Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-27
2001-04-24
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S210030
Reexamination Certificate
active
06221859
ABSTRACT:
BACKGROUND OF THE INVENTION
Within the last decade, enterococcus has become the second most common pathogen isolated in nosocomial infections. The ability of recent enterococcal isolates (i.e.,
Enterococcus
(
E.
)
faecium, Enterococcus
(
E.
)
faecalis
) to rapidly acquire multidrug resistance to all available antimicrobials and to disseminate resistance determinants through the exchange of genetic elements has resulted in a serious therapeutic dilemma. Antibiotic resistance of enterococcus is characterized according to its susceptibility to two glycopeptides—vancomycin (VANCO) and teicoplanin (TEICO) and is accordingly divided into three major classes of VANCO resistant enterococci (VRE) (phenotypes VanA, VanB, VanC and perhaps even a new class). Enterococcal VanA isolates (
E. faecium
and
E. faecalis
) are resistant to high levels of VANCO (MIC≧64 &mgr;g/mL) and to TEICO (MIC≧16 &mgr;g/mL) and its plasmid transferable resistance is inducible by VANCO or TEICO, while class VanB isolates demonstrate moderate levels of resistance to VANCO (≈8-64 &mgr;g/mL and retain susceptibility to TEICO (MIC<2 &mgr;g/mL). Resistance to VanB isolates is induced by VANCO but is not thought to be transferable. Phenotypic class VanC VANCO resistance is found in
Enterococcus
(
E.
)
gallinarum
and
Enterococcus
(
E.
)
casseliflavus,
which possess low-level resistance to VANCO (MIC≧4 and ≦32 &mgr;g/mL) but retain susceptibility to TEICO (MIC≦1 &mgr;g/mL).
VanA resistant
E. faecium
(VREF) is intrinsically resistant to most &bgr;-lactam (cell-wall active) antibiotics by virtue of the relatively low affinity of their penicillin-binding proteins (PBPs), which are important enzymes in cell wall biosynthesis. &bgr;-lactam antibiotics inhibit bacterial growth through their binding of PBPs. Enterococci contain a normally low affinity PBP (PBP5) which in some recent isolates appears to be over produced and, in some cases, genetically modified.
Emergence of strains with resistance to most &bgr;-lactam, aminoglycoside and quinolone antibiotics when used as monotherapy have left only glycopeptides alone and in combination with aminoglycosides as the first line of defense against isolates resistant to &bgr;-lactam agents. For example, treatment of serious enterococcal infections usually includes combinations of VANCO with a number of moderately active &bgr;-lactams or aminoglycosides. However, this final therapeutic option is waning to the more recent isolation of enterococcal strains with high-level resistance to glycopeptides. Due to the isolation of enterococccal organisms that produce &bgr;-lactamases in addition to the discovery of VRE isolates with high resistance to nearly all &bgr;-lactam antibiotics, etc. (which usually occurs following monotherapy) an increased intensity in the search to discover new and innovative anti-enterococcal drugs is ever pressing.
SUMMARY OF THE INVENTION
The present invention relates to novel 2-(naphthosultamyl)methyl-carbapenem antibacterial agents or pharmaceutically acceptable salts thereof in combination with other antibiotics such as &bgr;-lactams, aminoglycosides, fluoroquinolones, related quinolones and naphthyridines, chloramphenicol, macrolides, ketolides, azalides, Synercid®, tetracyclines, glycopeptides, novobiocin, oxazolidinones and the like or a combination thereof. The combination is useful against gram positive microorganisms, especially methicillin resistant
Staphylococcus aureus
(MRSA), methicillin resistant
Staphylococcus epidermidis
(MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS).
The present invention also relates to novel 2-(naphthosultamyl)methyl-carbapenem antibacterial agents or pharmaceutically acceptable salts thereof in combination with other &bgr;-lactams, which are useful in treating and preventing enterococcal infections. The combinations have anti-PBP5 activity as well as activity against the critical PBPs of sensitive isolates. The antibacterial compositions of the present invention thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens.
Another aspect of the invention is concerned with the use of the novel antibiotic compositions in the treatment of bacterial infections.
REFERENCES:
patent: 4309438 (1982-01-01), Christensen et al.
patent: 4479947 (1984-10-01), Christensen et al.
patent: 4539208 (1985-09-01), Kahan et al.
patent: 5494666 (1996-02-01), Bohringer et al.
patent: 5637579 (1997-06-01), Hubschwerlen et al.
patent: 5756725 (1998-05-01), Wilkening et al.
patent: 0 007 614 (1980-02-01), None
patent: 0 072 014 (1983-02-01), None
Remington: the Science and Practice of Pharmacy, 19th Edition Mack Publishing Co., chapter 76, pp. 1298-1299, 1995.
Dorso Karen L.
Gill Charles J.
Jackson Jesse J.
Kohler Joyce
Silver Lynn L.
Ayler Sylvia A.
Daniel Mark R.
Jagoe Donna
Krass Frederick
Merck & Co. , Inc.
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