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Doxycycline is an excellent adjunctive therapy for MGD management.
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Tetracyclines 101
The tetracycline group is comprised of bacteriostatic antibiotics that demonstrate activity against a wide range of aerobic and anaerobic gram-positive and gram-negative bacteria. Tetracyclines bind to bacterial ribosome and inhibit bacterial protein synthesis.
It is important to note, however, that the rise of antimicrobial resistance has eroded the bactericidal activity of these agents–––and tetracycline in particular. The most commonly used members of this group are doxycycline and minocycline. Despite increased antimicrobial resistance, tetracyclines are still used in the treatment of Rocky Mountain spotted fever, typhus, Chlamydia, Lyme disease and several other “uncommon” conditions.1
Doxycycline and minocycline are the most frequently prescribed members of the tetracycline group, and are the most commonly used tetracyclines in eye care. Both of these agents have a much better absorption profile than tetracycline, which is absorbed at a rate of 60% to 80%. On an empty stomach, oral doses of doxycycline and minocycline are absorbed at rates of 95% and 100%, respectively. As the dosage increases, so too does the volume of unabsorbed drug.
Absorption mostly takes place in the stomach and upper small intestine, and occurs greater in the fasting state. Tetracycline absorption may be impaired by the concurrent ingestion of dairy products, antacids, aluminum hydroxide gels; calcium, magnesium and iron or zinc salts; bismuth subsalicylate (e.g., Pepto-Bismol), and dietary iron and zinc supplements. Doxycycline and minocycline are less affected by these substances than other tetracyclines, and administration with milk or calcium containing foods is unlikely to impair absorption substantially. Regardless, co-administration of antacids or mineral supplements still should be avoided.
Typical Applications of Doxycycline in Eye Care
Several conditions have an indication for doxycycline treatment, including ocular/acne rosacea, meibomian gland dysfunction (MGD), recurrent corneal erosion (RCE) and chronic corneal wounds.2-6 Doxycycline has obvious antimicrobial properties; however, the tetracycline family also exhibits a strong anti-inflammatory action when used in sub-antimicrobial concentrations. For example––these medications have been shown to inhibit the production of pro-inflammatory mediators, thus reducing the production of inflammatory compounds such as cytokines and chemokines, and in particular, matrix-metalloproteineases (MMP).6,7
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Rosacea is typically managed with 50mg to 100mg doxycycline QD to BID.
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• Rosacea is a chronic inflammatory condition of the facial skin. Affected patients usually present with complaints of flushing, blushing and sensitive skin. Ocular manifestations are common in patients with rosacea, with characteristic symptoms of redness, irritation or burning of the eyes. In my experience, most dermatologists prescribe 50mg to 100mg doxycycline or minocycline QD to BID for the treatment of rosacea. Controlled-release doxycycline 40mg (Oracea, Galderma Laboratories) is also effective, and this specific combination has been found to be a useful alternative to higher doses of doxycycline.4,5
• Blepharitis and MGD are common ocular conditions that result in significant ocular discomfort and visual disruption. Standard therapy for these conditions is lid hygiene, which includes the use of warm compresses and lid scrubs/massages to clean the debris from the lids and stimulate meibomian gland secretion. With its demonstrated anti-inflammatory activity, however, doxycycline is an excellent adjunctive therapy for MGD management.
Traditionally, clinicians often prescribed doxycycline dosages as high as 200mg/day for the treatment of MGD. However, recent studies have shown that a lower dose of doxycycline is equally effective—without the potential side effects and risk of microbial resistance. One study group noted improvements in dry eye symptoms in patients with chronic MGD who were refractory to conventional therapy, including warm compression, lid massage and topical antibiotic use, after ingestion of low-dose doxycycline hyclate (20mg BID).5 They also noted that this dosage had no antimicrobial effect, and patients exhibited better compliance than initially anticipated secondary to the low incidence of side effects.2
• RCE patients typically experience recurrent episodes of early morning ocular surface pain, photophobia and lacrimation. The disorder frequently follows a shallow corneal injury (e.g., corneal abrasion secondary to fingernail scratch), but also may be non-traumatic in origin (e.g., secondary to epithelial basement membrane dystrophy). Common clinical signs of RCE include loosely elevated epithelium, epithelial microcysts, corneal epithelial defects, stromal infiltrates and opacities.
Common treatment options include ocular lubricants, bandage contact lenses, topical hyperosmotics, epithelial debridement, serum eye drops, anterior stromal puncture and phototherapeutic keratectomy. MMPs are known to be upregulated in the cornea in patients with RCE, and doxycycline––with its known ability to inhibit MMP––has been proposed as a potential treatment option.
In one study, patients with RCE received 50mg oral doxycycline 50mg BID and topical fluorometholone 0.1% TID for at least four weeks. After eight weeks of treatment, 71% of the subjects were symptom free. Further, 73% of patients denied any symptoms suggestive of relapse at either six or 12 months, respectively.3
• Chronic corneal wound healing requires a balance between tissue proteases and their inhibitors. Because doxycycline significantly reduces inflammation and elevated levels of pro-inflammatory cytokines, it may be of value in the healing of chronic wounds. For example––severe burns often lead to ocular surface failure, as well as corneal vascularization, perforation and opacity. Conventional treatment protocols such as anti-inflammatory treatments (hormone and immune inhibitors, auto-serum, non-steroidal anti-inflammatory drugs), amniotic membrane transplantation or amniotic membrane patching often are inadequate.
Currently, the Low-Dose Doxycycline in the Treatment of Corneal Burn trial is recruiting patients in an effort to determine whether small doses of oral doxycycline (50mg BID for two weeks; 50mg QD for 10 weeks) in concert with topical doxycycline, can accelerate corneal epithelium healing after ocular surface burn and effectively inhibit inflammation-mediated corneal angiogenesis.6
The Contraceptives Controversy
For more than 40 years, there has been much debate surrounding antibiotic use and oral contraceptive failure. The first report suggesting such an interaction was published in 1971, based on case reports of women who experienced breakthrough bleeding while taking oral contraception and the antibiotic rifampin (which is classified as an enzyme-inducing antibiotic).8 After 1971, several additional reports were published suggesting that other antibiotics (non-enzyme inducing antibiotics, including doxycycline) might also cause oral contraception failure.8,9 Subsequently, official warnings were created by the FDA that advised women to use backup methods of contraception when taking any form of antibiotic in conjunction with their oral contraception—in particular, rifampin.9 Nonetheless, it is important to note that many recent studies have found no evidence to suggest that non-enzyme inducing antibiotics, in fact, cause oral contraception failure.9
It is important for providers to keep up to date with drug recommendations, in order to provide their female patients with the proper information with respect to antibiotic and oral contraception. That being said, if you look in the Physicians Drug Reference under “drug interactions,” it indicates that doxycycline may render oral contraceptives less effective.10
So, what should you do when presented with a female patient who needs doxycycline? The research states that there isn’t an appreciable risk; however, under the prescribed drug interaction is an indication that oral contraception may be less effective. I’m not quite sure I have the answer to that particular dilemma, but if you plan to be conservative, then warning female patients in childbearing years to take other precautions would seem to be prudent.
Systemic antibiotics play an important role in managing several ocular conditions. In optometry, doxycycline is the most commonly prescribed systemic antibiotic. It is used in the management of a variety of conditions, including blepharitis, MGD and RCE.
Because doxycycline has a number of applications, it is crucial that clinicians understand both the uses and associated risks of this versatile antibiotic. Due to the current national shortage in availability of doxycycline, it is important that you check your local availability before prescribing it.
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Doxy in Short Supply?
If you have tried to prescribe doxycycline in the past several months, you may have noticed that it isn’t as easy to obtain as it once was, and that the cost has dramatically increased. Further, it no longer appears on many $4/$10 drug plans. The American Society of Health-Profession Pharmacists released a drug shortage bulletin in November 2013, which included doxycycline.11 Several of the manufacturing companies have attributed this to a scarcity of raw materials. If doxycycline is unavailable, an alternative antibiotic may be required. Minocycline, for example, has comparable broad-spectrum antimicrobial activity to that of doxycycline. However, doxycycline is often preferred over minocycline because of associated adverse effects. Therefore, a different medication class entirely may be preferred over minocycline, depending on the indication. The bottom line––when choosing an alternative to doxycycline, use your best clinical judgment. If doxycycline is available, do not substitute if it is the clear drug of choice for the specified indication.11 |
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Other Common Side Effects of Oral Tetracycline Use
• Permanent discoloration of the teeth if used during the last half of pregnancy, infancy or childhood (less than eight years of age). The larger the dose is relative to body weight, the more intense the enamel discoloration. • May decrease fibula growth rate in premature births. • Photosensitivity—manifested by an exaggerated sunburn reaction—may occur, and should be discontinued at the first evidence of skin erythema. Instruct patients to consider liberal use of sunscreen or sunblock. • Epigastric burning and distress, abdominal discomfort, nausea, vomiting and diarrhea may occur with medium- to long-term use. Tolerability can be improved by administering these drugs with food. • May cause increased intracranial pressure (idiopathic intracranial hypertension) in young infants––even when given in the usual therapeutic doses. The pressure promptly returns to normal when therapy is discontinued. This complication rarely occurs in older individuals. • Overgrowth of micro-organisms that are not affected by doxycycline, which may lead to certain types of infections (e.g., vaginal).1 |
Dr. Lonsberry is a professor at Pacific University in Portland, Ore, and is the clinic director for the Portland Vision Center.
1. Brunton LB, Lazo JS, Parker KL (eds.). Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed. Section VII. Chemotherapy of Microbial Diseases, Chapter 55. Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents. New York: McGraw-Hill; 2005.
2. Yoo SE, Lee DC, Chang MH. The effect of low-dose doxycycline therapy in chronic meibomian gland dysfunction. Kor J Ophthalmol. 2005 Dec;19(4):258-63.
3. Wang L, Tsang H, Coroneo M. Treatment of recurrent corneal erosion syndrome using the combination of oral doxycycline and topical corticosteroid. Clin Exp Ophthalmol. 2008 Feb;36(1):8-12.
4. Berman B, Zell D. Subantimicrobial dose doxycycline: a unique treatment for rosacea. Cutis. 2005 Apr;75(4):19-24.
5. van Zuuren EJ, Graber MA, Hollis S, et al. Interventions for rosacea. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003262.
6. Liang D, Huang J. Low-dose doxycycline in the treatment of corneal burn. Identifier: NCT01886560. Available at: http://clinicaltrials.gov/show/NCT0188656010. Accessed January 15, 2014.
7. Krakauer T, Buckley M. Doxycycline is anti-inflammatory and inhibits staphylococcal exotoxin-induced cytokines and chemokines. Antimicrob Agents Chemother. 2003 Nov;47(11):3630-3.
8. Anderson KC, Schwartz MD, Lieu SO. Antibiotics and OC effectiveness. JAAPA. 2013 Jan;26(1):11.
9. Toh S, Mitchell AA, Anderka M, et al. National Birth Defects Prevention Study. Antibiotics and oral contraceptive failure: A case-crossover study. Contraception. 2011 May;83(5):418-25.
10. PDR.net. Drug Summary. Doxycycline tablets. Available at: www.pdr.net/drug-summary/doxycycline-tablets?druglabelid=2659. Accessed December 18, 2013.
11. American Society of Health-System Pharmacists. Current Drug Shortage Bulletin: Doxycycline Capsules and Tablets. Available at: www.ashp.org/DrugShortages/Current/Bulletin.aspx?id=977. Accessed December 2, 2013.
12. Weinberg JM. The anti-inflammatory effects of tetracyclines. Cutis. 2005 Apr;75(4): 6-11.
