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Blood Dyscrasias and Topical Ophthalmic Chloramphenicol
LETTERS TO THE JOURNAL col ointment and chloramphenicol combined with other antibiotics. Severity and onset time of the dyscrasias did not correlate with the total dosage of chloramphenicol administered. Total doses of the topical ophthalmic chloramphenicol ranged from 0.03 to 1.64 g (median, 0.09 g). Duration of exposure to this antibiotic ranged from 18 to 1,460 days (median, 120 days). In six patients the antibiotic was used for less than two months before the onset of the blood dyscrasia. Fatal outcomes were reported in 12 patients, seven patients' symptoms were reversible, and four patients were not followed up. Although all reporting ophthalmologists and hematologists believed there was a possible cause-and-effect relationship, this is doubtful because there is a small incidence in the general population (3:1,000,000 per year)." That all cases were just a chance event and not related to the drug, in our opinion, is also improbable because the incidence is small in the general population. The sale of topical ocular chloramphenicol in the United States decreased 90% within two years after publication of an article,' and the major ophthalmic pharmaceutical companies are no longer promoting or have discontinued this product. Listings of chloramphenicol products from Parke-Davis (Morris Plains, New Jersey) in the Physicians' Desk Reference for Ophthalmologyvf" begin with a bold-type warning, and a statement outlined in a box stating that aplastic anemia and death have been reported after topical ocular use, along with a statement that "less potentially dangerous agents"4 P 300 should be used if they provide
Blood Dyscrasias and Topical Ophthalmic Chloramphenicol F. T. Fraunfelder, M.D., R. L. Morgan, Ph.D., and A. A. Yunis, M.D. Department of Ophthalmology, Casey Eye Institute, Oregon Health Sciences University. Inquiries to F. T. Fraunfelder, M.D., Casey Eye Institute, Oregon Health Sciences University, 3375 S.W. Terwilliger Blvd., Portland, OR 97201-4197.
The National Registry of Drug-induced Ocular Side Effects (Casey Eye Institute, Oregon Health Sciences University, Portland, Oregon) has received reports of 23 patients with blood dyscrasias that may be related to topical ocular administration of chloramphenicol. These reports include seven published cases."! The 16 unpublished cases were not fully investigated but are included in our study because the reporting physicians thought that topical ophthalmic chloramphenicol was associated with the blood dyscrasias. Twelve patients had aplastic anemias, six patients had pancytopenias, one patient had a bone marrow depression, two patients had leukopenias, two patients had thrombocytopenias, and one patient had agranulocytosis. The patients ranged in age from 33 to 82 years (median, 66 years), and approximately 15 of these patients were women. Two of the patients had a family history of pernicious anemia. Approximately two thirds of the patients received 0.5% chloramphenicol solution. The remaining patients were evenly divided between receiving 1.0% chlorampheni-
THE JOURNAL welcomes letters that describe unusual clinical or pathologic findings, experimental results, and new instruments or techniques. The title and the names of all authors appear in the Table of Contents and are retrievable through the Index Medicus and other standard indexing services. Letters must not duplicate data previously published or submitted for publication. Each letter must be accompanied by a signed disclosure statement and copyright transfer agreement published in each issue of THE JOURNAL. Letters must be typewritten, double-spaced, on 8 1h x ll-inch bond paper with 1 Ih-inch margins on all four sides. (See Instructions to Authors.) An original and two copies of the typescript and figures must be sent. The letters should not exceed 500 words of text. A maximum of two black-and-white figures may be used; they should be cropped or reducible to a width of 3 inches (one column). Color figures cannot be used. References should be limited to five. Letters may be referred to outside editorial referees for evaluation or may be reviewed by members of the Editorial Board. All letters are published promptly after acceptance. Authors do not receive galley proofs but if the editorial changes are extensive, the corrected typescript is submitted to them for approval. These instructions markedly limit the opportunity for an extended discussion or review. Therefore, THE JOURNAL does not publish correspondence concerning previously published letters. 812
Vol. 115, No.6
Letters to The Journal
effective treatment. Allergan's (Irvine, California) chloramphenicol warning is weaker and placed in the middle of their product-information data.4p.243 No other companies give chloramphenicol product-information data in the recent Physicians' Desk Reference for Ophthalmology. Although the exact mechanism of aplastic anemia from chloramphenicol remains unknown, recent work supports the hypothesis of an individual metabolic predisposition": A nitroreduction derivative of chloramphenicol (nitroso chloramphenicol or hydroxylamine) or another metabolite of chloramphenicol produced by the predisposed patient results in DNA damage in stem cells, which leads to blood dyscrasias. The ultimate toxic derivative of chloramphenicol may be produced in the marrow in situ, thus making the marrow both the site of metabolic conversion and the target of injury.' Genotoxicity in stem cells may make them nonproliferative, or alternatively, may initiate immune-mediated marrow damage. The occurrence of aplastic anemia in association with small doses of chloramphenicol such as in topical ophthalmic preparations is consistent with the hypothesis of an individual metabolic predisposition. Subjecting patients to this potential risk is difficult to justify if other bacteriostatic agents are available to treat the infection. We think the only time topical ophthalmic chloramphenicol should be used is when the infecting organism resists all other antibiotics.
References 1. Fraunfelder, F. T., Bagby, G. c., [r., and Kelly, D. ].: Fatal aplastic anemia following topical administration of ophthalmic chloramphenicol. Am. J. Ophthalmol. 93:356,1982. 2. Issaragrisil, S., and Piankijagum, A.: Aplastic anemia following topical administration of ophthalmic chloramphenicol. Report of a case and review of the literature. J. Med. Assoc. Thai. 68:309,1985. 3. International Agranulocytosis and Aplastic Anemia Study: Incidence of aplastic anemia. The relevance of diagnostic criteria. Blood 70: 1718, 1987. 4. Physicians' Desk Reference for Ophthalmology, ed. 20. Montvale, New Jersey, Medical Economics Data, 1992, pp. 300, 243. 5. Yunis, A. A.: Chloramphenicol. Relation of structure to activity and toxicity. Annu. Rev. Pharmacol. Toxicol, 28:83, 1988.
813
Transient Myopia, Angle-closure Glaucoma, and Choroidal Detachment After Oral Acetazolamide Joseph T. Fan, M.D., Douglas H. Johnson, M.D., and Rick R. Burk, o.n, Department of Ophthalmology, Mayo Clinic and Mayo Foundation (J.T.F., D.H.J.); and Jones Eye Clinic (R.R.B).
Inquiries to Douglas H. Johnson, M.D., Department of Ophthalmology, Mayo Clinic, 200 First St. S.W., Rochester, MN 55905.
A 70-year-old healthy woman had uncomplicated phacoemulsification with placement of a posterior chamber intraocular lens in her right eye on Dec. 4, 1991. The patient received a 500-mg acetazolamide sequel orally the night before the operation as routine preoperative medication. The operation was successful; on March 4, 1992, visual acuity was R.E.: 20/20 with -1.25 +1.25 x 19 and L.E.: was 20/100, plano, with a moderate nuclear sclerotic cataract. The night before the planned cataract removal from the left eye, the patient again received a 500-mg acetazolamide sequel. The next morning, preoperatively, the patient noted blurriness in both eyes. The examination disclosed visual acuity to be R.E.: 20/20 with -4.25 +1.50 x 20, and L.E.: 20/200 with no refraction improvement. Anterior chambers were shallow, and the angles were closed. Intraocular pressure was R.E.: 38 mm Hg and L.E.: 45 mm Hg. Pupillary reactions were normal. Ophthalmoscopy disclosed peripheral choroidal detachment in the right eye but the left fundus was not clearly visible. The patient was treated with timolol maleate, 0.5%, twice a day, and prednisolone acetate, 1.0%, three times a day. The patient was examined at the Mayo Clinic two days later. Visual acuity was R.E.: 20/30 with -3.00 sphere, and L.E.: 20/100 with -2.00 sphere. Intraocular pressure was R.E.: 19 mm Hg and L.E.: 21 mm Hg. The photogrammetric method! determined the anterior chamber depths were 2.0 mm centrally and 1.3 mm midperipherally in the right eye, and 1.5 mm centrally and 0.7 mm midperipherally in the left eye. Anterior chamber volumes were 134 ,...1 in the right eye and 86 ,...1 in the left eye. Gonioscopy disclosed that the angles were open superiorly and inferiorly but closed nasally and temporally in the right eye. Gonioscopy
Blood Dyscrasias and Topical Ophthalmic Chloramphenicol F. T. Fraunfelder, M.D., R. L. Morgan, Ph.D., and A. A. Yunis, M.D. Department of Ophthalmology, Casey Eye Institute, Oregon Health Sciences University. Inquiries to F. T. Fraunfelder, M.D., Casey Eye Institute, Oregon Health Sciences University, 3375 S.W. Terwilliger Blvd., Portland, OR 97201-4197.
The National Registry of Drug-induced Ocular Side Effects (Casey Eye Institute, Oregon Health Sciences University, Portland, Oregon) has received reports of 23 patients with blood dyscrasias that may be related to topical ocular administration of chloramphenicol. These reports include seven published cases."! The 16 unpublished cases were not fully investigated but are included in our study because the reporting physicians thought that topical ophthalmic chloramphenicol was associated with the blood dyscrasias. Twelve patients had aplastic anemias, six patients had pancytopenias, one patient had a bone marrow depression, two patients had leukopenias, two patients had thrombocytopenias, and one patient had agranulocytosis. The patients ranged in age from 33 to 82 years (median, 66 years), and approximately 15 of these patients were women. Two of the patients had a family history of pernicious anemia. Approximately two thirds of the patients received 0.5% chloramphenicol solution. The remaining patients were evenly divided between receiving 1.0% chlorampheni-
THE JOURNAL welcomes letters that describe unusual clinical or pathologic findings, experimental results, and new instruments or techniques. The title and the names of all authors appear in the Table of Contents and are retrievable through the Index Medicus and other standard indexing services. Letters must not duplicate data previously published or submitted for publication. Each letter must be accompanied by a signed disclosure statement and copyright transfer agreement published in each issue of THE JOURNAL. Letters must be typewritten, double-spaced, on 8 1h x ll-inch bond paper with 1 Ih-inch margins on all four sides. (See Instructions to Authors.) An original and two copies of the typescript and figures must be sent. The letters should not exceed 500 words of text. A maximum of two black-and-white figures may be used; they should be cropped or reducible to a width of 3 inches (one column). Color figures cannot be used. References should be limited to five. Letters may be referred to outside editorial referees for evaluation or may be reviewed by members of the Editorial Board. All letters are published promptly after acceptance. Authors do not receive galley proofs but if the editorial changes are extensive, the corrected typescript is submitted to them for approval. These instructions markedly limit the opportunity for an extended discussion or review. Therefore, THE JOURNAL does not publish correspondence concerning previously published letters. 812
Vol. 115, No.6
Letters to The Journal
effective treatment. Allergan's (Irvine, California) chloramphenicol warning is weaker and placed in the middle of their product-information data.4p.243 No other companies give chloramphenicol product-information data in the recent Physicians' Desk Reference for Ophthalmology. Although the exact mechanism of aplastic anemia from chloramphenicol remains unknown, recent work supports the hypothesis of an individual metabolic predisposition": A nitroreduction derivative of chloramphenicol (nitroso chloramphenicol or hydroxylamine) or another metabolite of chloramphenicol produced by the predisposed patient results in DNA damage in stem cells, which leads to blood dyscrasias. The ultimate toxic derivative of chloramphenicol may be produced in the marrow in situ, thus making the marrow both the site of metabolic conversion and the target of injury.' Genotoxicity in stem cells may make them nonproliferative, or alternatively, may initiate immune-mediated marrow damage. The occurrence of aplastic anemia in association with small doses of chloramphenicol such as in topical ophthalmic preparations is consistent with the hypothesis of an individual metabolic predisposition. Subjecting patients to this potential risk is difficult to justify if other bacteriostatic agents are available to treat the infection. We think the only time topical ophthalmic chloramphenicol should be used is when the infecting organism resists all other antibiotics.
References 1. Fraunfelder, F. T., Bagby, G. c., [r., and Kelly, D. ].: Fatal aplastic anemia following topical administration of ophthalmic chloramphenicol. Am. J. Ophthalmol. 93:356,1982. 2. Issaragrisil, S., and Piankijagum, A.: Aplastic anemia following topical administration of ophthalmic chloramphenicol. Report of a case and review of the literature. J. Med. Assoc. Thai. 68:309,1985. 3. International Agranulocytosis and Aplastic Anemia Study: Incidence of aplastic anemia. The relevance of diagnostic criteria. Blood 70: 1718, 1987. 4. Physicians' Desk Reference for Ophthalmology, ed. 20. Montvale, New Jersey, Medical Economics Data, 1992, pp. 300, 243. 5. Yunis, A. A.: Chloramphenicol. Relation of structure to activity and toxicity. Annu. Rev. Pharmacol. Toxicol, 28:83, 1988.
813
Transient Myopia, Angle-closure Glaucoma, and Choroidal Detachment After Oral Acetazolamide Joseph T. Fan, M.D., Douglas H. Johnson, M.D., and Rick R. Burk, o.n, Department of Ophthalmology, Mayo Clinic and Mayo Foundation (J.T.F., D.H.J.); and Jones Eye Clinic (R.R.B).
Inquiries to Douglas H. Johnson, M.D., Department of Ophthalmology, Mayo Clinic, 200 First St. S.W., Rochester, MN 55905.
A 70-year-old healthy woman had uncomplicated phacoemulsification with placement of a posterior chamber intraocular lens in her right eye on Dec. 4, 1991. The patient received a 500-mg acetazolamide sequel orally the night before the operation as routine preoperative medication. The operation was successful; on March 4, 1992, visual acuity was R.E.: 20/20 with -1.25 +1.25 x 19 and L.E.: was 20/100, plano, with a moderate nuclear sclerotic cataract. The night before the planned cataract removal from the left eye, the patient again received a 500-mg acetazolamide sequel. The next morning, preoperatively, the patient noted blurriness in both eyes. The examination disclosed visual acuity to be R.E.: 20/20 with -4.25 +1.50 x 20, and L.E.: 20/200 with no refraction improvement. Anterior chambers were shallow, and the angles were closed. Intraocular pressure was R.E.: 38 mm Hg and L.E.: 45 mm Hg. Pupillary reactions were normal. Ophthalmoscopy disclosed peripheral choroidal detachment in the right eye but the left fundus was not clearly visible. The patient was treated with timolol maleate, 0.5%, twice a day, and prednisolone acetate, 1.0%, three times a day. The patient was examined at the Mayo Clinic two days later. Visual acuity was R.E.: 20/30 with -3.00 sphere, and L.E.: 20/100 with -2.00 sphere. Intraocular pressure was R.E.: 19 mm Hg and L.E.: 21 mm Hg. The photogrammetric method! determined the anterior chamber depths were 2.0 mm centrally and 1.3 mm midperipherally in the right eye, and 1.5 mm centrally and 0.7 mm midperipherally in the left eye. Anterior chamber volumes were 134 ,...1 in the right eye and 86 ,...1 in the left eye. Gonioscopy disclosed that the angles were open superiorly and inferiorly but closed nasally and temporally in the right eye. Gonioscopy