Azithromycin and Doxycyline for Dry Eye
There are many online posts by patients who have been desperate to try anything to relieve their dry eye symptoms. It is frustrating for patients that science has not discovered a cure for dry eye yet. It is frustrating for physicians that we do not have a cure to provide for patients. Despite what some patients say online, most physicians are honestly trying to find the needed help their patients are so desperately seeking. We have IPL and Intraductal Gland Probing in our office and have many patients who have been very happy with their treatment. Still, however, neither IPL, nor Intraductal Gland Probing, nor Lipiflow for that matter, have a 100% guarantee, which is frustrating for patients and for physicians alike who have in good faith acquired this technology or learned these techniques in the case of Intraductal Gland Probing hoping to help their patients, who often include their relatives and neighbors who they honestly want to help.
All the treatments on Step Ladder Dry Eye sheet are attempts to provide some relief to our patients even if we cannot yet provide a cure: https://drcremers.com/2015/07/new-innovations-in-dry-eye-treatments.html
One item that I have been hesitant to add is noted in a post below by a desperate patient:
“After a failed Lipiflow procedure in Feb 2014 & many other treatments since 2009, I actually listened to my mom who also had MGD and she had her DR prescribe Azithromycin 500mg about 9 months ago to use for 6 days and it worked so well for her that her dry eye symptoms improved significantly for about 9 months. When I heard this I had hard time believing it but on April 4 2014 I asked my ophthalmologist if I can try it and I have notice my eyes at night are not as dry and when I awake they open more easily and feel more moist. I have not added any other treatments recently and at least for my condition this antibiotic has been the most effective and all for $10.”
The issue with this post is that most eyeMDs try not to prescribe oral Azithromycin 500mg given potential systemic side effects and that the FDA did not technically approve Azithromycin orally for treatment of meibomian gland dysfunction:
The risks and benefits of antibacterial therapy should be considered in prescribing decisions. Pharmacologic and epidemiologic data point to lethal arrhythmias as a potential consequence of QT-interval prolongation with use of azithromycin, other macrolides, and fluoroquinolones. This possibility should give clinicians pause when they’re considering prescribing antibacterial drugs, especially for patients with preexisting cardiovascular risk factors or clinical conditions in which antibacterial drug therapy has limited benefits. http://www.nejm.org/doi/full/10.1056/NEJMp1302726
FDA-approved indications for azithromycin include:
- Acute bacterial exacerbations of chronic pulmonary disease
- Acute bacterial sinusitis
- Community-acquired pneumonia
- Uncomplicated skin and skin structure infections
- Urethritis and cervicitis
- Genital ulcer disease
Abnormal Heart Activity and Sudden Cardiac Death
In May 2012, a study in the New England Journal of Medicine reported an increase in cardiovascular death in patients treated with azithromycin compared with patients treated with amoxicillin, ciprofloxacin or no drug. The study was prompted by evidence found in FDA adverse events databases that azithromycin promotes irregular heartbeats, which caused the study’s authors to hypothesize that incidences of cardiovascular death may increase for patients on the drug. Researchers concluded that patients at a high risk for cardiovascular death, including those with existing QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate or patients taking drugs to treat arrhythmias, were more likely to die while taking azithromycin than patients on other antibiotics or none at all.
The risk of death while on azithromycin increased proportionally with the patients’ Cardiovascular Risk Score: The study found 245 excess deaths in patients with the highest risk scores, compared with just 9 excess deaths in patients with the lowest risk scores. Since this increased death rate did not continue once patients finished their 5-day courses of azithromycin, researchers concluded the increased risk must stem from the drug and only last as long as the drug remains in the body.
Following this study, the FDA issued a public statement detailing the study and warning that the Z-Pak may have previously unknown side effects relating to risk of cardiovascular death. In March 2013, based on new studies funded by Pfizer in response to the research in the New England Journal of Medicine, the FDA issued a stronger public warning that azithromycin, including brand names Zithromax, Zmax, Azithrocin and Azin, “can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm.”
People with diabetes, a high risk of heart failure, or a previous heart attack are at the most risk of abnormal heart rhythms while taking Zithromax. The authors of the New England Journal study say doctors should consider prescribing a different drug, such as amoxicillin, for such high-risk patients. For the vast majority of patients who have no heart problems, there is no increased risk. The original NEJM study found only 47 additional deaths per 1 million courses of treatment, most of which occurred in patients with serious pre-existing heart conditions.
A recent study sponsored by the Danish Medical Research Council found no evidence of increased risk of death for young and middle-aged adults without heart problems who took Zithromax compared with those who took a different antibiotic such as penicillin. Researchers concluded that “any increased risk of cardiovascular death associated with azithromycin is restricted to high-risk patients” with a history of heart disease or problems.
Hepatotoxicity (Toxic Liver Disease)
Because Zithromax is metabolized and processed in the liver, patients with liver problems or abnormal liver function may be at risk of serious problems from the drug. Hepatotoxicity (toxic liver disease) and hepatitis have been reported in patients taking Zithromax, occasionally resulting in death. Zithromax should be discontinued if there are signs of hepatitis, such as fatigue, muscle aches, loss of appetite, dark urine or abdominal discomfort.
Serious allergic reactions to Zithromax have been reported, including angioedema (rapid swelling), anaphylaxis (allergic shock), and skin reactions. In rare cases, these reactions resulted in death.
The study below showing the benefit of oral Azithromycin in Posterior Blepharitis was published in Brazil. There has been no publication in the US to reproduce their results as of this posting.
Oral Azithromycin for Treatment of Posterior Blepharitis
Igami, Thais Zamudio MD*†; Holzchuh, Ricardo MD*†; Osaki, Tammy Hentona MD†; Santo, Ruth Miyuki MD, PhD*; Kara-Jose, Newton MD, PhD*; Hida, Richard Y MD*†
From the *Department of Ophthalmology, Hospital das Clínicas of Universidade de São Paulo (USP), Sao Paulo, Brazil; and †Department of Ophthalmology, Santa Casa de São Paulo, Sao Paulo, Brazil.
Received for publication June 27, 2010; revision received November 9, 2010; accepted November 17, 2010.
Financial support: None.
No authors have any financial/conflicting interests to disclose.
Reprints: Richard Yudi Hida, Rua Afonso de Freitas, 488 apt 61, Paraiso, São Paulo, Brazil 04006-052 (e-mail: email@example.com).
Purpose: To evaluate the effects of oral azithromycin in patients with posterior blepharitis.
Methods: Twenty-six eyes of 13 patients with posterior blepharitis diagnosed by a qualified ophthalmologist were enrolled in this study. Patients were instructed to use oral azithromycin 500 mg per day for 3 days in 3 cycles with 7-day intervals. Subjective clinical outcomes were graded and scored 1 day before and 30 days after the end of the treatment (53 days after initiating the treatment) based on severity scores of: (1) eyelid debris; (2) eyelid telangiectasia; (3) swelling of the eyelid margin; (4) redness of the eyelid margin; and (5) ocular mucus secretion. For the assessment of global efficacy, patients were asked by the investigator to rate the subjective symptoms (eyelid itching, ocular itching, eyelid hyperemia, ocular hyperemia, ocular mucus secretion, photophobia, foreign body sensation, and dry eye sensation) on a scale of 0 (no symptoms) to 5 (severe symptoms). Break-up time, Schirmer I test, corneal fluorescein staining score, and rose bengal staining score were also performed in all patients.
Results: All clinical outcomes scoring showed statistically significant improvement after oral azithromycin, except for eyelid swelling. Average subjective symptom grading improved statistically after treatment with oral azithromycin, except for eyelid hyperemia, photophobia, and foreign body sensation. Average tear film break-up time values showed statistically significant improvement after the treatment with oral azithromycin. No statistically significant improvement was observed on average values of Schirmer I test, corneal fluorescein staining score, and rose bengal staining score.
Conclusions: The combination of multiple clinical parameters shown in this study supports the clinical efficacy of pulsed oral azithromycin therapy for the management of posterior blepharitis.
Less Systemically Invasive Options to Treat Dry Eye:
1. Intense Pulse Light Therapy
3. Intraductal Gland Probing
Intense pulsed light therapy for the treatment of evaporative dry eye disease.
- 1Department of Ophthalmology, Cornea, External Disease, and Refractive Surgery, Duke Eye Center, Durham, North Carolina, USA.
PURPOSE OF REVIEW:
Evaporative dry eye disease is one of the most common types of dry eye. It is often the result of chronic meibomian gland dysfunction (MGD) and associated ocular rosacea. Evaporative dry eye and MGD significantly reduce patient’s quality of life. Traditional treatments, such as artificial tears, warm compresses, and medications, such as topical cyclosporine, azithromycin, and oral doxycycline, provide some relief; however, many patients still suffer from dry eye symptoms. Intense pulsed light (IPL) therapy, which has been used extensively in dermatology to treat chronic skin conditions, is a relatively new treatment in ophthalmology for patients with evaporative dry eye disease.
There are very few studies published on the use of IPL in patients with dry eye disease. The present review describes the theoretical mechanisms of IPL treatment of MGD and ocular rosacea. Personal clinical experience and recently presented data are reported as well.
IPL therapy has promising results for evaporative dry eye patients. There are statistically significant improvements in clinical exam findings of dry eye disease. More importantly, patients report subjective improvement in their symptoms. More research is needed in this area to help understand the mechanism of dry eye disease and how it can be effectively treated.
Another alternative is to use:
Topical Azithromycin and Oral Doxycycline Therapy
This makes more sense as Topical Azithromycin has fewer risks. The issue I have with these “Topical Azithromycin” studies is that almost all of them have been sponsored by Inspire Pharmaceuticals which makes Azasite (Topial Azithromycin: there is no generic version yet).**
Also, I would love to do a study where only 20mg or 50mg of Doxycycline once per day is used as this is the dose Dr. Folkman at Harvard Medical School found was the best dose for Doxy’s anti-inflammatory effect.
Subjects were provided 1% topical azithromycin ophthalmic solution (Azasitetm, Inspire Pharmaceuticals, Inc, Raleigh, NC) with instructions to use one drop twice daily for two days then once daily for the four week duration of the treatment phase of the study. Subjects were instructed not to instill medication the morning of examinations. Oral doxycycline hyclate (100 mg) was taken twice a day for two months of therapy.
Meibomian gland dysfunction (MGD) is a common clinical problem that is often associated with evaporative dry eye disease. Alterations of the lipids of the meibomian glands have been identified in several studies of MGD. This prospective, observational, open label clinical trial documents the improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment.
Subjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp. Symptoms of MGD were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation and phase transition parameters, and meibum protein content were measured using Fourier transform infrared spectroscopy (FTIR) and principal component analysis (PCA). Terpenoids, short chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (1H-NMR) spectrometer.
Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion towards normal. Compared to 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, changes in ordering of the lipids and phase transition temperature were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the FTIR PCA scores and relative area of the 1H-NMR resonance at 1.26 ppm. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the 1H-NMR resonances at 5.2 and 7.9 ppm to normal levels. The level of meibum protein and meibum lipid oxidation were not influenced by azithromycin or doxycycline treatment.
**Supported by Public Health Service research grant EY017094-03 (Bethesda, MD., U.S.A.), the Kentucky Lions Eye Foundation, an unrestricted grant from Research to Prevent Blindness Inc., and a grant from Inspire Pharmaceuticals, Inc.
Topical Azithromycin and Oral Doxycycline Therapy of Meibomian Gland Dysfunction: A Comparative Clinical and Spectroscopic Pilot Study
This study shows the benefit of Azithromycin on the Meibomian Glands though this was an in vitro study.
Meibomian gland dysfunction (MGD) is believed to be the leading cause of dry eye disease (DED), which affects tens of millions of Americans.1
Of particular interest, the most common pharmaceutical treatment for the management of MGD in the United States is the off-label use of topical azithromycin.2
This macrolide antibiotic is presumed to be effective because of its anti-inflammatory and antibacterial actions, which may suppress the MGD-associated posterior blepharitis and growth of bacteria on the eyelid.3
However, to our knowledge, no published, peer-reviewed data demonstrate that azithromycin has the ability to act directly on the human meibomian gland to enhance this tissue’s function and to ameliorate the pathophysiology of MGD.
We hypothesize that azithromycin can act directly on human meibomian gland epithelial cells to stimulate their differentiation, enhance the quality and quantity of their lipid production, and promote their holocrine secretion. Our purpose was to begin to test our hypothesis.
Immortalized human meibomian gland epithelial cells (IHMGECs; passages 20-22) were cultured in the presence or absence of 10% fetal bovine serum as previously reported.4
Cells were treated with the ethanol vehicle or azithromycin (10 µg/mL; Santa Cruz Biotechnology) for varying periods. Cellular morphological appearance was recorded, cells were counted with a hemocytometer, and lipid accumulation was assessed by staining cells with LipidTOX green neutral lipid stain (Invitrogen Corp) according to reported methods.4
Staining fluorescent intensities were quantified using ImageJ software (http://rsbweb.nih.gov/ij/index.html
). Statistical analyses were performed with t
test (2-tailed, unpaired).
Our results show that azithromycin induces a striking, time-dependent accumulation of lipid in IHMGECs (Figure 1
A). Within 3 days of azithromycin exposure, the number, size, and staining intensity of intracellular lipid-containing vesicles had markedly increased as compared with those of vehicle-treated control cells. This azithromycin effect on lipids appeared to become maximal at days 3 to 7 of the study (Figure 1
Effect of Azithromycin on the Lipid Accumulation and Morphology of Immortalized Human Meibomian Gland Epithelial Cells
Cells were treated with ethanol vehicle or azithromycin in serum-containing media for 7 days. Results are representative of 3 separate experiments. A, Appearance of cellular lipids. Cells were fixed and stained with LipidTOX green neutral lipid stain and 4’,6-diamidino-2-phenylindole (DAPI; red nuclear stain) (Invitrogen Corp) (original magnification ×400). B, LipidTOX staining intensity. Means are reported as fold-change compared with control values on the same day. Error bars indicate standard error. C, Cellular morphology. Images were taken prior to LipidTOX staining. Azithromycin-induced cellular maturation and vesicle accumulation were often followed by cell disruption and vesicle release (arrowhead, day 7) (original magnification ×200).aSignificantly greater than control (P < .005).
Evaluation of cellular morphology indicated that azithromycin may promote terminal maturation of IHMGECs given that vesicle accumulation was often followed by a cell break-up and vesicle release (Figure 1
In contrast to these effects, azithromycin reduced the proliferation of IHMGECs. As shown in Figure 2
, this result was found irrespective of whether IHMGECs were cultured under proliferation or differentiation conditions.
Influence of Azithromycin on Proliferation of Immortalized Human Meibomian Gland Epithelial Cells
Cells were cultured in the absence (A) or presence (B) of serum for up to 7 days. Cell numbers at day 0 represent the baseline, and data are reported as mean ± standard error. Similar results were found in 2 additional studies.aSignificantly less than control (P < .005).
This study supports our hypothesis that azithromycin can act on human meibomian gland epithelial cells and stimulate their lipid accumulation. This azithromycin effect appears to be paralleled by a cellular maturation, a decreased proliferation, and a holocrine-like secretion.
This azithromycin action is quite notable because MGD is thought to be the most common cause of DED.1
Typically, the meibomian glands produce and release a lipid mixture that promotes the stability and prevents the evaporation of the tear film, thereby playing an essential role in ocular surface health. Conversely, MGD destabilizes the tear film and increases its evaporation. Meibomian gland dysfunction is caused primarily by hyperkeratinization of the terminal duct epithelium and reduced secretion quality, and it leads to cystic dilatation of glandular ducts, acinar cell death, and lipid deficiency.1
The end result is DED, characterized by a cycle of tear film hyperosmolarity and ocular surface stress and leading to increased friction, inflammation, and damage to the eye.5
The effect of moderate to severe DED is analogous to conditions such as dialysis and severe angina and is associated with significant pain, role limitations, low vitality, and poor general health.5
Given our finding that azithromycin stimulates the function and differentiation of IHMGECs in vitro, it is possible that this antibiotic may prove beneficial as a treatment for MGD and its associated DED in vivo.
Published Online: December 19, 2013. doi:10.1001/jamaophthalmol.2013.6030.
Study concept and design: Liu, Sullivan.
Acquisition of data: Liu.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: Liu, Sullivan.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Liu, Sullivan.
Obtained funding: Liu, Sullivan.
Administrative, technical, or material support: Kam, Ding.
Study supervision: Liu, Sullivan.
Conflict of Interest Disclosures: Schepens Eye Research Institute is planning to submit a provisional patent based, in part, on the data presented in the article. No other disclosures were reported.
Funding/Support: This work was supported by grant EY05612 from the National Institutes of Health, the Margaret S. Sinon Scholar in Ocular Surface Research Fund, and the Guoxing Yao Research Fund.
Role of the Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.