Effectiveness of nystatin in polysymptomatic patients.

A randomised, double-blind trial with nystatin versus placebo in general practice. 

Heiko Santelmann, Even Lærum, Jørgen Rønnevig^a, and Hans E Fagertun^b,

Department of General Practice and Community Medicine, University of Oslo, 0317 Oslo,
^a Alpharma AS, 0212 Oslo and ^b Parexel Medstat AS, 2001 Lillestrøm, Norway. 

Correspondence to: Dr. H. Santelmann, Holmenveien 1, 0374 Oslo, Norway. E-mail: drheiko@online.no  

Santelmann H, Lærum E, Rønnevig J and Fagertun HE. Effectiveness of nystatin in polysymptomatic patients. A randomised, double-blind trial with nystatin versus placebo in general practice. Family Practice 2001; 18: 258–265. 

Received 15 October 1999; Revised 10 October 2000; Accepted 8 January 2001.  

Abstract  

 
Background. Antifungal therapy has been claimed to be effective in polysymptomatic patients with diffuse symptoms from multiple body systems and even well defined diseases, traditionally not related to fungi. Hypersensitivity to fungus proteins and mycotoxins has been proposed as the cause.

Methods. We conducted a 4-week randomised, double-blind, placebo-controlled study in 116 individuals selected by a 7-item questionnaire to determine whether the antifungal agent nystatin given orally was superior to placebo. At the onset of the study, the patients were free to select either their regular diet or a sugar- and yeast-free diet, which resulted in four different subgroups: nystatin + diet (ND); placebo + diet (PD); nystatin (N); and placebo (P).

Results. Nystatin was significantly better than placebo in reduction of the overall symptom score (P < 0.003). In six of the 45 individually recorded symptoms, the improvement was significant (P < 0.01). All three active treatment groups reduced their overall symptom scores significantly (P < 0.0001), while the placebo regimen had no effect (P = 0.83). The benefit of diet was significant within both the nystatin (ND > N) and the placebo groups (PD > P).

Conclusions. Nystatin is superior to placebo in reducing localised and systemic symptoms in individuals with presumed fungus hypersensitivity as selected by a 7-item questionnaire. This superiority is probably enhanced even further by a sugar- and yeast-free diet.

Keywords. Candida albicans, general practice, nystatin, polysymptomatic, yeast. 

Introduction  

 
It is generally known by primary care physicians that about half of the medical evaluations of out-patient polysymptomatic patients fail to elucidate a specific causative disease. The symptom patterns often suggest the possibility of a systemic disease process involving multiple body systems. The patient may complain of chronic fatigue, poor concentration, impaired memory, respiratory tract symptoms, gastrointestinal distress, pains in muscles and joints, skin problems, recurrent infections, urogenital problems, etc. All too often, the diagnosis given to the patient is in terms such as ‘stress’, ‘psychosomatic symptoms’ or an assurance that ‘there is nothing physically wrong’.

A number of these patients have been reported to have had an unexpected marked improvement in their symptoms when antifungal drugs were administered to treat various fungal infections. In addition, there are increasing numbers of reports that drugs possessing antifungal activity have been remarkably effective in a number of well-defined diseases.¹ There are also reports of cures of chronic fatigue, allergic conditions including bronchial asthma, pre-menstrual distress, multiple sclerosis and autism² with a regimen of diet free from yeasts, moulds and sugars,^3,4 antifungal medication and sometimes desensitisation by Candida extract.⁵ An immunological response to fungal antigens or a reaction to fungal toxins (mycotoxins), yeast-produced alcohols and other metabolic products have all been suggested as an explanation for these phenomena.^3,6

Many of the reported benefits have occurred with the use of nystatin, an antifungal agent usually prescribed for the treatment of Candida albicans infections, the most common pathogenic fungus in humans. This has led to a belief that C.albicans must be the cause of the underlying disorder, a conclusion which has ignored the fact that nystatin is actually a broad spectrum antifungal antibiotic effective against many different species of fungi.

The proponents in the USA for a C.albicans aetiology of the involved symptoms and/or diseases have called the phenomena ‘The yeast connection’, ‘Candidiasis hypersensitivity syndrome’ and, most recently, ‘Candida-related complex’ (CRC). In the UK, the entity is often referred to as ‘The gut fermentation syndrome’.

The Candida hypothesis lacks a specific diagnostic test to support the validity of the concept. The diagnostic methods are limited to a combination of patient history, questionnaires, provocative challenge to yeast antigens and response to a broad treatment programme. There are no published controlled studies supporting a positive effect of antifungal medication or antifungal diet alone on patients thought to have CRC.^7–9  

In this study, we use the term ‘fungus-related disease’ (FRD) for a condition showing improvement with antifungal treatment. It was not the purpose of this study to identify the specific fungal species that may be playing an etiological role. Rather, the objectives of our study were to determine whether the antifungal agent nystatin, administered orally to patients with presumed FRD, was superior to placebo as assessed by change in overall symptom score and in specific symptoms from baseline, and to evaluate the influence of diet on the outcome. We believe that our research has provided results which are consistent with the stated objectives of this study. 

Methods 

 
The study took place at an urban (Oslo) and a suburban (Mandal) centre. Volunteers were invited through the press from all parts of Norway. FRD was verified by using the questionnaire FRDQ-7 (Table 1). This questionnaire was developed to identify responders to nystatin and/or antifungal diet in an open study based on a historic group of 380 patients previously selected by symptoms and a CRC questionnaire⁴ to classify the clinical diagnosis of FRD according to a sustained beneficial effect of nystatin and/or a sugar- and yeast-free diet. In order to determine the relevance of individual items of the CRC scheme, a gradual statistical discrimination analysis was carried out and resulted in the 7-item questionnaire (FRDQ-7) characterising the historic patient population (H Santelmann, E Lærum and J Rønnevig, unpublished). 

TABLE 1
Questionnaire FRDQ-7

Selection criteria
Within 3 months, 1620 persons volunteered. Of these, 954 were excluded due to being aged under 18 or over 75 years or because they were pregnant or lactating, dependent on a diet, or taking antibiotics, corticosteroids or other immunosuppressive agents orally or systemically during the 2 weeks prior to the start of the study. They were also excluded if they were receiving oral antimycotics and/or a sugar- and yeast-free diet 2 months prior to assessment of eligibility, or if they were unable to attend for two control evaluations. Five hundred and forty-six volunteers were excluded due to a low FRDQ-7 score (<10 out of 21). Among the 120 persons enrolled, 103 were women and 17 were men, with a mean age of 39 years (range 22–69). 

Study design
The study was carried out as a double-blind, randomised placebo-controlled, multicentre trial with block design and diet as block factor. Patients were randomly assigned to receive either nystatin or placebo for a period of 4 weeks (Fig. 1). This part of the study was double-blind and the codes were stored sealed until all data from all patients were delivered to an independent statistical institute for evaluation. 

FIGURE 1
Study design

 
Treatment regimens
Two hundred milligrams of nystatin powder (1 112 000 IU) or cornflour were packaged in transparent gelatine capsules. Blinded observers could not detect any difference between the two types of capsules. Patients were instructed to swallow one capsule unopened, three times a day, after meals, with a non-alcoholic liquid for 4 weeks. In cases of adverse effects, the patients were instructed to decrease the dose to one capsule daily, increase to three capsules within 1 week and continue for 4 weeks altogether. 

At the start of the study, patients were free to choose between a modified sugar- and yeast-free diet, in compliance with a food list, or their regular diet for the period of the study. We used this approach because a double-blind diet regimen appeared to be extremely difficult to manage and exceeded the capacity of our study. We chose voluntary selection of diet to enhance compliance. By this means, we obtained four subgroups: nystatin plus sugar- and yeast-free diet (ND), placebo plus sugar- and yeast-free diet (PD), nystatin (N) and placebo (P). 

Patients in the diet groups obtained a list of foods to avoid, those containing sugars, yeasts or moulds, i.e. honey, jam, sweets, ice cream, lemonade, fruit juices (except freshly prepared), alcohol, cheese, and breads and pastries containing yeast. Additionally, they were asked not to consume more than half a glass of milk or yoghurt daily. Artificial sweeteners such as aspartame, saccharin and xylitol, and bread made with baking powder were allowed. 

Evaluation
Upon entry to the study and 4 weeks after starting the capsules, the patients filled in a questionnaire referring to 45 different symptoms derived from the 70 questions in the CRC questionnaire which were related to localised and systemic symptoms (Table 3). The scores ranged from 0 to 3 (absent, mild, moderate or severe). Improvement in individual symptoms was noted on the basis of a decline in the severity grade. The overall symptom score was calculated as the sum of the severity grades of all 45 symptoms. Since deterioration resulted in a higher score after treatment, it was conceivable that patients could achieve negative symptom scores. 

  denotes p-values < 0.01. Values were estimated by analysis of covariance. ND denotes nystatin plus diet, N denotes nystatin, PD denotes placebo plus diet, and P denotes placebo.

TABLE 3
Analysis of individual symptoms after adjustment for baseline symptom score and age

 
Two questionnaires, the EPQ¹⁰ and the GHQ-28¹¹, were administered on entry to assess more objectively the presence of special characteristics such as neuroticism, dissimulation or depression, and to control for homogeneity of the groups. At the end of the treatment, the remaining capsules were counted and the patients asked to report adverse effects related to the capsules, their compliance with the chosen diet and any use of other medication during the trial. They were also asked to guess whether they had received nystatin or placebo. All participants were evaluated at the two centres by one person (HS). 

Statistical analysis
Baseline comparability between the treatment groups with regard to possible co-factors and other baseline characteristics was assessed by analysis of variance (ANOVA). The ANOVA model included nystatin/placebo, diet/no diet and possible interaction between the two effects. In addition, analysis of covariance, with the baseline symptom score and age as co-factors, was applied. 

The nystatin and placebo mean values were compared statistically, as well as the means in the four subgroups derived from treatment and diet. This was assessed by using Duncan's multiple-range test and Dunnett's test.¹² The changes within each group were analysed using the one-sample t-test. Fisher's exact test for contingency tables larger than 2 x 2¹³ was applied when comparing subgroups with regard to categorical variables. To reduce multisignificance, the significance level was set to 1% in tests, and a test power of 80% was planned for. The test power was based on assumptions of a difference in proportional improvement in symptom score between the nystatin and placebo groups of at least 10% and an SD of 20% (hence an efficacy size of 0.5). All tests were applied two-sided. Continuously distributed variables were presented as mean values, and the primary variable also with a 95% confidence interval (CI). Categorical variables were presented as rates. The data management and the statistical analysis were carried out with Statistical Analysis System (SAS^®). 

Ethics
The study was performed in accordance with the most recent revision of the Declaration of Helsinki (Hong Kong, 1989). The local ethical committee approved the trial. Volunteers were entitled to indemnity according to Norwegian legal requirements. 

Results

 
Study population
Four of the 120 enrolled patients were excluded on completion of the study and review of the files because of treatment with antibiotics (n = 2), corticosteroids (n = 1) and hospitalisation (n = 1) during the trial. Five patients from the diet groups were transferred to groups N and P, as appropriate, due to deviations from the sugar- and yeast-free diet. Three patients in each group did not comply with the treatment as a consequence of side effects, but were included in the analysis; thus 116 patients could be evaluated; ND 18, N 38, PD 30 and P 30 (Fig. 1). A comparison of the baseline data between the nystatin and placebo groups did not reveal any significant differences (Table 2). The enrolled patients showed no special characteristics regarding dissimulation, neuroticism, extroversion–introversion, general somatic symptoms, anxiety, depression and social dysfunction compared with normal populations.^10,11 The four subgroups were statistically comparable with regard to patient characteristics and baseline symptom score.