspension at increasing a composite outcome of clinical success (clinical cure or improvement) (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Treatment success

Systematic review		 434 people
4 RCTs in this analysis		 Proportion of people with clinical cure 14 days
118/148 (80%) with fluconazole tablets
214/286 (75%) with topical itraconazole (suspension used in a swish-and-swallow mode)
RR 1.05
95% CI 0.94 to 1.16
P = 0.38 		Not significant

Systematic review		 37 people
Data from 1 RCT		 Proportion of people with clinical cure 14 days
17/18 (94%) with fluconazole 50 mg
12/19 (63%) with ketoconazole 200 mg
RR 1.5
95% CI 1.04 to 2.15
P = 0.029 		Small effect size fluconazole 50 mg

Systematic review		 278 people
Data from 1 RCT		 Proportion of people with clinical cure
130/135 (96%) with fluconazole
139/143 (97%) with posaconazole
RR 1.32
95% CI 0.36 to 4.83 		Not significant
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Adverse effects

No data from the following reference on this outcome.

Different doses of the same oral antifungal drug:

We found one systematic review (search date 2009), which identified two RCTs comparing different doses of fluconazole versus each other.

Treatment success

Different doses of the same antifungal drug compared with each other A single dose of fluconazole (750 mg or 150 mg) may be as effective as a lower daily dose of the drug (150 mg or 50 mg) for 7 or 14 days at increasing treatment success in people with HIV infection (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Treatment success

RCT		 220 people with HIV and oropharyngeal candidiasis
In review 		Proportion of people with clinical cure 14 days
105/110 (95%) with fluconazole 150 mg daily for 14 days
105/110 (95%) with fluconazole 750 mg single dose
RR 1.00
95% CI 0.94 to 1.06 		Not significant

RCT		 220 people with HIV and oropharyngeal candidiasis
In review 		Proportion of people relapsing 42 days
12/100 (12.0%) with fluconazole 150 mg daily for 14 days
12/94 (12.8%) with fluconazole 750 mg single dose
RR 0.94
95% CI 0.44 to 1.99 		Not significant

Systematic review		 56 people
Data from 1 RCT		 Proportion of people with clinical cure 28 days
26/28 (93%) with fluconazole 50 mg daily for 7 days
21/28 (75%) with fluconazole 150 mg single dose
RR 1.24
95% CI 0.98 to 1.52 		Not significant
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 220 people with HIV and oropharyngeal candidiasis
In review 		Proportion of people reporting adverse effects
6/110 (5%) with fluconazole 150 mg daily for 14 days
8/110 (7%) with fluconazole 750 mg single dose
Significance not assessed
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Further information on studies

41/110 (37%) people in the fluconazole single-dose group and 39/110 (35%) people in the fluconazole 14-day group used highly active antiretroviral therapy (HAART). Adverse events were mild. Because most of the trial participants were in an advanced stage of HIV infection and AIDS, abnormalities in full blood count and liver function tests were common, but no clinically significant changes were seen in either arm of the study, except in one person in the single-dose fluconazole group with greatly raised ALT and AST; but the person was asymptomatic and the levels returned to normal.

Comment

Once-daily dosing is likely to increase adherence to treatment. Non-adherence was reported with clotrimazole because of the inconvenience of taking multiple doses.

Adverse effects of antifungal treatment:

The most frequently reported adverse effects in the RCTs were gastrointestinal symptoms (nausea, diarrhoea, and vomiting). Altered taste, dry mouth, headache, and rashes were also recorded. There were no withdrawals in two RCTs from adverse effects. Six RCTs (1211 people) reported adverse events with fluconazole (11 people), posaconazole (7 people), itraconazole (14 people), clotrimazole (12 people), and nystatin (1 person), resulting in withdrawal from the study. These adverse events were considered to be drug-induced. The RCT comparing miconazole nitrate versus ketoconazole found similar rates of adverse effects between the two groups, with the exception of vomiting.

Gentian violet is the first-line medication for oral candidiasis in South Africa, but the visible purple staining of the oral tissues can lead patients to be stigmatised as HIV-seropositive, and gentian violet is therefore unpopular with patients. Lemon grass Cymbopogan citratus and citrus lemon have known antifungal properties and are not associated with staining of the tissues.

Substantive changes

Antifungal treatment in people with HIV infection New evidence added, including one systematic review updated. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2012 Feb 20;2012:1304.

Continuous antifungal prophylaxis versus intermittent antifungal treatment

Summary

Continuous prophylaxis with antifungal agents may not increase the risk of developing antifungal resistance compared with intermittent prophylaxis, but it may be no more effective at reducing the number of attacks in people with HIV infection the majority of whom were receiving highly active antiretroviral treatment (HAART).

Benefits and harms

Intermittent antifungal treatment versus continuous antifungal prophylaxis:

We found one systematic review (search date 2009, 2 RCT, 891 people).

Mortality

Intermittent antifungal treatment compared with continuous antifungal prophylaxis We don't know whether intermittent fluconazole treatment is more effective than continuous fluconazole prophylaxis at reducing mortality in people with HIV infection who were receiving highly active antiretroviral treatment (HAART) and had a CD4+ cell count <150 cells/microlitre (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality

RCT		 829 people with HIV, CD4+ cell count <150 cells/microlitre, receiving highly active antiretroviral treatment (HAART)
In review 		Death
31/413 (8%) with oral fluconazole (200 mg 3 times weekly) given continuously
40/416 (10%) with intermittent fluconazole (loading dose 400 mg, followed by 200 mg for 6–13 days)
P = 0.28 		Not significant
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No data from the following reference on this outcome.

Drug-induced resistance to treatment

Intermittent antifungal treatment compared with continuous antifungal prophylaxis We don't know whether intermittent fluconazole treatment is more effective than continuous fluconazole prophylaxis at preventing antifungal resistance or at reducing the time to development of fluconazole-refractory oral candidiasis in people with HIV infection, the large majority of whom were receiving highly active antiretroviral treatment (HAART) and had a CD4+ cell count <150 cells/microlitre (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Drug-induced resistance to treatment

RCT		 68 people with oral candidiasis (20 people received continuous prophylaxis with fluconazole; 48 people received intermittent treatment with fluconazole 200 mg daily)
In review 		Development of acquired resistance mean of 11 months
9/16 (56%) with continuous prophylaxis with fluconazole
13/28 (46%) with intermittent treatment with fluconazole 200 mg daily
P = 0.75 		Not significant

RCT		 829 people with HIV, CD4+ cell count <150 cells/microlitre, receiving highly active antiretroviral treatment (HAART)
In review 		Fluconazole-refractory oropharyngeal candidiasis or oesophageal candidiasis 42 months
17/413 (4.1%) with oral fluconazole (200 mg 3 times weekly) given continuously
18/416 (4.3%) with intermittent fluconazole (loading dose 400 mg, followed by 200 mg for 6–13 days)
Significance not assessed

RCT		 829 people with HIV, CD4+ cell <150 cells/microlitre, receiving HAART
In review 		Time to development of fluconazole-refractory oropharyngeal candidiasis or oesophageal candidiasis after 24 months' treatment
with oral fluconazole (200 mg 3 times weekly) given continuously
with intermittent fluconazole (loading dose 400 mg, followed by 200 mg for 6–13 days)
Absolute results not reported
P = 0.88 		Not significant

RCT		 829 people with HIV, CD4+ cell count <150 cells/microlitre, receiving HAART
In review 		Time to development of fluconazole-refractory oropharyngeal candidiasis or oesophageal candidiasis after 42 months' treatment
with oral fluconazole (200 mg 3 times weekly) given continuously
with intermittent fluconazole (loading dose 400 mg, followed by 200 mg for 6–13 days)
Absolute results not reported
P = 0.97 		Not significant
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Prevention of oral candidiasis

Intermittent antifungal treatment compared with continuous antifungal prophylaxis We don't know whether intermittent fluconazole treatment and continuous fluconazole prophylaxis differ in effectiveness at reducing episodes of oral candidiasis in people with HIV infection, the large majority of whom were receiving highly active antiretroviral treatment (HAART) and had a CD4+ cell count <150 cells/microlitre (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Prevention of oral candidiasis

Systematic review		 891 people - the majority (829 people) of whom with HIV with CD4+ cell count <150 cells/microlitre, receiving highly active antiretroviral treatment (HAART)
2 RCTs in this analysis		 Proportion of people relapsing 11 to 24 months
22/436 (5%) with continuous fluconazole
40/455 (9%) with intermittent fluconazole
RR 0.65
95% CI 0.23 to 1.83
P = 0.42 		Not significant
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 829 people with HIV, CD4+ cell count <150 cells/microlitre, receiving highly active antiretroviral treatment (HAART)
In review 		Discontinued treatment owing to adverse effects
10/413 (2.4%) with oral fluconazole (200 mg 3 times weekly) given continuously
2/416 (0.5%) with intermittent fluconazole (loading dose 400 mg, followed by 200 mg for 6–13 days)
Significance not assessed

RCT		 829 people with HIV, CD4+ cell count <150 cells/microlitre, receiving HAART
In review 		Thrombocytopenia (<50,000 platelets/microlitre)
8/327 (2.4%) with oral fluconazole (200 mg 3 times weekly) given continuously
1/334 (0.3%) with intermittent fluconazole (loading dose 400 mg, followed by 200 mg for 6–13 days)
P = 0.02 		Effect size not calculated intermittent fluconazole
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Further information on studies

Oropharyngeal candidiasis or oesophageal candidiasis was defined as no response to fluconazole 200 mg daily for 14 days in oropharyngeal candidiasis or 21 days in oesophageal candidiasis.

Antifungal sensitivity testing followed the National Committee for Clinical Laboratory Standards guidelines.

Comment

Optimal treatment regimens to reduce the risk of acquiring resistance have not been adequately evaluated. In a prospective observational study of protease inhibitor treatment, 93 people with HIV infection and a history of recurrent oropharyngeal candidiasis were followed up for 1 year. Oropharyngeal candidiasis was diagnosed in 2/30 (7%) people given protease inhibitors and 23/63 (37%) people given other treatment (P less than or equal to 0.001; CI not reported). In the second RCT, 53% of participants completed treatment. Immunomodulating antiretroviral treatments (e.g., highly active antiretroviral treatment [HAART]) act indirectly as antifungal-sparing agents by reducing the number of recurrences of oropharyngeal candidiasis, thereby reducing exposure to antifungal drugs and the potential risk of resistance. In industrialised nations, the continuous use of fluconazole cannot be recommended except for those individuals experiencing recurrent oropharyngeal candidiasis, given the reduction in fungal infections associated with HAART and the lack of survival benefits associated with continuous fluconazole. In resource-poor settings, where access to HAART is limited, mortality attributable to fungal infections is considerable; therefore, fluconazole prophylaxis may offer greater benefits.

Substantive changes

Continuous antifungal prophylaxis versus intermittent antifungal treatment One systematic review updated, new data added. Categorisation of "Intermittent treatment in people with HIV infection and acute episodes of oropharyngeal candidiasis (no reduction in antifungal resistance compared with continuous prophylaxis)" unchanged (Unlikely to be beneficial).

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