- Email: [email protected]
Corneal complications and NSAIDs
Letters to the Editor Author reply Dear Editor: In our in vitro study, we investigated the adherence of an ocular isolate of Staphylococcus epidermidis to polymethyl methacrylate (PMMA) and Acrysof intraocular lenses (IOLs). The numbers of adherent bacteria were studied in two fashions: scanning electron microscopy and direct counting of viable adherent bacteria released by sonication. Scanning electron microscopy revealed that in both IOL types, the number of organisms increased steadily with incubation times, and Acrysof IOLs were more permissive to staphylococcal adherence than PMMA IOLs. In the experiment performed by culturing adherent bacteria released by sonication, S. epidermidis adherence to PMMA IOLs increased steadily with longer incubation. Conversely, the number of bacteria released from Acrysof IOLs decreased steadily with longer incubation. After 3 minutes’ incubation, Acrysof IOLs seemed to be more permissive to S. epidermidis adherence than PMMA IOLs. However, at 90 minutes, Acrysof IOLs had a lower viable bacterial count than PMMA IOLs. Therefore, we concluded that Acrysof IOLs seemed to be less permissive to bacterial adherence with longer incubation. The reason why direct counting of bacteria was different in the two sets of experiments involving the Acrysof IOLs is not clear. One possible explanation for this discrepancy could be that Acrysof material may have a toxic timedependent effect on bacterial cells, which may eventually reduce the bacterial colonization of the lens. It is important to stress that the culture method can detect only viable bacteria, whereas in scanning electron microscopy the total number of bacteria includes both live and dead organisms. However, more extensive in vitro studies are necessary to establish whether Acrysof material really has a toxic timedependent effect on S. epidermidis. As stated earlier, in the experiment performed by culturing adherent bacteria released by sonication, we found that S. epidermidis adherence to PMMA IOLs increased steadily with longer incubation. Dr. Linnola’s criticism of this conclusion is difficult to understand. Indeed, scanning electron microscopy of IOLs after sonication revealed only rare adherent organisms, thus demonstrating the efficacy of the sonication method (see Results). This means that almost all bacteria attached to the IOLs were dislodged by sonication. As a result, direct counting of bacteria on agar plates reflected the number of viable bacteria formerly attached to the IOLs. Dr. Linnola found that Acrysof IOLs showed “better biocompatibility” than PMMA IOLs and suggests that “if an IOL is able to attach bacterial cells to its surface, then it can as well be biocompatible enough to allow lens epithelial cells (LECs) to attach to its surface and, with help of LECs, attach to the capsular bag.” We do not believe that our study supports his findings, as he claims, because it does not provide evidence of the “better biocompatibility” of Acrysof IOLs. Furthermore, we have to remember that LECs are eukaryotes, and bacterial cells are prokaryotes. The mechanisms of adhesion to biomaterials involving eukaryotes are completely different from those involving bacterial cells. For example, production of a polysac-
charide glycocalix (slime), which is crucial for bacterial colonization of biomaterials, is typical of bacteria. More extensive in vitro and clinical studies are necessary to explain the mechanisms by which S. epidermidis adheres to IOLs. Identification of the factors promoting adherence of S. epidermidis to IOL surfaces is critical if we wish to understand how this organism causes postoperative endophthalmitis. ANTONIO PINNA, MD STEFANIA ZANETTI, PHD LEONARDO A. SECHI, PHD DONATELLA USAI, PHD MARIA P. FALCHI, PHD FRANCESCO CARTA, MD Sassari, Italy
Corneal Complications and NSAIDs Dear Editor: The Guest Editorial by Dr. Allan Flach in the July 2000 issue of Ophthalmology is highly critical of the manner in which ASCRS, ASOA, Dr. Kenneth Rosenthal, and several tabloids handled the issue of corneal complications attributed to the use of topical nonsteroidal antiinflammatory drugs (NSAIDs). As a full-time academician and associate journal editor, I agree with his assertion that the peer-review process is the ideal (though still imperfect) arbiter of scientific validity. However, as a clinician and guardian of my patient’s best interests, I believe that it is foolhardy, impractical, and unethical to always await peer-reviewed reports before intervening in matters that affect patient safety. I will not address the details of Dr. Flach’s editorial, because Dr. Masket discusses them in his letter. However, I do want to examine and rebut some of the perjorative language used by Dr. Flach: 1. “. . . great confusion can result if we overreact to preliminary information”: Of course there was, and still is, confusion about the incidence and pathogenesis of these problems. This is true of all new problems. But the solution to confusion is acquisition of data, discussion, and scientific studies—all of which have been or are being conducted. 2. “. . . an expensive disservice”: To whom? To the patients whose sight has been saved? To the physicians who have been spared seeing this occur in their patients? Regrettably, the NSAID manufacturers have incurred increased expenses because of decreased sales, the cost of the additional advertising, and, for one manufacturer, removal of the product from the marketplace. 3. “. . . one wonders why any magazine would want to publish incomplete or inaccurate information”: On the contrary, why would any magazine or anyone try to withhold information that relates to patient safety? Should everyone wait the required months or longer for publication of a peer-reviewed study? If the medications were being used for a critical clinical need, then withdrawing them would be a grave matter. But NSAIDs after cataract surgery have only been proven to reduce postoperative inflammation, a task that can
1519
Ophthalmology Volume 108, Number 9, September 2001 be accomplished by topical corticosteroids. Reduced use of NSAIDs after cataract surgery pales in its consequences to eyes lost from corneal melting. 4. “. . . may give a garbled message that interferes with good patient care”: How has this in any way interfered with good patient care? Is it good patient care to persist with treatments that have uncertain benefit and yet lead to perforation of the eye? Good patient care is responding to all information and acting in patients’ best interests, while awaiting definitive scientific understanding. 5. “. . . tabloids . . . have the same standards of veracity to uphold”: Absolutely true, but what about the converse approach? How could withholding reports of lost eyes represent a more honest approach? 6. “The tabloids cannot duck their responsibility to be reasonable and accurate”: Surprisingly, Dr. Flach fails to mention a single instance in which the tabloids were either unreasonable, nor were they inaccurate in any way that jeopardized patient care. It is hard to see what this editorial contributes. It does not provide new information that helps with our understanding of this problem. It does not suggest any new approaches or studies that are not already in progress. It demeans individuals and publications that have performed a public service by publicizing an issue of great clinical importance and by providing a public forum for discussion of this problem. I certainly agree with the spirit of Dr. Flach’s editorial that all of us must do our best to be scientific, accurate, and diligent in our pursuit of the truth. However, I strongly dispute Dr. Flach’s assertion that the process that occurred violated this principle. The process he condemns undoubtedly saved eyes while the scientific inquiry continues. DOUGLAS D. KOCH, MD Houston, Texas Author reply Dear Editor: I am pleased that Dr. Koch “agrees with the spirit of my editorial, that all of us must do our best to be scientific, accurate, and diligent in our pursuit of the truth,” and that “the peer review process is the ideal (though still imperfect) arbiter of scientific validity.” Furthermore, I am certain we all agree with his comment that “good patient care is responding to all information and acting in patients’ best interests.” Therefore, I do not understand how he so readily condones the fact that these corneal complications were reported on multiple occasions without a careful clinical description of the problem, without knowing the drug(s) involved, how the drugs were used, how long the drug(s) was used, why the nonsteroidal antiinflammatory drug (NSAID) was used (i.e., what was the diagnosis or indication for use), the type of surgery (if any) associated with the complication, coexistent diseases, and treatments that may predispose to or even be responsible for some of the observed corneal complications. I continue to believe that if more information was requested at the time of these events and if one or more of the usual resources for reporting drug toxicities were used, such as the National Drug Resistry, the drug manufacturers involved, the Food and Drug Adminis-
1520
tration (FDA), or the FDA’s MEDWATCH (all or any of which provide wonderful peer review), these toxicities could have been more efficiently and effectively treated and prevented. Dr. Koch also states, “Reduced use of NSAIDs after cataract surgery pales in its consequences to eyes lost from corneal melting.” He asks the question, “Is it good patient care to persist with treatments that have uncertain benefit and yet lead to perforation of the eye?” These comments suggest that Dr. Koch is convinced that the postoperative use of NSAIDs after cataract surgery relates directly to the corneal melts. He might be correct. However, the most recent detailed reports of corneal melts associated with diclofenac use do not describe a corneal toxicity associated with the postoperative treatment of patients after cataract surgery.1 In fact, one cannot be certain from these five recent reports what the diagnosis was that suggested topical NSAIDs were indicated. In light of these unclear indications for treatment, it may be important to recall that dry eyes, even in asymptomatic patients, predispose to corneal melts with or without coexistent surgery or medical therapy.2,3 In addition, there are many topically applied drugs, including corticosteroids, that can cause a keratitis, interfere with wound healing, or even result in corneal melting.4 – 6 If one or more of these drugs were used in place of diclofenac in the manner described in these case reports, it is quite possible that similar toxicities would have been observed. These recent reports1 bring to mind a quote from Sir William Osler that Dr. Fred M. Wilson II provided us with many years ago, which seems timely to recall at present:6 “In the fight which we have to wage incessantly against ignorance and quackery among the masses and follies of all sorts among the classes, diagnosis, not drugging, is our chief weapon of offence. Lack of systematic personal training in the methods of the recognition of disease leads to the misapplication of remedies, to long courses of treatment when treatment is useless, and so directly to the lack of confidence in our methods which is apt to place us in the eyes of the public on a level with empirics and quacks.”7 ALLAN FLACH, MD Corte Madera, California References 1. Lin JC, Rapuano CJ, Laibson PR, et al. Corneal melting associated with use of topical nonsteroidal anti-inflammatory drugs after ocular surgery. Arch Ophthalmol 2000;118:1129 –32. 2. Pfister RR, Murphy GE. Corneal ulceration and perforation associated with Sjogren’s Syndrome. Arch Ophthalmol 1980; 98:89 –94. 3. Radtke N, Meyers S, Kaufman HE. Sterile corneal ulcers after cataract surgery in keratoconjunctivitis sicca. Arch Ophthalmol 1978;96:51–2. 4. Burnstein NL. Corneal cytotoxicity of topically applied drugs, vehicles and preservatives. Surv of Ophthalmol 1980;25:25–30. 5. Thygeson P. Controversies in Ophthalmology. Philadelphia, PA: WB Saunders Co, 1977; 450 – 69. 6. Wilson FM II. Adverse external ocular effects of topical ophthalmic therapy: an epidemiologic, laboratory, and clinical study. Trans Am Ophthalmol Soc 1983;81:854 –965. 7. Osler W ed. Aequanimitas, with Other Addresses to Medical Students, Nurses, and Practioners of Medicine, 3 ed. Philadelphia: P. Blakiston’s Son and Co., 1932;283.
charide glycocalix (slime), which is crucial for bacterial colonization of biomaterials, is typical of bacteria. More extensive in vitro and clinical studies are necessary to explain the mechanisms by which S. epidermidis adheres to IOLs. Identification of the factors promoting adherence of S. epidermidis to IOL surfaces is critical if we wish to understand how this organism causes postoperative endophthalmitis. ANTONIO PINNA, MD STEFANIA ZANETTI, PHD LEONARDO A. SECHI, PHD DONATELLA USAI, PHD MARIA P. FALCHI, PHD FRANCESCO CARTA, MD Sassari, Italy
Corneal Complications and NSAIDs Dear Editor: The Guest Editorial by Dr. Allan Flach in the July 2000 issue of Ophthalmology is highly critical of the manner in which ASCRS, ASOA, Dr. Kenneth Rosenthal, and several tabloids handled the issue of corneal complications attributed to the use of topical nonsteroidal antiinflammatory drugs (NSAIDs). As a full-time academician and associate journal editor, I agree with his assertion that the peer-review process is the ideal (though still imperfect) arbiter of scientific validity. However, as a clinician and guardian of my patient’s best interests, I believe that it is foolhardy, impractical, and unethical to always await peer-reviewed reports before intervening in matters that affect patient safety. I will not address the details of Dr. Flach’s editorial, because Dr. Masket discusses them in his letter. However, I do want to examine and rebut some of the perjorative language used by Dr. Flach: 1. “. . . great confusion can result if we overreact to preliminary information”: Of course there was, and still is, confusion about the incidence and pathogenesis of these problems. This is true of all new problems. But the solution to confusion is acquisition of data, discussion, and scientific studies—all of which have been or are being conducted. 2. “. . . an expensive disservice”: To whom? To the patients whose sight has been saved? To the physicians who have been spared seeing this occur in their patients? Regrettably, the NSAID manufacturers have incurred increased expenses because of decreased sales, the cost of the additional advertising, and, for one manufacturer, removal of the product from the marketplace. 3. “. . . one wonders why any magazine would want to publish incomplete or inaccurate information”: On the contrary, why would any magazine or anyone try to withhold information that relates to patient safety? Should everyone wait the required months or longer for publication of a peer-reviewed study? If the medications were being used for a critical clinical need, then withdrawing them would be a grave matter. But NSAIDs after cataract surgery have only been proven to reduce postoperative inflammation, a task that can
1519
Ophthalmology Volume 108, Number 9, September 2001 be accomplished by topical corticosteroids. Reduced use of NSAIDs after cataract surgery pales in its consequences to eyes lost from corneal melting. 4. “. . . may give a garbled message that interferes with good patient care”: How has this in any way interfered with good patient care? Is it good patient care to persist with treatments that have uncertain benefit and yet lead to perforation of the eye? Good patient care is responding to all information and acting in patients’ best interests, while awaiting definitive scientific understanding. 5. “. . . tabloids . . . have the same standards of veracity to uphold”: Absolutely true, but what about the converse approach? How could withholding reports of lost eyes represent a more honest approach? 6. “The tabloids cannot duck their responsibility to be reasonable and accurate”: Surprisingly, Dr. Flach fails to mention a single instance in which the tabloids were either unreasonable, nor were they inaccurate in any way that jeopardized patient care. It is hard to see what this editorial contributes. It does not provide new information that helps with our understanding of this problem. It does not suggest any new approaches or studies that are not already in progress. It demeans individuals and publications that have performed a public service by publicizing an issue of great clinical importance and by providing a public forum for discussion of this problem. I certainly agree with the spirit of Dr. Flach’s editorial that all of us must do our best to be scientific, accurate, and diligent in our pursuit of the truth. However, I strongly dispute Dr. Flach’s assertion that the process that occurred violated this principle. The process he condemns undoubtedly saved eyes while the scientific inquiry continues. DOUGLAS D. KOCH, MD Houston, Texas Author reply Dear Editor: I am pleased that Dr. Koch “agrees with the spirit of my editorial, that all of us must do our best to be scientific, accurate, and diligent in our pursuit of the truth,” and that “the peer review process is the ideal (though still imperfect) arbiter of scientific validity.” Furthermore, I am certain we all agree with his comment that “good patient care is responding to all information and acting in patients’ best interests.” Therefore, I do not understand how he so readily condones the fact that these corneal complications were reported on multiple occasions without a careful clinical description of the problem, without knowing the drug(s) involved, how the drugs were used, how long the drug(s) was used, why the nonsteroidal antiinflammatory drug (NSAID) was used (i.e., what was the diagnosis or indication for use), the type of surgery (if any) associated with the complication, coexistent diseases, and treatments that may predispose to or even be responsible for some of the observed corneal complications. I continue to believe that if more information was requested at the time of these events and if one or more of the usual resources for reporting drug toxicities were used, such as the National Drug Resistry, the drug manufacturers involved, the Food and Drug Adminis-
1520
tration (FDA), or the FDA’s MEDWATCH (all or any of which provide wonderful peer review), these toxicities could have been more efficiently and effectively treated and prevented. Dr. Koch also states, “Reduced use of NSAIDs after cataract surgery pales in its consequences to eyes lost from corneal melting.” He asks the question, “Is it good patient care to persist with treatments that have uncertain benefit and yet lead to perforation of the eye?” These comments suggest that Dr. Koch is convinced that the postoperative use of NSAIDs after cataract surgery relates directly to the corneal melts. He might be correct. However, the most recent detailed reports of corneal melts associated with diclofenac use do not describe a corneal toxicity associated with the postoperative treatment of patients after cataract surgery.1 In fact, one cannot be certain from these five recent reports what the diagnosis was that suggested topical NSAIDs were indicated. In light of these unclear indications for treatment, it may be important to recall that dry eyes, even in asymptomatic patients, predispose to corneal melts with or without coexistent surgery or medical therapy.2,3 In addition, there are many topically applied drugs, including corticosteroids, that can cause a keratitis, interfere with wound healing, or even result in corneal melting.4 – 6 If one or more of these drugs were used in place of diclofenac in the manner described in these case reports, it is quite possible that similar toxicities would have been observed. These recent reports1 bring to mind a quote from Sir William Osler that Dr. Fred M. Wilson II provided us with many years ago, which seems timely to recall at present:6 “In the fight which we have to wage incessantly against ignorance and quackery among the masses and follies of all sorts among the classes, diagnosis, not drugging, is our chief weapon of offence. Lack of systematic personal training in the methods of the recognition of disease leads to the misapplication of remedies, to long courses of treatment when treatment is useless, and so directly to the lack of confidence in our methods which is apt to place us in the eyes of the public on a level with empirics and quacks.”7 ALLAN FLACH, MD Corte Madera, California References 1. Lin JC, Rapuano CJ, Laibson PR, et al. Corneal melting associated with use of topical nonsteroidal anti-inflammatory drugs after ocular surgery. Arch Ophthalmol 2000;118:1129 –32. 2. Pfister RR, Murphy GE. Corneal ulceration and perforation associated with Sjogren’s Syndrome. Arch Ophthalmol 1980; 98:89 –94. 3. Radtke N, Meyers S, Kaufman HE. Sterile corneal ulcers after cataract surgery in keratoconjunctivitis sicca. Arch Ophthalmol 1978;96:51–2. 4. Burnstein NL. Corneal cytotoxicity of topically applied drugs, vehicles and preservatives. Surv of Ophthalmol 1980;25:25–30. 5. Thygeson P. Controversies in Ophthalmology. Philadelphia, PA: WB Saunders Co, 1977; 450 – 69. 6. Wilson FM II. Adverse external ocular effects of topical ophthalmic therapy: an epidemiologic, laboratory, and clinical study. Trans Am Ophthalmol Soc 1983;81:854 –965. 7. Osler W ed. Aequanimitas, with Other Addresses to Medical Students, Nurses, and Practioners of Medicine, 3 ed. Philadelphia: P. Blakiston’s Son and Co., 1932;283.