Chloramphenicol Eye Drops: Should we continue using in threatening Keratitis & Endophthalmitis

Chloramphenicol eye drops are low cost and little irritative effect on the cornea, have good conjunctival and aqueous humor penetration as a broad spectrum antibiotic. Nowadays, it is rarely being used in the United States for the past 30 years, giving an advantage of efficacy in this era of increasing antibiotic resistance. Why are we not using them? The main reason behind the initial stoppage of topical chloramphenicol use was case reports that implied there was an association between chloramphenicol eye drops and the development of aplastic anemia.

INTRODUCTION

 

Chloramphenicol eye drops are low cost and little irritative effect on the cornea, have good conjunctival and aqueous humor penetration as a broad spectrum antibiotic. Nowadays, it is rarely being used in the United States for the past 30 years, giving an advantage of efficacy in this era of increasing antibiotic resistance. Why are we not using them? The main reason behind the initial stoppage of topical chloramphenicol use was case reports that implied there was an association between chloramphenicol eye drops and the development of aplastic anemia. In 1982, Fraunfelder published a case report of fatal aplastic anemia, with the citation of 3 other cases. Fraunfelder strongly suggested the risk of aplastic anemia was not worth continued use of topical chloramphenicol. Following this article, use of chloramphenicol eye drops in the United States decreased by 80%. By 1995, after use of topical chloramphenicol eye drops, 23 cases of aplastic anemia were documented in the National Registry of Drug-induced Ocular Side Effects. The patients in these cases had an age range of 33 to 82 years and had a median duration exposure of 120 days, and 12 of these patients died. cited these cases to argue that chloramphenicol eye drops should not be used as first-line treatment of bacterial conjunctivitis in Great Britain. Finally, in 2007 the Fraunfelders used the World Health Organization’s classification system for drug-related adverse events to categorize the relationship between aplastic anemia and chloramphenicol eye drops as “probable.” However, multiple reviews and debates from the 1980s to the early 2000s, including a 2013 review by the Fraunfelder father-son team, came to the same conclusion: An association between topical chloramphenicol and aplastic anemia is, at best, “possible.” These reviews found that many of the cited cases were poorly documented, and some patients were also taking other drugs associated with blood dyscrasias. The cases without these issues could be attributed to idiopathic anemia. Further refutation of a connection between ocular chloramphenicol and aplastic anemia comes from analysis of populations in whom topical chloramphenicol is commonly used. Hong Kong uses chloramphenicol 100 to 400 times more frequently than most western countries; however, its death rate from aplastic anemia is 0.4 per 1000 deaths, less than half of the 1 in 1000 deaths in England and Wales. An article using data from 2 international case-control studies found no association between topical chloramphenicol and aplastic anemia. Among 426 cases of aplastic anemia and 3118 controls, 7 subjects used chloramphenicol eye drops within 6 months before admission. These subjects were all in the control group. A prospective case-control study of aplastic anemia from Spain found those who used topical chloramphenicol within the prior 6 months had a nonstatistically significant 3.77 (95% confidence internal, 0.80–15.47) higher odds of developing aplastic anemia compared with controls. The same study, which found cases by contacting every hospital within a population of 4.2 million people, estimated the rate of aplastic anemia after use of topical chloramphenicol to be 0.36 cases/ 1 million weeks of treatment used high-performance liquid chromatography to investigate serum accumulation of chloramphenicol after topical therapy. Patients in this study received chloramphenicol drops 4 times daily for 1 to 2 weeks. Samples drawn 4 hours after patients’ last doses did not have a detectable level of chloramphenicol in the subjects’ serum. The lack of a detectable level of chloramphenicol in patients’ serum makes it difficult to support that its metabolites could reach a level that would cause a blood dyscrasia. Between the years 2004 and 2007, ocular chloramphenicol was purchased approximately 11.8 million times solely in England, including both prescription and overthe- counter sales. During that time, the Yellow Card Scheme, the United Kingdom’s system for collecting information on suspected safety concerns involving medicines, only received 6 reports of blood disorders, immune disorders, or infections that might be connected to ocular, ophthalmic, or intraocular chloramphenicol use. This method of estimating the cases of aplastic anemia associated with topical chloramphenicol is limited because of its reliance on self-reporting; however, in the face of increasing antibiotic resistance, chloramphenicol continues to be both a low-cost and effective option. Antibiotic resistance is a growing problem within ophthalmology. Fourth-generation fluoroquinolones, moxifloxacin, and gatifloxacin were developed to combat Pseudomonas aeruginosa infections resistant to second-generation fluoroquinolones, but there are increasingly frequent reports of fourth-generation fluoroquinolone-resistant keratitis. Recommendations for preventing the development of this resistance rely on reserving fourth-generation fluoroquinolones for serious infections, such as postoperative endophthalmitis. However, recent studies of antibiotic susceptibility in normal ocular flora have demonstrated as much as 10% to 20% resistance to second-and third-generation fluoroquinolones, leaving stronger, costlier antibiotics as alternatives for bacterial conjunctivitis. Antibiotic resistance is even greater in those who have previously received fluoroquinolones as endophthalmitis prophylaxis after intravitreal anti–vascular endothelial growth factor injections. Recent studies of antimicrobial resistance in Australia, the United Kingdom and China demonstrated that microbes isolated from hundreds of cases of bacterial keratitis are just as if not more, susceptible to chloramphenicol when compared with fluoroquinolones, especially in cases of methicillin-resistant Staphylococcus aureus. To combat the evolution of antibiotic resistance, why not use a topical antibiotic that is effective and costs more than $100 less than ofloxacin eye drops? Although Great Britain decided to allow over-thecounter purchase of topical chloramphenicol in 2005, a more conservative approach could be an effective solution in the United States.

 

SUMMARY:

 

We propose a trial period during which chloramphenicol is prescribed under the following restrictions:

(1) for vision-threatening keratitis or conjunctivitis cases that have failed a trial of first-line antibiotic drops;

(2) only in patients who have no personal or family history of blood dyscrasias;

(3) only in adults;

(4) only after obtaining written informed consent.

This adjustment would allow third- and fourth-generation fluoroquinolones to remain reserved for postoperative endophthalmitis or keratitis, as is currently recommended. They also suggested 1 drop should be used at a time with pressure on the lacrimal sac, for 14 days of use.

If there is no increase of aplastic anemia cases, topical chloramphenicol use could be expanded to simple bacterial conjunctivitis and other indications. With this approach, we may just find the old dog of topical chloramphenicol settling comfortably into its new house.

 

 

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3. Sjögren’s Syndrome

 

An old woman presented with a 5-month history of photophobia and pain with foreign-body sensation in both eyes. The visual acuity was 20/25 in each eye, and slitlamp examination showed conjunctival hyperemia, corneal epithelial erosions, and corneal endothelial folds.

 

Differential diagnosis:

 

Cat scratch disease, Sjögren’s syndrome,Trachoma, Behçet’s disease, Multiple sclerosis

 

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