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No Detectable Systemic Absorption of Topically Administered Ophthalmic Tobramycin
402
AMERICAN JOURNAL OF OPHTHALMOLOGY
of collection. Others have reported a closer correlation between hepatitis C virus seropositivity and viral RNA in the sera, 4 but these findings generally derived from premortem studies or solid organ donors artificially sus tained pending organ removal. In addition to the studies documenting trans fusion-associated hepatitis C, much of the con cern over the potential for transmission of hep atitis C virus by transplantation stems from reports of hepatitis C developing in recipients of solid organs from seropositive donors. 1,4 In such cases, however, infected blood may be transferred within the organ, whereas the cor nea is avascular, and hence would seem unlike ly to carry a substantial viral load even if obtained from a viremic individual. To test this hypothesis, the pairs of corneas corresponding to the six individuals found to have hepatitis C virus RNA in their serum were similarly screened by the same polymerase chain reac tion protocol, but no hepatitis C virus RNA was detected in any of these 12 corneas or in control corneas from seropositive, RNA-negative indi viduals. As a sensitivity control, serial dilutions of a serum containing known quantities of hepatitis C RNA were added to homogenized corneal tissue obtained from seronegative cadavers. To create a worst case, the mixture was allowed to incubate at room temperature for two hours before the extraction of nucleic acid. After incu bation, hepatitis C virus RNA was still readily detected by polymerase chain reaction amplifi cation up to a level of 104 viruses per milliliter in this reconstruction experiment. In conclu sion,, there was no correlation between hepati tis C virus seropositivity and the detection of hepatitis C virus RNA in the corneas of viremic donors. This finding, together with the unavail ability of a specific screening test that will identify acute hepatitis C virus infection, sug gests that rejection of otherwise transplantable corneas on grounds of donor hepatitis C virus seropositivity alone may not be justified on the basis of either the available scientific data or a cost-benefit analysis.
References 1. Pereira, B. J. G., Milford, E. L., Kirkman, R. L., Quan, S., Sayre, K. R., Johnson, P. J., Wilber, J. C , and Levey, A. S.: Prevalence of hepatitis C virus RNA in organ donors positive for hepatitis C antibody and
March, 1994
in the recipients of their organs. N. Engl. J. Med. 327:910, 1992. 2. Wright, T. L., Hsu, H., Donegan, E., Feinstone, S., Greenberg, H., Read, A., Ascher, N. L., Roberts, J. P., and Lake, J. R.: Hepatitis C virus not found in fulminant non-A, non-B hepatitis. Ann. Intern. Med. 115:111, 1991. 3. Romeo, J. M., Ulrich, P. P., Busch, M. P., and Vyas, G. N.: Analysis of hepatitis C virus RNA preva lence and surrogate markers of infection among sero positive voluntary blood donors. Hepatology 17:188, 1993. 4. Roth, D., Fernandez, J. A., Babischkin, S., deMattos, A., Buck, B. E., Quan, S., Olson, L., Burke, G. W., Nery, J. R., Esquenazi, V., Schiff, E. R„ and Miller, J.: Transmission of hepatitis C virus with solid organ transplantation. Incidence and clinical signifi cance. Transplant. Proc. 25:1476, 1993.
No Detectable Systemic Absorption of Topically Administered Ophthalmic Tobramycin Vadim Filatov, M.D., George Alexandrakis, B.A., Pétrie M. Rainey, M.D., Mark A. Perazella, M.D., and Peter Gloor, M.D. Departments of Ophthalmology and Visual Science (V.F., G.A., P.G.), Laboratory Medicine (P.M.R.), and Nephrology (M.A.P.), Yale University School of Medicine. Inquiries to Peter Gloor, M.D., Department of Ophthal mology and Visual Science, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06510. Timolol, atropine, and cyclopentolate can be detected in the blood after topical administra tion to the eye. 13 We treated two patients who required frequent administration of topical for tified tobramycin for infected corneal ulcers. One patient had renal insufficiency, and the other was an infant, so there was concern that the treatment might result in systemic drug accumulation and cause nephrotoxicity or ototoxicity. Serum tobramycin levels were ob tained to determine the extent of systemic ab sorption from topical administration. Case 1 A 67-year-old woman with chronic renal in sufficiency of unknown cause was seen because of an infected corneal ulcer of her left eye. Her initial treatment included gentamicin, 15 m g /
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Letters to The Journal
ml, one drop every hour for the first three days (total cumulative dose of about 50 mg). She then received tobramycin, 15 mg/ml, one drop every half hour tapered to every two hours over five days. After 36 hours of treatment with a cumulative topical tobramycin dose of about 50 mg, a random serum tobramycin level was less than 0.2 μ g / m l . After five days of treatment with a cumulative topical tobramycin dose of about 110 mg, serum and urine tobramycin levels were both less than 0.2 μ g / m l . Before treatment with aminoglycosides, her serum creatinine and blood urea nitrogen levels were 4.8 m g / d l and 36 m g / d l , respectively. During treatment her creatinine and blood urea nitrogen levels rose steadily. A consultant nephrologist could find no other cause for the decline in renal function, so the topical tobram ycin was discontinued after five days. Creati nine and blood urea nitrogen levels peaked at 6.6 m g / d l and 81 m g / d l on the day the tobram ycin was discontinued, declined over the subse quent week, and were 3.9 m g / d l and 41 m g / d l two months later. Case 2 A 3-month-old, 4.8-kg, healthy infant with bilateral corneal ulcers was treated with to bramycin, 15 m g / m l , one drop to each eye every half hour, as well as topical cefazolin. A random serum tobramycin serum level 24 hours after the initiation of treatment was less than 0.2 μg/ml. During this period the patient had received a cumulative topical tobramycin dose of about 70 mg. These two cases demonstrate that there is little systemic absorption of topically adminis tered fortified tobramycin. Because tobramycin was administered at least every two hours, drug levels obtained at random times are a reason able measure of the average serum concentra tion. Tobramycin levels below 0.2 μ g / m l can not reliably be distinguished from each other or from zero by the fluorescence polarization immunoassay used. In the first patient, renal insufficiency should have led to accumulation of any systemically absorbed tobramycin; however, her serum lev els were less than 0.2 μ g / m l . Yet, it is possible that the topical aminoglycosides caused her declining renal function. Although nephrotoxicity induced by gentamicin and tobramycin is rare when serum trough levels are less than 2.0 μg/ml, 4 proximal tubule cell reabsorption 5 might concentrate these drugs to locally toxic levels in the renal cortex. This effect might be
403
sufficient to cause serum creatinine and blood urea nitrogen levels to increase in patients with little renal function reserve. The second patient received a daily dose of topical tobramycin that was 2.5 times greater than the maximum recommended systemic dose for her weight. Yet, the serum tobramycin level in this patient was also less than the detection limit of the assay. In summary, there is little or no systemic absorption of topical ophthalmic tobramycin. However, until further information is accumu lated, it may be prudent to observe the renal function of patients who have renal insufficien cy and require frequent topical fortified amino glycosides.
References 1. Kaila, T., Salminen, L., and Huupponen, R.: Systemic absorption of topically applied ocular timolol. ]. Ocul. Pharmacol. 1:79, 1985. 2. Lahdes, K., Kaila, T., Huupponen, R., Salminen, L., and Iisalo, E.: Systemic absorption of topically applied ocular atropine. Clin. Pharmacol. Ther. 44:310, 1988. 3. Kaila, T., Huupponen, R., Salminen, L., and Iisalo, E.: Systemic absorption of ophthalmic cyclopentolate. Am. J. Ophthalmol. 107:562, 1989. 4. Zaske, D. E., Cipolle, R. J., Rothschafer, J. C, Solem, L. D., Mosier, N. R., and Strate, R. G.: Gentamycin pharmacokinetics in 1,640 patients. Method for control of serum concentrations. Antimicrob. Agents Chemother. 21:407, 1982. 5. Humes, H. D.: Aminoglycoside nephrotoxicity. Kidney Int. 33:900, 1988.
Photorefractive Keratectomy and Postoperative Pain Raymond S t e i n , M.D., F.R.C.S.(C), Harold A. S t e i n , M.D., F.R.C.S.(C), Albert C h e s k e s , M.D., F.R.C.S.(C), and Sean S y m o n s , M.P.H. Bochner Eye Institute and the University of Toronto. Inquiries to Raymond Stein, M.D., Bochner Eye Insti tute, 40 Prince Arthur Ave., Toronto, Ontario, Canada M5R 1A9. Photorefractive keratectomy has been associ ated with postoperative pain during the first 48
AMERICAN JOURNAL OF OPHTHALMOLOGY
of collection. Others have reported a closer correlation between hepatitis C virus seropositivity and viral RNA in the sera, 4 but these findings generally derived from premortem studies or solid organ donors artificially sus tained pending organ removal. In addition to the studies documenting trans fusion-associated hepatitis C, much of the con cern over the potential for transmission of hep atitis C virus by transplantation stems from reports of hepatitis C developing in recipients of solid organs from seropositive donors. 1,4 In such cases, however, infected blood may be transferred within the organ, whereas the cor nea is avascular, and hence would seem unlike ly to carry a substantial viral load even if obtained from a viremic individual. To test this hypothesis, the pairs of corneas corresponding to the six individuals found to have hepatitis C virus RNA in their serum were similarly screened by the same polymerase chain reac tion protocol, but no hepatitis C virus RNA was detected in any of these 12 corneas or in control corneas from seropositive, RNA-negative indi viduals. As a sensitivity control, serial dilutions of a serum containing known quantities of hepatitis C RNA were added to homogenized corneal tissue obtained from seronegative cadavers. To create a worst case, the mixture was allowed to incubate at room temperature for two hours before the extraction of nucleic acid. After incu bation, hepatitis C virus RNA was still readily detected by polymerase chain reaction amplifi cation up to a level of 104 viruses per milliliter in this reconstruction experiment. In conclu sion,, there was no correlation between hepati tis C virus seropositivity and the detection of hepatitis C virus RNA in the corneas of viremic donors. This finding, together with the unavail ability of a specific screening test that will identify acute hepatitis C virus infection, sug gests that rejection of otherwise transplantable corneas on grounds of donor hepatitis C virus seropositivity alone may not be justified on the basis of either the available scientific data or a cost-benefit analysis.
References 1. Pereira, B. J. G., Milford, E. L., Kirkman, R. L., Quan, S., Sayre, K. R., Johnson, P. J., Wilber, J. C , and Levey, A. S.: Prevalence of hepatitis C virus RNA in organ donors positive for hepatitis C antibody and
March, 1994
in the recipients of their organs. N. Engl. J. Med. 327:910, 1992. 2. Wright, T. L., Hsu, H., Donegan, E., Feinstone, S., Greenberg, H., Read, A., Ascher, N. L., Roberts, J. P., and Lake, J. R.: Hepatitis C virus not found in fulminant non-A, non-B hepatitis. Ann. Intern. Med. 115:111, 1991. 3. Romeo, J. M., Ulrich, P. P., Busch, M. P., and Vyas, G. N.: Analysis of hepatitis C virus RNA preva lence and surrogate markers of infection among sero positive voluntary blood donors. Hepatology 17:188, 1993. 4. Roth, D., Fernandez, J. A., Babischkin, S., deMattos, A., Buck, B. E., Quan, S., Olson, L., Burke, G. W., Nery, J. R., Esquenazi, V., Schiff, E. R„ and Miller, J.: Transmission of hepatitis C virus with solid organ transplantation. Incidence and clinical signifi cance. Transplant. Proc. 25:1476, 1993.
No Detectable Systemic Absorption of Topically Administered Ophthalmic Tobramycin Vadim Filatov, M.D., George Alexandrakis, B.A., Pétrie M. Rainey, M.D., Mark A. Perazella, M.D., and Peter Gloor, M.D. Departments of Ophthalmology and Visual Science (V.F., G.A., P.G.), Laboratory Medicine (P.M.R.), and Nephrology (M.A.P.), Yale University School of Medicine. Inquiries to Peter Gloor, M.D., Department of Ophthal mology and Visual Science, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06510. Timolol, atropine, and cyclopentolate can be detected in the blood after topical administra tion to the eye. 13 We treated two patients who required frequent administration of topical for tified tobramycin for infected corneal ulcers. One patient had renal insufficiency, and the other was an infant, so there was concern that the treatment might result in systemic drug accumulation and cause nephrotoxicity or ototoxicity. Serum tobramycin levels were ob tained to determine the extent of systemic ab sorption from topical administration. Case 1 A 67-year-old woman with chronic renal in sufficiency of unknown cause was seen because of an infected corneal ulcer of her left eye. Her initial treatment included gentamicin, 15 m g /
Vol. 117, No. 3
Letters to The Journal
ml, one drop every hour for the first three days (total cumulative dose of about 50 mg). She then received tobramycin, 15 mg/ml, one drop every half hour tapered to every two hours over five days. After 36 hours of treatment with a cumulative topical tobramycin dose of about 50 mg, a random serum tobramycin level was less than 0.2 μ g / m l . After five days of treatment with a cumulative topical tobramycin dose of about 110 mg, serum and urine tobramycin levels were both less than 0.2 μ g / m l . Before treatment with aminoglycosides, her serum creatinine and blood urea nitrogen levels were 4.8 m g / d l and 36 m g / d l , respectively. During treatment her creatinine and blood urea nitrogen levels rose steadily. A consultant nephrologist could find no other cause for the decline in renal function, so the topical tobram ycin was discontinued after five days. Creati nine and blood urea nitrogen levels peaked at 6.6 m g / d l and 81 m g / d l on the day the tobram ycin was discontinued, declined over the subse quent week, and were 3.9 m g / d l and 41 m g / d l two months later. Case 2 A 3-month-old, 4.8-kg, healthy infant with bilateral corneal ulcers was treated with to bramycin, 15 m g / m l , one drop to each eye every half hour, as well as topical cefazolin. A random serum tobramycin serum level 24 hours after the initiation of treatment was less than 0.2 μg/ml. During this period the patient had received a cumulative topical tobramycin dose of about 70 mg. These two cases demonstrate that there is little systemic absorption of topically adminis tered fortified tobramycin. Because tobramycin was administered at least every two hours, drug levels obtained at random times are a reason able measure of the average serum concentra tion. Tobramycin levels below 0.2 μ g / m l can not reliably be distinguished from each other or from zero by the fluorescence polarization immunoassay used. In the first patient, renal insufficiency should have led to accumulation of any systemically absorbed tobramycin; however, her serum lev els were less than 0.2 μ g / m l . Yet, it is possible that the topical aminoglycosides caused her declining renal function. Although nephrotoxicity induced by gentamicin and tobramycin is rare when serum trough levels are less than 2.0 μg/ml, 4 proximal tubule cell reabsorption 5 might concentrate these drugs to locally toxic levels in the renal cortex. This effect might be
403
sufficient to cause serum creatinine and blood urea nitrogen levels to increase in patients with little renal function reserve. The second patient received a daily dose of topical tobramycin that was 2.5 times greater than the maximum recommended systemic dose for her weight. Yet, the serum tobramycin level in this patient was also less than the detection limit of the assay. In summary, there is little or no systemic absorption of topical ophthalmic tobramycin. However, until further information is accumu lated, it may be prudent to observe the renal function of patients who have renal insufficien cy and require frequent topical fortified amino glycosides.
References 1. Kaila, T., Salminen, L., and Huupponen, R.: Systemic absorption of topically applied ocular timolol. ]. Ocul. Pharmacol. 1:79, 1985. 2. Lahdes, K., Kaila, T., Huupponen, R., Salminen, L., and Iisalo, E.: Systemic absorption of topically applied ocular atropine. Clin. Pharmacol. Ther. 44:310, 1988. 3. Kaila, T., Huupponen, R., Salminen, L., and Iisalo, E.: Systemic absorption of ophthalmic cyclopentolate. Am. J. Ophthalmol. 107:562, 1989. 4. Zaske, D. E., Cipolle, R. J., Rothschafer, J. C, Solem, L. D., Mosier, N. R., and Strate, R. G.: Gentamycin pharmacokinetics in 1,640 patients. Method for control of serum concentrations. Antimicrob. Agents Chemother. 21:407, 1982. 5. Humes, H. D.: Aminoglycoside nephrotoxicity. Kidney Int. 33:900, 1988.
Photorefractive Keratectomy and Postoperative Pain Raymond S t e i n , M.D., F.R.C.S.(C), Harold A. S t e i n , M.D., F.R.C.S.(C), Albert C h e s k e s , M.D., F.R.C.S.(C), and Sean S y m o n s , M.P.H. Bochner Eye Institute and the University of Toronto. Inquiries to Raymond Stein, M.D., Bochner Eye Insti tute, 40 Prince Arthur Ave., Toronto, Ontario, Canada M5R 1A9. Photorefractive keratectomy has been associ ated with postoperative pain during the first 48