Title Long-term follow-up of otomycosis and its

Title
Long-term follow-up of otomycosis and its
treatment with Bifonazole
Presenter:
Sarisa Romsaithong, M.D.
Faculty of Medicine KhonKaen University, Thailand
2011
1
International Short Course Training In
Research Methodology & Biostatistics
Critical Appraisal
Title
Long-term follow-up of otomycosis and its treatment with
Bifonazole
Presenter
Sarisa Romsaithong, M.D.
Faculty of Medicine, Khon Kaen University
Thailand 2011
2
Course: Critical appraisal
Module: How to read clinical journal
Objective: To be able to critical appraise the published medical
research article
Title:
Long-term follow-up of otomycosis and its treatment with
Bifonazole
Authors: A. Del Palacio, M.J. Lopez-suso, M.K. Moore, M.S. Cuetara,
C.Garcia-La Calle and A.R. Noriega
Journal: Journal of Medical and Veterinary Mycology (1993), 31, 435447
Presenter:
Sarisa Romsaithong
3
Contents
Page
1. Clinical scenario
4
2. Rational and Background
4
3. Searching strategies
6
4. Brief summary of article
8
5. Critical appraisal of the article
19
6. Attached selected article
25
4
Clinical scenario
In ENT clinic, otomycosis (fungal infection of the external ear) is not an
uncommon disease. The standard treatments are cleaning of fungal debris from
external ear canal and applying antifungal agent which has many agents and
formulations. In general practice it is more difficult to apply topical antifungal
cream than the otic drop preparation. There are two forms of preparations,
cream and solution. We would like to know the efficacy comparing between
these two types.
Clinical question
Is the efficacy of antifungal solution comparable with antifungal cream in
patients with otomycosis?
Type of question: Therapy
Background and rationale
Otomycosis is a superficial fungal infection of the external ear canal, in the
other way it is an otitis external which is caused by fungus. Predisposing factors
are warm, humid environment, swimming, immunocompromised host, selfinduced trauma (e.g. by cotton swabs) and previous using topical antibacterial/
steroid preparation.
Clinical presentations are ear pain, pruritus and aural fullness. Physical
examination reviews varying in color (white, black, grey, etc.) cotton or greasy
debris in the external ear canal and tympanic membrane. Common pathogens
are Aspergillus species and Candida species. Patients should be treated with
cleaning fungal debris combined with topical antifungal agent.
There is wide range of topical antifungal agents. Three main groups of
topical drugs are currently available.
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Acidifying agents
Burow’s solution, acetic acid and boric acid solution are acidifying agent
commonly used. The acidification helps inhibit bacterial and fungal growth. It has
been shown to treat most mild cases successfully.
Topical antifungal drugs
Clotrimazole, bifonazole, ketoconazole and miconazole are in imidazoles
group which are fungistatic and broad spectrum of activity against
dermatophytes, yeasts, molds and gram-positive bacteria. The commercially
available formulations for topical treatment include cream, gel ointment and
solution.
Topical antiseptics
Mercurochrome and tincture merthiolate are mercury compounds which
have shown good clinical and mycotic cure and low cost. But now Food and
Drug Administration (FDA) dose not approve these drugs anymore due to
mercury ingredient.
Tincture merthiolate is one of a common use as a topical antifungal agents
in Thailand because of its efficacy and low cost. Therefore, the question is which
antifungal drugs should be the next choice? Between acidifying agent and
imdazole group, acidifying agent usually works in mild case of otomycosis, or
use to prevent recurrent infection. Then if imidazoles group is the next choice,
which formulation is more suitable for the patients?
Then I start searching strategies.
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Searching strategies
Clinical questions: PICO
P : participant / problem patients with otomycosis
I : intervention
topical antifungal solution
C : comparison topical antifungal cream
O : outcome
clinical response
Searching:
Used PubMed by MEDLINE database by Clinical Queries (category:
therapy, scope: broad) use key words (searching on15 Aug 2011)
Query # 1
otomycosis the result showed 83 articles
Query # 2
otomycosis OR ((fung* OR mycos*) AND (ear OR otitis) AND
extern*), the result showed 293 articles
Query #3
search (#2) AND (clotrimazole OR bifonazole OR ketoconazole
OR miconazole OR imidazole ), result showed 41 articles
Among 41 articles, there were few randomized control trials (RCT) that
related to my question. Then I further searched in Scopus database with key
words as below .
otomycosis OR “fungal otits externa”, the result showed 273 articles.
When added AND treatment, the result showed 109 articles.
Then added AND (clotrimazole OR bifonazole OR ketoconazole OR
miconazole), the result show 46 articles. Among these papers, there were many
interesting articles but most of them were not RCT and some papers could not
be retrieved for full paper. There was an article “Long-term follow-up of
otomycosis and its treatment with bifonazole” which related with my research
question, and had randomized the treatments. So I chose this paper for this
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presentation. This article was published in an index journal with no impact factor.
However, it has been cited for 6 times.
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Brief summary of article
1.Title:
Long-term follow-up of otomycosis and its treatment with Bifonazole
Authors: A. Del Palacio, M.J. Lopez-suso, M.K. Moore, M.S. Cuetara,
C.Garcia-La Calle and A.R. Noriega
Source:
Journal of Medical and Veterinary Mycology (1993), 31, 435-447
2. Objective of the study:
To compare the clinical efficacy and tolerance of different forms
of bifonazole on the fungal and bacterial flora of the ear
3. Study design:
Pilot prospective randomized controlled trial
4. Methodology
Recruitment
- Patients with symptomatic otomycosis (confirm by direct microscopy
and culture) at OPD ENT, Hospital 12 de Octubre, Madrid, Spain
- Patients who are willing to consent the study
Exclusion criteria
- Patients who had had topical or systemic antifungal or antibacterial
within 4 weeks prior to the start of the study.
- Pregnant women
Randomly assigned treatment
This study did not mention how to random the patients
Intervention and follow up
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- Before antifungal therapy both groups had ear cleaning by ENT surgeon
under a Zeiss microscope (1.6 power) to remove the debris.
- The medication was applied once daily in external ear canal x 7days by
means of a wick (gauze strip 5x1cms) impregnated with either solution or
cream of bifonazole which was replaced daily.
- The patients were seen daily for changing gauze strip.
- Assessment was begun at 3 days, 2 weeks post treatment and 2.5 years
after treatment.
Micrological exam
- Before antifungal therapy KOH wet mount and fungal culture on
Sabouraud glucose agar were taken from debris under microscopy. MIC
(minimal inhibitory concentration) value was determined using a broth
double dilution test. Swabs were taken with sterile cotton wool tipped
applicator for bacterial growth and were inoculated on 2 blood agar plate
(one each for aerobic and anaerobic bacteria ), one McConkey’s agar plate
for Gram-negatives and chocolate agar for Haemophilus sp.
Primary outcome
- Clinical cure + negative fungal c/s
- Clinical cure + positive fungal c/s
- Clinical improve + negative / positive fungal c/s
- Therapeutic failure (no clinical response + positive c/s)
Secondary outcome
- Sign & symptom of otomycosis
- Fungi & bacteria culture before Tx
- Fungi & bacteria culture after Tx 3d, 2wk
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- Relapse (positive fungus in healed / improved pt)
- Tolerance of bifonazole in different forms
5. Statistical analysis
Wilcoxon test
- analyzed clinical improve (compare successive time points /each Tx)
Mann-Whitney U-test
- compare result each visit
Chi-square test
- compare mycological & bacteriological response(c/s) and relapse
rates
6. Results
From July to December 1987, 35 patients with otomycosis were
included in the study.
Five patients had bilateral fungal infection so there were 40 treated
sites in this study and 20 treated sites were divided in 2 groups for
analysis.
Two patients who had bilateral fungal infection were treated with
cream in both ears and the 3 other patients with solution in one side and
cream in the other.
Baseline characteristic between both groups were shown in table 1.
The patients’ characteristics were evenly distributed between both groups.
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-There were no significant differences between both groups in the
distribution of baseline sign and symptoms.
- The mean sum scores at baseline were also similar and pus was never
present in fungal otitis.
12
-The fungi and bacteria isolated are shown in Table 3.
-There was no association between the fungal species cultured and the
different accompanying bacteria.
-No significant association was found between severity of signs and
symptom before therapy and the presence or absence of each specific
group of bacteria and fungi.
There were 14ears with sterile bacterial cultures, whereas after
treatment all the sites had positive bacterial cultures (p= 0.00003, Fisher’s
test) as in Fig. 1.
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Assessment 3days and 2weeks after the end of therapy found that there
was no significant difference between both formulations in clinical and
mycological responses. (Table 4, 5)
14
15
- Five sites which had clinically relapsed at 2weeks were found no
significant association with positive or negative fungal culture at the
3days assessment (3sites relapsed from 33 negative cultures, 2sites
relapsed from 7 positive cultures)
- After treatment with bifonazole bacterial growth was obtained from all
ears but there was no significant association between fungal species
and bacterial cultured.
Tolerance:
- Seventeen ears (85%) were irritated by the solution.
ÆTwelve
ÆFive
patients had moderate itching and burning with each application.
patients had severe itching and burning.
- Three patients who had bilateral otomycosis had intolerance only in the
solution treated side. (The symptom lasted varied between min- 1 h)
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Long term follow-up
- Ten ears relapsed with otitis externa after periods ranging from 2.5
months to 2 years as the result in Table 6.
Risk factors for relapsed patients
- Ten fungal or bacterial relapses from 20ears with underlying conditions:
Eczema (5 patients), post-operative mastoid cavity (4 patients), tubal
moisture (4 patients), hearing aid (2 patients) and psoriasis (1 patient)
- The relapses rate at long time follow-up was significantly associated
with predisposing factors and underlying conditions. (p= 0.0073,
Fisher’s test)
- Eczema was significantly associated with fungal or bacterial otitis
externa (p= 0.001, Fisher’s test)
- Relapsed at 2 years were found no significant association with positive
or negative fungal culture at the 2 weeks after the end of treatment. (2
relapsed from 23 sites with negative fungal cultures, 4 relapsed from 17
sites with positive fungal cultures)
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- There are only 2 patients that relapsed with the same fungal species as
shown in Table 7 but patient No.24 had relapsed on the asymptomatic
ear at baseline and patient No.27 had additional C. parapsilosis.
- Patients relapsed with bacterial otitis always had abundant purulent
discharge.
7. Discussion
- The best evidence of fungal otitis externa is demonstration of abundant
yeasts or hyphae within the debris.
- In this study, Aspergillus niger was the predominant agent found in 27
out of 40 baseline.
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- Eczema was significantly risk factor in relapse rate (p= 0.001, Fisher’s
test)
- This study shows C. albicans and C. parapsilosis and other mycelia
fungi are part of the normal transient and fixed flora of the external ear
canal and sometimes shift to pathogenic status under the influence of
several factors.
- With long term relapses the underlying conditions and skin diseases
seem to be important with new emerging infecting species (either fungal
or bacterial)
- This study found purulent discharge is significantly associated with
bacterial otitis externa (Fisher’s test, p= <0.001), but always absent in
otomycosis. Therefore when pus is present in otitis externa, otomycosis
can be excluded.
- Imidazoles which have the theoretical advantage against Gram-positive
bacteria invitro does not seem to represent advantage in this study.
- This study stressed the need of using ear wig soaked with antifungal
compound to provide constant of tissue contact with prolong antifungal
effect.
- This study showed equal response of the different offending species.
- No significant difference in the clinical and mycological responses of the
patients with and without predisposing factors and underlying
conditions.
- Tolerance was excellent with cream formulation.
- Appropriate comparative trials are needed to establish whether specific
antifungal topical therapy offers any advantages compared to other
compounds in management of otomycosis.
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Critical appraisal of this article in therapy
1. General step for selection of the article
Title
: Did not clear and not correspond with the main objective.
Authors’ publication track record s :
The first author A Del Palacio was a staff at department of
microbiology, Hospital 12 de Octubre, Madrid, spain. He has published 144
articles as searched by using Scopus. M J Lopez –suso and M K Moore also
worked at the same place with the first author and has published 2 and 33
documents respectively.
Abstract
: - Did not systematically organize in each part.
- The purpose has not been mentioned.
- Some data summarized in abstract was not mentioned in the
result.
2. Are the results of this therapeutic trial valid?
• Was the assignment of patients to treatments randomized?
Uncertain: Although this study said that the patients were randomly
assigned to treatment, but did not mention the detail of how to do the
randomization.
• Was randomization list concealed?
Uncertain: The author did not mention about concealment , which can
cause a selection bias.
• Was follow- up of patients sufficiently long and complete?
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Yes: The follow-up time was long enough for day 3 and day 12 visits but
one year was seemed to be too long for this kind of disease. Usually 1
month is enough for follow-up to assess the relapse of otomycosis.
At the end of the study there were 36 sites that were completely
follow-up, 4 sites (10%) were loss follow-up which seemed not to affect the
result.
• Were all patients analyzed in the groups to which they were
randomized?
The authors did not mention whether they analyzed the results according
to the “intention-to-treat” principle or not. However they mentioned that all
relapse patients had been changed treatment into bifonazole cream. If
they counted the relapse group as using bifonazole cream, this analysed
will not be intention-to-treat principle.
• Were patients and clinician kept “blind” to treatment?
Because the methods of administration between using cream and solution
were different, so the patients and the doctors who gave the interventions
were not kept blind to the treatment. However blinding the patients might
not be important because the outcomes did not depend on the patients.
This study did not mention whether the outcome assessor was kept blind
to the treatment or not. The main outcome of this study was clinical
assessment. So blinding the outcome assessor was very important.
Moreover this study did not mention the criteria for clinical cured / improve,
the information bias can occur.
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• Were the groups treated equally, apart from the experimental
treatment?
Yes: During 7 days of treatment, every patient came to hospital to receive
the same treatment except the intervention drugs. However for the long
term follow up, they might have the different co-interventions.
• Were the groups similar at the start of the trial?
Yes: From the baseline characteristic in Table 1, they were similar.
• Was the statistical analysis appropriate?
This study used Wilcoxon test to compare successive time points for
each treatment group, Mann-Whitney U-test to compare result each visit
and Chi-square test to compare mycological & bacteriological
response(culture) and relapse rates.
However there were two types of Wilcoxon test, Wilcoxon signed
rank test and Wilcoxon rank sum (Mann-Whitney U-test. Wilcoxon signed
rank test is used in non-parametric dependence outcome for continuous
data and Wilcoxon rank sum (Mann-Whitney U-test) is used in nonparametric independent outcome for continuous data.
It seemed that the authors did not used Wilcoxon test as mentioned
in the statistical analysis part. However the main outcome used with Chisquare which was appropriate
• In summary, was this study valid/accepted?
From all of the above information, the validity is acceptable.
But to make it more valid for the next trial randomization technique,
concealment, contamination by treatment in the relapsed patients should
be considered. Besides, the measurement of primary outcome (clinical
response) should be clearly identified in criterions for the assessor.
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3. Are the valid results of this randomized trial important?
The results of treatment outcome were shown as below.
Otomycosis treated with bifonazole, assessed 3 days after treatment.
Cure rate of
otomycosis treated
with bifonazole
Relative
risk
reduction
(RRR)
Bifonazole Bifonazole
cream
solution
(CER)
EER
CER-EER
CER
CER-EER
8%
5%
20
95% CI
-23% to 32%
-4 to 3
65%
60%
Absolute risk
Number
reduction
needed to
(ARR)
treat (NNT)
1/ ARR
Otomycosis treated with bifonazole, assessed 14 days after treatment,
The result is in the table below.
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Cure rate of
otomycosis treated
with bifonazole
Relative
risk
reduction
(RRR)
Absolute risk
reduction
(ARR)
Number
needed
to treat
(NNT)
Bifonazole Bifonazole
cream
solution
(CER)
(EER)
CER-EER
CER
CER-EER
1/ ARR
7%
5%
20
95% CI
-22% to 31%
-5 to 3
75%
70%
From the result can conclude that “there is not enough evidence to
assume that bifonazole solution’s efficacy different from bifonazole
cream”.
4. Can you apply this valid, important evidence about therapy in
caring for your patient?
• Is your patient so different from those in the study that its results cannot
apply?
No, there is no difference, then the application can be done to my patients.
• Is the treatment feasible in your setting?
Not really, the whole concept of treatment is similar but there is no
bifonazole in Thailand anymore but there are other drugs in the same
group that can be used instead. And some details such as the technique of
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daily changing ear wig might not possible (it’s not convenience for the
patient to come to hospital everyday) but it can be modified.
• What are your patients’ potential benefits and harms from the therapy?
For benefits, they will receive the proper topical antifungal preparation, for
harms according to the drug is a topical application so the side effects are
not serious.
My conclusions
I concluded that the internal validity of this study is weak and there are
some points of views should be improved such as explaining the
randomization technique, concealment and design more proper treatment for
the relapsed patients. More important, the measurement of primary outcome
(clinical response) should be clearly identified in criterions for the assessor.
From the result of this study which is still inconclusive, then the external
validity is not accepted or used. Therefore it is a good beginning for the new
other trials to make a better studys.
In conclusion of my scenario, the answer is not clear. The new trial must
be designed.
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