CASE REPORT

A Case Report of Doxycycline-induced StevensJohnson Syndrome

Brian Lau, BS,* Divya Mutyala, MD, and Deepinder Dhaliwal, MD

Purpose: To report the clinical ndings of a case of Stevens

Johnson syndrome (SJS) precipitated by the use of systemic doxycycline.

Methods: Case report. Results: A 49-year-old man developed SJS with ocular involvement
after doxycycline use for respiratory symptoms. The patient developed persistent 2+ conjunctival injection and foreshortening of the conjunctival fornices in both eyes. The right eye had a 3 3 3.4 mm corneal epithelial defect with 50% thinning. The left eye had a 2.6 3 3 mm corneal ulcer with a central perforation and a at anterior chamber with 360 degrees of iridocorneal touch.

Conclusions: This case illustrates the unusual presentation of SJS induced by doxycycline. The prevalent use of systemic doxycycline in the practice of ophthalmology for eyelid-related and ocular surface disorders coupled with the detrimental long-term sequelae of SJS renders a careful reevaluation for alternatives.
Key Words: StevensJohnson syndrome, doxycycline (Cornea 2011;30:595597)

ystemic doxycycline is widely used within ophthalmology to treat many common ocular ailments, such as blepharitis, ocular rosacea, and keratitis sicca.1,2 As an antimetalloproteinase, doxycycline is also widely used to stabilize corneal melting. In this report, we introduce a patient presenting with StevensJohnson syndrome (SJS) precipitated by the use of oral doxycycline. To the best of our knowledge, this is the rst report in ophthalmic literature regarding doxycycline-induced SJS.

CASE REPORT
A 49-year-old man with no prior history of drug allergies and no concurrent medication usage, took doxycycline for a persistent cough
Received for publication January 21, 2010; revision received June 2, 2010; accepted June 28, 2010. From the *University of Pittsburgh Medical School, Pittsburgh, PA; and UPMC Eye Center, Cornea and External Disease Service, Department of Ophthalmology, University of Pittsburgh Medical Center, Eye and Ear Center, Pittsburgh, PA. Disclosures: None. Reprints: Dr. Deepinder Dhaliwal MD, UPMC Eye Center, Department of Ophthalmology, University of Pittsburgh School of Medicine, 203 Lothrop Street, Suite 800, Pittsburgh, Pennsylvania, 15213 (e-mail: dhaliwaldk@msx.upmc.edu). Copyright 2011 by Lippincott Williams & Wilkins

and sore throat. Approximately 24 hours after ingestion, the patient developed a diffuse and rapidly spreading rash over his face, upper extremities, and mouth. The rash involved approximately 50% of his total body surface area. Doxycycline was stopped immediately upon arrival to the hospital. Mycoplasma titers were drawn and were negative for an acute infection. During his hospital course, the patient required intubation secondary to worsening mucosal involvement of SJS. The patient was evaluated by dermatology; the rash was noted to be erythematous and vesicular with mixed turbid and necrotic eruption along with mucous membrane involvement. At the time of his initial evaluation, the differential diagnosis included an infectious etiology, such as varicella or disseminated zoster, drug-related erythema multiforme, SJS, or toxic epidermal necrolysis. Culture and immunohistochemical stains for herpes simplex virus 1 and 2 were negative. The initial skin biopsy from the left ank was notable for vacuolar interface change, necrotic keratinocytes, and focal subepidermal splitting that were most suggestive of a drug eruption. On his initial ophthalmic examination, the patient was sedated and visual acuity was not able to be assessed. His eyelids were swollen and matted shut with serous discharge. An epithelial defect was noted nasally on the right upper eyelid. Bilateral subconjunctival injection was noted diffusely. No symblephara were present. The patient was placed on tobramycin 0.3%/dexamethasone 0.1% ointment 4 times a day and ciprooxacin drops every 2 hours. The patient was followed during the next 3 weeks and developed symblephara that were lysed at the bedside with moistened cottontipped applicators. At discharge from the outside hospital, the patient had an epithelial defect OS without melting and punctate epitheliopathy OD. The patient was referred to the cornea service as an outpatient 3 days after discharge. He reported persistent pain, photophobia, and irritation in both eyes. His uncorrected visual acuity was 20/125 in the right eye and count ngers in the left eye with no improvement with pinhole in either eye. His pupils demonstrated normal reactivity, and the intraocular pressures were 11 mm Hg bilaterally. Slit-lamp examination was signicant for persistent moderate conjunctival injection and foreshortening in both eyes. The right eye had a 3 3 3.4 mm corneal epithelial defect with 50% thinning. The left eye had a 2.6 3 3 mm corneal ulcer with a central perforation and a at anterior chamber with 360 degrees of iridocorneal touch. A bandage contact lens and Ocuox 0.3% (Allergan, Irvine, CA) drops were administered in the right eye. Initially, the perforation in the left eye was successfully glued with cyanoacrylate glue 1%. The size of the perforation continued to enlarge over the next several days, and several unsuccessful attempts were made to glue the cornea. The patients right eye began to show signs of ulcer formation and further thinning to the level of Descemet membrane. The patient was taken to the operating room. Amniotic membrane was placed over the right cornea along with cyanoacrylate glue 1%, followed by a bandage contact lens and a bolster tarsorrhaphy (Figure 1). To repair the perforation of the left cornea, a 4-mm patch graft was performed over which amniotic membrane was placed. A bandage contact lens was then placed followed by a bolster tarsorrhaphy. The patient was placed on autologous serum eyedrops every 2 hours and www.corneajrnl.com |

Cornea  Volume 30, Number 5, May 2011

595

Lau et al

Cornea  Volume 30, Number 5, May 2011

fortied vancomycin (25 mg/mL) and fortied tobramycin (14 mg/mL) every hour in the right eye. In the left eye, he was placed on Ocuox 0.3% (Allergan) and medroxyprogesterone acetate 1% 4 times daily. The pathology report of the left cornea showed acute keratitis with ulceration, stromal scarring with pigment deposition, interface inltrate containing eosinophils, and focal 1+ perivascular immunoglobulin A deposits that were consistent with a drug eruption. Bacterial and fungal cultures were negative. One week postoperatively, the patient complained of increased redness and irritation OU. His examination revealed vision of 20/200 OD in the right eye and 20/100 in the left eye. He had notably increased conjunctival injection and inammation. Repeat amniotic membrane transplantation was performed along with permanent lateral tarsorrhaphies and thermal punctal occlusion in both eyes to maximize his ocular surface protection and lubrication. At his 3-month follow-up appointment, his best-corrected visual acuity revealed 20/50 OD (pin-hole [ph]: 20/40) and 20/200 OS (ph: no improvement). The graft in the left eye was clear with corneal neovascularizations inferiorly and nasally. The right eye had posterior synechiae and healed corneal epithelium with 10% thinning.

FIGURE 1. A 49-year-old man with ocular SJS in the operating room after corneal patch graft in the left eye and gluing in the right eye with bolster tarsorraphy.

DISCUSSION
SJS is part of a continuum that includes erythema multiforme and toxic epidermal necrolysis and is a reaction commonly caused by systemic drugs and mostly associated with widespread target lesions of the epidermis. Ocular complications include permanent visual loss because of corneal scarring or vascularization that may occur acutely together with or after the onset of skin involvement. A retrospective study cited that up to 81.3% of patients suffering from SJS develop a wide range of ocular manifestations including mild symptoms of conjunctivitis, eyelid edema, crusting, discharge, or moderate signs such as formation of pseudomembranes or corneal epithelial defects.3 Severe manifestations may include symblepharon, fornix foreshortening, and corneal ulceration with stromal melting.3 In studies of Western populations, antibiotics particularly of the sulfonamide class were the most common drug triggers of SJS.46 Other common causes were penicillins, non-steroidal antiinammatory drugs (NSAIDs), and anticonvulsants. To our knowledge, only 3 case reports in the dermatology literature cite doxycycline-induced SJS.79 Doxycycline is a tetracycline that works by inhibiting protein synthesis by binding with the 30S and possibly 50S ribosomal subunit(s) of susceptible bacteria.10 Independent of its antimicrobial activity, tetracyclines also have an antimetalloproteinase action that treats conditions resulting from collagen destruction, such as corneal melting.13,1116 Also, it aids in alleviating eye disorders by concentrating in the meibomian glands to create a more stable tear lm and improve the sensation of irritation and dryness. Doxycycline may also reduce fatty acid formation by bacteria on the eyelids that cause burning sensations in the eye. Finally, it also blunts the bodys response to infection and inammation and spares delicate tissues such as the cornea from scarring or destruction. Given these benets, oral doxycycline, dosed at 50100 mg twice a day, is widely prescribed by ophthalmologists for treatment of common syndromes such as blepharitis and ocular rosacea. In fact, amongst all dispensed prescriptions by physicians in 2008, doxycycline was listed as 1 of the top 200 in the US market.17 The wide use of doxycycline in the practice of ophthalmology makes its association with the devastating ramications of SJS ocular and systemic morbidity worrisome. We do not suggest that doxycycline should be removed from the ophthalmic arsenal but that more prudence and care be taken while prescribing. Alternatives for the treatment of bacterial and dry eye symptoms may be available. Despite the paucity of case reports of doxycycline precipitated SJS in ophthalmic literature, its prevalent use in the practice of ophthalmology coupled with the detrimental long-term sequelae of SJS supports an evaluation for alternatives. Further studies are needed to determine the effectiveness of ophthalmic topical agents and other alternatives for the treatment of common ophthalmic conditions such as blepharitis.

REFERENCES
1. McElvanney AM. Doxycycline in the management of Pseudomonas corneal melting: two case reports and a review of the literature. Eye Contacts Lens. 2003;29:258261. 2. Stone DU, Chodosh J. Oral tetracycline for ocular rosacea: an evidencebase review of literature. Cornea. 2004;23:106109. 3. Chang YS, Huang FC, Tseng SH, et al. Erythema multiforme, StevensJohnson syndrome, and toxic epidermal necrolysis: acute ocular manifestations, causes, and management. Cornea. 2007;26:123129. 4. Power WJ, Ghoraishi M, Merayo-Lloves J, et al. Analysis of the acute ophthalmic manifestations of the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum. Ophthalmology. 1995;102:16691676. 5. Wilkins J, Morrison L, White CR. Oculocutaneous manifestations of the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum. Dermatol Clin. 1992;10:571582. 6. Correia O, Chosidow O, Saiag P, et al. Evolving pattern of drug-induced toxic epidermal necrolysis. Dermatology. 1993;186:3237. 7. Cac NN, Messingham MJ, Sniezek PJ, et al. Stevens-Johnson syndrome induced by doxycycline. Cutis. 2007;79:119122.

596

| www.corneajrnl.com

q 2011 Lippincott Williams & Wilkins

Cornea  Volume 30, Number 5, May 2011

Doxycycline-induced StevensJohnson Syndrome

8. Curley RK, Verbov JL. Stevens-Johnson syndrome due to tetracyclinesa case report (doxycycline) and review of literature. Clin Exp Dermatol. 1987;12:124125. 9. Gallais V, Randrianjohanny A, Robineau M, et al. Stevens-Johnson syndrome caused by doxycycline. Presse Med. 1997;26(18):855. 10. Buck ML. Doxycycline for pediatric infections. Pediatr Pharm. 2003;9: 14. 11. Ralph RA. Tetracyclines and the treatment of corneal stromal ulceration. Cornea. 2000;19:274277. 12. Frucht-Pery J, Sagi E, Hemo I, et al. Efcacy of doxycycline and tetracycline in ocular rosacea. Am J Ophthalmol. 1993;116:8892. 13. Zengin N, Tol H, Gunduz K, et al. Meibomian gland dysfunction and tear lm abnormalities in rosacea. Cornea. 1995;14:144146.

14. Akpek EK, Merchant A, Pinar V, et al. Ocular rosacea: patient characteristics and follow-up. Ophthalmology. 1997;104:18631867. 15. Hope-Ross MW, Chell PB, Kervick GN, et al. Oral tetracycline in the treatment of recurrent corneal erosions. Eye. 1994;8:384388. 16. Culbertson WW, Huang AJ, Mandelbaum SH, et al. Effective treatment of phlyctenular keratoconjunctivitis with oral tetracycline. Ophthalmology. 1993;100:13581366. 17. IMS Health.Top-line Industry Data: 2008 U.S. Sales and Prescription Information. IMS Health Web site. Available at: www.imshealth.com/ portal/site/imshealth/menuitem.a46c6d4df3db4b3d88f611019418c22a/ &vgnextoid=85f4a56216a10210VgnVCM100000ed152ca2RCRD &;cpsextcurrchannel=1. Accessed April 9, 2009.

q 2011 Lippincott Williams & Wilkins

www.corneajrnl.com |

597