Potential Bacterial Contamination in Fluorescein-Anesthetic Solutions Lee R. Duffner, M.D., Stephen C. Pflugfelder, M.D., Sid Mandelbaum, M.D., and Linwood L. Childress, Pharm.D. To determine the ability of fluorescein-anesthetic combination solutions and their applicators to regain sterility, we contaminated four commercially available fluorescein-anesthetic solutions and their dropper tips with inocula of either Pseudomonas species or Staphylococcus species. No organisms could be cultured from Fluress one minute after inoculation of the solution or five minutes after inoculation of the dropper tip. In contrast, organisms were cultured from the other fluorescein-anesthetic preparations for at least one hour after bacterial inoculation into the solution or onto the dropper tip. These differences in the ability of fluoresceinanesthetic solutions to regain sterility after bacterial contamination were statistically significant. FLUORESCEIN SOLUTIONS used in ophthalmology have been a potential source of bacterial spread because of the propensity of Pseudomonas aeruginosa to grow in these solutions.' The introduction in 1966 of a fluorescein and benoxinate hydrochloride combination solution preserved with 1 % chlorobutanol and made available in a glass bottle with a pipette dropper (Fluress) is thought to have greatly decreased this risk. The antimicrobial properties of this preparation have been extensively reported.i" The importance of maintaining the dropper tip immersed in the solution has been demonstrated. 6ln recent years, other fluorescein-anesthetic solutions have become available from purveyors of generic pharmaceuticals. Although these are marketed as comparable or competitive to Fluress, they are neither pharmaceutical
Accepted for publication May 10, 1990. From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida. Reprint requests to Lee R. Duffner, M.D., 2740 Hollywood Blvd., Hollywood, FL 33020-4899.
©AMEJuCAN JOURNAL OF OPHTHALMOLOGY
110:199-202,
equivalents nor pharmaceutical alternatives under the definitions of the United States Food and Drug Administration." We undertook a laboratory evaluation of the relative resistance to contamination of several of these fluoresceinanesthetic products.
Material and Methods Four fluorescein-anesthetic combination products were evaluated: pipette dropper bottles of Fluress (Barnes-Hind, Inc., Sunnyvale, California) containing fluorescein sodium 0.25%, benoxinate hydrochloride 0.4%, and chlorobutanol 1 %, in a povidone plus boric acid solution; plastic squeeze dropper bottles of Fluorpro (Wilson Ophthalmic Corporation, Mustang, Oklahoma); and plastic squeeze dropper bottles and pipette dropper bottles of Fluorocaine (Akorn, Inc., Abita Springs, Louisiana). Both Fluorpro and Fluorocaine contain fluorescein sodium 0.25%, proparacaine hydrochloride 0.5%, and thimerosal 0.01 % in a povidone plus glycerin solution. All bottles (Figure)
Figure (Duffner and associates). Fluorescein combination solutions are available in glass bottles with a glass dropper and in plastic squeezable bottles with an integral dropper tip.
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were purchased from retail or wholesale drug suppliers. At least two different lot numbers for each preparation were included. All bottles were tested before their listed expiration date. The bacterial inocula used were prepared from human ocular isolates of P. aeruginosa and Staphylococcus aureus. Suspensions of organisms were serially diluted to contain 100,000 colony forming units of bacteria per milliliter. Eight bottles of each product were inoculated with 10 ~l (approximately 1,000 organisms) of the P. aeruginosa suspension by placing a micropipette directly into the solution in the bottle. Single drops from each bottle were then dropped from the squeeze bottle or dropper onto sheep blood agar plates at one minute, five minutes, 15 minutes, one hour, two hours, and 24 hours after the solution was inoculated. Each drop was spread on the culture plate with a sterile cotton-tipped applicator. Plates were incubated at room temperature (25 C). After 48 hours, the colonies were counted. If there were too many colonies on a plate to count accurately, they were recorded as too numerous to count. One uninoculated bottle of each product was cultured as a negative control, and the bacterial suspension was directly cultured as a positive control. Five bottles of each product were similarly inoculated with 10 ~l (approximately 1,000 organisms) of the S. aureus suspension. Single drops were cultured after the same time intervals and incubated as above. Again, one uninoculated bottle of each product was cultured as a negative control and the bacterial suspension was directly cultured as a positive control. Twenty-five bottles of each product were contaminated by placing 10 u.l of the P. aeruginosa suspension directly onto the dropper tip or onto the bottle tip opening. Each bottle was then inverted five times. A sterile cotton-tipped applicator moistened with nutrient broth was used to wipe the bottle or dropper tip, and the applicator was streaked onto a sheep blood agar plate. Five bottles of each product were cultured at one minute, 15 minutes, one hour, two hours, and 24 hours after intentional contamination of the tip. Positive and negative controls were cultured. These plates were incubated for 48 hours at 37 C and colonies were then counted. Twenty-four bottles of each product were contaminated on the dropper tip or bottle tip opening with 10 ~l of the S. aureus suspension. Four bottles of each product were similarly cultured using a broth-moistened cotton-
tipped applicator after one minute, 15 minutes, 30 minutes, one hour, two hours, and 24 hours. Positive and negative controls were cultured. The arithmetic mean number of colonies was calculated for each set of plates. If one or more plates in a set had colonies that were too numerous to count, the set was recorded as too numerous to count. Statistical analysis of the data was performed using Dunnett's multiple comparison test if the numerical means were recorded, or the Mann-Whitney V-test with a Bonferroni correction if one or more sets had colonies too numerous to count.
Results
No organisms grew from any of the fluorescein, benoxinate hydrochloride, and chlorobutanol samples inoculated directly into the solution (Fluress). Pseudomonas aeruginosa and S. aureus were recovered from samples of the fluorescein sodium, proparacaine hydrochloride, and thimerosal solution (Fluorpro and Fluoracaine) up to two hours after inoculation (Table 1). The difference in mean colony counts between Fluress and each of the other three products was statistically significant for P. aerugincsa up to 15 minutes (P = .015) and for S. aureus after two hours (P < .05). After inoculation onto the dropper tip or bottle tip, no P. aeruginosa grew from any of the Fluress samples. Of the four dropper tips contaminated with Staphylococcus and cultured after one minute, however, one bottle produced two colonies and one bottle produced one colony. Staphylococcus aureus did not grow from the other two Fluress dropper tips cultured after one minute, nor from any of the Fluress dropper tips cultured after more than one minute. There was growth of P. aeruginosa and S. aureus from samples of the other three products up to two hours after inoculation (Table 2). The difference from Fluress was significant up to 15 minutes after P. aeruginosa contamination for the Fluorpro samples and up to two hours for the Fluorocaine squeeze bottle samples (P < .05). The difference from Fluress after S. aureus contamination approached significance (P = .08) for up to two hours for the Fluorocaine squeeze bottle samples. No bacteria were recovered from any uninoculated negative control bottle. Direct cultures of the bacterial suspensions, the positive controls, all produced confluent growth.
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TABLE 1 MEAN COLONY COUNTS AFTER INOCULATION DIRECTLY INTO SOLUTION" TIME AFTER INOCULATION SOWTlON
1 MIN.
0
Fluress droppper bottle Fluorpro squeeze bottle Fluorocaine squeeze bottle Fluorocaine dropper bottle
TNTC TNTC TNTC
Fluress dropper bottle Fluorpro squeeze bottle Fluorocaine squeeze bottle Fluorocaine dropper bottle
0 17.3 26.8 2.0
10 MIN.
5 MIN.
Pseudomonas aeruginosa 0 0 7.3 7.3 7.7 7.7 2.7 2.7 Staphylococcus aureus 0 0 10.3 6.3 7.0 7.3 1.8 5.5
15 MIN.
1 HR.
2 HRS.
24 HRS.
0 6.7 5.7 3.3
0 0.4 0.6 2.4
0 0 0 0.5
0 0 0 0
0 11.0 13.3 2.5
0 10.5 12.5 5.8
0 10.8 6.3 3.0
0 0 0 0
·TNTC indicates too numerous to count.
Discussion
Although sterile paper strips impregnated with fluorescein may be used to instill fluorescein into the tear film, many ophthalmologists prefer the convenience of a combination fluorescein-anesthetic solution. Since the same bottle of solution is used on multiple patients, inadvertent contamination of the solution or the applicator could result in transmission of microorganisms from one patient to another. Prompt recovery of sterility after inadvertent bacterial contamination is an essential feature for a fluorescein-anesthetic solution. This study was designed to evaluate the ability of different
commercially available preparations to regain sterility. Although conducted in the laboratory, the components of the study were chosen to simulate the clinical setting. In clinical use, the dropper bottle tip is usually the entry point of the exogenous organism. Contamination of the dropper tip was therefore evaluated separately from contamination of the solution. Both plastic squeeze bottles and pipette dropper bottles were tested, because fluorescein-anesthetic solutions are available in each. The solution and dropper tips were evaluated at a variety of time periods after intentional contamination, as the time between consecutive uses of the container would vary clinically.
TABLE 2 MEAN COLONY COUNTS AFTER CONTAMINATION OF BOTILE TIP OR PIPETIE TIp· TIME AFTER INOCULATION SOWTION
1 MIN.
Fluress dropper bottle Fluorpro squeeze bottle Fluorocaine squeeze bottle Fluorocaine dropper bottle
0 105.0 80.6 23.0
Fluress dropper bottle Fluorpro squeeze bottle Fluorocaine squeeze bottle Fluorocaine dropper bottle
TNTC TNTC TNTC
0.8
·TNTC indicates too numerous to count.
15 MIN.
30 MIN.
Pseudomonas aeruginosa 0 105.0 94.0 11.6 Staphylococcus eureus 0 0 4.8 1.5 TNTC 60.0 11.3 TNTC
1 HR.
2 HRS.
24 HRS.
0 18.6 64.0 2.6
0 8.8 42.6 0
0 0 0 0
0 4.3 90.0 0.8
0 7.5 40.0 0.8
0 0 0 0
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AMERICAN JOURNAL OF OPHTHALMOLOGY
The fluorescein sodium, proparacaine hydrochloride, and thimerosal combination from either manufacturer (Fluoracaine or Fluorpro) did not regain sterility as quickly as the fluorescein, benoxinate hydrochloride, and chlorobutanol combination (Fluress) after either direct contamination of the solution with bacteria or after contamination of the tip of the container or the pipette dropper tip. This difference in ability to regain sterility after intentional contamination does not imply a defect in manufacture or storage of the products tested. Rather, it is probably because of differences in the properties of the combined components of the solutions. Benoxinate hydrochloride preserved with chlorobutanol may be more resistant to contamination than proparacaine hydrochloride combined with thimerosal. Benoxinate hydrochloride and proparacaine hydrochloride are both excellent surface anesthetics; only benoxinate hydrochloride, however, has bacteriostatic properties." Chlorobutanol and thimerosal are both commonly used as preservatives in ophthalmic solutions. Chlorobutanol has been shown to be a more rapid and effective preservative than thimerosal, which is characterized by its slow action.v" Chlorobutanol, however, is an effective preservative only in an acidic solution (below pH 6), and can permeate through polyethylene bottles." Therefore, it must be formulated precisely and stored in impermeable containers such as glass. Differences in the other components of the two formulations may also contribute to the observed variations in performance. Boric acid, a component of Fluress, is weakly bacteriostatiC,IO whereas glycerin, a component of the other solutions, is not. Povidone is a dispersing, wetting, and stabilizing agent. It improves the fluorescent performance of these solutions." Because it is a component of both of the formulations examined, it is not likely to account for the differences noted. The fluorescein sodium, proparacaine hydrochloride, and thimerosal solutions (Fluorocaine, Fluorpro. and others) are generically equivalent to each other. Conversely, they are neither pharmaceutical equivalents nor pharmaceutical alternatives to a preparation of fluorescein, benoxinate hydrochloride, and chlorobutanol, and could thus be expected to have different properties. Drug products are considered pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administratton.'-" Drug products are
considered pharmaceutical alternatives if they contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety, or are different dosage forms or strengths.l" Ophthalmologists using fluorescein sodium, proparacaine hydrochloride, and thimerosal solutions should be aware of their differences from the fluorescein, benoxinate hydrochloride, and chlorobutanol solution in packaging, anesthetic agent, preservative, vehicle, and ability to regain sterility. Our data demonstrate that bacteria can be cultured from fluorescein sodium, proparacaine hydrochloride, and thimerosal solutions for up to two hours after contamination. ACKNOWLEDGMENT
William Feuer, M.S., biostatistician, Department of Ophthalmology, University of Miami School of Medicine, performed the statistical analysis.
References 1. Vaughn, D. G.: The contamination of fluorescein solutions. Am. J. Ophthalmoi. 39:55, 1955. 2. Quickert, M. H.: A fluorescein-anesthetic solution for applanation tonometry. Arch. Ophthaimoi. 77:734,1967. 3. Holtz, S. J.: Clinical study of the safety of a fluorescein-anesthetic solution. Ann. Ophthaimoi. 7:1101, 1975. 4. Yelton, D. P., and German, C. J.: Fluress, fluorescein, and benoxinate. Recovery from bacterial contamination. J. Am. Optom. Assoc. 51:471, 1980. 5. Stewart, H. L.: Prolonged antibacterial activity of a fluorescein-anesthetic solution. Arch. Ophthalmol. 88:385, 1972. 6. Coad, C. T., Osato, M. S., and Wilhelmus, K. R.: Bacterial contamination of eyedrop dispensers. Am. J. Ophthalmol. 98:548, 1984. 7. U.S. Department of Health and Human Services: Approved Drug Products With Therapeutic Equivalence Evaluations, ed. 6. Washington, D.C., Food and Drug Administration, 1985, pp. 1/1-1/9. 8. Gennaro, A. R. (ed.): Remington's Pharmaceutical Sciences, ed. 17. Easton, Pennsylvania, Mack Publishing ce.. 1985, p. 1057. 9. Mullen, W., Shepherd, W., and Labovitz, J.: Ophthalmic preservatives and vehicles. Surv. Ophthalmol. 17:469, 1973. 10. Berkow, R. (ed.): The Merck Manual, ed. 15. Rahway, New Jersey, Merck and Co., 1987, p. 21. 11. Havener, W. H.: Ocular Pharmacology, ed. 5. St. Louis, C. V. Mosby, 1983, pp. 510-530. 12. Precup, A. V. (ed.): U.S.P. Dispensing Information, ed. 10, vol. 3. Rockville, Maryland, United States Pharmacopeial Convention, 1990, p. 1/1-1.
Accepted for publication May 10, 1990. From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida. Reprint requests to Lee R. Duffner, M.D., 2740 Hollywood Blvd., Hollywood, FL 33020-4899.
©AMEJuCAN JOURNAL OF OPHTHALMOLOGY
110:199-202,
equivalents nor pharmaceutical alternatives under the definitions of the United States Food and Drug Administration." We undertook a laboratory evaluation of the relative resistance to contamination of several of these fluoresceinanesthetic products.
Material and Methods Four fluorescein-anesthetic combination products were evaluated: pipette dropper bottles of Fluress (Barnes-Hind, Inc., Sunnyvale, California) containing fluorescein sodium 0.25%, benoxinate hydrochloride 0.4%, and chlorobutanol 1 %, in a povidone plus boric acid solution; plastic squeeze dropper bottles of Fluorpro (Wilson Ophthalmic Corporation, Mustang, Oklahoma); and plastic squeeze dropper bottles and pipette dropper bottles of Fluorocaine (Akorn, Inc., Abita Springs, Louisiana). Both Fluorpro and Fluorocaine contain fluorescein sodium 0.25%, proparacaine hydrochloride 0.5%, and thimerosal 0.01 % in a povidone plus glycerin solution. All bottles (Figure)
Figure (Duffner and associates). Fluorescein combination solutions are available in glass bottles with a glass dropper and in plastic squeezable bottles with an integral dropper tip.
AUGUST,
1990
199
200
August, 1990
AMERICAN JOURNAL OF OPHTIiALMOLOGY
were purchased from retail or wholesale drug suppliers. At least two different lot numbers for each preparation were included. All bottles were tested before their listed expiration date. The bacterial inocula used were prepared from human ocular isolates of P. aeruginosa and Staphylococcus aureus. Suspensions of organisms were serially diluted to contain 100,000 colony forming units of bacteria per milliliter. Eight bottles of each product were inoculated with 10 ~l (approximately 1,000 organisms) of the P. aeruginosa suspension by placing a micropipette directly into the solution in the bottle. Single drops from each bottle were then dropped from the squeeze bottle or dropper onto sheep blood agar plates at one minute, five minutes, 15 minutes, one hour, two hours, and 24 hours after the solution was inoculated. Each drop was spread on the culture plate with a sterile cotton-tipped applicator. Plates were incubated at room temperature (25 C). After 48 hours, the colonies were counted. If there were too many colonies on a plate to count accurately, they were recorded as too numerous to count. One uninoculated bottle of each product was cultured as a negative control, and the bacterial suspension was directly cultured as a positive control. Five bottles of each product were similarly inoculated with 10 ~l (approximately 1,000 organisms) of the S. aureus suspension. Single drops were cultured after the same time intervals and incubated as above. Again, one uninoculated bottle of each product was cultured as a negative control and the bacterial suspension was directly cultured as a positive control. Twenty-five bottles of each product were contaminated by placing 10 u.l of the P. aeruginosa suspension directly onto the dropper tip or onto the bottle tip opening. Each bottle was then inverted five times. A sterile cotton-tipped applicator moistened with nutrient broth was used to wipe the bottle or dropper tip, and the applicator was streaked onto a sheep blood agar plate. Five bottles of each product were cultured at one minute, 15 minutes, one hour, two hours, and 24 hours after intentional contamination of the tip. Positive and negative controls were cultured. These plates were incubated for 48 hours at 37 C and colonies were then counted. Twenty-four bottles of each product were contaminated on the dropper tip or bottle tip opening with 10 ~l of the S. aureus suspension. Four bottles of each product were similarly cultured using a broth-moistened cotton-
tipped applicator after one minute, 15 minutes, 30 minutes, one hour, two hours, and 24 hours. Positive and negative controls were cultured. The arithmetic mean number of colonies was calculated for each set of plates. If one or more plates in a set had colonies that were too numerous to count, the set was recorded as too numerous to count. Statistical analysis of the data was performed using Dunnett's multiple comparison test if the numerical means were recorded, or the Mann-Whitney V-test with a Bonferroni correction if one or more sets had colonies too numerous to count.
Results
No organisms grew from any of the fluorescein, benoxinate hydrochloride, and chlorobutanol samples inoculated directly into the solution (Fluress). Pseudomonas aeruginosa and S. aureus were recovered from samples of the fluorescein sodium, proparacaine hydrochloride, and thimerosal solution (Fluorpro and Fluoracaine) up to two hours after inoculation (Table 1). The difference in mean colony counts between Fluress and each of the other three products was statistically significant for P. aerugincsa up to 15 minutes (P = .015) and for S. aureus after two hours (P < .05). After inoculation onto the dropper tip or bottle tip, no P. aeruginosa grew from any of the Fluress samples. Of the four dropper tips contaminated with Staphylococcus and cultured after one minute, however, one bottle produced two colonies and one bottle produced one colony. Staphylococcus aureus did not grow from the other two Fluress dropper tips cultured after one minute, nor from any of the Fluress dropper tips cultured after more than one minute. There was growth of P. aeruginosa and S. aureus from samples of the other three products up to two hours after inoculation (Table 2). The difference from Fluress was significant up to 15 minutes after P. aeruginosa contamination for the Fluorpro samples and up to two hours for the Fluorocaine squeeze bottle samples (P < .05). The difference from Fluress after S. aureus contamination approached significance (P = .08) for up to two hours for the Fluorocaine squeeze bottle samples. No bacteria were recovered from any uninoculated negative control bottle. Direct cultures of the bacterial suspensions, the positive controls, all produced confluent growth.
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Vol. 110, No.2
TABLE 1 MEAN COLONY COUNTS AFTER INOCULATION DIRECTLY INTO SOLUTION" TIME AFTER INOCULATION SOWTlON
1 MIN.
0
Fluress droppper bottle Fluorpro squeeze bottle Fluorocaine squeeze bottle Fluorocaine dropper bottle
TNTC TNTC TNTC
Fluress dropper bottle Fluorpro squeeze bottle Fluorocaine squeeze bottle Fluorocaine dropper bottle
0 17.3 26.8 2.0
10 MIN.
5 MIN.
Pseudomonas aeruginosa 0 0 7.3 7.3 7.7 7.7 2.7 2.7 Staphylococcus aureus 0 0 10.3 6.3 7.0 7.3 1.8 5.5
15 MIN.
1 HR.
2 HRS.
24 HRS.
0 6.7 5.7 3.3
0 0.4 0.6 2.4
0 0 0 0.5
0 0 0 0
0 11.0 13.3 2.5
0 10.5 12.5 5.8
0 10.8 6.3 3.0
0 0 0 0
·TNTC indicates too numerous to count.
Discussion
Although sterile paper strips impregnated with fluorescein may be used to instill fluorescein into the tear film, many ophthalmologists prefer the convenience of a combination fluorescein-anesthetic solution. Since the same bottle of solution is used on multiple patients, inadvertent contamination of the solution or the applicator could result in transmission of microorganisms from one patient to another. Prompt recovery of sterility after inadvertent bacterial contamination is an essential feature for a fluorescein-anesthetic solution. This study was designed to evaluate the ability of different
commercially available preparations to regain sterility. Although conducted in the laboratory, the components of the study were chosen to simulate the clinical setting. In clinical use, the dropper bottle tip is usually the entry point of the exogenous organism. Contamination of the dropper tip was therefore evaluated separately from contamination of the solution. Both plastic squeeze bottles and pipette dropper bottles were tested, because fluorescein-anesthetic solutions are available in each. The solution and dropper tips were evaluated at a variety of time periods after intentional contamination, as the time between consecutive uses of the container would vary clinically.
TABLE 2 MEAN COLONY COUNTS AFTER CONTAMINATION OF BOTILE TIP OR PIPETIE TIp· TIME AFTER INOCULATION SOWTION
1 MIN.
Fluress dropper bottle Fluorpro squeeze bottle Fluorocaine squeeze bottle Fluorocaine dropper bottle
0 105.0 80.6 23.0
Fluress dropper bottle Fluorpro squeeze bottle Fluorocaine squeeze bottle Fluorocaine dropper bottle
TNTC TNTC TNTC
0.8
·TNTC indicates too numerous to count.
15 MIN.
30 MIN.
Pseudomonas aeruginosa 0 105.0 94.0 11.6 Staphylococcus eureus 0 0 4.8 1.5 TNTC 60.0 11.3 TNTC
1 HR.
2 HRS.
24 HRS.
0 18.6 64.0 2.6
0 8.8 42.6 0
0 0 0 0
0 4.3 90.0 0.8
0 7.5 40.0 0.8
0 0 0 0
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The fluorescein sodium, proparacaine hydrochloride, and thimerosal combination from either manufacturer (Fluoracaine or Fluorpro) did not regain sterility as quickly as the fluorescein, benoxinate hydrochloride, and chlorobutanol combination (Fluress) after either direct contamination of the solution with bacteria or after contamination of the tip of the container or the pipette dropper tip. This difference in ability to regain sterility after intentional contamination does not imply a defect in manufacture or storage of the products tested. Rather, it is probably because of differences in the properties of the combined components of the solutions. Benoxinate hydrochloride preserved with chlorobutanol may be more resistant to contamination than proparacaine hydrochloride combined with thimerosal. Benoxinate hydrochloride and proparacaine hydrochloride are both excellent surface anesthetics; only benoxinate hydrochloride, however, has bacteriostatic properties." Chlorobutanol and thimerosal are both commonly used as preservatives in ophthalmic solutions. Chlorobutanol has been shown to be a more rapid and effective preservative than thimerosal, which is characterized by its slow action.v" Chlorobutanol, however, is an effective preservative only in an acidic solution (below pH 6), and can permeate through polyethylene bottles." Therefore, it must be formulated precisely and stored in impermeable containers such as glass. Differences in the other components of the two formulations may also contribute to the observed variations in performance. Boric acid, a component of Fluress, is weakly bacteriostatiC,IO whereas glycerin, a component of the other solutions, is not. Povidone is a dispersing, wetting, and stabilizing agent. It improves the fluorescent performance of these solutions." Because it is a component of both of the formulations examined, it is not likely to account for the differences noted. The fluorescein sodium, proparacaine hydrochloride, and thimerosal solutions (Fluorocaine, Fluorpro. and others) are generically equivalent to each other. Conversely, they are neither pharmaceutical equivalents nor pharmaceutical alternatives to a preparation of fluorescein, benoxinate hydrochloride, and chlorobutanol, and could thus be expected to have different properties. Drug products are considered pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administratton.'-" Drug products are
considered pharmaceutical alternatives if they contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety, or are different dosage forms or strengths.l" Ophthalmologists using fluorescein sodium, proparacaine hydrochloride, and thimerosal solutions should be aware of their differences from the fluorescein, benoxinate hydrochloride, and chlorobutanol solution in packaging, anesthetic agent, preservative, vehicle, and ability to regain sterility. Our data demonstrate that bacteria can be cultured from fluorescein sodium, proparacaine hydrochloride, and thimerosal solutions for up to two hours after contamination. ACKNOWLEDGMENT
William Feuer, M.S., biostatistician, Department of Ophthalmology, University of Miami School of Medicine, performed the statistical analysis.
References 1. Vaughn, D. G.: The contamination of fluorescein solutions. Am. J. Ophthalmoi. 39:55, 1955. 2. Quickert, M. H.: A fluorescein-anesthetic solution for applanation tonometry. Arch. Ophthaimoi. 77:734,1967. 3. Holtz, S. J.: Clinical study of the safety of a fluorescein-anesthetic solution. Ann. Ophthaimoi. 7:1101, 1975. 4. Yelton, D. P., and German, C. J.: Fluress, fluorescein, and benoxinate. Recovery from bacterial contamination. J. Am. Optom. Assoc. 51:471, 1980. 5. Stewart, H. L.: Prolonged antibacterial activity of a fluorescein-anesthetic solution. Arch. Ophthalmol. 88:385, 1972. 6. Coad, C. T., Osato, M. S., and Wilhelmus, K. R.: Bacterial contamination of eyedrop dispensers. Am. J. Ophthalmol. 98:548, 1984. 7. U.S. Department of Health and Human Services: Approved Drug Products With Therapeutic Equivalence Evaluations, ed. 6. Washington, D.C., Food and Drug Administration, 1985, pp. 1/1-1/9. 8. Gennaro, A. R. (ed.): Remington's Pharmaceutical Sciences, ed. 17. Easton, Pennsylvania, Mack Publishing ce.. 1985, p. 1057. 9. Mullen, W., Shepherd, W., and Labovitz, J.: Ophthalmic preservatives and vehicles. Surv. Ophthalmol. 17:469, 1973. 10. Berkow, R. (ed.): The Merck Manual, ed. 15. Rahway, New Jersey, Merck and Co., 1987, p. 21. 11. Havener, W. H.: Ocular Pharmacology, ed. 5. St. Louis, C. V. Mosby, 1983, pp. 510-530. 12. Precup, A. V. (ed.): U.S.P. Dispensing Information, ed. 10, vol. 3. Rockville, Maryland, United States Pharmacopeial Convention, 1990, p. 1/1-1.
