Oral azithromycin versus doxycycline in meibomian gland dysfunction: a randomised double-masked open-label clinical trial

Mohsen Bahmani Kashkouli; Ali Jalili Fazel; Victoria Kiavash; Marzieh Nojomi; Leila Ghiasian

doi:10.1136/bjophthalmol-2014-305410

Responses

Clinical science

Oral azithromycin versus doxycycline in meibomian gland dysfunction: a randomised double-masked open-label clinical trial

Compose a Response to This Article

Compose Response

Title *

Author Information

Contributors
First Name and Middle Initial * First or given name, e.g. 'Peter'. Last Name * Your last, or family, name, e.g. 'MacMoody'. Email Address * Your email address, e.g. higgs-boson@gmail.com Occupation * Your role and/or occupation, e.g. 'Orthopedic Surgeon'. Affiliation * Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.

Statement of Competing Interests

Competing interests? *

Yes

Please describe the competing interests

PLEASE NOTE:

A rapid response is a moderated but not peer reviewed online response to a published article in a BMJ journal; it will not receive a DOI and will not be indexed unless it is also republished as a Letter, Correspondence or as other content. Find out more about rapid responses.
We intend to post all responses which are approved by the Editor, within 14 days (BMJ Journals) or 24 hours (The BMJ), however timeframes cannot be guaranteed. Responses must comply with our requirements and should contribute substantially to the topic, but it is at our absolute discretion whether we publish a response, and we reserve the right to edit or remove responses before and after publication and also republish some or all in other BMJ publications, including third party local editions in other countries and languages
Our requirements are stated in our rapid response terms and conditions and must be read. These include ensuring that: i) you do not include any illustrative content including tables and graphs, ii) you do not include any information that includes specifics about any patients,iii) you do not include any original data, unless it has already been published in a peer reviewed journal and you have included a reference, iv) your response is lawful, not defamatory, original and accurate, v) you declare any competing interests, vi) you understand that your name and other personal details set out in our rapid response terms and conditions will be published with any responses we publish and vii) you understand that once a response is published, we may continue to publish your response and/or edit or remove it in the future.
By submitting this rapid response you are agreeing to our terms and conditions for rapid responses and understand that your personal data will be processed in accordance with those terms and our privacy notice.

I agree to and have read the terms and conditions for rapid responses and BMJ Privacy Notice *

CAPTCHA

This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

Other responses

Jump to comment:

Re:Data inconclusive to recommend oral azithromycin over oral doxycycline in meibomian gland dysfunction
Mohsen B Kashkouli
Published on: 22 March 2016
Data inconclusive to recommend oral azithromycin over oral doxycycline in meibomian gland dysfunction
Michel J. Belliveau
Published on: 22 March 2016
An additional explanation for azithromycin's efficacy in treating meibomian gland dysfunction
Yang Liu
Published on: 22 March 2016

Published on: 22 March 2016
Re:Data inconclusive to recommend oral azithromycin over oral doxycycline in meibomian gland dysfunction
- Mohsen B Kashkouli, Ophthalmic Plastic Surgery
- Other Contributors:
  Marzieh Nojomi
We would like to thank Michel J. Belliveau for the comments on our recently published trial(1) on comparing the oral Azithromycin with doxycycline. All the concerns regarding the data presentation are being addressed in the following paragraphs. The null hypothesis had been written in the study design (ClinicalTrials.gov; NCT01783860) which was not mentioned in the article because of word number limitation. It was a tw...
Show More

We would like to thank Michel J. Belliveau for the comments on our recently published trial(1) on comparing the oral Azithromycin with doxycycline. All the concerns regarding the data presentation are being addressed in the following paragraphs. The null hypothesis had been written in the study design (ClinicalTrials.gov; NCT01783860) which was not mentioned in the article because of word number limitation. It was a two-tail hypothesis: "there is not any difference in severity of disease (measured by sign and symptom checklist) at the last follow-up across two groups of treatment (Oral Azithromycin versus Doxycycline)." The sample size calculation was based on the references 12 and 14 of our article which have been cited in the method section. (1) Prior validation is recommended for a questionnaire and not for grading the signs and symptoms of a disease. While a standard questionnaire (like quality of life questionnaire) requires a prior validation because of different subjective feeling and responses to each question, symptom and sign grading could be differently used in different studies based on the aim of study. Furthermore, all of grading systems of symptoms and signs in our study have already been extensively used in the previous studies and workshops on blepharitis without a prior validation. Since cases with lost follow up were less than 10% of all participants, it does not violate the results. (2-4) In fact, drop out of samples up to 20% of sample size is acceptable and does not violate the results. (2-4) Regarding to writing all confidence intervals, table 3 shows a detailed statistical analysis of both groups expanding what has been mentioned in the text without a need to increase the word number of the text. (1) By applying The Bonferroni multiple comparisons test to the data in Table 4, there is still one significant (conjunctival redness) and one marginally significant (ocular surface staining) score favoring the Azithromycin group. (1) Such a significant difference (even in one sign score) was big enough to lead to a significantly better mean total sign score (of seven signs) in the azithromycin group(1) to which the conclusion was written. Whether a significantly better mean total sign score of azithromycin group has rooted from one or more than one of the signs does not violate the conclusion that azithromycin resulted in a significantly better total mean sign score and therefore is recommended over doxycycline. Even if there was no any significant differences between symptom and sign scores of two groups, azithromycin would still be recommended for its shorter duration of treatment, lesser side effects, and cheaper price. In conclusion, we believe the data are conclusive enough to recommend azithromycin over doxycycline in patients with meibomian gland dysfunction because of a significantly better improvement of sign score, shorter duration of treatment, lesser side effects, and lower price. References 1. Kashkouli MB, Fazel AJ, Kiavash V, Nojomi M, Ghiasian L. Oral azithromycin versus doxycycline in meibomian gland dysfunction: a randomised double masked open label clinical trial. Br J Ophthalmol. 2014 Aug 19. [Epub ahead of print] 2. Peterson JC, Pirraglia PA, Wells MT, Charlson ME. Attrition in longitudinal random controlled trials: home visits make a difference. Medical Research Metodology 2012;12:178 3. Armijo-Olivo S, Warren S, Magee D. Intention to treat analysis, compliance, drop-outs and how to deal with missing data in clinical research: a review. Physical Therapy Review 20109;14:36-49 4. Fewtrell MS, Kennedy K, Singhal A, et al. How much loss to follow-up is acceptable in long-term randomized trials and prospective studies? Arch Dis Child 2008;93:458-461
Conflict of Interest:
None declared
Show Less

Conflict of Interest:
None declared.
- Back to top
Published on: 22 March 2016
Data inconclusive to recommend oral azithromycin over oral doxycycline in meibomian gland dysfunction
- Michel J. Belliveau
Kashkouli and colleagues (1) have studied a subject with high clinical relevance. Meibomian gland dysfunction is prevalent and treatment often unsatisfactory. Oral azithromycin has advantages over oral doxycycline including dosing and side effects as reviewed in the article.
There are a few problems with the methods to be highlighted so that readers can draw accurate conclusions, and validation studies be constr...
Show More

Kashkouli and colleagues (1) have studied a subject with high clinical relevance. Meibomian gland dysfunction is prevalent and treatment often unsatisfactory. Oral azithromycin has advantages over oral doxycycline including dosing and side effects as reviewed in the article.
There are a few problems with the methods to be highlighted so that readers can draw accurate conclusions, and validation studies be constructed appropriately. This is done in point form below.
-Statement of a null hypothesis a priori would have been helpful to interpret the trial as a non-inferiority or superiority design. (2)
-The sample size calculation was designed "to detect at least 1.8 differences". It is not clear why this number was chosen and cannot be gleaned from the cited articles. Was the trial adequately powered to meet the aims of assessing efficacy and safety?
-Ideally, a new scale as used in the study should be validated before use in a trial.
-Ten patients were lost to follow-up. Their baseline characteristics should be reported and compared to those who completed follow-up. (3) Intention-to-treat analysis can determine the maximum effect on the results of those lost to follow-up by assuming the extremes of outcome and recalculating. (4) The null hypothesis is important to assign the extremes appropriately.
-"Symptoms significantly improved in both groups (p=0.001, 95%CI -2.2 to -0.7)". A similar statement exists for clinical signs. There are two groups and there should be a 95%CI for each. It cannot be determined to which group these values correspond.
-The Bonferroni multiple comparisons test applies to the data shared in Table 4. With seven variables, the p value for significance is 0.007 (0.05/7). Therefore, ocular surface staining is no longer significant in this conservative model.
The potential impact of repeated dosing of oral azithromycin on bacterial resistance was not addressed in the discussion and also deserves comment from the authors.
In light of these concerns, conclusions from this study should be tempered until the results are validated.
1. Kashkouli MB, Fazel AJ, Kiavash V, Nojomi M, Ghiasian L. Oral azithromycin versus doxycycline in meibomian gland dysfunction: a randomized double masked open label clinical trial. Br J Ophthalmol ePub 19 Aug 2014.
2. Committee for Proprietary Medicinal Products. Points to consider on switching between superiority and non-inferiority. Br J Clin Pharmacol 2001; 52:223-228.
3. Groenwold RHH, Moons KGM, Vandenbroucke JP. Randomized trials with missing outcome data: how to analyze and what to report. CMAJ 2014; 186:1153-1157.
4. Guyatt GH, Sackett DL, Cook DJ. Users' guides to the medical literature. II. How to use an article about therapy or prevention. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA 1993; 270:2598-2601.
Conflict of Interest:
None declared
Show Less

Conflict of Interest:
None declared.
- Back to top
Published on: 22 March 2016
An additional explanation for azithromycin's efficacy in treating meibomian gland dysfunction
- Yang Liu
- Other Contributors:
  Juan Ding, David A. Sullivan
We would like to congratulate Dr. Kashkouli et al for their recently published paper "Oral azithromycin versus doxycycline in meibomian gland dysfunction: a randomized double masked open label clinical trial". The authors found that azithromycin induced a significantly better overall clinical response than doxycycline, and attributed this effect to the antibacterial and anti-inflammatory effects of azithromycin. However,...
Show More

We would like to congratulate Dr. Kashkouli et al for their recently published paper "Oral azithromycin versus doxycycline in meibomian gland dysfunction: a randomized double masked open label clinical trial". The authors found that azithromycin induced a significantly better overall clinical response than doxycycline, and attributed this effect to the antibacterial and anti-inflammatory effects of azithromycin. However, we would like to suggest an additional explanation for their results. We have discovered that azithromycin can directly increase lipid accumulation and promote terminal differentiation of human meibomian gland epithelial cells in vitro.1 This effect may be due to azithromycin's cationic amphiphilic structure and an associated phospholipidosis.2 We have also discovered that the stimulatory action of azithromycin on human meibomian gland epithelial cells is unique, and cannot be duplicated by exposure to doxycycline, minocycline or tetracycline.2 3 In effect, this lipid- promoting activity of azithromycin may improve the quality of meibomian gland secretions, alleviate the evaporative dry eye, and attenuate such additional signs as conjunctival redness and ocular surface staining. Overall, this ability of azithromycin to promote human meibomian gland epithelial cell function may account for its greater efficacy, as compared to doxycycline, in alleviating the signs and symptoms of human meibomian gland dysfunction.
References
1. Liu Y, Kam WR, Ding J, et al. Effect of azithromycin on lipid accumulation in immortalized human meibomian gland epithelial cells. JAMA ophthalmol 2014;132(2):226-8. 2. Liu Y, Kam WR, Ding J, et al. One man's poison is another man's meat: using azithromycin-induced phospholipidosis to promote ocular surface health. Toxicology 2014;320:1-5. 3. Liu Y, Kam WR, Ding J, et al. The effect of macrolide and tetracycline antibiotics on lipid expression in human meibomian gland epithelial cells. ARVO abstract 2014.
Conflict of Interest:
A provisional patent has been filed around the technology mentioned in our paper. The intellectual property for the application is owned by the Schepens Eye Research Institute/Massachusetts Eye and Ear.
Show Less

Conflict of Interest:
None declared.
- Back to top

Main menu

Plain text

PLEASE NOTE:

Vertical Tabs

Other responses

Jump to comment:

Conflict of Interest:

Conflict of Interest:

Conflict of Interest:

Log in using your username and password

Main menu

Log in using your username and password

You are here

Plain text

PLEASE NOTE:

Vertical Tabs

Other responses

Jump to comment:

Conflict of Interest:

Conflict of Interest:

Conflict of Interest:

Read the full text or download the PDF:

Log in using your username and password