A C T A O P H T H A L M O L O G I C A VOL. 5 3 1975
Department o f Ophthalmology. University o f Illinois Eye and Ear Infirmary, Chicago, Illinois (Hemi: Morton F. Goldberg, M . D . )
INTRAVITREAL INJECTION OF VANCOMYCIN IN EXPERIMENTAL STAPHYLOCOCCAL ENDOPHTHALMITIS BY
PAUL HOMER, GHOLAM A. PEYMAN, JEFF KOZIOL and DONALD SANDERS
Toxicity, clearance, and therapeutic effectiveness of intravitreal vancomycin hydrochloride injection in experimentally induced staphylococcal endophthalmitis were evaluated. Vancomycin was found to be nontoxic in a single, 1 mg/O.l ml intravitreal dose. Therapeutic levels of vancomycin were present in the vitreous for over 72 hours and in the aqueous during a period from 6 to 48 hours after injection. Injection of a methicillinresistant Stapliylococcus anreus produced a panophthalmitis in our systemically treated controls, whereas in the rabbits treated by intraocular injection, the course of the infection was significantly altered.
Key words: vancomycin - intravitreal injection - endophthalmitis antibiotics.
-
Supported by a grant from the National Institutes of Health, PHS EY 1107-02, and the Illinois Lions Foundation. Received December 27, 1974.
31 1
Paul H o m e r , Gliolam A . Peyman, J e f f Koziol and Donald Sanders
Sta/diylococcus aureus has been estimated to be responsible for up to half of postsurgical bacterial endophthalmitis (Allen et al. 1964). T h e infection progresses rapidly, and even with prompt treatment, useful vision is lost in the majority of cases. Despite treatment with corticosteroids and antibiotics, the prognosis is poor, due partially to poor penetration into the vitreous compartment by antibiotics administered systemically, subconjunctivally, or topically. T h e sources of staphylococcus are many. A direct relationship between staphylococcus on the lid margin and those recovered from postoperative endophthalmitis has been shown through phage typing of the strains (Locatcher-Khorazo et a]. 1960). Other possible sources of staphylococcal infection are direct extension from a periorbital abscess or the surgeon’s nasal flora. There are two major problems in treating staphylococcal endophthalmitis. First, conventional modes of therapy, i.e., subconjunctival, topical, and systemic administration of drugs effective against staphylococcus, do not achieve adequate levels in the vitreous (Deyer 1962; Furguiele 1960, 1964, 1967 and Leopold 1945, 1946). The second problem involves rapidly emerging strains of staphylococcus resistant to previously effective drugs. Methicillin, once the drug of choice against penicillinase-producing staphylococcus, is no longer as effective. Staphylococci insensitive to this agent have been isolated from patients in Europe, Africa, and the United States, the frequency varying from 0.3 o / o to 4 o / o . Such strains are usually resistant to penicillin G , streptomycin sulfate, kanamycin sulfate, chloramphenicol, and the tetracyclines, and frequently to lincomycin hydrochloride monohydrate, and the cephalosporin derivatives (Goodman et al. 1970). T o solve the first problem. Peyman (1974); May (1974) and Daily (1973) have had marked success a t achieving adequate intraocular drug levels by intravitreal injection of various drugs. The second problem of drug resistance can be solved only by using newer and more potent drugs against staphylococci. Vancomycin hydrochloride, which we decided to use in this investigation, is relatively new. T h e primary action of vancomycin is against S . uurcus, inhibiting most staphylococcal cultures with under 6 pg of drug per ml. A study a t Jefferson University Hospital showed that vancomycin was the only drug of 11 tested effective against every staphylococcal culture tested over a 5-year period (Wise 1973). Vancomycin is not chemically related to any of the presently used antimicrobial agents, and cross resistance with other antimicrobial agents has not been demonstrated. Vancomycin inhibits bacterial cell wall synthesis, probably by interference with glycopeptide polymerization (Goodman et al. 1970). W e administered vancomycin intravitreally, as effective intraocular levels of the drug can not be achieved by the usual three inodes of treatment (Pryor et al. 1962). 312
lntravitreal Vancomycin
Materials and Methods Commercially available vancomycin (Vancocin Hydrochloride, 500 mg in a 10 ml rubber-stoppered ampule) was used in all parts of this study. Distilled water was added to each ampule to dilute the amount of vancomycin to the required concentration. Toxicity
Ten albino rabbits each weighing 2 to 3 kg were anesthetized with intravenous pentobarbital sodium and given 0.12 mg of intramuscular atropine to control excessive secretions. Two drops of 1 o/o cyclopentolate hydrochloride and two drops of 0.5 O/O proparacaine hydrochloride were instilled into the conjunctival sac on both eyes of each rabbit for pupillary dilation and topical anesthesia. The superior and inferior rectus muscles were grasped with toothed forceps for stabilization of the eyeball. A 27-gauge needle attached to a tuberculin syringe was inserted into the vitreous a t the temporal pars plana. T h e needle was directed posteriorly into the vitreous to avoid contact with the lens. When the bevel of
Table I .
Toxicity of vancomycin
drug injected, mg
injected
0.25 0.5 1.o
1 1
2 2 2 2 3" 2'
2.0 3.0 4.0 5.0 10.0
200.0
1
500.0
2
Total 18 "One rabbit in each group injected in the right eye only. The left eyes, serving as controls, each received 0.1 ml of normal saline. 313
Pair1 Homer, GIiolam A . Peyman, Jeff Koziol and Donald Sanders
the needle could be seen centrally in the vitreous, anterior paracentesis with a %-gauge needle was done and 0.1 ml of vancomycin hydrochloride was injected. W e varied the concentration of vancomycin injected from 0.25 mg to 500 mg per 0.1 ml of distilled water (Table I). Two of the rabbits were injected in the right eye only, one with 5 mg and one with 10 mg; the left eyes, injected with 0.1 ml of normal saline, served as controls. After injection the eyes were dilated daily with 1 O/O cyclopentolate and observed ophthalmoscopically for changes. At 2 weeks the animals were killed. The eyes were enucleated and examined histologically. Clearance
Eight albino rabbits each weighing 2 to 3 kg were anesthetized and dilated as previously described. Each rabbit received an 0.1 ml injection of 1 mg of vancomycin hydrochloride in both eyes. T h e rate of clearance from the aqueous and vitreous was then determined. A t 0, 1, 2, 4, 6, 24, 48, and 72 hours, the rabbits were killed. T h e eyes were enucleated and immediately frozen in liquid nitrogen. The vitreous and aqueous were then dissected from the eye. T h e samples were put in an antibiotic medium with a p H of 8.0. Sarcina lutca was used as the indicator organism. With this procedure, we were able to detect the presence of vancomycin to 9 ,ug/ml. Below that, there were no zones of inhibition. Treatment of experimentally induced endophthalmltis
Ten albino rabbits, anesthetized as previously described, received intravitreal injections of 10,000 methicillin-resistant S. aweus organisms into each eye. The 10 rabbits were then divided into two equal groups; one group received therapy at 8 hours and the other group at 12 hours. Treatment consisted of a single intravitreal injection of 1 mg of vancomycin into the right eye. All 10 rabbits received 25 nig/kg intravenously, and the left eye served as a control. T h e rabbits were observed hourly for the first 12 hours and then once a day for 2 weeks. At the end of this time, the rabbits were killed and the eyes were studied histologically.
Results Toxicity
Gross observation. The cornea, lens, and media appeared clear after intravitreal administration of less than 5 mg of vancomycin. At dosages of 5 mg or greater,
314
Intravitreal Vancomycin
a whitish reaction was noted in the vitreous that lasted 2 weeks. At that time electroretinograms were done on the rabbits’ eyes and compared to ERGs done prior to injection of vancomycin. The ERGs on the rabbits given 1 mg of vancomycin or less were interpreted as normal.
Histologic evaluation. The eyes injected with 1 mg or less showed no toxic changes histologically (Fig. 1). At 2 to 5 mg there was evidence of localized toxicity to the retina (Fig. 2). The extent of the damage to the retina increased in proportion to the dose of vancomycin injected. At dosages greater than 10 mg, there was total retinal destruction. The two control eyes were completely normal histologically. From these results, we determined that a safe intravitreal dose of vancomycin is 1 mg.
Fig. 1 . Photomicrograph of eye 2 weeks after intravitreal injection of 1 mg of vancomycin The histologic appearance of the retina (R) is completely normal. C indicates choroid (hematoxylin and eosin, x 250).
315
Purr1 H o m e r , Gholam A . Peyman, Jeff Koziol and Donald Sanders
F i g . 2. Photomicrograph of retina (R) and choroid (C) showing degeneration of photoreceptor outer segments. Eye received 5 mg intravitreally (hematoxylin and eosin, x 250).
Table 11. Clearance of vancomycin from vitreous and aqueous
Hours
0 1
2 4 G
24 48 72
Level in vitreous, p g
Level in aqueous, p g
500 550 475 400 260 300
No zone No zone No zone No zone
190 130
316
37 25 9
No zone
Intravitreal Vancomycin Clearance
The results of the clearance study can be seen in Table 11. Intravitreal injection gave immediate therapeutic levels in the vitreous (Fig. 3). The peak intravitreal level of 550 p g was over 50 times the needed inhibitory concentration for almost any staphylococcal infection encountered clinically. The vitreous level was still high as long as 72 hours after injection. Aqueous levels were detectable 6 hours after injection and stayed significantly elevated for at least 42 more hours. There were probably levels in the therapeutic range 48 hours after injection, but our assay was not sensitive enough to detect antibiotic levels under 9 pgJml. Treatment of experimentally induced endophthalmitis
The first evidence of infection occurred 4 to 8 hours after injection when pinpoint opacities surrounded by cloudy media were first seen in the posterior
E
4
EFFECTIVE THERAPEUTIC CONCENTRATION
6
12
24
36
48
60
72
84
HOURS
Fig. 3. Results of clearance study from aqueous and vitreous after intravitreal injection of 1 mg of vancomycin.
317
Paul Homer, Gholam A . Peyman, J e f f Koziol and Donald Sanders
Fig. 4.
Section of untreated globe 2 weeks after injection of methicillin-resistant S. anreus. Note inflammatory exudate in vitreous and anterior chamber and signs of phthisis bulbi (hematoxylin and eosin, x 9).
segment. The control eyes showed a rapidly progressing panophthalmitis. At the end of 2 weeks, there was a diffuse opacity throughout the eyes and they were filled with pus. Perilimbal hyperemia was also seen. The control eyes all progressed to phthisis bulbi (Fig. 4). Of the 10 eyes treated with vancomycin, only one eye progressed to destruction of the retina and phthisis bulbi. In the nine remaining eyes, there was a n iritis that lasted for 1 to 2 days, then resolved. After 2 days the red reflex was present, and 2 weeks later the media was clear and fundus detail was present. There were no significant differences between the eyes treated 8 hours after infection (Fig. 5 ) and those treated 12 hours after infection.
Discussion This study reaffirms the value of intravitreal injection in endophthalmitis. Pryor, Apt & Leopold (1962) were not able to achieve therapeutic vitreous levels by intravenous, subconjunctival, or topical administration of vancomycin, but 318
Intravitreal Vancomycin
Fig. 5. Whole section of eye treated intravitreally with 1 mg of vancomycin 8 hours after inoculation of methicillin-resistant S. aurezis (hematoxylin and eosin, x 9).
they did reach levels in the aqueous of 16 pg/ml after intravenous administration in rabbits with chemically inflamed eyes. W e achieved levels over twice as high (37 &ml) in the aqueous after intravitreal injection, although it took 6 hours to reach those peak levels in the aqueous as opposed to 1 hour after intravenous injection in the study by Pryor, Apt & Leopold. Even if vancomycin were as effective when administered systemically as when intravitreally administered, the obvious disadvantages of systemic administration are possible nephrotoxicity and ototoxicity. One valid argument against the administration of vancomycin intraocularly is the possibility of retinal toxicity. In our study, we showed that 1 mg of vancomycin appears to be nontoxic to the retina as well as to the rest of the eye. In addition, this dosage achieves greater than the needed concentration to eradicate most cases of staphylococcal endophthalmitis. With rapidly emerging new strains of drug-resistant staphylococcus, vancomycin may be the drug of choice for suspected cases of staphylococcal endophthalmitis. 319
Pun1 Homcr, Gholmn A . Peymun, Jef! Koziol rind Donulrl Sunders
References Allen, H. F. & Mangiaracine, A. B. (1964) Bacterial endophthalmitis after cataract extraction. Arch. Ophthal. 72, 454-462. Daily, M. J., Peyman, G. A. & Fishman, G. (1973) Intravitreal injection of methicillin for treatment of endophthalmitis. Amer. /. Ophthal. 76, 343-350. Deyer, H. A. & Maas, E. R. (1962) The penetration of several new penicillins into the eye. Ophthalmologica 144, 316- 322. Furgiuele, F. P., Sery, T. & Leopold, I. H. (1960) Newer antibiotics: Their intraocular penetration. Amer. J. Ofihthal. 50, 614-621. Furgiuele, F. P. (1964) New antibiotics: Their intraocular penetration. Amer. /. Ophthal. 58, 443-447. Furgiuele, F. P. (19G7) Ocular penetration and tolerance of gentamicin. Amer. /. Ophthal. 64, 421-426. Goodman, L. S. & Gilman, A. (1970) The Pharmacological Basis of Therapeutics. pp. 1292-1293, Macmillan Co., New York. Leopold, I. H. (1945) Intravitreal penetration of penicillin and penicillin therapy of infections of the vitreous. Arch. Ophthal. 3.3, 21 1-216. Leopold, I. H. (1 946) Intravitreal penetration of streptomycin following systemic and local administration. Arch. Ophthal. 35, 33-38. Locatcher-Khorazo, D. & Gutierrez, E. (1960) Bacteriophage typing of Staphylococczis atireus. Arch. Ophthal. 63, 774-787. May, D. R., Ericson, E. S. & Peyman, G. A. (1974) Intraocular injection of gentamicin: Single injection therapy of bacterial endophthalrnitis. Arch. Ophthal. 91, 487-489. Peyman, G. A., May, D. R. & Ericson, E. S. (1974) Intraocular injection of gentamicin: Toxic effects and clearance. Arch. Ophthal. 92, 42-47. Pryor, J. G., Apt, L. & Leopold, I. H. (1962) Intraocular penetration of vancomycin. Arch. Ophthal. 67, 608-611. Wise, K. I. (1973) Modern management of severe staphylococcal disease. Medicine 52. 295-304.
Author’s address: Gholam A. Peyman, M.D., University of Illinois, Eye and Ear Infirmary, 1855 West Taylor Street, Chicago, Illinois 60612, U.S.A.
320
Department o f Ophthalmology. University o f Illinois Eye and Ear Infirmary, Chicago, Illinois (Hemi: Morton F. Goldberg, M . D . )
INTRAVITREAL INJECTION OF VANCOMYCIN IN EXPERIMENTAL STAPHYLOCOCCAL ENDOPHTHALMITIS BY
PAUL HOMER, GHOLAM A. PEYMAN, JEFF KOZIOL and DONALD SANDERS
Toxicity, clearance, and therapeutic effectiveness of intravitreal vancomycin hydrochloride injection in experimentally induced staphylococcal endophthalmitis were evaluated. Vancomycin was found to be nontoxic in a single, 1 mg/O.l ml intravitreal dose. Therapeutic levels of vancomycin were present in the vitreous for over 72 hours and in the aqueous during a period from 6 to 48 hours after injection. Injection of a methicillinresistant Stapliylococcus anreus produced a panophthalmitis in our systemically treated controls, whereas in the rabbits treated by intraocular injection, the course of the infection was significantly altered.
Key words: vancomycin - intravitreal injection - endophthalmitis antibiotics.
-
Supported by a grant from the National Institutes of Health, PHS EY 1107-02, and the Illinois Lions Foundation. Received December 27, 1974.
31 1
Paul H o m e r , Gliolam A . Peyman, J e f f Koziol and Donald Sanders
Sta/diylococcus aureus has been estimated to be responsible for up to half of postsurgical bacterial endophthalmitis (Allen et al. 1964). T h e infection progresses rapidly, and even with prompt treatment, useful vision is lost in the majority of cases. Despite treatment with corticosteroids and antibiotics, the prognosis is poor, due partially to poor penetration into the vitreous compartment by antibiotics administered systemically, subconjunctivally, or topically. T h e sources of staphylococcus are many. A direct relationship between staphylococcus on the lid margin and those recovered from postoperative endophthalmitis has been shown through phage typing of the strains (Locatcher-Khorazo et a]. 1960). Other possible sources of staphylococcal infection are direct extension from a periorbital abscess or the surgeon’s nasal flora. There are two major problems in treating staphylococcal endophthalmitis. First, conventional modes of therapy, i.e., subconjunctival, topical, and systemic administration of drugs effective against staphylococcus, do not achieve adequate levels in the vitreous (Deyer 1962; Furguiele 1960, 1964, 1967 and Leopold 1945, 1946). The second problem involves rapidly emerging strains of staphylococcus resistant to previously effective drugs. Methicillin, once the drug of choice against penicillinase-producing staphylococcus, is no longer as effective. Staphylococci insensitive to this agent have been isolated from patients in Europe, Africa, and the United States, the frequency varying from 0.3 o / o to 4 o / o . Such strains are usually resistant to penicillin G , streptomycin sulfate, kanamycin sulfate, chloramphenicol, and the tetracyclines, and frequently to lincomycin hydrochloride monohydrate, and the cephalosporin derivatives (Goodman et al. 1970). T o solve the first problem. Peyman (1974); May (1974) and Daily (1973) have had marked success a t achieving adequate intraocular drug levels by intravitreal injection of various drugs. The second problem of drug resistance can be solved only by using newer and more potent drugs against staphylococci. Vancomycin hydrochloride, which we decided to use in this investigation, is relatively new. T h e primary action of vancomycin is against S . uurcus, inhibiting most staphylococcal cultures with under 6 pg of drug per ml. A study a t Jefferson University Hospital showed that vancomycin was the only drug of 11 tested effective against every staphylococcal culture tested over a 5-year period (Wise 1973). Vancomycin is not chemically related to any of the presently used antimicrobial agents, and cross resistance with other antimicrobial agents has not been demonstrated. Vancomycin inhibits bacterial cell wall synthesis, probably by interference with glycopeptide polymerization (Goodman et al. 1970). W e administered vancomycin intravitreally, as effective intraocular levels of the drug can not be achieved by the usual three inodes of treatment (Pryor et al. 1962). 312
lntravitreal Vancomycin
Materials and Methods Commercially available vancomycin (Vancocin Hydrochloride, 500 mg in a 10 ml rubber-stoppered ampule) was used in all parts of this study. Distilled water was added to each ampule to dilute the amount of vancomycin to the required concentration. Toxicity
Ten albino rabbits each weighing 2 to 3 kg were anesthetized with intravenous pentobarbital sodium and given 0.12 mg of intramuscular atropine to control excessive secretions. Two drops of 1 o/o cyclopentolate hydrochloride and two drops of 0.5 O/O proparacaine hydrochloride were instilled into the conjunctival sac on both eyes of each rabbit for pupillary dilation and topical anesthesia. The superior and inferior rectus muscles were grasped with toothed forceps for stabilization of the eyeball. A 27-gauge needle attached to a tuberculin syringe was inserted into the vitreous a t the temporal pars plana. T h e needle was directed posteriorly into the vitreous to avoid contact with the lens. When the bevel of
Table I .
Toxicity of vancomycin
drug injected, mg
injected
0.25 0.5 1.o
1 1
2 2 2 2 3" 2'
2.0 3.0 4.0 5.0 10.0
200.0
1
500.0
2
Total 18 "One rabbit in each group injected in the right eye only. The left eyes, serving as controls, each received 0.1 ml of normal saline. 313
Pair1 Homer, GIiolam A . Peyman, Jeff Koziol and Donald Sanders
the needle could be seen centrally in the vitreous, anterior paracentesis with a %-gauge needle was done and 0.1 ml of vancomycin hydrochloride was injected. W e varied the concentration of vancomycin injected from 0.25 mg to 500 mg per 0.1 ml of distilled water (Table I). Two of the rabbits were injected in the right eye only, one with 5 mg and one with 10 mg; the left eyes, injected with 0.1 ml of normal saline, served as controls. After injection the eyes were dilated daily with 1 O/O cyclopentolate and observed ophthalmoscopically for changes. At 2 weeks the animals were killed. The eyes were enucleated and examined histologically. Clearance
Eight albino rabbits each weighing 2 to 3 kg were anesthetized and dilated as previously described. Each rabbit received an 0.1 ml injection of 1 mg of vancomycin hydrochloride in both eyes. T h e rate of clearance from the aqueous and vitreous was then determined. A t 0, 1, 2, 4, 6, 24, 48, and 72 hours, the rabbits were killed. T h e eyes were enucleated and immediately frozen in liquid nitrogen. The vitreous and aqueous were then dissected from the eye. T h e samples were put in an antibiotic medium with a p H of 8.0. Sarcina lutca was used as the indicator organism. With this procedure, we were able to detect the presence of vancomycin to 9 ,ug/ml. Below that, there were no zones of inhibition. Treatment of experimentally induced endophthalmltis
Ten albino rabbits, anesthetized as previously described, received intravitreal injections of 10,000 methicillin-resistant S. aweus organisms into each eye. The 10 rabbits were then divided into two equal groups; one group received therapy at 8 hours and the other group at 12 hours. Treatment consisted of a single intravitreal injection of 1 mg of vancomycin into the right eye. All 10 rabbits received 25 nig/kg intravenously, and the left eye served as a control. T h e rabbits were observed hourly for the first 12 hours and then once a day for 2 weeks. At the end of this time, the rabbits were killed and the eyes were studied histologically.
Results Toxicity
Gross observation. The cornea, lens, and media appeared clear after intravitreal administration of less than 5 mg of vancomycin. At dosages of 5 mg or greater,
314
Intravitreal Vancomycin
a whitish reaction was noted in the vitreous that lasted 2 weeks. At that time electroretinograms were done on the rabbits’ eyes and compared to ERGs done prior to injection of vancomycin. The ERGs on the rabbits given 1 mg of vancomycin or less were interpreted as normal.
Histologic evaluation. The eyes injected with 1 mg or less showed no toxic changes histologically (Fig. 1). At 2 to 5 mg there was evidence of localized toxicity to the retina (Fig. 2). The extent of the damage to the retina increased in proportion to the dose of vancomycin injected. At dosages greater than 10 mg, there was total retinal destruction. The two control eyes were completely normal histologically. From these results, we determined that a safe intravitreal dose of vancomycin is 1 mg.
Fig. 1 . Photomicrograph of eye 2 weeks after intravitreal injection of 1 mg of vancomycin The histologic appearance of the retina (R) is completely normal. C indicates choroid (hematoxylin and eosin, x 250).
315
Purr1 H o m e r , Gholam A . Peyman, Jeff Koziol and Donald Sanders
F i g . 2. Photomicrograph of retina (R) and choroid (C) showing degeneration of photoreceptor outer segments. Eye received 5 mg intravitreally (hematoxylin and eosin, x 250).
Table 11. Clearance of vancomycin from vitreous and aqueous
Hours
0 1
2 4 G
24 48 72
Level in vitreous, p g
Level in aqueous, p g
500 550 475 400 260 300
No zone No zone No zone No zone
190 130
316
37 25 9
No zone
Intravitreal Vancomycin Clearance
The results of the clearance study can be seen in Table 11. Intravitreal injection gave immediate therapeutic levels in the vitreous (Fig. 3). The peak intravitreal level of 550 p g was over 50 times the needed inhibitory concentration for almost any staphylococcal infection encountered clinically. The vitreous level was still high as long as 72 hours after injection. Aqueous levels were detectable 6 hours after injection and stayed significantly elevated for at least 42 more hours. There were probably levels in the therapeutic range 48 hours after injection, but our assay was not sensitive enough to detect antibiotic levels under 9 pgJml. Treatment of experimentally induced endophthalmitis
The first evidence of infection occurred 4 to 8 hours after injection when pinpoint opacities surrounded by cloudy media were first seen in the posterior
E
4
EFFECTIVE THERAPEUTIC CONCENTRATION
6
12
24
36
48
60
72
84
HOURS
Fig. 3. Results of clearance study from aqueous and vitreous after intravitreal injection of 1 mg of vancomycin.
317
Paul Homer, Gholam A . Peyman, J e f f Koziol and Donald Sanders
Fig. 4.
Section of untreated globe 2 weeks after injection of methicillin-resistant S. anreus. Note inflammatory exudate in vitreous and anterior chamber and signs of phthisis bulbi (hematoxylin and eosin, x 9).
segment. The control eyes showed a rapidly progressing panophthalmitis. At the end of 2 weeks, there was a diffuse opacity throughout the eyes and they were filled with pus. Perilimbal hyperemia was also seen. The control eyes all progressed to phthisis bulbi (Fig. 4). Of the 10 eyes treated with vancomycin, only one eye progressed to destruction of the retina and phthisis bulbi. In the nine remaining eyes, there was a n iritis that lasted for 1 to 2 days, then resolved. After 2 days the red reflex was present, and 2 weeks later the media was clear and fundus detail was present. There were no significant differences between the eyes treated 8 hours after infection (Fig. 5 ) and those treated 12 hours after infection.
Discussion This study reaffirms the value of intravitreal injection in endophthalmitis. Pryor, Apt & Leopold (1962) were not able to achieve therapeutic vitreous levels by intravenous, subconjunctival, or topical administration of vancomycin, but 318
Intravitreal Vancomycin
Fig. 5. Whole section of eye treated intravitreally with 1 mg of vancomycin 8 hours after inoculation of methicillin-resistant S. aurezis (hematoxylin and eosin, x 9).
they did reach levels in the aqueous of 16 pg/ml after intravenous administration in rabbits with chemically inflamed eyes. W e achieved levels over twice as high (37 &ml) in the aqueous after intravitreal injection, although it took 6 hours to reach those peak levels in the aqueous as opposed to 1 hour after intravenous injection in the study by Pryor, Apt & Leopold. Even if vancomycin were as effective when administered systemically as when intravitreally administered, the obvious disadvantages of systemic administration are possible nephrotoxicity and ototoxicity. One valid argument against the administration of vancomycin intraocularly is the possibility of retinal toxicity. In our study, we showed that 1 mg of vancomycin appears to be nontoxic to the retina as well as to the rest of the eye. In addition, this dosage achieves greater than the needed concentration to eradicate most cases of staphylococcal endophthalmitis. With rapidly emerging new strains of drug-resistant staphylococcus, vancomycin may be the drug of choice for suspected cases of staphylococcal endophthalmitis. 319
Pun1 Homcr, Gholmn A . Peymun, Jef! Koziol rind Donulrl Sunders
References Allen, H. F. & Mangiaracine, A. B. (1964) Bacterial endophthalmitis after cataract extraction. Arch. Ophthal. 72, 454-462. Daily, M. J., Peyman, G. A. & Fishman, G. (1973) Intravitreal injection of methicillin for treatment of endophthalmitis. Amer. /. Ophthal. 76, 343-350. Deyer, H. A. & Maas, E. R. (1962) The penetration of several new penicillins into the eye. Ophthalmologica 144, 316- 322. Furgiuele, F. P., Sery, T. & Leopold, I. H. (1960) Newer antibiotics: Their intraocular penetration. Amer. J. Ofihthal. 50, 614-621. Furgiuele, F. P. (1964) New antibiotics: Their intraocular penetration. Amer. /. Ophthal. 58, 443-447. Furgiuele, F. P. (19G7) Ocular penetration and tolerance of gentamicin. Amer. /. Ophthal. 64, 421-426. Goodman, L. S. & Gilman, A. (1970) The Pharmacological Basis of Therapeutics. pp. 1292-1293, Macmillan Co., New York. Leopold, I. H. (1945) Intravitreal penetration of penicillin and penicillin therapy of infections of the vitreous. Arch. Ophthal. 3.3, 21 1-216. Leopold, I. H. (1 946) Intravitreal penetration of streptomycin following systemic and local administration. Arch. Ophthal. 35, 33-38. Locatcher-Khorazo, D. & Gutierrez, E. (1960) Bacteriophage typing of Staphylococczis atireus. Arch. Ophthal. 63, 774-787. May, D. R., Ericson, E. S. & Peyman, G. A. (1974) Intraocular injection of gentamicin: Single injection therapy of bacterial endophthalrnitis. Arch. Ophthal. 91, 487-489. Peyman, G. A., May, D. R. & Ericson, E. S. (1974) Intraocular injection of gentamicin: Toxic effects and clearance. Arch. Ophthal. 92, 42-47. Pryor, J. G., Apt, L. & Leopold, I. H. (1962) Intraocular penetration of vancomycin. Arch. Ophthal. 67, 608-611. Wise, K. I. (1973) Modern management of severe staphylococcal disease. Medicine 52. 295-304.
Author’s address: Gholam A. Peyman, M.D., University of Illinois, Eye and Ear Infirmary, 1855 West Taylor Street, Chicago, Illinois 60612, U.S.A.
320
