HK1036593B - Use of oxazolidinones in the manufacture of a medicament for treating non-topical infections - Google Patents

Description

Use of oxazolidinones for the production of a medicament for the treatment of non-topical infections

1. Field of the invention

The present invention is a treatment for the treatment of non-topical infections by topical administration of a known pharmaceutically acceptable oxazolidinone antibacterial agent.

2. Background of the invention

U.S. Pat. Nos. 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, which are well known to those skilled in the art.

U.S. Pat. No. 5,688,792 discloses various oxazolidinone antibiotics which can be administered orally, parenterally or topically. The topical application is by means of a gel or cream vehicle.

PCT patent application PCT/US97/07124 published as International publication WO97/42954 discloses a method of transdermally administering a number of antimicrobial agents for the treatment or prevention of systemic bacterial diseases, comprising the use of a DMSO/water carrier containing at least 10% DMSO. None of the antimicrobial agents in international publication WO97/42954 includes oxazolidinones, nor does the present invention use any DMSO.

U.S. Pat. No. 3,743,727 discloses a method of enhancing penetration of various types of antimicrobial agents into and across the outer membrane barrier of an animal to be treated which comprises sufficient DMSO to substantially enhance penetration of the antimicrobial agent. None of these antimicrobial agents include oxazolidinones, nor is any DMSO used in the present invention.

PCT patent application PCT/US84/00899, published as International publication WO85/00108, discloses a method of treating acne with a topical formulation containing an antibacterial agent in DMSO. None of these antibacterial agents include oxazolidinones, nor is any DMSO used in the present invention.

U.S. patent 4,943,435 discloses a transdermal patch for controlled release of nicotine. This is a small molecule and not an antibacterial agent.

Summary of The Invention

A method of treating a non-topical infection selected from the group consisting of ear infections, skin and soft tissue infections, acne, infected wounds, bacteremia in a useful warm blooded mammal in need of such treatment which comprises topically administering a pharmaceutical formulation comprising a transdermally effective amount of an oxazolidinone.

Detailed Description

Various oxazolidinone antibiotics are disclosed in U.S. Pat. No. 5,688,792, which discloses that they can be administered orally, parenterally or topically. For topical administration, no special definition is made, but the ordinary meaning is used. "local" is defined in the "Dorland graphic medicine dictionary" (26 th edition, 1981, page 1377) as "attached to a specific surface, applied to an area of the skin as a topical anti-infective agent and affecting only the area to which it is applied: thus, topical administration refers to administration to an area of the skin where the administered drug affects only the area to which it is applied. This is clearly different from transdermal administration. The difference between "topical" and "transdermal" is that: transdermal administration refers to the topical administration of an agent for the purpose of releasing the agent to an adjacent, underlying, or remote site or tissue distinct from the site of administration. For the oxazolidinones of the invention, it is understood that: topical application is to the top of the skin, and this is not an antibacterial active site located below or remote from the site of topical application. Oxazolidinones may have antibacterial activity on the skin to which they are applied, but this is concomitant with the intended site of action. The infection treated is a non-topical infection.

The present invention is a method of treating an infection selected from the group consisting of ear infections, skin and soft tissue infections, acne, infected wounds, bacteremia in a useful warm blooded mammal in need of such treatment comprising topically administering a transdermally effective amount of an oxazolidinone.

Within the scope of the present invention, useful warm-blooded mammals include humans, companion animals such as dogs, cats, and commercially important mammals such as horses, cattle, pigs. Preferably the mammal is a human, dog or cat; more preferably a human.

Oxazolidinones of the invention are known, see examples 1 to 6 (oxazolidinones). Preferably the oxazolidinone is selected from:

(S) -N- [ [3- [ 3-fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl ] -phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide,

(S) -N- [ [3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide,

[4(S) -cis ] - (-) -N- [ [3- [ 3-fluoro-4- (tetrahydro-1-oxo-2H-thiopyran-4-yl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide,

n- ((5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) -phenyl) -2-oxooxazolidin-5-ylmethyl) acetamide,

(S) -N- [ [3- [5- (3-pyridinyl) thiophen-2-yl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide and

(S) -N- [ [3- [5- (4-pyridinyl) pyridin-2-yl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide hydrochloride. More preferably the oxazolidinone is selected from:

(S) -N- [ [3- [ 3-fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl ] -phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide,

(S) -N- [ [3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide and

[4(S) -cis ] - (-) -N- [ [3- [ 3-fluoro-4- (tetrahydro-1-oxo-2H-thiopyran-4-yl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; even more preferably the oxazolidinone is (S) -N- [ [3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide.

Infections treated with the present invention include ear infections, skin and soft tissue infections, acne, infected wounds, and bacteremia, which are not topical infections, but infections of underlying tissues.

Ear infections can be caused by either gram-positive or gram-negative bacteria, or a mixture of both. Approximately 60% of ear infections are caused by gram-positive bacteria, and in these cases, the methods of the present invention would be useful for treating ear infections. If the treatment is not successfully performed, there are two serious consequences: one is that the tympanic membrane may rupture, resulting in reduced hearing; secondly, infection of surrounding tissues, including bone, can occur and lead to more serious life threatening conditions. Ear infections are most often caused by streptococcus pneumoniae, sometimes by both streptococcus pneumoniae and haemophilus influenzae. It will be apparent to those skilled in the art that when fever or ear pain occurs in a patient or the patient experiences ear pain and an ear examination reveals a swollen tympanic membrane and fluid is observed behind the tympanic membrane, the patient needs to be treated for an ear infection. Otic infections are treated by administering the desired oxazolidinone directly into the infected ear using pharmaceutical formulations in the form of solutions, suspensions or emulsions. A preferred transdermally effective amount of an oxazolidinone for the treatment of ear infections is from about 0.1% to about 10%; more preferably, the transdermally effective amount is about 0.2% to about 2%. Oxazolidinones should be administered 2 to 4 times daily for 3 to 14 days. Such a content is preferred if 0.25-1ml of the pharmaceutical formulation contains oxazolidinone to be administered each time.

Skin and soft tissue infections are the most common infections caused by staphylococci and streptococci. Such infections are very difficult to treat with known antibiotics because their location and failure to treat often requires additional treatment procedures. These infections include skin infections (cellulitis and superficial infections) and skin-related soft tissue infections (subcutaneous tissue infections and abscesses and myositis) when (gram-positive) bacteria are present in the epidermis, the dermis beneath the epidermis, the fat layer and/or the muscle layer. It will be apparent to those skilled in the art that when a patient develops inflammation, redness, or tenderness of a part of the body with fever, the patient needs to be treated for a soft tissue and/or skin infection. Skin and soft tissue infections are treated by administering the required oxazolidinone directly to the affected area using a suitable pharmaceutical dosage form. Preferably the oxazolidinone is administered in the form of a pharmaceutical formulation such as a cream, ointment, gel or emulsion and preferably the pharmaceutical formulation is administered or dosed 2 to 4 times daily, preferably 2 or 3 times daily, until body temperature returns to normal and 24 hours after redness, swelling and inflammation has disappeared. Preferably a transdermally effective amount for the treatment of skin and soft tissue infections is from about 0.2% to about 40%; more preferably from about 0.4% to about 10%. Other sanitary precautions known to those skilled in the art should also be taken.

Acne refers to acne severe enough to require treatment by a physician, and is known as acne vulgaris. Acne vulgaris is caused by the anaerobic bacterium, propionibacterium acnes, which occurs in the clogged and inflamed sebaceous glands or ducts of human skin, in particular of the skin of teenagers. These infections occur only below the surface of the skin and require treatment of this area. Although not life threatening, severe acne can lead to scarring of the skin and emotional damage. Acne is preferably treated with pharmaceutical preparations such as creams, ointments, gels, emulsions, suspensions, solutions and patches. The transdermally effective amount of oxazolidinone is preferably from about 0.1% to about 10%; more preferably from about 0.2% to about 6%. Acne is treated 2 to 4 times per day until it is controlled to the satisfaction of the patient and the treating physician.

Trauma refers to (and includes) trauma resulting from natural causes such as accidents and intentional wounds (such as those resulting from surgery). Because of the open access to the body in penetrating wounds, gram-positive microorganisms are often able to enter and cause infection. These infections can be very serious and even life-threatening. Since staphylococci (staphylococcus) organisms are located on our skin, once a wound has occurred, these microorganisms enter the body through the wound for whatever reason. By definition, a wound is not only on a surface, but also includes an infected area under the skin. Wounds were treated 2 to 4 times per day until the infection disappeared.

Bacteremia is an infection in which bacteria are present in the blood and can be cultured microbiologically from blood samples. Bacteremia is caused by gram-positive organisms, which in this patent have been identified as being preferably treated with pharmaceutical compositions of oxazolidinones, including creams, ointments, gels, emulsions, suspensions, and the like. Preferably a transdermally effective amount of about 1% to about 40%; more preferably, the transdermally effective amount is from about 5% to about 20%. Bacteremic infections are treated 2 to 4 times per day until the infection disappears.

Gram-positive microorganisms causing infections treated with the oxazolidinones of the invention include staphylococci, streptococci and enterococci. Preferably the infection is caused by staphylococci. Important species of these genera are Staphylococcus aureus, Staphylococcus epidermidis and Staphylococcus haemolyticus. The oxazolidinones of the invention can also treat gram negative bacterial infections caused by anaerobic bacteria such as bacteroides fragilis.

By "treating infections of the ear, skin and soft tissue, acne, infected wounds and bacteremia and the like in a useful warm blooded mammal in need of such treatment" is meant that the mammal is suffering from an infection which causes problems in the mammal, whether it is fever, pain such as ear pain, swelling, infection of tissue or wounds and inflammation. Treating an infection refers to administering the oxazolidinone to the mammal such that a sufficient concentration of oxazolidinone is obtained in the affected area of the mammal to kill the microorganisms present and/or reduce their rate of proliferation (increase) until the body's natural defense mechanisms reduce the unwanted microorganisms to a level that does not cause clinical problems. "treating" also includes preventing infection, or preventing a smaller infection from progressing to a larger infection, particularly acne. Although patients may not observe obstructed or inflamed sebaceous glands or ducts, they may still be present, but at a very light stage. The treatment of teenagers suffering from acne to prevent its appearance in the future is also included within the scope of "treatment" as used in this patent.

In the method of the present invention, oxazolidinone drugs can be used either alone or in combination with each other. In addition, they may be used in combination with other antibacterial agents administered orally. In addition, oxazolidinones can be used with non-antibacterial agents in the treatment of the infections of the invention.

The exact dosage and frequency of administration will depend upon the particular oxazolidinone employed, the particular condition being treated, the severity of the condition being treated, the age, weight, general health of the particular patient, and other drugs that the individual may be receiving as are well known to those of skill 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 being treated.

Definition and contract

The following definitions and explanations are for terms used throughout this document, including the specification and claims.

Definition of

All temperatures are in degrees Celsius.

THF means tetrahydrofuran.

DMF refers to dimethylformamide.

Brine refers to a saturated aqueous solution of sodium chloride.

Chromatography (column chromatography and flash chromatography) refers to the purification/separation of compounds expressed in (carrier, eluent). It should be understood that: appropriate fractions were combined and concentrated to give the desired compound.

Ether refers to diethyl ether.

TLC refers to thin layer chromatography.

When a solvent pair is used, the ratio of solvents used is volume/volume (v/v).

When the solubility of the solid in the solvent is used, the ratio of solid to solvent is weight/volume (wt/v).

Pharmaceutically acceptable refers to those properties and/or substances that are acceptable to the patient from a pharmacological/toxicological point of view, as well as those properties and/or substances that are acceptable to the pharmaceutical preparation chemist from a physical/chemical point of view with respect to composition, formulation, stability, patient acceptability and bioavailability, etc.

Oxazolidinones refer to the compounds of examples 1 to 6 of the present invention.

Examples

It is believed that one skilled in the art can, using the preceding description, practice the present invention without further elaboration. The following specific examples describe how to prepare the various compounds of the invention and/or to carry out the various methods of the invention, but are illustrative only and do not limit the disclosure in any way whatsoever. One skilled in the art will quickly recognize suitable variations for the reactants and reaction conditions and techniques in each step.

Example 1 (S) -N- [ [3- [ 3-fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl ] -phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

(S) -N- [ [3- [ 3-fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl ] -phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide is known, see example 1 of U.S. Pat. No. 5,652,238.

Example 2 (S) -N- [ [3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

(S) -N- [ [3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide is known, see example 5 of U.S. Pat. No. 5,688,792.

Example 3 [4(S) -cis ] - (-) -N- [ [3- [ 3-fluoro-4- (tetrahydro-1-oxo-2H-thiopyran-4-yl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

A mixture of (S) - (-) -N- [ [3- [ 3-fluoro-4- (3, 6-dihydro-2H-thiopyran-4-yl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide S-oxide (international publication WO97/09328, 4.50g) and platinum oxide (697mg) in methanol (164ml) was shaken on a parr apparatus under an atmosphere of hydrogen at 40psi for 18 hours. The catalyst was then removed by filtration through celite, the filtrate concentrated under reduced pressure and the residue chromatographed on silica gel (230-400 mesh, 350g) eluting with a gradient of methanol/dichloromethane (3/97-7/93). The appropriate fractions (those with Rf 0.44 in TLC; methanol/chloroform, 10/90) were combined and concentrated to give the title compound, mp 203-204 °.

Example 4N- ((5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) phenyl) -2-oxooxazolidin-5-ylmethyl) acetamide

N- ((5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) phenyl) -2-oxooxazolidin-5-ylmethyl) acetamide is known, see International publication WO97/27188 (example 4).

1-tert-Butoxycarbonyl-3-oxopiperazine (21.6g) was dissolved in dry DMF (500ml) and potassium tert-butoxide (24.2g) was added. The mixture was stirred at 20-25 ℃ for 30 minutes, then 1- (4-methylphenylsulfonyloxy) -2-fluoroethane (journal of medicinal chemistry 23(9), 985-90(1980), 25.9g) was added and stirring was continued at the same temperature for 24 hours. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and concentrated. The residue was dissolved in isopropanol and diluted with isohexane to form a precipitate, which was removed by filtration. The mixture was analyzed by chromatography (silica; gradient elution with isopropanol increasing in polarity from 0 to 50% in isohexane) to give 1-tert-butoxycarbonyl-4- (2-fluoroethyl) -3-oxopiperazine.

1-tert-Butoxycarbonyl-4- (2-fluoroethyl) -3-oxopiperazine (6.65g) was dissolved in dichloromethane (500ml), cooled in an ice bath and trifluoroacetic acid (150ml) was added. The mixture was stirred at the same temperature for 2 hours. Removal of the solvent gave a crude product, which was dissolved in a minimum volume of ethyl acetate. The 1- (2-fluoroethyl) -2-oxopiperazine precipitated out as the monotrifluoroacetate salt by slow addition of ether.

1- (2-fluoroethyl) -2-oxopiperazine trifluoroacetate (6.1g) was dissolved in propionitrile (100 ml). To the mixture was added N, N-diisopropylethylamine (13ml), followed by 3, 4-difluoronitrobenzene (3.39g), and the mixture was heated under reflux for 18 hours. The solvent was removed and the residue was chromatographed (silica; gradient elution with methanol in dichloromethane with a polarity increasing from 0 to 4%) to give 3-fluoro-4- (4- { 2-fluoroethyl } -3-oxopiperazin-1-yl) nitrobenzene.

3-fluoro-4- (4- { 2-fluoroethyl } -3-oxopiperazin-1-yl) nitrobenzene (4.35g) was dissolved in a mixture of ethyl acetate (250ml) and DMF (5ml), and the solution was purged with argon. Palladium (10% on carbon, 200mg) was added and the mixture was hydrogenated at ambient pressure. After the gas absorption had ceased, the mixture was filtered through celite and the solvent was removed. The residue was dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate and the solvent was removed to give 5-amino-2- [4- (2-fluoroethyl) -3-oxopiperazin-1-yl ] fluorobenzene, which was used without further purification.

5-amino-2- (4- [ 2-fluoroethyl ] -3-oxopiperazin-1-yl) fluorobenzene (2.6g) was dissolved in dry dichloromethane (50ml) under argon. Pyridine (1.03ml) was added and the mixture was cooled to-20 °. Benzyl chloroformate (1.6ml) was added and the mixture stirred at-20 ℃ for 10 minutes, then the temperature was raised to 20-25 ℃ for more than 1.5 hours. The solvent was removed, the residue was dissolved in dichloromethane and washed with sodium bicarbonate solution. After drying over magnesium sulfate and removal of the solvent, the residue was chromatographed (silica, gradient elution with methanol in dichloromethane with a polarity increasing from 0 to 5%) to give 5-benzyloxycarbonylamino-2- (4- [ 2-fluoroethyl ] -3-oxopiperazin-1-yl) fluorobenzene.

A solution of lithium tert-butoxide was prepared by adding n-butyllithium (1.6M in hexane, 2.9ml) to a stirred solution of tert-butanol (0.43g) in anhydrous THF (10ml) under argon at-10 ℃. After cooling to-70 ℃ a solution of 5-benzyloxycarbonylamino-2- (4- [ 2-fluoroethyl ] -3-oxopiperazin-1-yl) fluorobenzene (1.5g) in dry THF (15ml) was added. After 10 minutes, (R) -glycidyl butyrate (0.67g) in dry THF (15ml) was added to the resulting mixture, stirring was continued at-70 ℃ for 15 minutes, and then the temperature was raised to 20-25 ℃ for more than 16 hours. Methanol (10ml) was added followed by saturated sodium bicarbonate solution (20ml) and water (10 ml). The organic phase was separated and extracted into ethyl acetate (3 × 25ml), washed with brine and dried over magnesium sulfate. The solvent was removed and the residue was purified by chromatography (silica; gradient elution with methanol in dichloromethane with polarity increasing from 0 to 3%) to give (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 (0.8g) was dissolved in pyridine (15ml) and the mixture was cooled to 0 °. To the mixture was added triethylamine (0.38ml) and methanesulfonyl chloride (0.19ml), and stirring was continued at 20-25 ℃ for 2 hours. The solvent was removed and the residue was dissolved in dichloromethane, washed with water, brine, dried over magnesium sulfate and concentrated. The resulting residue was triturated with ether to give (5R) -3- (3-fluoro-4- [4- (2-fluoroethyl) -3-oxopiperazin-1-yl ] phenyl) -5- (methanesulfonyloxymethyl) oxazolidin-2-one (0.76g), which was used without further purification.

(5R) -3- (3-fluoro-4- [4- (2-fluoroethyl) -3-oxopiperazin-1-yl ] -5- (methylsulfonyloxymethyl) oxazolidin-2-one (719mg) was dissolved in dry DMF (15ml) and sodium azide (647mg) was added to the mixture, the mixture was heated at 80 ℃ for 6 hours and then concentrated to dryness the resulting residue was dissolved in ethyl acetate, washed twice with water and dried over magnesium sulfate the solvent was removed to give (5R) -5-azidomethyl-3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) phenyl) oxazolidin-2-one (413mg), it was used without further purification.

(5R) -5-Azidomethyl-3- (3-fluoro-4- [4- (2-fluoroethyl) -3-oxopiperazin-1-yl ] phenyl) oxazolidin-2-one (360mg) was dissolved in dry DMF (20ml) and the mixture was washed with argon. Palladium (10% on carbon, 72mg) was added followed by acetic anhydride (0.17ml) and the mixture was stirred at 20-25 ℃ under hydrogen confined in a balloon for 3 hours. The mixture was filtered through celite, concentrated to dryness and partitioned between ethyl acetate and water. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated. The residue is chromatographed (silica gel; gradient elution with methanol/dichloromethane having a polarity which increases from 0 to 2.5%). The appropriate fractions were combined and concentrated to give the title compound.

Example 5 (S) -N- [ [3- [5- (3-pyridyl) thiophen-2-yl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

(S) -N- [ [3- [5- (3-pyridinyl) thiophen-2-yl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide is known, see U.S. Pat. No. 5,698,574 (example 124).

Example 6 (S) -N- [ [3- [5- (4-pyridinyl) pyridin-2-yl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide hydrochloride

(S) -N- [ [3- [5- (4-pyridinyl) pyridin-2-yl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide hydrochloride was prepared following the basic procedure of examples 36 and 52 of U.S. Pat. No. 5,627,181, with non-critical changes but using a 4-pyridinyl adduct.

Example A treatment of people with acne with oxazolidinone salves

1 male, 14 years old, 70 kg heavy, had red and swollen pustules on the face, neck, chest and back, indicating that he had acne. It was administered with an ointment containing 30mg/ml of (S) -N- [ [3- [ 3-fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl ] -phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide for treatment, twice daily until redness and abscesses disappeared. After administration of oxazolidinone, redness and enlarged pustules were greatly reduced.

Example B treatment of a human with an otic infection with an oxazolidinone solution

1 child, 7 years old, 28 kg, with a bulging tympanic membrane, with liquid observed behind the tympanic membrane, and having developed a fever to 102 ° F (38.39 ℃) for two days, these signs indicate that he has otitis media. 10 drops of a solution containing 10mg/ml of (S) -N- [ [3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide are dripped into the ears of the patient twice a day for 10 days by using a dropper, and the external auditory meatus is immediately blocked by cotton after each dripping. After 10 days, the fever subsided and the pain disappeared.

Example C treatment of humans with postoperative wound infection with oxazolidinone cream

1 female aged 40, was found to have inflamed redness at the incision site one day after surgery, with a fever of 101F (38.33C) or greater. The surgical dressing was removed and the incision site covered with a cream containing 15% [4(S) -cis ] - (-) -N- [ [3- [ 3-fluoro-4- (tetrahydro-1-oxo-2H-thiopyran-4-yl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide followed by application of fresh dressing. The cream is administered 2 to 3 times daily until body temperature has returned to normal for 24 hours and there are no signs of redness and tenderness.

Example D treatment of a person with a wound infection with an oxazolidinone gel

1 female, 22 years old, weighing 65 kg, whose fingers were pricked with a rose two days ago, and whose fingers were now severely swollen and painful, was treated by administering a gel containing 1% of N- ((5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxopiperazin-1-yl) phenyl) -2-oxooxazolidin-5-ylmethyl) acetamide, twice daily for 10 days. After treatment with antibiotics, the inflamed site was lightly covered with sterile bandage. The wound is healed.

Example E treatment of persons with bacteremic infections with cream

A female, 46 years old, weighing 74 kilograms, at a body temperature above 101F (38.33C) for 3 consecutive days, assessed for bacteremia, was treated by administering a cream containing 10% (S) -N- [ [3- [ 3-fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl ] -phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide. The cream was applied to her arms twice daily until the fever returned to normal.

Claims (18)

1. Use of an oxazolidinone and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of a non-topical infection selected from the group consisting of ear infections, skin and soft tissue infections, bacteremia, in a mammal in need of such treatment, said medicament being a pharmaceutical formulation for topical administration comprising a transdermally effective amount of an oxazolidinone which is (S) -N- [ [3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide.

2. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 1 where the mammal is a human.

3. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 1 where the mammal is a dog or cat.

4. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 1 where the infection is an ear infection.

5. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 4 where the pharmaceuticauy formulation is a solution, suspension or emulsion.

6. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 4 where the transdermally effective amount of oxazolidinone in the pharmaceutical formulation is from 0.1 to 10% weight/volume.

7. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 6 where the transdermally effective amount of oxazolidinone in the pharmaceutical formulation is from 0.2 to 2% weight/volume.

8. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 1 where the infection is a skin and soft tissue infection.

9. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 8 where the pharmaceuticauy formulation is a cream, ointment, gel or emulsion.

10. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 8 where the transdermally effective amount of oxazolidinone in the pharmaceutical formulation is from 0.2 to 40% weight/volume.

11. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 10 where the transdermally effective amount of oxazolidinone in the pharmaceutical formulation is from 0.4 to 10% weight/volume.

12. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 1 where the infection is bacteremia.

13. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 12 where the pharmaceuticauy formulation is a cream, ointment, gel, emulsion or suspension.

14. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 12 where the transdermally effective amount of oxazolidinone in the pharmaceutical formulation is from 1 to 40% weight/volume.

15. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 12 where the transdermally effective amount of oxazolidinone in the pharmaceutical formulation is from 5 to 20% weight/volume.

16. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 1 where the infection is caused by staphylococci, streptococci and enterococci.

17. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 16 where the infection is caused by staphylococci.

18. Use of an oxazolidinone and pharmaceuticauy acceptable salts thereof for the manufacture of a medicament according to claim 1 where the pharmaceuticauy formulation is for administration 2 to 4 times per day.