Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
Reexamination Certificate
1999-02-08
2001-12-04
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
C514S159000, C514S161000, C514S166000
Reexamination Certificate
active
06326364
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application various publications are referenced within parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains.
1. The Field of the Invention
This invention relates to the medical arts. In particular, it relates to a method of inhibiting bacterial growth in the gastrointestinal tract of a human or non-human vertebrate by using an antimicrobial agent.
2. Discussion of the Related Art
Antimicrobial or antibiotic agents are used in the treatment of bacterial infections, especially of the gastrointestinal tract. Gastrointestinal infections affect millions of people world-wide, especially children, and pose an increasing health hazard in hospital settings.
Of course, bacteria inhabit healthy intestines to the benefit of their human and animal hosts. Anaerobic bacteria, including the
Bacteroides fragilis
group and Clostridium species are common members of the intestinal microflora of healthy individuals, and non-toxigenic strains can be transmitted without causing disease symptoms. (B. A. Cunha,
Nosocomial diarrhea
, Crit. Care Clin. 14(2):329-38 [1998]; H. Kato et al., Application of typing by pulsed-yield gel electrophoresis to the study of
Clostridium difficile
in a neonatal intensive care unit, J. Clin. Microbiol. 32(9):2067-70 [1997]; V. O. Rotimi and B. I. Duerden, Bacteroides species in the normal neonatal faecal flora, J. Hyg. [Lond.] 87(2):299-304 [1981]; B. I. Duerden, The isolation and identification of Bacteroides spp. From the normal human faecalflora, J. Med. Microbiol. 13(1):69-78 [1980]; S. S. Long and R. M. Swenson, Development of anaerobic flora in healthy newborn infants, J. Pediatr. 91(2):298-301 [1977]). Other pathogenic bacterial strains have an adverse effect on their hosts.
For example, enterotoxigenic strains of
Bacteroides fragilis
are associated with diarrhea in humans. (S. K. Niyogi et al., Association of enterotoxigenic
Bacteroides fragilis
with childhood diarrhoea, Indian J. Med. Res. 105:167-69 [1997]; R. B. Sack et al., Enteroloxigenic
Bacteroides fragilis
: epidemiologic studies of its role as a human diarrhoeal pathogen, J. Diarrhoeal Dis. Res. 10(1):4-9 [1992]). And patients with Crohn's disease were reported to have higher numbers of
B. fragilis
group bacteria in their intestines than healthy controls. (J. G. Ruseler-van Embden and H.C. Both-patoir, Anaerobic gram-negative faecal flora in patients with Crohn's disease and healthy subjects, Antonie van Leeuwenhoek 49(2):125-32 [1983]).
More prominent agents of gastrointestinal disease than Bacteroides, are the Clostridium species, especially
C. difficile
and
C. perfringens
. Clostridium species are gram-positive, spore-forming anaerobes; some strains that colonize the human intestines can, under certain circumstances, release potent protein exotoxins that induce inflammation of the intestinal mucosa. (M. L. Job and N. F. Jacobs, Jr., Drug-induced
Clostridium difficile
-associated disease, Drug Saf. 17(1):37-46 [1997]). For example, antibiotics and other chemotherapeutic agents can induce the expression of Toxins A and B from
Clostridium difficile
. (B. A. Cunha [1998]). Agents known to have a high potential to induce
C. difficile
-associated disease are aminopenicillins, cephalosporins and clindamycin. (M. L. Job and N. F. Jacobs, Jr., Drug-induced
Clostridium difficile
-associated disease, Drug. Saf. 17(1):37-46 [1997]; Y. Hutin et al., Prevalence of and risk factors for
Clostridium difficile
colonization at admission to an infectious diseases ward, Clin. Infect. Dis. 24(5):920-24 [1997]; C. D. Settle and M. H. Wilcox [1996]).
In developed countries, the great majority of cases of
C. difficile
infection are hospital-acquired, and the number of nosocomial clostridial infections is reported to be rising. (C. D. Settle and M. H. Wilcox, Review article: antibiotic-induced
Clostridium difficile
infection, Aliment. Pharmacol. Ther. 10(6):835-41[1996]; J. S. Brazier, The epidemiology and typing of
Clostridium difficile
, J. Antimicrob. Chemother. 41 Suppl. C:47-57 [1998]; S. Tabaqchali and M. Wilks, Epidemiological aspects of infections caused by
Bacteroides fragilis
and
Clostridium difficile
, Eur. J. Clin. Microbiol. Infect. Dis. 11(11): 1049-57 [1992]; C. R. Clabots et al., Acquisition of
Clostridium difficile
by hospitalized patients: evidence for colonized new admissions as a source of infection, J. Infect. Dis. 166(3):561-67 [1992]).
A nosocomial pleural infection with
C. difficile
, following surgical insertion of a chest drain has also been reported (A. J. Simpson et al., Nosocomial empyema caused by
Clostridium difficile
, J. Clin. Pathol. 49(2):172-73 [1996]), but intestinal infections are the greatest problem.
Nosocomial diarrhea due to gastrointestinal infection with
C. difficile
has become a major health care problem, causing 20-30% of all nosocomial diarrheas and affecting up to 8% of hospitalized patients. (L. R. Peterson and P. J. Kelly, The role of the clinical microbiology laboratory in the management of
Clostridia difficile
-associated diarrhea, Infect. Dis. Clin. North Am. 7(2):277-93 [1993]).
Clostridium difficile
is considered to be the premier cause of diarrhea among hospitalized patients. (M. Delmee et al., Treatment of
Clostridium difficile
colitis. Summary of a round table held in Brussels on Mar. 3, 1994, Acta Clin. Belg. 50(2):114-116 [1995]).
An infection of
C. difficile
can add an average of three weeks to a patient's hospital stay. (C. D. Settle and M. H. Wilcox [1996]). Symptoms may include, diarrhea, self-limited colitis, toxic megacolon or potentially lethal fulminant pseudomembranous colitis. Intestinal infection with
C. difficile
has also been linked to reactive arthritis. (I. H. Kocar et al., Clostridium infection in patients with reactive arthritis of undetermined etiology, Scand. J. Rheumatol. 27(5):357-62 [1998]; R. K. Cleary,
Clostridium difficile
-associated diarrhea and colitis: clinical manifestations, diagnosis, and treatment, Dis. Colon. Rectum 41(11):1435-49 [1998]). Bacteraemia and subsequent sepsis is another possible complication of intestinal infection by
C. difficile
. (P. Naaber et al., Bacterial translocation, intestinal microflora and morphological changes of intestinal mucosa in experimental models of
Clostridium difficile
infection, J. Med. Microbiol. 47(7):591-98 [1998]; R. J. Feldman et al., Bacteremia due to
Clostridium difficile
: case report and review of extraintestinal
C. Difficile
infections, Clin. Infect. Dis. 20(6):1560-62 [1995]). In at least one nosocomial outbreak, 17 patients died from
C. difficile
infection. (C. D. Settle and M. H. Wilcox [1996]).
Clostridium difficile
intestinal infections in children, unassociated with antibiotic use or hospital stays, can cause chronic diarrhea and failure to grow. (T. E. Liston,
Clostridium difficile
toxin associated with chronic diarrhea and failure to gain weight, Clin. Pediatr. (Phila.) 22(6):458-60 [1983]).
In developing countries,
C. difficile
is also thought to be a causal agent of wide-spread acute cliarrheal disease. (S. K. Niyogi et al., Prevalence of
Clostridium difficile
in hospitalized patients with acute diarrhoea in Calcutta, J. Diarrhoeal Dis. Res. 9(1):16-19 [1991]; S. Q. Akhtar, Isolation of
Clostridium difficile
from diarrhoea patients in Bangladesh, J. Trop. Med. Hyg. 90(4):189-92 [1987]).
Enterotoxigenic strains of
C. perfringens
are linked with a significant number of cases of antibiotic-associated diarrhea, especially among elderly hospitalized patients, children, and infants. (A. Wada et al., Nosocomia
Lin Henry C.
Pimentel Mark
Cedars-Sinai Medical Center
Sidley Austin Brown & Wood
Weddington Kevin E.
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