Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-21
2003-04-08
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S236800, C514S376000, C514S192000, C514S198000
Reexamination Certificate
active
06544991
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to compositions having antibacterial activity, and methods of treating bacterial infections. More particularly, the invention relates to the use of an oxazolidinone compound, sulbactam, and ampicillin in treating a patient having a bacterial infection.
2. Description of the Related Technology
Many classes of compounds, including aminoglycosides, oxazolidinones, and &bgr;-lactams, have been described for the treatment of infectious diseases, particularly bacterial infections. As the use of the these antibacterial agents becomes more widespread, the emergence of new resistant strains of bacteria is imminent. The new resistant strains, for example, methicillin-resistant
Staphylococcus aureus
(MRSA), vancomycin-resistant Enterococci (VRE), vancomycin-resistant
Staphylococcus aureus
(VRSA), glycopeptide-intermediate
Staphylococcus aureus
(GISA), and vancomycin-intermediate
Staphylococcus aureus
(VISA), have reduced susceptibility to known antibacterial agents, creating an ongoing need for developing effective therapeutic measures.
Oxazolidinones are known to have good activity against gram-positive microorganisms. In particular, the oxazolidinone compounds have demonstrated beneficial characteristics in treating urinary tract infections, caused by resistant bacterial agents including infections induced by vancomycin-resistant Enterococci.
The &bgr;-lactam, D-(−)-&agr;-aminobenzylpenicillin (ampicillin), has been described as a useful nutritional supplement for the treatment of mastitis in cattle, and as an antibacterial therapeutic agent in poultry and human beings. Another &bgr;-lactam compound, penicillanic acid, 1,1-dioxide (sulbactam), has been described for enhancing the effectiveness of several &bgr;-lactam antibiotics, including ampicillin. The synergistic antibacterial activity of an ampicillin active agent in combination with sulbactam is reported in
Drugs
33, 577-609 (1987) and
J. Antimicrob. Chemother.
17, 389-396 (1986).
Despite the known activities of oxazolidinone and &bgr;-lactam compounds, there remains an ongoing need for additional antibacterial compositions. A beneficial composition would provide a method for treating bacterial infections caused by resistant strains of infectious agents.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to a composition containing an oxazolidinone compound, sulbactam, and ampicillin active agents. The composition demonstrates antibacterial activity against a broad spectrum of antibacterial agents.
In another aspect, the invention relates to method of treating a bacterial infection comprising administering oxazolidinone, sulbactam, and ampicillin active agents. The method encompasses the administration of antibacterial effective amounts of oxazolidinone and ampicillin and an antibacterial enhancing amount of sulbactam, separately or in admixture.
Yet another aspect of the invention relates to the use of a composition comprising an antibacterial effective amount of an oxazolidinone, an antibacterial effective amount of ampicillin, and an antibacterial enhancing amount of sulbactam for the manufacture of a medicament for preventing or treating a bacterial infection.
These and other aspects, advantages, and features of the invention will become apparent from the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to the administration of effective amounts of active agents useful for treating bacterial infections and, more particularly, bacterial infections caused by extremely resistant bacterial microorganisms. The treatment of the invention exhibits antibacterial activity against isolates of various extremely resistant strains of bacteria including, for example, but not limited to, staphylococci, enterococci, and steptococci that are sensitive or resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, glycopeptides, macrolides, quinolones, steptogramins, and lipopeptides.
The enhanced activity of an oxazolidinone, for example linezolid, when used in combination with sulbactam and ampicillin provides a surprisingly effective, synergistic activity in treating resistant strains of bacteria, including extremely resistant strains of bacteria such as MRSA, VRE, VRSA, GISA, and VISA.
As used herein, the term “antibacterial effective amount” refers to an amount effective to prevent development of, or to alleviate any existing symptoms of an infection caused by bacteria, for example, particularly resistant strains of staphylococci, enterococci, and streptococci.
The term “antibacterial enhancing amount”, as used herein, refers to an amount sufficient to provide a synergistic, typically more than additive, effect when used in combination with a desired antibacterial agent. Determination of an “antibacterial effective amount” and “antibacterial enhancing amount” is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
In previously unreported efforts, scientists at Pharmacia Corporation (Kalamazoo, Mich., U.S.A.) have observed imperceptible differences between the antibacterial activity of linezolid alone and the activity of linezolid in combination with ampicillin. See, In vitro
Activity of Linezolid Combined with other Antibacterial Agents,
Poster Presentation, No. 1252. In light of the absence of synergistic activity between linezolid and ampicillin, it is a surprising result that linezolid demonstrates synergistic activity with a combination of sulbactam and ampicillin.
Oxazolidinones suitable for the invention typically are gram-positive antibacterial agents. Certain oxazolidinone compounds useful in the invention have been described in U.S. Pat. No. 5,688,792 and in U.S. Pat. No. 5,880,118, the entire disclosures of which are both incorporated herein by reference. Suitable oxazolidinone compounds have the formula:
or is a pharmaceutically acceptable salt thereof, wherein:
X is O, S, SO, SO
2
, SNR
11
, NC(O)R
11
, and S(O)NR
11
;
n is 0, 1, or 2;
R is selected from the group consisting of:
hydrogen;
C
1
-C
8
alkyl optionally substituted with one or more substituents selected from the group consisting of F, Cl, hydroxy, C
1
-C
8
alkoxy, C
1
-C
8
acyloxy, or —CH
2
— phenyl;
C
3
-C
6
cycloalkyl;
amino;
C
1
-C
8
alkylamino;
C
1
-C
8
dialkylamino; or
C
1
-C
8
alkoxy;
R
1
at each occurrence is hydrogen, except when X is O, then R
1
is independently selected from the group consisting of H, CH
3
, CN, CO
2
H, CO
2
R, and (CH
2
)
m
R
10
, wherein m is 1 or 2;
R
2
at each occurrence is independently selected from the group consisting of H, F, and Cl;
R
3
is H, except when X is O and R
1
is CH
3
, then R
3
is H or CH
3
;
R
10
is selected from the group consisting of H, OH, OR, OCOR, NH
2
, NHCOR, and N(R
11
)
2
; and
R
11
at each occurrence is independently selected from the group consisting of H, p-toluensulfonyl, and C
1
-C
4
alkyl optionally substituted with one or more substituents selected from the group consisting of Cl, F, OH, C
1
-C
8
alkoxy, amino, C
1
-C
8
alkylamino, and C
1
-C
8
dialkylamino.
The carbon content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C
i
-C
j
defines the number of carbon atoms present from the integer “i” to the integer “j” inclusive. Thus, C
1
-C
4
alkyl refers to an alkyl group of 1 to 4 carbon atoms, inclusive, for example, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. C
1
-C
8
alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomeric forms thereof.
As used herein, the term “pharmaceutically acceptable salts” refers to organic and inorganic acid addition salts of the parent compound. Examples of salts useful for the invention are, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citr
Batts Donald H.
Hiramatsu Keiichi
Darnley James D.
Delacroix-Muirheid C.
Jones Dwayne C.
Pharmacia & Upjohn Company
Pharmacia & Upjohn Company
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