Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
1999-04-09
2001-11-13
Achutamurthy, Ponnathapu (Department: 1652)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C435S212000, C435S219000
Reexamination Certificate
active
06315996
ABSTRACT:
This invention pertains to a method to treat Staphylococcus infections of the eye.
The eye is relatively impermeable to micro-organisms and other environmental elements. However, if the integrity of the cornea is breached by trauma, a sight-threatening bacterial infection can result.
Staphylococcus aureus, Pseudomonas aeruginosa,
and
Streptococcus pneunoniae
are the most common bacterial pathogens associated with infection of compromised corneas. Bacterial enzymes and toxins, as well as factors associated with the host immune response, can lead to tissue destruction during corneal infection. A successful antibacterial agent must both be active against the pathogen and be able to reach the pathogen. See M. C. Callegan et al., “Pharmokinetic considerations in the treatment of bacterial keratitis,” Clin. Pharmocokinet., vol. 27, pp. 129-149 (1994).
The cornea provides a protective barrier against invading organisms and other harmful substances. The cornea has three primary layers (epithelium, stroma, and endothelium) that maintain mechanical integrity, proper hydration, and transparency for adequate vision. Because the cornea is not vascularized, systemic drugs do not readily permeate the cornea and are generally not used for therapy of ocular bacterial infections. Topical application of antibiotics is the preferred delivery method. However, corneal impermeability presents a barrier not only to invading micro-organisms, but also to the penetration of many drugs into the eye, especially water-soluble antibacterial agents. For example, cephalosporins, aminoglycosides and penicillins diffuse less readily across the epithelium than lipid-soluble antibacterials, such as chlorampenicol and rifampicin. To facilitate diffusion across the cornea, antibiotics used to treat bacterial ocular infections are generally small molecules, with molecular weights between 300 and 1500 Daltons: cefazolin, 476 Daltons; ciprofloxacin, 356 Daltons; gentamicin, 463 Daltons; norfloxacin, 319 Daltons; ofloxacin, 361 Daltons; tobaymycin, 467 Daltons; and vancomycin, 1480 Daltons. See Callegan et al, 1994; and Physicians Desk Reference, 50
th
Edition, Medical Economics Company, Montvale, N.J., pp. 472-474, 1456, 1481-1483, 1567, 1617, 2360-2361 (1996).
Drug penetration into infected corneal tissues is a limitation of standard therapies that contributes to treatment failure.
Staphylococcus is the most frequently isolated bacterial genus involved in serious eye infections.
S. aureus
is found as flora of the face and anterior nostrils in asymptomatic carriers. This pathogen is readily transferred manually to an injured or compromised cornea. Without effective inhibition or killing of the infecting Staphylococcus, the eye can be damaged to such a degree that removal of the entire eye is necessary.
Staphylococcus is a genus of Gram-positive bacteria that has been recognized for decades as both a powerful pathogenic organism and a bacterium that frequently evolves new stages of antibiotic resistance. The development of new antimicrobial therapies for Staphylococcus infections is considered a high priority. Numerous antibiotics that were once effective against this organism are now unable to treat infections caused by many Staphylococcus strains. Among the most difficult strains to treat are those designated as methicillin-resistant
Staphylococcus aureus
(“MRSA”). MRSA strains are commonly isolated from hospital-acquired infections. Most MRSA strain can now be treated with only one commercially available antibiotic, vancomycin. Unfortunately, vancomycin is a slow-acting drug that often causes toxic reactions. Complicating the situation even further is the recent isolation of MRSA strains that do not respond to vancomycin therapy. See Smith et al., “Emergence of vancomycin-resistant
Staphylococcus aureus,
New England Journal of Medicine, vol. 340, pp. 493-501 (1999); and Hiramatsu et al., “Methicillin-resistant
Staphylococcus aureus
clinical strain with reduced vancomycin susceptibility,” Journal of Antimicrobial Chemotherapy, vol. 40, pp. 135-136 (1997). Thus, there is a clear need for new drugs to treat Staphylococcus infections.
Keratitis caused by Staphylococcus is most often treated by chemotherapy. Topical cefazolin (5.0% in artificial tears), often used in combination with a fortified aminoglycoside (0.3%), and fluoroquinolones (0.3% ciprofloxacin or ofloxacin) are the antibiotics most often employed for treating Staphylococcus keratitis. (Callegan et al., 1994). Topical antibiotic drops are applied as frequently as once every 15 to 30 minutes for 48 hours or longer. Methicillin-resistant
Staphylococcus aureus
(“MRSA”) strains resistant to multiple antibiotics have been treated successfully with ciprofloxacin; however, the susceptibility of MRSA strains to fluoroquinolones has declined rapidly in the past several years. Less than half of the recently-isolated MRSA strains remain susceptible. The increasing incidence of fluoroquinolone-resistant MRSA strains has dictated that vancomycin therapy (5.0%) be employed for most MRSA infections. Of greater importance is the recent emergence of MRSA stains not susceptible to vancomycin. The emergence of such strains has created a situation in which infected patients cannot be treated by any commercial antibiotic currently available; such strains have required use of experimental antibiotics for therapy.
Lysostaphin, a protein of 27,000 Daltons, is a bacterial endopeptidase that is highly lethal to
S. aureus
and
S. epidermidis.
It was initially isolated from a strain of
Staphylococcus simulans.
See C. A. Schindler et al., “Lysostaphin: A new bacteriolytic agent for the staphylococcus,” Proc.N.A.S., vol. 51, pp. 414-421 (1964); C. A. Schindler et al., “Purification and properties of lysostaphin-a lytic agent for
Staphylococcus aureus,”
Biochim. Biophys. Acta, vol. 97, pp. 242-250 (1996); W. A. Zygmunt et al., “In vitro effect of lysostaphin, neomycin, and bacitracin on
Staphylococcus aureus,”
Canadian Journal of Microbiology, vol. 12, pp. 204-206 (1966); W.A. Zygmunt et al., “Lytic action of lysostaphin on susceptible and resistant strains of
Staphylococcus aureus,”
Canadian Journal of Microbiology, vol. 13, pp. 845-853 (1967); W. A. Zygmunt et al., “Susceptibility of coagulase-negative Staphylococcus to lysostaphin and other antibiotics,” Applied Microbiology, vol. 16, pp. 1168-1173 (1968); W. A. Zygmunt et al., “Lysostaphin: Model for a specific enzymatic approach to infectious disease,” Progress in Drug Research, vol. 16, pp. 309-333 (1972); and H. P. Browder et al., “Lysostaphin: Enzymatic mode of action,” Biochemical and Biophysical Research Communications, vol. 19, pp. 383-389 (1965).
Lysostaphin has been shown to be effective in lowering
S. aureus
infections located internally (e.g., mastitis in mammary glands and aortic valve endocarditis) when lysostaphin was injected systemically or into the infected tissues. See A. J. Bramley et al., “Effects of lysostaphin on
Staphylococcus aureus
infections of the mouse mammary gland,” Research in Veterinary Science, vol. 49, pp. 120-121 (1990); E. R. Oldham et al., “Lysostaphin: Use of a recombinant bactericidal enzyme as a mastitis therapeutic,” J. Dairy Sci., vol. 74, pp. 4175-4182 (1991); and M. W. Climo et al., “Lysostaphin treatment of experimental methicillin-resistant
Staphylococcus aureus
aortic valve endocarditis,” Antimicrobial Agents and Chemotherapy, vol. 42, pp. 1355-1360 (1998). Topical application of lysostaphin has been used to treat
S. aureus
attached to nasal epithelial cells in the nares. See R. R. Martin et al., “The selective activity of lysostaphin in vivo,” Journal of Laboratory and Clinical Medicine, vol. 70, pp. 1-8 (1967); K. E. Quickel, Jr., et al., “Efficacy and safety of topical lysostaphin treatment of persistent nasal carriage of
Staphylococcus aureus,”
Applied Microbiology, vol. 22, pp. 446-450 (1971); and R. Aly et al., “Role of teichoic acid in the binding of
Staphylococcus aureus
to nasal epithelial cells,” Journal of Infectious Diseases, vol. 141, pp
Achutamurthy Ponnathapu
Board of Supervisors of Louisiana State University and Agricultu
Davis Bonnie J.
Runnels John H.
Tung Peter P.
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