1Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil.2Henry C. Witelson Ocular Pathology Laboratory, Department of Ophthalmology, McGill University, Montreal,

Quebec, Canada.3External Disease and Cornea Unit, Department of Ophthalmology, Montreal General Hospital, McGill University

Health Center, Montreal, Quebec, Canada.The authors have no financial interest in this paper.

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JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICSVolume 21, Number 2, 2005© Mary Ann Liebert, Inc.

Corneal Endothelial Deposits Associated with Rifabutin Use

ANAMARIA BAPTISTA COUTINHO,1–3 DEVINDER CHEEMA,3 PATRICIA R. PEREIRA,1,2

JOÃO P. SOUZA FILHO,1,2 and MIGUEL N. BURNIER, JR.2

ABSTRACT

Purpose: The aim of this study was to report on the possible development of corneal en-dothelial deposits resulting from the use of rifabutin.

Methods: Case series consisting of 3 patients treated with rifabutin were retrospectivelystudied. Two of the patients were infected with human immunodeficiency virus. A cornealand external disease specialist performed a complete ophthalmologic exam and obtained med-ical histories of the patients.

Results: All cases developed corneal endothelial deposits after previous use of rifabutin.The deposits were bilateral, yellow-white colored, stellate, and mainly peripheral.

Conclusions: In these 3 cases, the unique positive ocular finding was corneal endothelialdeposits, which may be related to the use of rifabutin.

INTRODUCTION

Disseminated Mycobacterium avium complex(MAC) infection may eventually occur in a

significant number of patients with acquired im-munodeficiency syndrome (AIDS). Rifabutin isfrequently administered to AIDS patients as aprophylaxis for MAC infection or in combinationwith other antimycobacterial drugs to treat a doc-umented disseminated MAC infection. Immuno-competent patients may also be treated with ri-fabutin as part of a multiple drug regimen forsystemic infection caused by atypical mycobacte-ria.1,2

Rifabutin is a semisynthetic antimycobacterialagent similar to rifampicin in structure and ac-

tivity. It has a broad antibiotic spectrum and in-hibits RNA-polymerase.3,4

Previous reports have described ocular side-ef-fects resulting from rifabutin use.4 Uveitis has already been described as an ophthalmologic ad-verse effect of rifabutin therapy.4–10 Retinal vas-culopathy associated with uveitis and hypopyonhave also been reported.2 Rifabutin may also causelens deposits.4 In addition, rifabutin has recentlybeen implicated as the cause of asymptomatic bi-lateral endothelial deposits.2,5,11,12

In this paper, we present 3 cases with bilateralendothelial deposits, presumably related to theuse of rifabutin. Two of these patients were infected with human immunodeficiency virus(HIV). A corneal and external disease specialist

performed a complete ophthalmologic exam andobtained medical histories of the patients.

CASE REPORT

Case 1

A 40-year-old HIV-positive white male whohad been examined regularly for 8 years was re-ferred for a routine follow-up evaluation. The pa-tient offered no complaints. He had no history ofprevious cytomegalovirus (CMV) retinitis. Hismedications included indinavir, lamivudine-zi-dovudine, acyclovir, and fenofibrate. He receivedrifabutin 300 mg per day for 3 years and had beenoff the medication for 8 years. He also took sulfamethoxazole-trimethoprim and didanosine.The CD4 T-lymphocyte count during this periodwas less than 100 cells per mm3. On examination,his best-corrected vision was 20/25 in each eye.The slit-lamp examination showed bilateral, retic-ular, slightly yellow-pigmented posterior cornealdeposits that formed a ring around the cornealperiphery (Fig. 1A and B). They were present atthe level of the endothelium (Fig. 1C). Intraocu-lar pressure (IOP) was 12 mmHg in each eye.There was neither any sign of inflammation orany evidence of active or previous CMV retinitis.No treatment was administered, and the patientwas observed. He was reexamined 6 months, 18months, and 30 months later, and the cornealfindings had not changed.

Case 2

A 56-year-old asymptomatic white male waspresented for a routine follow-up examination.He had no complaints. His history indicated thathe had been HIV-positive since 1992 and hadbeen receiving treatment since then. He had nohistory of eye disease. He was taking tenofovir,ritonavir, enfuvirtide, atazanavir, and didano-sine. His best-corrected vision acuity was 20/20in each eye. There were no signs of ocular in-flammation. The intraocular pressure was 14mmHg (both eyes). The fundus examination wasalso normal. The only positive finding was thepresence of bilateral endothelial deposits. Theywere white in color, stellate, and more confluentin the periphery. A detailed past history indicateda CD4 T-lymphocyte count of 87 cells per mm3

and the use of rifabutin 300 mg per day for 5years. However, the patient had been off the med-

RIFABUTIN USE 167

FIG. 1. Slip lamp photographs of case 1: (A): Slip lampexamination showing white-yellow pigmented posteriorcorneal deposits that formed a ring around the cornealperiphery (right eye). (B): Slip lamp examination show-ing white-yellow pigmented posterior corneal depositsthat formed a ring around the corneal periphery (left eye).(C): Slip lamp examination showing the corneal depositslocated within the cornea at the level of the endothelium(black arrow).

A

B

C

ication for 7 years before his referral to the eyeclinic. He was reexamined 6 and 9 months later,and the corneal findings remained the same.

Case 3

An 11-year-old asymptomatic white femalewas referred to the corneal clinic for evaluationof new corneal findings that were noted on rou-tine examination. She had no history of eye dis-ease. She had a history of previous lymph nodetuberculosis treated with rifabutin, ethambutol,and clarithromycin. The rifabutin regimen usedwas 300 mg per day for 8 months and the patienthad been off the medication for 14 months at that time. This patient was HIV-negative. Herbest-corrected vision acuity was 20/30 (right eye)and 20/25 (left eye). The slit-lamp examinationdemonstrated 360 degree C bilateral peripheralendothelial deposits. They were yellow-white,stellate, and mainly located in the periphery.There was no associated uveitis. The intraocularpressure was within normal limits of OU. The pa-tient was followed-up 10 months after the firstconsultation and the corneal findings had notchanged.

COMMENT

Some medications have been reported to resultin corneal deposition. With these medications, thedeposits usually occur in the epithelial layer.Only 2 medications have been reported to depositat the level of the endothelium: amiodarone and

rifabutin.5,11 None of our patients were takingamiodarone (Table 1).

Smith et al.11 described bilateral posteriorcorneal deposits as the cause of asymptomatic en-dothelial deposits in children with HIV who wereprophylactically treated with rifabutin. Six of 25children had diffuse, small endothelial stellatedeposits. As in our patients, these children didnot have concurrent active uveitis. Recently, pos-terior corneal deposits were reported as theunique finding in asymptomatic patients whohad received rifabutin.2,5,12 In our series, all pa-tients had a history of rifabutin use. None of thesepatients are still receiving rifabutin. They had dis-continued rifabutin use for at least 1 year.

The deposits are usually bilateral, and initiallyperipheral and stellate.2,5,12 Of interest is the factthat these deposits occur without any associateduveitis. Another cause of endothelial precipitatesin patients with HIV previously reported is CMVretinitis.5 None of our patients had ever been in-fected with CMV in the present or during thepast. These endothelial deposits do not appear toresolve upon termination of rifabutin therapy inthe short to medium term. A longer period of ob-servation is required to determine if these de-posits change in the long term.2

Without additional information, such as acorneal biopsy, we can only speculate as to thecause of these corneal deposits. We believe theseunique corneal endothelial deposits may be theresult of toxicity of rifabutin or a combination ofmedications that these patients have received.Long-term side-effects of these new medicationshave yet to be identified. Further investigation to

COUTINHO ET AL.168

TABLE 1. PATIENTS’ CHARACTERISTICS AND FINDINGS

Location/Patient pigmentation of Anterior CMV

N (age/sex) deposits uveitis retinitis HIV Medications (previously used)

1 40/M Endothelium/ No No � Indinavir, lamivudine-zidovudine,Yellow-white acyclovir, fenofibrate

(rifabutin, didanosine)(sulfamethoxazole-trimethoprim)

2 56/M Endothelium/ No No � Tenofovir, ritonavir, enfuvirtide,White atazanavir, didanosine,

(rifabutin)

3 11/F Endothelium/ No No � (Rifabutin),Yellow-white (ethambutol, clarithromycin)

Age, years; M, male; F, female; CMV, cytomegalovirus; HIV, human immunodeficiency virus.

unravel the source of these deposits may teach usmore about HIV, CMV, and the pharmacology ofthe medications used by these patients.

REFERENCES

1. Arevalo, J.F., Russack, V., and Freeman, W.R. Newophthalmic manifestations of presumed rifabutin-re-lated uveitis. Ophthal. Surg. Lasers. 28:321–324, 1997.

2. Golchin, B., and McClellan, K. Corneal endothelial de-posits secondary to rifabutin prophylaxis for My-cobacterium avium complex bacteraemia. Br. J. Oph-thalmol. 87:798–799, 2003.

3. Skinner, M.H., and Blaschke, T.F. Clinical pharmaco-kinetics of rifabutin. Clin. Pharmacokinet. 28:115–125,1995.

4. Ponjavic, V., Granse, L., Stigmar, E.B., et al. Retinaldysfunction and anterior segment deposits in a pa-tient treated with rifabutin. Acta. Ophthalmol. Scand.80:553–556, 2002.

5. Chu, D.S., Zaidman, G.W., Meisler, D.M., et al. Hu-man immunodeficiency virus-positive patients withposterior intracorneal precipitates. Ophthalmology 108:1853–1857, 2001.

6. Jacobs, D.S., Piliero, P.J., Kuperwaser, M.G., et al.Acute uveitis associated with rifabutin use in patientswith human immunodeficiency virus infection. Am.J. Ophthalmol. 118:716–722, 1994.

7. Saran, B.R., Maguire, A.M., Nichols, C., et al. Hy-popyon uveitis in patients with acquired immunode-

ficiency syndrome treated for systemic Mycobacteriumavium complex infection with rifabutin. Arch. Oph-thalmol. 112:1159–1165, 1994.

8. Karbassi, M., and Nikou, S. Acute uveitis in patientswith acquired immunodeficiency syndrome receivingprophylactic rifabutin. Arch. Ophthalmol. 113:699–701,1995.

9. Fuller, J.D., Stanfield, L.E.D., and Craven, D.E. Ri-fabutin prophylaxis and uveites. N. Engl. J. Med.330:1315–1316, 1994.

10. Shafran, S.D., Deschenes, J., Miller, M., et al. Uveitesand pseudojaundice during a regimen of clar-ithromycin, rifabutin, and ethambutol. N. Engl. J. Med.330:438–439, 1994.

11. Smith, J.A., Mueller, B.U., Nussenblatt, R.B., et al.Corneal endothelial deposits in children positive forhuman immunodeficiency viris receiving rifabutinprophylaxis for Mycobacterium avium complex bac-teremia. Am. J. Ophthalmol. 127:164–169, 1999.

12. Holland, S.P., Chang, C.W., Vagh, M., et al. Cornealendothelial deposits in patients with HIV infection orAIDS: Epidemiologic evidence of the contribution ofrifabutin. Can. J. Ophthalmol. 34:204–209, 1999.

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3775 University Street, Room 216H3A 2B4 Montreal Quebec,

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E-mail: anamariacoutinho@hotmail.com

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