MXPA01000413A - Oxazolidinones to treat eye infections - Google Patents

Abstract

The present invention involves a method of treating an ophthalmic infection in a useful warm blooded mammal who is in need of such treatment which comprises topical administration of an ophthalmologicallly effective amount of an OXAZOLIDINONE.

Description

OXAZOLIDINONES TO TREAT EYE INFECTIONS BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is a method for treating various ophthalmic infections with pharmaceutically useful and known oxazolidinone antibacterials. 2. Description of the Related Art U.S. Patents 5,164,510, 5,231,188, 5,565,571, 5,652,238, 5,688,792, 5,698,574 and 5,627,181 all disclose various oxazolidinone antibiotics that are well known to those skilled in the art. U.S. Patent 5,688,792 discloses various oxazolidinone antibiotics which can be administered orally, parenterally or topically. Topical application is carried out by vehicle in gel or cream. Many of the presentations and announcements submitted from May 11 to 16, 1997 in the Association for Research in Vision and Ophthalmology presented many evidences that resistant microorganisms become a significant problem. Review of Ophthalmology, 94 (January 1997) discusses the use of antibacterial / antibiotic agents for ophthalmic uses. It is stated that the "big gun" of topical antibiotics is vancomycin although it is poorly tolerated. It is further disclosed that other antibacterial agents such as, for example, the two fluoroquinolones, ciprofloxacin and ofloxacin, as well as other agents such as, for example, cephalosporins and an aminoglycoside. It seems that while the agents of choice are fluoroquinolones, more effective agents are needed and fluoroquinolones have the advantage of a very rapid de novo resistance development. The Investigative Ophthalmology & Visual Science, 37 (3) Extracts 4060-B846 and 4056-B842 (1996) both state that while there is no resistance to ciprofloxacin in gram-positive organisms in the late 1980s or early 1990s, significant resistance developed to mid 1990. The Investigative Ophthalmology & Visual Science, 39 (4) Extracts 4951-B70 and 4950-B701 (1998) both expose problems with the increased susceptibility (increased resistance) of S. a ureus due to the use of a broad spectrum of antibiotics in the treatment of ophthalmic infections. This makes it harder for doctors to treat eye infections.

BRIEF DESCRIPTION OF THE INVENTION A method for treating an ophthalmic infection in a warm-blooded, useful mammal in need of this treatment and comprising the topical administration of an ophthalmologically effective amount of an OXAZOLIDINONE is disclosed.

DETAILED DESCRIPTION OF THE INVENTION The method of the present invention is a method for treating an ophthalmic infection in a useful, warm-blooded mammal in need of this treatment and comprising the topical administration of an ophthalmologically effective amount of an OXAZOLY DINONE. U.S. Patent 5,688,792 which teaches various oxazolidinone antibiotics rebels that they could be administered orally, parenterally or topically. There are several antibacterial agents that can be used topically, although they are too toxic to be used ophthalmologically and to treat bacterial infections of the eye. Useful warm-blooded mammals that are within the scope of the present invention include humans, pets such as, for example, dogs, cats, and commercially important mammals such as, for example, horses, cattle, pigs. It is preferred that the mammal be a human being, a dog or a cat; more preferably a human being. The OXAZOLIDINONES of the present invention are known, see EXAMPLES 1 to 5 (OXAZOLIDINONES). It is preferred that the OXAZOLI DINONE is selected from the group consisting of (S) -N- [[3- [3-fluoro-4- [4- (hydroxy acetyl) -1-piperazinyl] phenyl] -2-oxo- 5-oxazolidinyl] methyl] -acetamide, (S) -N - [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide, N- (( 5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) phenyl) -2-oxo-oxazolidin-5-ylmethyl) acetamide, (S) -N - [[3- [5- (3-pyridyl) thiophen-2-yl] -2-oxo-5-oxazolidinyl] methyl] acetamide and Hydrochloride of (S) -N- [[3- [5- (4- pyridyl) pyrid-2-yl] -2-oxo-5-oxazolidinyl] methyl] acetamide; it is more preferred that the OXAZOLIDINONE be selected from the group consisting of: (S) -N - [[3- [3-fluoro-4- [4- (hydroxyacetyl) -l-piperazinyl] -phenyl] -2-oxo- 5-oxazolidinyl] methyl] -acetamide and (S) -N - [[3- [3-fluoro-4- (4-morph 1-inyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide. Even more preferred is that OXAZOLI DINONE is (S) -N- [[3- [3-fluoro-4- (4-morfo-1-ynyl) phenyl] -2-oxo-5-oxazolidinyl] -methyl] -acetamide. Ophthalmic infections of this invention refer to inflammation of the conjunctiva (conjunctivitis) by sphincterus sclerosis, and trematococcus, and inflammation of the cornea (keratitis) caused by the same organisms and corneal ulcers. Bacterial conjunctivitis is the most common form of infectious conjunctivitis and bacterial keratitis that is taken into account for 65 to 90% of all corneal infections. It is preferred that the ophthalmic infection be bacterial keratitis and bacterial conjunctivitis.

The gram-positive microorganisms that cause the ophthalmic infections treated by the OXAZOLIDINONES of the present invention include Staphylococci, Streptococci, Enterococci, Bacillus, Corynebacterium, Chlamydia and Neisseria. It is preferred that the microorganism be a Staphilococci, Streptococci or Enterococci. It is more preferred that the infection be caused by Stapghilococci and / or Streptococci. The important species of these genera are Staphloccus aureus, Streptococcus viridans, Staphloccus epidermidis and Streptococcus pneumoniae. The OXAZOLI DINONAS of the present invention also treat gram-positive and gram-negative infections caused by anaerobes such as, for example, Bacteroi is fragile. Ophthalmic infections are treated by administering the desired OXAZOLIDINONES directly to the eye by the use of a pharmaceutical formulation consisting of a solution, cream, ointment, emulsion, suspension and slow release formulations. It is preferred that the pharmaceutical formulation is a solution, cream, ointment, emulsion and suspension; it is preferred that the pharmaceutical ophthalmic formulation be a solution. It is preferred that the ophthalmologically effective amount of OXAZOLI DINONA for treating ophthalmic infections is between about 0.3% and 20%, it is more preferred that the ophthalmologically effective amount be between about 0.5% and 18%. It is even more preferred that the ophthalmologically effective amount be between about 6% and 16%. OXAZOLIDINONE should be administered in the pharmaceutical formulation two to four times a day for 7 to 10 days or until the infection has disappeared. It is preferred if between 0.03 and 2.0 ml of an ophthalmic pharmaceutical formulation containing OXAZOLIDINONE is used each time it is administered. It is more preferred if it is administered from about 0.05 (about 1 drop) to about 0.25 ml (about 5 drops). International Publication WO96 / 06581 discloses a treatment fluid container having at least one opening of sufficient diameter and wherein the fluid is under sufficient pressure to discharge the solution as a jet and / or separate droplets. These known treatment fluid containers are useful in administration solutions containing the OXAZOLIDINONES. The inserts are also useful for the administration of OXAZOLI DINONAS solutions to the eye. In the method of the present invention, the OXAZOLIDINONES can be used either individually or in combination with each other. In addition, they can be used in combination with other antibacterial agents. In addition, the OXAZOLIDINONES can be used with non-antibacterial agents in the treatment of the infections of this invention. The exact dose and frequency of administration depends on the particular OXAZOLIDINONE used, the particular condition that will be treated, the severity of the condition that will be treated, the age, weight, the general physical condition of the particular patient, other medications that the individual can being taken as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the OXAZOLIDINONE in the patient's blood and / or the patient's response to the particular condition to be treated.

DEFINITIONS The following definitions and explanations are for the terms as used throughout this document including both the specification and the claims. All temperatures are in degrees Celsius. THF refers to tetrahydrofuran. DMF refers to dimethylformamide. Saline refers to a saturated aqueous solution of sodium chloride. Chromatography (column and flash chromatography) refers to the purification / separation of the compounds expressed as (support, eluent). It should be understood that the appropriate fractions are pooled and concentrated to provide the desired compounds. Ether refers to diethyl ether. TLC refers to thin layer chromatography. When solvent pairs are used, the proportions of the solvents used will be in volume / volume (v / v). When the solubility of a solid in a solvent is used, the ratio of the solid to the solvent is weight / volume (w / v).

Pharmaceutically acceptable refers to those properties and / or substances that are acceptable to the patient from a pharmacological / toxicological point of view and to the chemical-pharmaceutical manufacture from a physical / chemical point of view regarding the composition, formulation, stability, acceptance for the patient and bioavailability. OXAZOLIDINONE refers to the compounds of EXAMPLES 1 to 5 of the present invention.

EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the foregoing description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and / or perform the various processes of the invention and should be interpreted only as illustrative and not as limitations of the preceding discussion in any manner whatsoever. Those skilled in the art will readily recognize suitable variations from the methods as well as for the reactants as well as for reaction conditions and techniques. EXAMPLE 1 (S) -N- [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide The (S) -N - [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide is known, see U.S. Patent 5,652,238 , EXAMPLE 1. EXAMPLE 2 (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide The (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2 -oxo-5-oxazolidinyl] methyl] acetamide is known, see U.S. Patent 5, 688, 792, EXAMPLE 5. EXAMPLE 3 N- ((5S) -3- (3-Fluoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) phenyl) -2-oxooxazolidin-5-ylmethyl) acetamide The N- ((5S) -3- (3-Fluoro-4 - (- (2-fluoroet i 1) -3-oxopiperazin-1-yl) phenyl) -2-oxooxazolidin-5-ylmethyl) acetamide is known, see Publication International W097 / 27188 (Example 4). The l-t-Butoxycarbonyl-3-oxopiperazine (21.6 g) is dissolved in dry DMF (500 ml) and potassium t-butoxide (24.2 g) is added. The mixture is stirred at 20-25 ° for 30 minutes, then l- (4-methylphenylsulfonyloxy) -2-f luoroethane (J, Med. Ch em., 23 (9), 985-90 (1980), 25.9) is added. g) and stirring continues at the same temperature for 24 hours. The solvent is removed and the residue is partitioned between ethyl acetate and water. The organic phase is washed with water and concentrated. The residue is dissolved in isopropanol and diluted with iso-hexane to form a precipitate which is removed by filtration. The mixture is subjected to chromatography (silica, eluting with a gradient in polarity increase of 0 to 50% isopropanol in iso-hexane) to provide 1-t-butoxy carboni 1-4- (2-fluoroethyl) -3-oxopiperazine . The l-t-Butoxycarbonyl-4- (2-fluoroethyl) -3-oxopiperazine (6.65 g) is dissolved in dichloromethane (500 ml), cooled in an ice bath and trifluoroacetic acid (150 ml) is added. The mixture is stirred at the same temperature for 2 hours. The solvent is removed to provide a crude product which is dissolved in the minimum volume of ethyl acetate. The slow addition of ether causes the precipitation of 1- (2-f-luoroethyl) -2-oxopiperazine as the salt of the mono-trifluoroacetic acid.

The trifluoroacetate of 1- (2-Fluoroethyl) -2-oxopiperazine (6.1 g) is dissolved in acetonitrile (100 ml). N, N-Diisopropylethylamine (13 ml) is added to the mixture, followed by 3,4-difluoronit-benzene (3.39 g) and the mixture is refluxed for 18 hours. The solvent is removed and the residue is subjected to chromatography (silica, eluting with an increasing polarity gradient of 0 to 4% methanol in dichloromethane) to provide 3-fluoro-4- (4 -. {2-fluoroethyl} -3-oxopiperacin-1-yl) nit-benzene. 3-Fluoro-4- (4. {2-fluoroethyl) -3-oxopiperazoline-1) nitrobenzene (4.35 g) is dissolved in a mixture of ethyl acetate (250 ml) and DMF (5 ml). ) and the solution is washed with argon. Palladium is added (10% on charcoal, 200 mg) and the mixture is hydrogenated under ambient pressure. After the gas extraction is complete, the mixture is filtered through celite and the solvent is removed. The residue is extracted into ethyl acetate, washed twice with water, dried over magnesium sulfate and the solvent is removed to give 5-amino-2- [4- (2-fluoroethyl) -3-oxopiperacin-1 -yl] fluorobenzene which is used without further purification. 5-Amino-2- (4- [2-fluoroethyl] -3-oxopiperazin-1-yl) fluorobenzene (2.6 g) is dissolved in dry dichloromethane (50 ml) under argon. Pyridine (1.03 ml) is added and the mixture is cooled to -20 °. Benzyl chloroformate (1.6 ml) is added and the mixture is stirred for 10 minutes at -20 °, before allowing the temperature to increase from 20 to 25 ° for 1.5 hours. The solvents are removed and the residue is dissolved in dichloromethane and washed with sodium bicarbonate solution. After drying over magnesium sulfate and removing the solvent, the residue is subjected to chromatography (silica, eluting with a gradient in polarity increase of 0 to 5% methanol in dichloromethane) to give 5-benzyloxycarbonylamino-2- (4- [2-fluoroethyl] -3-oxopiperazin-1-yl) fluorobenzene. A solution of lithium t-butoxide is prepared by adding n-butyl lithium (1.6 M in hexane, 2.9 ml) to a stirred solution of t-butanol (0.43 g) in anhydrous THF (10 ml) at -10 ° under argon . After cooling to -70 °, a solution of the formula 5-benzyloxycarbonylamino-2- (4- [2-fluoroethyl] -3-oxopiperazin-1-yl) fluorobenzene (1.5 g) in dry THF is added. (15 ml). After 10 minutes, (R) -glycidylbutyrate (0.67 g) in dry THF (15 ml) is added to the resulting mixture and stirring is continued at -70 ° for 15 minutes, before allowing the temperature to rise from 20 to 25 ° for 16 hours. Methanol (10 ml) is added, followed by saturated sodium bicarbonate solution (20 ml) and water (10 ml). The organic phase is separated and extracted into ethyl acetate (3 x 25 ml), washed with saline and dried over magnesium sulfate. The solvent is removed and the residue is purified by chromatography (silica, eluting with a gradient in polarity increase of 0 to 3% methanol in dichloromethane) to provide (5R) -3- (3-fluoro-4 - [4- (2-fluoroethyl) -3-oxopiperazin-1-yl] phenyl) -5-hydroxymethyloxazolidin-2-one. (5R) -3- (3-Fluoro-4- [4- (2-fluoroethyl) -3-oxopiperazin-1-yl] phenyl) -5-hydroxymethyloxazolidin-2-one (0.8 g) is dissolved in pyridine ( 15 ml) and the mixture is cooled to 0 °. Triethylamine (0.38 ml) methanesulfonyl chloride is added to the mixture (0.19 ml) and stirring is continued at 20-25 ° during 2 hours. The solvent is removed and the residue is dissolved in dichloromethane, washed with water, saline, dried over magnesium sulfate and concentrated. The resulting residue is triturated with ether to provide (5R) -3- (3-fluoro-4- [4- (2-fluoroethyl) -3-oxopiperazin-1-yl] phenyl) -5- (methanesulfonyloxymethyl) oxazolidin-2 -one (0.76 g) which is used without further purification. The (5R) -3- (3-Fluoro-4- [4- (2-fluoroethyl) -3-oxopiperazin-1-yl] phenyl) -5- (methanesulfonyloxymethyl) -oxazolidin-2-one (719 mg) is Dissolve in dry DMF (15 ml) and add sodium azide (647 mg) to the mixture. The mixture is heated at 80 ° for 6 hours and then concentrated to dryness. The resulting residue is dissolved in ethyl acetate, washed twice with water and dried over magnesium sulfate. Removal of the solvent gives (5R) -5-azidomethyl-3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) phenyl) -oxa zolidin-2 -one (413) mg) which is used without further purification. (5R) -5-Azidomet il-3- (3-f luoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) phenyl) -oxazolidin-2-one (360 mg) is It is dissolved in dry DMF (20 ml) and the mixture is purged with argon. Palladium (10% on charcoal, 72 mg) is added, followed by acetic anhydride (0.17 ml) and the mixture is stirred at 20-25 ° under hydrogen confined in a balloon for 3 hours. The mixture is filtered through celite, concentrated to dryness and partitioned between ethyl acetate and water. The organic extract is washed with saline, dried over magnesium sulfate and concentrated. The residue is subjected to chromatography (silica gel, eluting with a gradient in polarity increase from 0 to 2.5% methanol / dichloromethane). The appropriate fractions are collected and concentrated to provide the title compound. EXAMPLE 4 (S) -N- [[3- [5- (3-Pyridyl) thiophen-2-yl] -2 -oxo-5 -xa zol idini 1] methyl] acetamide The (S) -N - [[ 3- [5- (3-Pyridyl) thiophen-2-yl] -2-oxo-5-oxazolidinyl] met yl] acetamide is known, see U.S. Patent 5,698,574 (EXAMPLE 124). EXAMPLE 5 (S) -N- [[3- [5- (4-Pyridyl) pyrid-2-yl] -2-oxo-5-oxazolidinyl] methyl] -acetamide hydrochloride The hydrochloride of (S) -N- [[3- [5- (4-Pyridyl) pyrid-2-yl] -2-oxo-5-oxazolidinyl] methyl] -acetamide is prepared following the general procedure of U.S. Patent 5,627,181 EXAMPLES 36 and 52 and making non-critical variations, but using a 4-pyridinyl adduct. EXAMPLE 6 Bacterial Keratitis A 32-year-old male complains of pain in the eye when he blinks and blurred or blurred vision b. When the doctor performs an examination, the cornea seems imperceptibly less transparent than the normal cornea and may have real ulcers on its surface. The diagnosis is infectious keratitis of bacterial etiology that is confirmed by laboratory results. The doctor prescribes a 10% solution of (S) -N - [[3- [3-fluoro-4- (4-morfo1inyl) phenyl] -2-oxo-5-oxa zol idinyl] met il] acet amide and instructs the patient to administer 3 to 5 drops of the solution on the surface of the eye four times a day for 7 days. EXAMPLE 7 Bacterial Conjunctivitis A ten-year-old girl complains of reddened and swollen eyelids and the presence of mucus secretions over her eye that interfere with vision. The diagnosis is conjunctivitis and the doctor prescribes a solution of oxazolidinone that contains 12% of (S) -N- [[3- [3-fluoro- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide and instructs the patient to administer 3 drops on the surface of the eye three times a day for 10 days.

Claims (32)

1. CLAIMS 1. Use of an oxazolidinone selected from: (S) -N - [[3- [3-fluoro-4- [4- (hydroxyacetyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -acetamide, (S) -N- [[3- [3-fluoro-4- (4-morfo-1-ynyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide, N - ((5S) - 3- (3-Fluoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) phenyl) -2-oxo-oxazolidin-5-ylmethyl) acetamide, (S) -N - [[3 - [5- (3-pyridyl) thiophen-2-yl] -2-oxo-5-oxa zol idinyl] met i 1] acet amide; and (S) -N- [[3- [5- (4-pyridyl) pyrid-2-yl] -2-oxo-5-oxazolidinyl] methyl] acetamide hydrochloride, for the manufacture of a medicament for direct administration to the eye of a warm-blooded mammal, for the treatment of an ophthalmic infection.
2. 2. The use according to claim 1, wherein the mammal is a human being.
3. 3. The use according to claim 1, wherein the mammal is a dog or a cat.
4. 4. The use according to any of the preceding claims, wherein the oxazolidinone is: (S) -N - [[3- [3-fluoro-4- [4- (idroxyacetyl) -1-piperazinyl] phenyl] -2-oxo- 5-oxazolidinyl] methyl] -acetamide, or (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide,
5. 5. The use according to claim 4, wherein the oxazolidinone is: (S) -N - [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide,
6. 6. The use according to any of the preceding claims, wherein the medicament is a solution, cream, ointment, emulsion, suspension or slow-release formulation.
7. 7. The use according to claim 6, wherein the medicament is a solution, cream, ointment, emulsion or suspension.
8. 8. The use according to claim 8, wherein the medicament is a solution in an insert or a fluid container for treatment.
9. 9. The use according to any of the preceding claims, to be administered 2 to 4 times a day.
10. 10. The use according to any of the preceding claims, wherein the amount of oxazolidinone in the medicament is from 0.3% to 20%.
11. 11. The use according to claim 10, wherein the amount of oxazolidinone is from 0.5% to 18%.
12. 12. The use according to any of the preceding claims, wherein the infection is caused by Staphylococcus, Streptococcus, Enterococcus, Bacillus, Corynebacterium, Chlamydia or Neisseria.
13. 13. The use according to claim 12, wherein the infection is caused by Staphylococcus, Streptococcus or Enterococcus.
14. 14. The use according to claim 13, wherein the infection is caused by S t aph i l coccus or S t rep t ococcus.
15. 15. The use according to any of the preceding claims, wherein the infection is bacterial keratitis, bacterial conjunctivitis or a corneal ulcer.
16. 16. The use according to claim 15, wherein the infection is bacterial keratitis or bacterial conjunctivitis.
17. 17. A method for treating an ophthalmic infection in a warm-blooded mammal in need of this treatment, comprising the administration, directly to the eye of the mammal, of an ophthalmologically effective amount of an oxazolidinone selected from the group consisting of: (S) -N - [[3- [3-fluoro-4- [4- (hydroxy acetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide, (S) -N- [[3- [3-fluoro-4- (-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide, N - ((5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) phenyl) -2-oxo-oxazolidin-5-ylmethyl) acetamide, (S) -N - [[3- [5- (3-pyridyl) thiophen-2-yl] - 2-oxo-5-oxazolidinyl] met il] acetamide; and (S) -N- [[3- [5- (4-pyridyl) pyrid-2-yl] -2-oxo-5-oxazolidinyl] methyl] acetamide hydrochloride,
18. 18. A method according to claim 17; wherein the useful warm-blooded mammal is a human being.
19. 19. A method according to claim 17, wherein the useful warm-blooded mammal is a dog or a cat.
20. 20. The use according to claim 17, wherein the oxazolidinone is selected from the group consisting of (S) -N - [[3- [3-fluoro-4- [4- (hydroxyacetyl) -l-piperazinyl] phenyl] - 2-oxo-5-oxazolidinyl] methyl] -acetamide and (S) -N - [[3- [3-fluoro-4- (4-mormolinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide
21. 21. A method according to claim 20, wherein the oxazolidinone is: (S) -N- [[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl ] acetamide,
22. 22. A method according to claim 17, wherein the oxazolidinone is administered in a pharmaceutical formulation selected from the group consisting of a solution, cream, ointment, emulsion, suspension and slow release formulations.
23. 23. A method according to claim 22, wherein the oxazolidinone is administered in a pharmaceutical formulation selected from the group consisting of a solution, cream, ointment, emulsion and suspension.
24. 24. A method according to claim 22, wherein the solution is administered in an insert or a fluid container for treatment.
25. 25. A method according to claim 17, wherein the oxazolidinone is administered 2 to 4 times a day.
26. 26. A method according to claim 17, wherein ophthalmologically effective amount is from 0.3% to 20%.
27. 27. A method according to claim 26, wherein ophthalmologically effective amount is from 0.5% to 18%.
28. 28. A method according to claim 17, wherein the infection is caused by Staphylococcus, Streptococcus, Enterococcus, Bacillus, Corynebacterium, Chlamydia or Neisseria.
29. 29. A method according to claim 29, wherein the infection is caused by Staphylococcus, Streptococcus and Enterococcus.
30. 30. A method according to claim 29, wherein the infection is caused by Staphylococcus and Streptococcus.
31. 31. A method according to claim 17; wherein the ophthalmic infection is selected from the group consisting of bacterial keratitis, bacterial conjunctivitis and corneal ulcers.
32. 32. The method according to claim 31, wherein the ophthalmic infection is bacterial keratitis and bacterial conjunctivitis ^ s¿i? ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^