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Experimental Corneal Infections
V O L . 66, N O . 3
L I G H T C O A G U L A T I O N OF M A L I G N A N T M E L A N O M A
until nearly three years after initiation of treatment.
REFERENCES
1. François, J. : Treatment of malignant melanoma of the choroid by photo-coagulation. In : Boniuk, M . (ed.) Ocular and Adnexal Tumors. New and Controversial Aspects. St. Louis, Mosby, 1964, p. 356. 2. François, J. : Treatment of malignant melanoma of the choroid by light coagulation. Tr. Ophth. Soc U . K . 85:179, 1965. 3. François, J. : Traitement des mélanomes malins de la choroïde par la photocoagulation. Modern Problems in Ophthalmology. Symposium Club Gonin, Munich, 1966. Basel, Karger, 1968, p. 8. 4. François, J. and Weekers, R. : La photocoagulation en ophtalmologie. Bull. Soc. Beige Ophtal. 139:1, 1965.
SUMMARY
Forty-nine cases of malignant melanoma of the choroid were treated with light coagulation two years ago or longer. Thirty-eight ( 7 8 % ) have been cured for two to nine years. Resorption of the residual pigments is very slow, requiring at least three years. De Pintelaan 115
EXPERIMENTAL EVALUATION MILES
A.
GALIN,
OF N A L I D I X I C
RICHARD A.
M.D.,
CORNEAL
ACID I N
AND
447
INFECTIONS
PROTEUS A N D PSEUDOMONAS KERATITIS
DAVIDSON, M.D.,
MILTON
BEST,
L A U R E N C E S.
HARRIS,
M.D.
M.D.
New York Gram-negative eye infections frequently produce significant ocular morbidity and loss of function. Particularly damaging is the Pseudomonas species, which is frequently incriminated in severe eye infections. For example, only 10% of 96 eyes in a study of Pseudomonas ophthalmitis retained vision better than 6/60, and 50% were subjected to evisceration or enucleation. 1
The severity of gram-negative ocular infections and their poor prognoses may relate to characteristics of the organisms, to inadequate ocular defense systems, to poorly effective chemotherapeutic agents, or to easily transferred bacterial resistance. The bactericidal drugs that may be used systemically with most efficacy in gram-negative infections include certain semi-synthetic penicillins, the cephalosporins, kanamycin, and the polymixins. These penicillins have been employed in Proteus infections whereas Colistin (polymixin E ) has been em2
8
From the Department of Ophthalmology, New York Medical College. This study was aided in part by a U S P H S Grant NB-07162 from the National Institute of Neurological Diseases and Blindness.
ployed effectively against Pseudomonas. A new agent, nalidixic acid, has recently been introduced and is claimed to be bacteriostatic and bactericidal for a variety of gram-negative organisms, including Pseudomonas and Proteus. Much of the data on the efficacy of the semi-synthetic penicillins and nalidixic acid, however, are based on clinical responsiveness to systemic administration in urinary tract infections. Few studies have appeared comparing the efficacy of these drugs in the eye.* This controlled study was undertaken to compare the effectiveness of a semi-synthetic penicillin, nalidixic acid, and Colistin in experimentally induced corneal infections in rabbits. PROCEDURE
Nalidixic acid has been found to be effective in vitro against common strains of Pseudomonas in concentrations ranging from 80 to 500 mcg/ml. A 4% aqueous solution of this agent was formulated to provide high concentrations of drug. Similarly, high concentrations of Colistin and ampicillin 5
448
AMERICAN JOURNAL OF OPHTHALMOLOGY
were also formulated as 4% aqueous solutions. ' In a preliminary investigation of possible irritating effects, two drops of 4% nalidixic acid ophthalmic solution were instilled into the conjunctival sac of the normal right eyes of five rabbits four times a day for five days. Transient, slight conjunctival congestion appeared shortly after instillation. At the end of five days there was no evidence of any ocular abnormality. Similar studies were carried out with the 4% solutions of Colistin and ampicillin with essentially the same results. 6 7
S E P T E M B E R , 1968
Pseudomonas infection was induced. Infections were graded as follows : Minimal ( + )—the area of corneal involvement was less than 1 mm in diameter, there was no exudate, but the conjunctiva was inflamed (fig. 2 ) .
Twenty-one female albino rabbits were used for the main experiment. Anesthesia was induced with 30 mg/kg of intravenous thiopental sodium. Three drops of 0.4% benoxinate hydrochloride (Dorsacaine) were applied to all corneas which were then inoculated with 18-hour cultures of either Proteus mirabilis (trypticase-soy broth) or Pseudomonas aeruginosa (heart-brain infusion broth).* Inoculation was done by the Hessburg method, which can be relied upon to produce infection: 6-0 silk surgical sutures of the same length on atraumatic needles were immersed in the culture medium for 10 minutes. These sutures were then placed in an intracorneal tract 1-2 mm in length without entering the anterior chamber. A simple surgical knot was tied and the sutures were left in place (fig. 1 ) . Both eyes of 12 animals were inoculated with Proteus and nine other animals received bilateral Pseudomonas inoculations. In all animals the left eye served as a control and was treated with two drops of saline hourly. All eyes were examined hourly and cultures were taken frequently. Treatment was begun six to eight hours after inoculation, at which time definite corneal infections were noticeable. In three animals] 4% nalidixic acid was administered subconjunctival^, as well as topically, after 8
* Both organisms recently isolated from hospital patients, and cultured in the indicated media.
Fig. 1 (Galin, Davidson, Harris and Best). Hessburg technique for producing corneal infection by use of a contaminated suture. Appearance of eye just after suture placement.
Fig. 2 (Galin, Davidson, Harris and Best). Grade 1-f infection, 8 hours after contaminated suture placement.
V O L . 66, N O . 3
EXPERIMENTAL CORNEAL INFECTIONS
449
Moderate (2+)—extensive but not complete involvement of the cornea, with conjunctival inflammation and exudate (fig. 3). Severe (3 + )—extensive corneal involvement with hypopyon or perforation (fig. 4 ) . RESULTS
1. All eyes (42) showed minimal corneal reactions eight hours after inoculation. At 36 hours, 20 of 21 ( 9 5 % ) of the control eyes
Fig. 3 (Galin, Davidson, Harris and Best). Grade 2 + infection, 24 hours after contaminated suture placement.
Fig. 4 (Galin, Davidson, Harris and Best). Grade 3 + infection, 36 hours after contaminated suture placement.
Fig. 5 (Galin, Davidson, Harris and Best). Rabbit eye with Pseudomonas infection, 36 hours after inoculation and 28 hours after beginning topical Colistin therapy.
showed massive corneal opacification and hypopyon. 2. In Pseudomonas infections, there was no difference between eyes treated with nalidixic acid and the controls. Both groups progressed to massive corneal involvement and hypopyon. Cultures repeatedly grew out Pseudomonas. 3. In contrast, Colistin was highly effective against Pseudomonas infections. Pretreatment cultures for Pseudomonas were positive, but all cultures subsequent to therapy were negative (fig. 5 ) . 4. Proteus infections were effectively controlled by either nalidixic acid or ampicillin, though nalidixic acid was more prompt in controlling the infection. Furthermore, cultures of eyes treated with nalidixic acid all were negative within six hours after therapy was instituted, whereas one-third of the animals treated with ampicillin had positive cultures until 24 hours after therapy (fig. 6 ) . At the end of five days, there was no evidence of keratopathy, conjunctivitis or any other abnormality in ( 3 ) or ( 4 ) above, despite initial "take." Table 1 shows the state of experimental and control eyes in 18 animals after 8, 16, 24 and 36 hours of treatment. (The three Pseudomonas-'miected animals treated topically and subconjunctivally with nalidixic acid are not listed, but responded no differently from those treated only topically.)
450
AMERICAN JOURNAL OF OPHTHALMOLOGY
S E P T E M B E R , 1968
mum dosage levels need further study. Since nalidixic acid proved as effective as ampicillin in controlling experimental Proteus mirabilis, it would appear to be useful in this regard. Here, too, further data on ocular effects and dosage levels need to be obtained. Persons with penicillin allergy are usually allergic to ampicillin also, and nalidixic acid may find use in such patients with proven Proteus mirabilis infections of the cornea. In the nonallergic patient, a combination of these agents might also be advantageous in bacteriologically diagnosed infections, due to the ease with which resistance to a single drug may occur. It must be borne in mind that resistance may occur even in organisms originally sensitive to an agent. Thus, in the most extensive and careful study done so far on the bactericidal properties of nalidixic acid, four of 103 strains of Pseudomonas aeruginosa isolated from the urine o í patients with significant bacteriuria showed sensitivity when tested with 30-mcg discs, and none of 25 strains was sensitive to 100 meg per ml in tube dilution studies ; 145 of
Fig. 6 (Galin, Davidson, Harris and Best). Rabbit eye with Proteus infection, 36 hours after inoculation and 28 hours after beginning topical nalidixic acid therapy.
DISCUSSION
Nalidixic acid had no effect on experimental Pseudomonas aeruginosa infections of the cornea, even when administered subconjunctivally and topically, whereas Colistin rapidly controlled such infections, and thus should be considered a superior agent for such infections. Its effect on ocular tissue when administered topically and also opti-
9
TABLE 1 SEVERITY OF INFECTION WITH PROTEUS M I R A B I L I S OR PSEUDOMONAS AERUGINOSA DURING TREATMENT WITH NALIDIXIC ACID (N) COLISTIN (C) OR AMPICILLIN ( A ) , GRADED 1 + T O 3 + . LEFT EYES TREATED WITH 0.9% SALINE ONLY
Animal No.
1 2 3 4 5 6
7 8
9
10 11 12
8 Hours O.S. O.D. N N N N N N A A A A A A
+ + + + + + + + + + + +
+ + + + + + + + + + + +
+ + + + + +
+ + + + + +
Proteus 16 Hours O.S. O.D.
+
2 +
+ + + + + + + + + +
2 + 2 +
+ + 2+ + 2+ 2+
2 2 2 2
+ + + +
24 Hours O.D. O.S.
+ + + + + + 2+ + 2+
+ + +
2 2 2 3 2 2 2 2 2 2 2
+ + + +
++ + + + + + +
36 Hours O.D. O.S.
+ + + 0 + 0 + +/2+
+/2 + 0
+ +
3 + 3 + 3 + 3+
+
3 + 3 + 3 + 343 + 3 + 3+
Pseudomonas
13 14 15 16 17 18
N N N C C
c
2 + 2 + 2 +
+ + +
2+ 2+
+
2 + 2+ 2 +
2 + 3+ 2 +
+ + +
2 2 2 3 2 2
+ + + + + +
3+ 3 + 3+
+ + +
3 + 3 + 3 + 3 + 3 + 3+
V O L . 66, N O . 3
EXPERIMENTAL CORNEAL INFECTIONS
152 strains of Proteus mirabilis did show in vitro sensitivity. The same authors report the rapid appearance of resistant strains of the same and different organisms during therapy. For example, in 13 patients with organisms initially sensitive to nalidixic acid, urinary pathogens were replaced by resistant strains of the same species and serotype within 48 hours after therapy was begun. One of these thirteen was Proteus mirabilis. There was no change, however, in the in vitro susceptibility of these strains to other antimicrobial agents. Unfortunately, there is no equivalent data in the literature concerning ocular use of this drug. It would appear logical, therefore, to treat gram-negative ocular infections with a spectrum of drugs, even when the laboratory diagnosis has been made. Prior to positive cultures, this form of combined therapy is often the only sensible procedure, and the addition of nalidixic acid to the list of efficacious drugs for certain gram-negative infections may therefore prove fruitful. SUMMARY
In a controlled study involving comparisons of topical Colistin and ampicillin, a 4 % aqueous solution of nalidixic acid topically administered was tested in experimental infections with Pseudomonas aeruginosa and Proteus mirabilis produced in rabbit corneas
451
by the Hessburg procedure. This form of nalidixic acid was ineffective against Pseudomonas, but highly effective against Proteus. The effectiveness of Colistin against Pseudomonas and ampicillin against Proteus was reconfirmed. 1249 Fifth Avenue (10029) REFERENCES
1. Havener, W . H . : Ocular Pharmacology. St. Louis, Mosby, 1966, p. 124. 2. Watanabe, T. : Infective heredity of multiple drug resistance in bacteria. Bact Rev. 27:87, 1963. 3. Smith, H . W . and Halls, S. : Observations on infective drug resistance in Britain. Brit. Med. J. 1:266, 1966. 4. Kurose, Y . and Leopold, I. H. : Intraocular penetration of ampicillin. Arch. Ophth. 73:361, 1965. 5. Deitz, W . H., Froelich, E. J. and Bailey, J. H . : The in vitro antibacterial properties of nalidixic acid, a new drug active against gram-negative organisms. In Sylvester, J. D. (ed.) : Antimicrobial Agents and Chemotherapy—1963. Ann Arbor, Michigan, Am. Soc. Microbiol. 583, 1964. 6. Hessburg, P. C. : Treatment of Pseudomonas keratitis in humans. Am. J. Ophth. 61:896, 1966. 7. Aerea, P., Brown, D. M., Turner, D. H . and Wilson, M . J. : Pharmacology and chemotherapy of ampicillin—a new broad-spectrum penicillin. Brit. J. Pharm. 18:356, 1962. 8. Hessburg. P. C . Truant, J. P. and Penn. W . P. : Corneal infections in experimental animals. Am. J. Ophth. 53:359. 1962. 9. Ronald A . R.. Turck, M . and Petersdorf, R G. : A critical evaluation of nalidixic acid in urinary tract infections. New England J. Med. 275:1081, 1966.
L I G H T C O A G U L A T I O N OF M A L I G N A N T M E L A N O M A
until nearly three years after initiation of treatment.
REFERENCES
1. François, J. : Treatment of malignant melanoma of the choroid by photo-coagulation. In : Boniuk, M . (ed.) Ocular and Adnexal Tumors. New and Controversial Aspects. St. Louis, Mosby, 1964, p. 356. 2. François, J. : Treatment of malignant melanoma of the choroid by light coagulation. Tr. Ophth. Soc U . K . 85:179, 1965. 3. François, J. : Traitement des mélanomes malins de la choroïde par la photocoagulation. Modern Problems in Ophthalmology. Symposium Club Gonin, Munich, 1966. Basel, Karger, 1968, p. 8. 4. François, J. and Weekers, R. : La photocoagulation en ophtalmologie. Bull. Soc. Beige Ophtal. 139:1, 1965.
SUMMARY
Forty-nine cases of malignant melanoma of the choroid were treated with light coagulation two years ago or longer. Thirty-eight ( 7 8 % ) have been cured for two to nine years. Resorption of the residual pigments is very slow, requiring at least three years. De Pintelaan 115
EXPERIMENTAL EVALUATION MILES
A.
GALIN,
OF N A L I D I X I C
RICHARD A.
M.D.,
CORNEAL
ACID I N
AND
447
INFECTIONS
PROTEUS A N D PSEUDOMONAS KERATITIS
DAVIDSON, M.D.,
MILTON
BEST,
L A U R E N C E S.
HARRIS,
M.D.
M.D.
New York Gram-negative eye infections frequently produce significant ocular morbidity and loss of function. Particularly damaging is the Pseudomonas species, which is frequently incriminated in severe eye infections. For example, only 10% of 96 eyes in a study of Pseudomonas ophthalmitis retained vision better than 6/60, and 50% were subjected to evisceration or enucleation. 1
The severity of gram-negative ocular infections and their poor prognoses may relate to characteristics of the organisms, to inadequate ocular defense systems, to poorly effective chemotherapeutic agents, or to easily transferred bacterial resistance. The bactericidal drugs that may be used systemically with most efficacy in gram-negative infections include certain semi-synthetic penicillins, the cephalosporins, kanamycin, and the polymixins. These penicillins have been employed in Proteus infections whereas Colistin (polymixin E ) has been em2
8
From the Department of Ophthalmology, New York Medical College. This study was aided in part by a U S P H S Grant NB-07162 from the National Institute of Neurological Diseases and Blindness.
ployed effectively against Pseudomonas. A new agent, nalidixic acid, has recently been introduced and is claimed to be bacteriostatic and bactericidal for a variety of gram-negative organisms, including Pseudomonas and Proteus. Much of the data on the efficacy of the semi-synthetic penicillins and nalidixic acid, however, are based on clinical responsiveness to systemic administration in urinary tract infections. Few studies have appeared comparing the efficacy of these drugs in the eye.* This controlled study was undertaken to compare the effectiveness of a semi-synthetic penicillin, nalidixic acid, and Colistin in experimentally induced corneal infections in rabbits. PROCEDURE
Nalidixic acid has been found to be effective in vitro against common strains of Pseudomonas in concentrations ranging from 80 to 500 mcg/ml. A 4% aqueous solution of this agent was formulated to provide high concentrations of drug. Similarly, high concentrations of Colistin and ampicillin 5
448
AMERICAN JOURNAL OF OPHTHALMOLOGY
were also formulated as 4% aqueous solutions. ' In a preliminary investigation of possible irritating effects, two drops of 4% nalidixic acid ophthalmic solution were instilled into the conjunctival sac of the normal right eyes of five rabbits four times a day for five days. Transient, slight conjunctival congestion appeared shortly after instillation. At the end of five days there was no evidence of any ocular abnormality. Similar studies were carried out with the 4% solutions of Colistin and ampicillin with essentially the same results. 6 7
S E P T E M B E R , 1968
Pseudomonas infection was induced. Infections were graded as follows : Minimal ( + )—the area of corneal involvement was less than 1 mm in diameter, there was no exudate, but the conjunctiva was inflamed (fig. 2 ) .
Twenty-one female albino rabbits were used for the main experiment. Anesthesia was induced with 30 mg/kg of intravenous thiopental sodium. Three drops of 0.4% benoxinate hydrochloride (Dorsacaine) were applied to all corneas which were then inoculated with 18-hour cultures of either Proteus mirabilis (trypticase-soy broth) or Pseudomonas aeruginosa (heart-brain infusion broth).* Inoculation was done by the Hessburg method, which can be relied upon to produce infection: 6-0 silk surgical sutures of the same length on atraumatic needles were immersed in the culture medium for 10 minutes. These sutures were then placed in an intracorneal tract 1-2 mm in length without entering the anterior chamber. A simple surgical knot was tied and the sutures were left in place (fig. 1 ) . Both eyes of 12 animals were inoculated with Proteus and nine other animals received bilateral Pseudomonas inoculations. In all animals the left eye served as a control and was treated with two drops of saline hourly. All eyes were examined hourly and cultures were taken frequently. Treatment was begun six to eight hours after inoculation, at which time definite corneal infections were noticeable. In three animals] 4% nalidixic acid was administered subconjunctival^, as well as topically, after 8
* Both organisms recently isolated from hospital patients, and cultured in the indicated media.
Fig. 1 (Galin, Davidson, Harris and Best). Hessburg technique for producing corneal infection by use of a contaminated suture. Appearance of eye just after suture placement.
Fig. 2 (Galin, Davidson, Harris and Best). Grade 1-f infection, 8 hours after contaminated suture placement.
V O L . 66, N O . 3
EXPERIMENTAL CORNEAL INFECTIONS
449
Moderate (2+)—extensive but not complete involvement of the cornea, with conjunctival inflammation and exudate (fig. 3). Severe (3 + )—extensive corneal involvement with hypopyon or perforation (fig. 4 ) . RESULTS
1. All eyes (42) showed minimal corneal reactions eight hours after inoculation. At 36 hours, 20 of 21 ( 9 5 % ) of the control eyes
Fig. 3 (Galin, Davidson, Harris and Best). Grade 2 + infection, 24 hours after contaminated suture placement.
Fig. 4 (Galin, Davidson, Harris and Best). Grade 3 + infection, 36 hours after contaminated suture placement.
Fig. 5 (Galin, Davidson, Harris and Best). Rabbit eye with Pseudomonas infection, 36 hours after inoculation and 28 hours after beginning topical Colistin therapy.
showed massive corneal opacification and hypopyon. 2. In Pseudomonas infections, there was no difference between eyes treated with nalidixic acid and the controls. Both groups progressed to massive corneal involvement and hypopyon. Cultures repeatedly grew out Pseudomonas. 3. In contrast, Colistin was highly effective against Pseudomonas infections. Pretreatment cultures for Pseudomonas were positive, but all cultures subsequent to therapy were negative (fig. 5 ) . 4. Proteus infections were effectively controlled by either nalidixic acid or ampicillin, though nalidixic acid was more prompt in controlling the infection. Furthermore, cultures of eyes treated with nalidixic acid all were negative within six hours after therapy was instituted, whereas one-third of the animals treated with ampicillin had positive cultures until 24 hours after therapy (fig. 6 ) . At the end of five days, there was no evidence of keratopathy, conjunctivitis or any other abnormality in ( 3 ) or ( 4 ) above, despite initial "take." Table 1 shows the state of experimental and control eyes in 18 animals after 8, 16, 24 and 36 hours of treatment. (The three Pseudomonas-'miected animals treated topically and subconjunctivally with nalidixic acid are not listed, but responded no differently from those treated only topically.)
450
AMERICAN JOURNAL OF OPHTHALMOLOGY
S E P T E M B E R , 1968
mum dosage levels need further study. Since nalidixic acid proved as effective as ampicillin in controlling experimental Proteus mirabilis, it would appear to be useful in this regard. Here, too, further data on ocular effects and dosage levels need to be obtained. Persons with penicillin allergy are usually allergic to ampicillin also, and nalidixic acid may find use in such patients with proven Proteus mirabilis infections of the cornea. In the nonallergic patient, a combination of these agents might also be advantageous in bacteriologically diagnosed infections, due to the ease with which resistance to a single drug may occur. It must be borne in mind that resistance may occur even in organisms originally sensitive to an agent. Thus, in the most extensive and careful study done so far on the bactericidal properties of nalidixic acid, four of 103 strains of Pseudomonas aeruginosa isolated from the urine o í patients with significant bacteriuria showed sensitivity when tested with 30-mcg discs, and none of 25 strains was sensitive to 100 meg per ml in tube dilution studies ; 145 of
Fig. 6 (Galin, Davidson, Harris and Best). Rabbit eye with Proteus infection, 36 hours after inoculation and 28 hours after beginning topical nalidixic acid therapy.
DISCUSSION
Nalidixic acid had no effect on experimental Pseudomonas aeruginosa infections of the cornea, even when administered subconjunctivally and topically, whereas Colistin rapidly controlled such infections, and thus should be considered a superior agent for such infections. Its effect on ocular tissue when administered topically and also opti-
9
TABLE 1 SEVERITY OF INFECTION WITH PROTEUS M I R A B I L I S OR PSEUDOMONAS AERUGINOSA DURING TREATMENT WITH NALIDIXIC ACID (N) COLISTIN (C) OR AMPICILLIN ( A ) , GRADED 1 + T O 3 + . LEFT EYES TREATED WITH 0.9% SALINE ONLY
Animal No.
1 2 3 4 5 6
7 8
9
10 11 12
8 Hours O.S. O.D. N N N N N N A A A A A A
+ + + + + + + + + + + +
+ + + + + + + + + + + +
+ + + + + +
+ + + + + +
Proteus 16 Hours O.S. O.D.
+
2 +
+ + + + + + + + + +
2 + 2 +
+ + 2+ + 2+ 2+
2 2 2 2
+ + + +
24 Hours O.D. O.S.
+ + + + + + 2+ + 2+
+ + +
2 2 2 3 2 2 2 2 2 2 2
+ + + +
++ + + + + + +
36 Hours O.D. O.S.
+ + + 0 + 0 + +/2+
+/2 + 0
+ +
3 + 3 + 3 + 3+
+
3 + 3 + 3 + 343 + 3 + 3+
Pseudomonas
13 14 15 16 17 18
N N N C C
c
2 + 2 + 2 +
+ + +
2+ 2+
+
2 + 2+ 2 +
2 + 3+ 2 +
+ + +
2 2 2 3 2 2
+ + + + + +
3+ 3 + 3+
+ + +
3 + 3 + 3 + 3 + 3 + 3+
V O L . 66, N O . 3
EXPERIMENTAL CORNEAL INFECTIONS
152 strains of Proteus mirabilis did show in vitro sensitivity. The same authors report the rapid appearance of resistant strains of the same and different organisms during therapy. For example, in 13 patients with organisms initially sensitive to nalidixic acid, urinary pathogens were replaced by resistant strains of the same species and serotype within 48 hours after therapy was begun. One of these thirteen was Proteus mirabilis. There was no change, however, in the in vitro susceptibility of these strains to other antimicrobial agents. Unfortunately, there is no equivalent data in the literature concerning ocular use of this drug. It would appear logical, therefore, to treat gram-negative ocular infections with a spectrum of drugs, even when the laboratory diagnosis has been made. Prior to positive cultures, this form of combined therapy is often the only sensible procedure, and the addition of nalidixic acid to the list of efficacious drugs for certain gram-negative infections may therefore prove fruitful. SUMMARY
In a controlled study involving comparisons of topical Colistin and ampicillin, a 4 % aqueous solution of nalidixic acid topically administered was tested in experimental infections with Pseudomonas aeruginosa and Proteus mirabilis produced in rabbit corneas
451
by the Hessburg procedure. This form of nalidixic acid was ineffective against Pseudomonas, but highly effective against Proteus. The effectiveness of Colistin against Pseudomonas and ampicillin against Proteus was reconfirmed. 1249 Fifth Avenue (10029) REFERENCES
1. Havener, W . H . : Ocular Pharmacology. St. Louis, Mosby, 1966, p. 124. 2. Watanabe, T. : Infective heredity of multiple drug resistance in bacteria. Bact Rev. 27:87, 1963. 3. Smith, H . W . and Halls, S. : Observations on infective drug resistance in Britain. Brit. Med. J. 1:266, 1966. 4. Kurose, Y . and Leopold, I. H. : Intraocular penetration of ampicillin. Arch. Ophth. 73:361, 1965. 5. Deitz, W . H., Froelich, E. J. and Bailey, J. H . : The in vitro antibacterial properties of nalidixic acid, a new drug active against gram-negative organisms. In Sylvester, J. D. (ed.) : Antimicrobial Agents and Chemotherapy—1963. Ann Arbor, Michigan, Am. Soc. Microbiol. 583, 1964. 6. Hessburg, P. C. : Treatment of Pseudomonas keratitis in humans. Am. J. Ophth. 61:896, 1966. 7. Aerea, P., Brown, D. M., Turner, D. H . and Wilson, M . J. : Pharmacology and chemotherapy of ampicillin—a new broad-spectrum penicillin. Brit. J. Pharm. 18:356, 1962. 8. Hessburg. P. C . Truant, J. P. and Penn. W . P. : Corneal infections in experimental animals. Am. J. Ophth. 53:359. 1962. 9. Ronald A . R.. Turck, M . and Petersdorf, R G. : A critical evaluation of nalidixic acid in urinary tract infections. New England J. Med. 275:1081, 1966.