Abstract
Background
Nystatin is sometimes used prophylactically in patients with severe immunodeficiency or in the treatment of fungal infection in such patients, although its effect seems to be equivocal.
Objectives
To study whether nystatin decreases morbidity and mortality when given prophylactically or therapeutically to patients with severe immunodeficiency.
Search methods
We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles.
Selection criteria
Randomised clinical trials comparing nystatin with placebo, an untreated control group, fluconazole or amphotericin B.
Data collection and analysis
Data on mortality, invasive fungal infection and colonisation were independently extracted by both authors. A random‐effects model was used unless the P value was greater than 0.10 for the test of heterogeneity.
Main results
We included 14 trials (1569 patients). The drugs were given prophylactically in 12 trials and as treatment in two. Eleven trials were in acute leukaemia, solid cancer, or bone marrow recipients; one in liver transplant patients; one in critically ill surgical and trauma patients; and one in AIDS patients. Nystatin was compared with placebo in three trials, with fluconazole in 10, and amphotericin B in one; the dose varied from 0.8 MIE to 72 MIE daily and was 2 mg/kg/d in a liposomal formulation. The effect of nystatin was similar to that of placebo on fungal colonisation (relative risk (RR) 0.85, 95% confidence interval (CI) 0.65 to 1.13). There was no statistically significant difference between fluconazole and nystatin on mortality (RR 0.75, 95% CI 0.54 to 1.03) whereas fluconazole was more effective in preventing invasive fungal infection (RR 0.40, 95% CI 0.17 to 0.93) and colonisation (RR 0.50, 95% CI 0.36 to 0.68). There were no proven fungal infections in a small trial that compared amphotericin B with liposomal nystatin. The results were very similar if the three studies that were not performed in cancer patients were excluded. For the 2011 and 2014 updates no additional trials were identified for inclusion.
Authors' conclusions
Nystatin cannot be recommended for prophylaxis or the treatment of Candida infections in immunodepressed patients.
Plain language summary
Prevention and treatment of fungal infections with nystatin in severely immunodepressed patients
People on chemotherapy for cancer, receiving a transplant or with AIDS are at risk of fungal infections. These infections can be life‐threatening, especially when they spread throughout the body. Nystatin is sometimes given as a routine preventive measure or as treatment in these patients. The review found that nystatin was no better than placebo (no treatment).
Background
Nystatin is often used for treatment of oral candidiasis in otherwise healthy patients, for example in patients with candidiasis after antibiotic therapy or in patients with denture stomatitis. The drug is also sometimes used prophylactically in patients with severe immunodeficiency, for example in patients undergoing antileukaemic chemotherapy or bone marrow transplantation or in patients with AIDS. We reviewed the relevant clinical trials in patients with severe immunodeficiency.
Objectives
To study whether nystatin decreases morbidity and mortality when given prophylactically or therapeutically to patients with severe immunodeficiency.
Methods
Criteria for considering studies for this review
Types of studies
All randomised trials, irrespective of language, which compared nystatin with placebo, an untreated control group, fluconazole or amphotericin B were eligible. Fluconazole and amphotericin B were chosen as active comparators as in a previous Cochrane review of placebo controlled trials (Gøtzsche 1997; Gøtzsche 2002) they appeared to be the most effective antifungal agents.
Types of participants
Patients with severe immunodeficiency predisposing to fungal infection, for example patients undergoing antileukaemic chemotherapy or bone marrow transplantation and patients with AIDS.
Types of interventions
Experimental: nystatin. Control: placebo, no treatment, fluconazole or amphotericin B.
Types of outcome measures
Mortality
Invasive fungal infection (defined as a positive blood culture, oesophageal candidiasis, lung infection or microscopically confirmed deep tissue involvement)
Colonisation
Harms
Search methods for identification of studies
Electronic searches
We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles.
The search strategy used is in Appendix 1.
The search strategies have been developed and executed by the author team.
Searching other resources
This has not been carried out since 2007 as we have not found it worthwhile.
Data collection and analysis
Data extraction and management
Decisions on which trials to include and which variables to use when a number of options were available for the same outcome were based on the methods sections of the trials. Details on diagnosis, drug, dose, randomisation and blinding methods, number of randomised patients, number of patients excluded from analysis, deaths, invasive fungal infections and colonisation were independently extracted by both authors; differences in the data extracted were resolved by consensus.
We defined invasive fungal infection as a positive blood culture, oesophageal candidiasis, lung infection or microscopically confirmed deep tissue infection (Gøtzsche 2002). We excluded cases of oropharyngeal and vulvovaginal candidiasis, skin infections, Candida in the urine and vaguely described infections.
Data synthesis
The outcomes were meta‐analysed as relative risks with the Mantel‐Haenszel technique. Since heterogeneity of the studies was expected because of various designs, diagnoses, drugs, doses and routes of administration, and criteria for fungal invasion and colonisation a random‐effects model was used. A fixed‐effect model analysis was preferred, however, if the P value was greater than 0.10 for the test of heterogeneity. Ninety‐five per cent confidence intervals were presented.
Results
Description of studies
We identified 18 potentially relevant reports. Four were subsequently excluded. A trial in which only 12 patients received nystatin failed due to serious problems with compliance (Hoppe 1995); another reported only the number of 'Candida‐free' days (which was 18 on both nystatin and on placebo) (Williams 1977); the third report was a duplicate publication (Ellis 1994); and in the fourth trial, which compared nystatin with amphotericin B (Epstein 2004), all 40 patients received systemic fluconazole 200 mg/d, which is an effective treatment. Of the 14 included trials 3 were published as abstracts only (Feusner 1994; Powles 1999; Tian 1997).
The drugs were given prophylactically in 12 trials and as treatment in 2 (Flynn 1995; Pons 1997). Acute leukaemia was the most common disease in eight trials; two trials concerned exclusively (Feusner 1994) or mainly (Flynn 1995) patients with cancer, one mainly patients receiving a bone marrow transplant (Powles 1999), one patients receiving a liver transplant (Lumbreras 1996), one critically ill surgical and trauma patients (Savino 1994), and one AIDS patients (Pons 1997). Nystatin was compared with placebo or no treatment in 3 trials, with fluconazole in 10, and with amphotericin B in one; all drugs were given orally apart from the amphotericin B trial (Powles 1999). The daily dose of nystatin in adults varied from 0.8 MIE to 72 MIE daily, and was 2 mg/kg/d in a liposomal formulation. In three trials the participants were children (Feusner 1994; Flynn 1995; Groll 1997). Length of follow‐up was stated in only three trials (Ellis 1994; Lumbreras 1996; Powles 1999). Although one of the trials was described as a two‐armed study (Groll 1997), 18 of the patients were also included in a report of a three‐armed study (Ninane 1994). We have previously drawn attention to this curious discrepancy but it has not been explained (Johansen 1999).
For the 2011 and 2014 updates no additional trials were identified for inclusion.
Risk of bias in included studies
We adopted broad quality assessment criteria and considered the risk of bias to be be low if the randomisation method was concealed, for example if central randomisation, use of sealed envelopes, a code provided by a pharmacy or a company was described; and if the generation of the allocation sequence was adequate (for example random numbers) and the trial was placebo controlled and blinded. Concealment of treatment allocation was reported in three trials (Ellis 1994; Flynn 1995; Savino 1994). Blinding was reported in five trials; the control group received saline in one trial (Epstein 1992), the double‐dummy technique was used in one trial (Young 1999), and the assessors were blinded in three trials (Ellis 1994; Flynn 1995; Pons 1997). Losses to follow‐up and exclusions were reasonably low apart from one trial (Young 1999) where the only reliable data were those for mortality (Characteristics of included studies).
Effects of interventions
None of the three placebo‐controlled trials reported on deaths or on invasive fungal infection according to our criteria. One trial reported five cases of sepsis on nystatin and two on placebo but the definition of sepsis included positive cultures from at least three sites (Savino 1994). The effect of nystatin was similar to that of placebo on fungal colonisation; the total number of colonisations on nystatin was 53 out of 164 patients while it was 57 out of 147 on placebo (relative risk (RR) 0.85, 95% confidence interval (CI) 0.65 to 1.13).
There was no statistically significant difference between fluconazole and nystatin on mortality (RR 0.75, 95% CI 0.54 to 1.03) whereas fluconazole was considerably more effective in preventing invasive fungal infection (RR 0.40, 95% CI 0.17 to 0.93) and colonisation (RR 0.50, 95% CI 0.36 to 0.68). There was marked heterogeneity for colonisation (P value < 0.001), which was driven by an unusually large effect of fluconazole in one of the two treatment trials in which the patients had oropharyngeal thrush (Flynn 1995) and a very small effect in one of the prophylactic trials (Groll 1997). The heterogeneity was probably caused by the lack of a consistent definition of colonisation. If these two studies were excluded the heterogeneity disappeared whereas the RR was virtually the same as before (RR 0.48, 95% CI 0.39 to 0.58). The results were also similar for all three outcomes if the studies that were not performed in cancer patients were excluded. There were no proven fungal infections in a small trial that compared amphotericin B with liposomal nystatin (4 out of 15 versus 2 out of 16 patients died) (Powles 1999).
The results were similar for the trials with adequate concealment of allocation, but the power was low for a comparison with those trials that did not provide information on the randomisation method.
The reporting of harms was variable from trial to trial, and some trials reported no data at all (Table 1). Treatment discontinuations were most commonly caused by nausea, vomiting, and liver enzyme increases; and oral administration of nystatin was described as difficult in two trials.
1. Harms.
| Trial | Experimental drug | Control | Number of patients | Harms |
| Epstein 1992 | nystatin | saline | 50 versus 36 | No data |
| Savino 1994 | nystatin | none | 75 versus 72 | No data |
| Buchanan 1985 | nystatin | fluconazole | 39 versus 39 | No data |
| Egger 1995 | nystatin | fluconazole | 46 versus 43 | Treatment discontinuations: 3 (poor tolerance and severe vomiting) versus 1 (rising liver enzymes). Oral administration of nystatin was difficult in patients receiving therapy for more than 2 weeks |
| Ellis 1994 | nystatin | fluconazole | 48 versus 42 | Treatment discontinuations: none for more than one day at the time; Nausea: 3 versus 0; Severe calf cramps: 0 versus 1. Several patients had difficulties in sucking the trouches due to mucositis. More patients on fluconazole had minor bilirubin changes; mean increases in liver enzymes similar in the two groups |
| Feusner 1994 | nystatin | fluconazole | 178 total | Treatment discontinuations: 0 versus 5 (1 seizure, 2 vomiting, 1 nausea, 1 rash); Other harms: 21 versus 25 (mostly gastrointestinal) |
| Flynn 1995 | nystatin | fluconazole | 88 versus 94 | Treatment discontinuations: 0 versus 2 (gastrointestinal effects); "Clinical side effects thought to be related to treatment": 3 versus 7 (mostly gastrointestinal); Liver function test abnormalities: 7% versus 8% |
| Groll 1997 | nystatin | fluconazole | 25 versus 25 | Treatment discontinuations: none; Nausea and gastrointestinal discomfort: 0 versus 3; Pruritus: 0 versus 1; Elevated liver enzymes: 3 versus 7 |
| Lumbreras 1996 | nystatin | fluconazole | 67 versus 76 | Treatment discontinuations: 0 versus 1 (confusion); Adverse events ascribed to drugs: 25% versus 33%; Mild gastrointestinal symptoms: 19% versus 9%; Acute renal failure: 12% versus 13%; Liver enzymes: "no differences" (no data) |
| Pons 1997 | nystatin | fluconazole | 84 versus 83 | Treatment discontinuations: 2 versus 3 (adverse effects or abnormal laboratory values, including 1 vomiting versus 1 nausea and 1 liver enzymes increase); Other harms: no data |
| Tian 1997 | nystatin | fluconazole | 40 versus 40 | No data |
| van Delden 1995 | nystatin | fluconazole | 33 versus 36 | Treatment discontinuations: 4 (1 mucositis, 1 rash, 1 vomiting) versus 0; Rash: 3 versus 6 |
| Young 1999 | nystatin | fluconazole | 78 versus 86 | Treatment discontinuations: 11 versus 6 (reasons not specified, most common were gastrointestinal adverse effects); Liver enzyme increase: 19 versus 7; Other harms: similar (extensive table on harms) |
| Powles 1999 | nystatin | amphotericin B | 16 versus 15 | Treatment discontinuations: 6 versus 3; Infusion related toxicity: 15 versus 10; Renal impairment: 0 vs 3; Liver dysfunction: 0 versus 2 |
Discussion
Nystatin is an old drug which is still frequently used for the prophylaxis and treatment of Candida infections. However, it is widely recognized as being a relatively ineffective drug. Nystatin is almost insoluble and it is not recommended for use in cancer patients with neutropenia (Working Party 1995). We could confirm this recommendation, at least in patients with severe immunodeficiency, which was the type of patients we included in this review. Nystatin was no better than placebo and this finding is strengthened by the fact that the difference between fluconazole and nystatin was very similar to the difference between fluconazole and placebo, which we have reported on previously (Gøtzsche 1997; Gøtzsche 2002). Whether nystatin is effective in patients who are not immunodepressed is a different matter that needs a separate review.
Authors' conclusions
Implications for practice.
The effect of nystatin given orally to immunodepressed patients was no better than that of placebo, whereas it was inferior to the effect of fluconazole. Nystatin cannot be recommended for prophylaxis or treatment of Candida infections in immunodepressed patients.
Implications for research.
There seems to be little scope for further trials of nystatin given orally to immunodepressed patients since more effective antifungal agents exist, and since the effect of nystatin was at placebo level.
What's new
| Date | Event | Description |
|---|---|---|
| 8 March 2017 | Review declared as stable | Intervention no longer in general use. |
History
Review first published: Issue 2, 2000
| Date | Event | Description |
|---|---|---|
| 7 July 2014 | New citation required but conclusions have not changed | No new trials identified for inclusion |
| 7 July 2014 | New search has been performed | Literature searches updated |
| 14 September 2011 | New search has been performed | Review updated with new search details. No new studies were identified for inclusion. |
| 18 July 2011 | Amended | Searches re‐run July 2011. |
| 5 February 2008 | New search has been performed | Minor update |
| 5 November 2007 | New search has been performed | New studies found and included or excluded:One new outcome added (harms), one excluded trial added (Epstein) |
| 29 July 2002 | New search has been performed | Substantive amendment |
Acknowledgements
We wish to thank our funders for the research grants which made this review possible.
The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological, Neuro‐oncology, Orphan Cancer Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.
Appendices
Appendix 1. PubMed search strategy
#1: random* OR control* OR blind* #2: nystatin OR amphotericin OR fluconazol* OR itraconazol* OR ketoconazol* OR miconazol* OR voriconazol* #3: bone‐marrow OR cancer* OR fungemia OR hematologic* OR malignan* OR neoplas* OR neutropeni* OR granulocytopeni* OR leukemi* OR lymphom* #4: #1 AND #2 AND #3.
Data and analyses
Comparison 1. Nystatin versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Colonisation | 3 | 311 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.65, 1.13] |
1.1. Analysis.
Comparison 1 Nystatin versus placebo, Outcome 1 Colonisation.
Comparison 2. Fluconazole versus nystatin.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Colonisation | 9 | 947 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.36, 0.68] |
| 2 Fungal invasion | 6 | 617 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.40 [0.17, 0.93] |
| 3 Death | 6 | 692 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.54, 1.03] |
2.1. Analysis.
Comparison 2 Fluconazole versus nystatin, Outcome 1 Colonisation.
2.2. Analysis.
Comparison 2 Fluconazole versus nystatin, Outcome 2 Fungal invasion.
2.3. Analysis.
Comparison 2 Fluconazole versus nystatin, Outcome 3 Death.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Buchanan 1985.
| Methods | Allocation concealment: NA Blinding: none | |
| Participants | 78 patients with acute leukaemia, prophylactic Excluded: NA | |
| Interventions | Experimental: nystatin suspension 1 MIE x 6 Control: no treatment | |
| Outcomes | Colonisation Infections | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
| Blinding (performance bias and detection bias) All outcomes | High risk | |
Egger 1995.
| Methods | Allocation concealment: NA Blinding: none | |
| Participants | 90 patients with acute leukaemia, prophylactic Excluded: 1 | |
| Interventions | Experimental: fluconazole 400 mg orally or iv once daily Control: nystatin suspension 24 MIE x 3 and miconazole inhalations x 3 | |
| Outcomes | Colonisation Infections Use of escape drug | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
| Blinding (performance bias and detection bias) All outcomes | High risk | |
Ellis 1994.
| Methods | Allocation concealment: computer generated code at pharmacy Blinding: observer and analysis | |
| Participants | 94 patients with acute leukaemia, prophylactic Excluded: 4 | |
| Interventions | Experimental: fluconazole 200 mg orally once daily Control: mouthwash with nystatin 0.5 MIE, benadryl elixir and cepacol x 4 and clotrimazole troches 10 mg x 2 | |
| Outcomes | Colonisation Infections Deaths | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Low risk | A ‐ Adequate |
Epstein 1992.
| Methods | Allocation concealment: NA Blinding: saline as control treatment | |
| Participants | 99 patients with acute leukaemia, prophylactic Excluded: 13 | |
| Interventions | Experimental: nystatin suspension 1.5 MIE x 4 Control: saline | |
| Outcomes | Colonisation Oral mucositis | |
| Notes | Factorial design | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
Feusner 1994.
| Methods | Allocation concealment: NA Blinding: NA | |
| Participants | 178 children with neutropenia after chemotherapy, prophylactic Excluded: NA | |
| Interventions | Experimental: fluconazole 6 mg/kg/d Control: nystatin 0.4 MIE x 4 | |
| Outcomes | Colonisation Infections | |
| Notes | Published as abstract only | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
Flynn 1995.
| Methods | Allocation concealment: computer generated code held by pharmacist Blinding: observer | |
| Participants | 186 children with immunodeficiency (92 cancer, 64 HIV, 30 immunosuppressive disorder and/or therapy) and oral candidiasis, treatment Excluded: 27 | |
| Interventions | Experimental: fluconazole suspension 2 mg/kg/d Control: nystatin suspension 0.4 MIE x 4 | |
| Outcomes | Colonisation Deaths Clinical symptoms | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Low risk | A ‐ Adequate |
| Blinding (performance bias and detection bias) All outcomes | Low risk | |
Groll 1997.
| Methods | Allocation concealment: NA Blinding: none | |
| Participants | 60 children with acute leukaemia, prophylactic Excluded: 10 | |
| Interventions | Experimental: fluconazole suspension 3 mg/kg/d Control: nystatin suspension 0.05 MIE/kg/d | |
| Outcomes | Colonisation Infections Deaths | |
| Notes | Although this is described as a two‐armed study, 18 of the patients were also included in a report of a three‐armed study (Ninane 1994). This discrepancy has not been explained | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
| Blinding (performance bias and detection bias) All outcomes | High risk | |
Lumbreras 1996.
| Methods | Allocation concealment: NA Blinding: none | |
| Participants | 143 patients with a liver transplant, prophylactic Excluded: none | |
| Interventions | Experimental: fluconazole capsule 100 mg daily Control: nystatin suspension 1 MIE x 4 | |
| Outcomes | Colonisation Infections Deaths | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
| Blinding (performance bias and detection bias) All outcomes | High risk | |
Pons 1997.
| Methods | Allocation concealment: NA Blinding: observer | |
| Participants | 167 patients with AIDS and oropharyngeal candidiasis, treatment Excluded: 29 | |
| Interventions | Experimental: fluconazole suspension 100 mg daily Control: nystatin suspension 0.5 MIE x 4 | |
| Outcomes | Colonisation Deaths Clinical cure | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
| Blinding (performance bias and detection bias) All outcomes | Low risk | |
Powles 1999.
| Methods | Allocation concealment: NA Blinding: NA | |
| Participants | 31 cancer patients with neutropenia, mostly bone marrow recipients, empiric Excluded: four patients were "non‐evaluable" | |
| Interventions | Experimental: amphotericin B 0.8 mg/kg/d iv over 4 h Control: liposomal nystatin 2 mg/kg/d i.v. over 2 h | |
| Outcomes | Normalisation of temperature Tolerability Infections Deaths | |
| Notes | Patients completing 5 days of treatment were "evaluable". No patients developed proven fungal infection. Not clear how many died | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
Savino 1994.
| Methods | Allocation concealment: sealed envelopes drawn sequentially Blinding: none | |
| Participants | 147 critically ill surgical and trauma patients, prophylactic Excluded: none | |
| Interventions | Experimental: nystatin 2 MIE x 4 Control: no treatment | |
| Outcomes | Colonisation Infections Deaths | |
| Notes | Data on infections and deaths were not divided on treatment groups according to our definitions. Four‐armed study, with ketoconazole and clotrimazole in addition | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Low risk | A ‐ Adequate |
| Blinding (performance bias and detection bias) All outcomes | High risk | |
Tian 1997.
| Methods | Allocation concealment: NA Blinding: NA | |
| Participants | 80 patients with acute leukaemia and other haematologic malignancies, prophylactic Excluded: NA | |
| Interventions | Experimental: fluconazole 50 mg daily Control: nystatin 0.5 MIE x 3 | |
| Outcomes | Colonisation Infections | |
| Notes | Abstract, few data | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
van Delden 1995.
| Methods | Allocation concealment: NA Blinding: none | |
| Participants | 74 cancer patients with neutropenia, mostly leukaemia, prophylactic Excluded: 1 in fluconazole group, 6 in nystatin group | |
| Interventions | Experimental: fluconazole 100 mg daily as capsule (iv if not tolerated) Control: nystatin 0.8 MIE/d as solution | |
| Outcomes | Colonisation Infections Deaths Use of escape drug | |
| Notes | Trial stopped prematurely because of other trial results | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
| Blinding (performance bias and detection bias) All outcomes | High risk | |
Young 1999.
| Methods | Allocation concealment: NA Blinding: double‐blind (double‐dummy technique) Patients could be enrolled more than once (no data given) | |
| Participants | 164 leukaemic patients with neutropenia after chemotherapy, prophylactic Excluded: 1 from mortality analysis, 55 from other efficacy analyses | |
| Interventions | Experimental: fluconazole 200 mg daily Control: nystatin 6 MIE daily | |
| Outcomes | Colonisation Infections Deaths | |
| Notes | The validity of this trial is greatly reduced by the many exclusions, some of which appear rather dubious, eg 12 versus 0 patients were excluded because of "incorrect dosing" although all patients recieved the same doses because of the double‐dummy technique. Intention‐to‐treat analysis rendered significant findings non‐significant | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | B ‐ Unclear |
| Blinding (performance bias and detection bias) All outcomes | Low risk | |
NA: not available
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Carpentieri 1978 | Not a randomised trial |
| DeGregorio 1982 | Not a randomised trial |
| Epstein 2004 | All 40 patients received systemic fluconazole, 200 mg/d, which is an effective treatment |
| Hoppe 1995 | Failed because of serious compliance problems |
| Williams 1977 | No relevant data, only "Candida‐free days" |
Differences between protocol and review
There was no separate protocol for this review as we were asked by the editors of JAMA to do an additional meta‐analysis on nystatin when we published our review on fluconazole (Johansen 1999); we therefore based the current review as part of the protocol for the fluconazole review.
Contributions of authors
HKJ wrote the draft meta‐analysis protocol, HKJ and PG contributed equally to selection of trials, data extraction and writing of the manuscript. Guarantors: both authors.
Sources of support
Internal sources
Rigshospitalet, Denmark.
External sources
JASCHA‐fonden, Denmark.
Nordic Council of Ministers, Denmark.
The Swedish Society of Medicine, Sweden.
Declarations of interest
Peter C Gøtzsche ‐ nothing to declare Helle Krogh Johansen ‐ nothing to declare
Stable (no update expected for reasons given in 'What's new')
References
References to studies included in this review
Buchanan 1985 {published data only}
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