Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds bacterium or component thereof or substance produced...
Reexamination Certificate
1997-08-20
2001-09-18
Navarro, Albert (Department: 1645)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds bacterium or component thereof or substance produced...
C424S130100, C424S150100, C424S167100, C530S389100, C530S389500
Reexamination Certificate
active
06290960
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to clostridial antitoxin and vaccine therapy for humans and other animals. Antitoxins which neutralize the pathologic effects of clostridial toxins are provided. Vaccines which prevent the morbidity and mortality associated with clostridial diseases are provided.
BACKGROUND OF THE INVENTION
The genus Clostridium is comprised of gram-positive, anaerobic, spore-forming bacilli. The natural habitat of these organisms is the environment and the intestinal tracts of humans and other animals. Indeed, clostridia are ubiquitous; they are commonly found in soil, dust, sewage, marine sediments, decaying vegetation, and mud. [See e.g., P. H. A. Sneath et al., “
Clostridium,” Bergey's Manual® of Systematic Bacteriology
, Vol. 2, pp. 1141-1200, Williams & Wilkins (1986).] Despite the identification of approximately 100 species of Clostridium, only a small number have been recognized as etiologic agents of medical and veterinary importance. Nonetheless, these species are associated with very serious diseases, including botulism, tetanus, anaerobic cellulitis, gas gangrene, bacteremia, pseudomembranous colitis, and clostridial gastroenteritis. Table 1 lists some of the species of medical and veterinary importance and the diseases with which they are associated. As virtually all of these species have been isolated from fecal samples of apparently healthy persons, some of these isolates may be transient, rather than permanent residents of the colonic flora.
TABLE 1
Clostridium Species of Medical and Veterinary Importance*
Species
Disease
C. aminovalericum
Bacteriuria (pregnant women)
C. argentinense
Infected wounds; Bacteremia; Botulism; Infections of
amniotic fluid
C. baratii
Infected war wounds; Peritonitis; Infectious processes of
the eye, ear and prostate
C. beijerinckikii
Infected wounds
C. bifermentans
Infected wounds; Abscesses; Gas Gangrene; Bacteremia
C. botulinum
Food poisoning; Botulism (wound, food, infant)
C. butyricum
Urinary tract, lower respiratory tract, pleural cavity, and
abdominal infections; Infected wounds; Abscesses;
Bacteremia
C. cadaveris
Abscesses; Infected wounds
C. carnis
Soft tissue infections; Bacteremia
C. chauvoei
Blackleg
C. clostridioforme
Abdominal, cervical, scrotal, pleural, and other
infections; Septicemia; Peritonitis; Appendicitis
C. cochlearium
Isolated from human disease processes, but role in
disease unknown.
C. difficile
Antimicrobial-associated diarrhea; Pseudomembranous
enterocolitis; Bacteremia; Pyogenic infections
C. fallax
Soft tissue infections
C. ghnoii
Soft tissue infections
C. glycolicum
Wound infections; Abscesses; Peritonitis
C. hastiforme
Infected war wounds; Bacteremia; Abscesses
Infected war wounds; Gas gangrene; Gingival plaque
C. histolyticum
isolate
C. indolis
Gastrointestinal tract infections
C. innocuum
Gastrointestinal tract infections; Empyema
C. irregulare
Penile lesions
C. leptum
Isolated from human disease processes, but role in
disease unknown.
C. limosum
Bacteremia; Peritonitis; Pulmonary infections
C. malenominatum
Various infectious processes
Infected wounds; Gas gangrene; Blackleg, Big head
C. novyi
(ovine); Redwater disease (bovine)
C. oroticum
Urinary tract infections; Rectal abscesses
C. paraputrificum
Bacteremia; Peritonitis; Infected wounds; Appendicitis
C. perfringens
Gas gangrene; Anaerobic cellulitis; Intra-abdominal
abscesses; Soft tissue infections; Food poisoning;
Necrotizing pneumonia; Empyema; Meningitis;
Bacteremia; Uterine Infections; Enteritis necrotans;
Lamb dysentery; Struck; Ovine Enterotoxemia;
C. putrefaciens
Bacteriuria (Pregnant women with bacteremia)
C. putrificum
Abscesses; Infected wounds; Bacteremia
C. ramosum
Infections of the abdominal cavity, genital tract, lung,
and biliary tract; Bacteremia
C. sartagoforme
Isolated from human disease processes, but role in
disease unknown.
C. septicum
Gas gangrene; Bacteremia; Suppurative infections;
Necrotizing enterocolitis; Braxy
C. sordellii
Gas gangrene; Wound infections; Penile lesions;
Bacteremia; Abscesses; Abdominal and vaginal
infections
C. sphenoides
Appendicitis; Bacteremia; Bone and soft tissue
infections; Intraperitoneal infections; Infected war
wounds; Visceral gas gangrene; Renal abscesses
C. sporogenes
Gas gangrene; Bacteremia; Endocarditis; central nervous
system and pleuropulmonary infections; Penile lesions;
Infected war wounds; Other pyogenic infections
C. subterminale
Bacteremia; Empyema; Biliary tract, soft tissue and
bone infections
C. symbiosum
Liver abscesses; Bacteremia; Infections resulting due to
bowel flora
C. tertium
Gas gangrene; Appendicitis; Brain abscesses; Intestinal
tract and soft tissue infections; Infected war wounds;
Periodontitis; Bacteremia
C. tetani
Tetanus; Infected gums and teeth; Corneal ulcerations;
Mastoid and middle ear infections; Intraperitoneal
infections; Tetanus neonatorum; Postpartum uterine
infections; Soft tissue infections, especially related to
trauma (including abrasions and lacerations); Infections
related to use of contaminated needles
C. thermosaccharolyticum
Isolated from human disease processes, but role in
disease unknown.
*Compiled from P.G. Engelkirk et al. “Classification”, Principles and Practice of Clinical Anaerobic Bacteriology, pp. 22-23, Star Publishing Co., Belmont, CA (1992); J. Stephen and R.A. Petrowski, “Toxins Which Traverse Membranes and Deregulate Cells,” in Bacterial Toxins, 2d ed., pp. 66-67, American Society for Microbiology (1986); R. Berkow and A.J. Fletcher (eds.), “Bacterial Diseases,
# ” Merck Manual of Diagnosis and Therapy, 16th ed., pp. 116-126, Merck Research Laboratories, Rahway, N.J. (1992); and O.H. Sigmund and C.M. Fraser (eds.), “Clostridial Infections,” Merck Veterinary Manual, 5th ed., pp. 396-409, Merck & Co., Rahway, N.J. (1979).
In most cases, the pathogenicity of these organisms is related to the release of powerful exotoxins or highly destructive enzymes. Indeed, several species of the genus Clostridium produce toxins and other enzymes of great medical and veterinary significance. [C. L. Hatheway, Clin. Microbiol. Rev. 3:66-98 (1990).]
Perhaps because of their significance for human and veterinary medicine, much research has been conducted on these toxins, in particular those of
C. botulinum
and
C. difficile.
C. botulinum
Several strains of
Clostridium botulinum
produce toxins of significance to human and animal health. [C. L. Hatheway, Clin. Microbiol. Rev. 3:66-98 (1990).] The effects of these toxins range from diarrheal diseases that can cause destruction of the colon, to paralytic effects that can cause death. Particularly at risk for developing clostridial diseases are neonates and humans and animals in poor health (e.g., those suffering from diseases associated with old age or immunodeficiency diseases).
Clostridium botulinum
produces the most poisonous biological toxin known. The lethal human dose is a mere 10
−9
mg/kg bodyweight for toxin in the bloodstream. Botulinal toxin blocks nerve transmission to the muscles, resulting in flaccid paralysis. When the toxin reaches airway and respiratory muscles, it results in respiratory failure that can cause death. [S. Arnon, J. Infect. Dis. 154:201-206 (1986).]
C. botulinum
spores are carried by dust and are found on vegetables taken from the soil, on fresh fruits, and on agricultural products such as honey. Under conditions favorable to the organism, the spores germinate to vegetative cells which produces toxin. [S. Arnon, Ann. Rev. Med. 31:541 (1980).]
Botulism disease may be grouped into four types, based on the method of introduction of toxin into the bloodstream. Food-borne botulism results from ingesting improperly preserved and inadequately heated food that contains botulinal toxin. There were 355 cases of food-borne botulism in the United States between 1976 and 1984. [K. L. MacDonald et al., Am. J. Epidemiol. 124:794 (1986).] The death rate due to botulinal toxin is 12% and can be higher in particular risk groups. [C. O. Tacket et al., Am. J. Med. 76:794
Kink John A.
Stafford Douglas C.
Thalley Bruce S.
Medlen & Carroll LLP
Navarro Albert
Ophidian Pharmaceuticals Inc.
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