Compounds and methods for the treatment of bacterial dysentery using antibiotics and toxin binding oligosaccharide compositions

Abstract

This invention relates to the treatment of diarrhea and related conditions caused by pathogenic E. coli infection. More specifically, this invention is drawn to the unexpected discovery that by administering a composition which binds and removes the shiga like toxins (SLT) produced by pathogenic E. coli whenever an antibiotic is administered, improved treatment is provided. Novel compositions containing both antibiotic and toxin binding composition and methods of treatment which use simultaneous administration toxin binding composition whenever antibiotic is administered are provided. These compositions and methods kill the enteric E. coli organisms which produce the conditions and neutralize the SLT produced by the organisms and/or released from the organisms when they are killed. Thus, these compositions and methods are better able to ameliorate the symptoms of the infection and inhibit progression of this infection into hemolytic uremic syndrome (HUS) than conventional treatment.

What is claimed is:  
     
         1 . A method to prevent or ameliorate one or more conditions mediated by enterohemorrhagic  E. coli  in a patient suffering from or susceptible to said condition, comprising simultaneously administering to the patient an effective amount of at least one antibiotic and an effective amount of at least one SLT binding oligosaccharide sequence covalently attached to a pharmaceutically acceptable inert support (oligosaccharide-support), wherein said oligosaccharide sequence binds SLT, and wherein the SLT bound to oligosaccharide-support is capable of being eliminated from the gastrointestinal tract.  
     
     
         2 . The method of    claim 1    wherein said antibiotic is selected from the group consisting of cefixime, tetracycline, ciprofloxacin, co-trimoxazole, mitomycin-C, fosfomycin and kanamycin.  
     
     
         3 . The method of    claim 1    wherein the oligosaccharide comprises the αGal(1→4)βGal subunit.  
     
     
         4 . The method of    claim 3    wherein the oligosaccharide is selected from the group consisting of αGal(1→4)βGal, αGal(1→4)βGal(1→4)βGlcNAc and αGal(1→4)βGal(1→4)βGlc.  
     
     
         5 . The method of    claim 1    wherein the oligosaccharide is bound to the support using a non-peptidyl linker.  
     
     
         6 . The method of    claim 1    wherein a single pharmaceutical composition containing the antibiotic and the SLT binding oligosaccharide-support is administered.  
     
     
         7 . The method of    claim 1    wherein the administration is performed within about 3 days of presentation of the infection.  
     
     
         8 . The method of    claim 1    wherein said oligosaccharide sequence has from 2 to 10 saccharide units.  
     
     
         9 . The method of    claim 5    wherein said linker arm is selected from the group consisting of: —(CH 2 ) 8 C(O)— and —NH—(CH 2 ) m —NHC(O)NH—, where m is an integer of from about 2 to about 10.  
     
     
         10 . A pharmaceutical composition useful in treating or preventing conditions associated with enterohemorrhagic  E. coli,  comprising: 
 a) an effective amount of at least one antibiotic;    b) at least one oligosaccharide sequence covalently attached to a pharmaceutically acceptable inert support (oligosaccharide-support), wherein said oligosaccharide sequence binds SLT; and    c) a pharmaceutically acceptable carrier, wherein the SLT bound to said oligosaccharide-support is capable of being eliminated from the gastrointestinal tract.    
     
     
         11 . The composition of    claim 10    wherein said at least one antibiotic is effective as a bactericide for said enterohemorrhagic  E. coli.    
     
     
         12 . The composition of    claim 10    wherein said antibiotic is-cefixime, tetracyclines ciprofloxacin, co-trimoxazole, mitomycin-C, fosfomycin and kanamycin.  
     
     
         13 . The composition of    claim 10    wherein the oligosaccharide comprises the αGal(1→4)βGal subunit.  
     
     
         14 . The composition of    claim 13    wherein the oligosaccharide is selected from the group consisting of αGal(1→4)βGal, αGal(1→4)βGal(1→4)βGlcNAc and αGal(1→4)βGal(1→4)βGlc.  
     
     
         15 . The composition of    claim 10    wherein the oligosaccharide is bound to the support using a non-peptidyl linker.  
     
     
         16 . The composition of    claim 10    wherein the composition is administered within about 3 days of presentation of the infection.  
     
     
         17 . The composition of    claim 10    wherein the composition is administered orally.  
     
     
         18 . The composition of    claim 10    wherein said oligosaccharide sequence has from 2 to 10 saccharide units.  
     
     
         19 . The composition of    claim 15    wherein said linker arm is selected from the group consisting of: —(CH 2 ) 8 C(O)— and —NH—(CH 2 ) m —NHC(O)NH—, where m is an integer of from about 2 to about 10.  
     
     
         20 . A method to prevent or ameliorate one or more conditions mediated by enterohemorrhagic  E. coli  in a patient suffering from or susceptible to said condition, comprising the steps of: 
 a) administering to the patient an effective amount of at least one SLT binding oligosaccharide sequence covalently attached to a pharmaceutically acceptable inert support (oligosaccharide-support), wherein said oligosaccharide sequence binds SLT; and, after step a)    b) simultaneously administering to the patient an effective amount of at least one antibiotic and an effective amount of at least one SLT binding oligosaccharide sequence covalently attached to a pharmaceutically acceptable inert support (oligosaccharide-support), wherein said oligosaccharide sequence binds    SLT, and wherein, following each administration, the SLT bound to said oligosaccharide-support is capable of being eliminated from the gastrointestinal tract.    
     
     
         21 . The method of    claim 20    wherein the antibiotic is cefixime, tetracycline, ciprofloxacin, co-trimoxazole, mitomycin-C, fosfomycin and kanamycin.  
     
     
         22 . The method of    claim 20    wherein the oligosaccharide comprises the αGal(1→4)βGal subunit.  
     
     
         23 . The method of    claim 20    wherein the oligosaccharide is selected from the group consisting of αGal(1→4)βGal, αGal(1→4)βGal(1→4)βGlcNAc and αGal(1→4)βGal(1→4)βGlc.  
     
     
         24 . The method of    claim 20    wherein the oligosaccharide is bound to the support using a non-peptidyl linker.  
     
     
         25 . The method of    claim 20    wherein a single pharmaceutical composition containing the antibiotic and the SLT binding oligosaccharide-support is administered following the initial administration of toxin binding composition alone.  
     
     
         26 . The method of    claim 20    wherein the administration is performed within about 3 days of presentation of the infection.  
     
     
         27 . The method of    claim 20    wherein said oligosaccharide sequence has from 2 to 10 saccharide units.  
     
     
         28 . The method of    claim 24    wherein said linker arm is selected from the group consisting of: —(CH 2 ) 8 C(O)— and —NH—(CH 2 ) m —NHC(O)NH—, where m is an integer of from about 2 to about 10.  
     
     
         29 . The method of    claim 1    wherein the inert support is silica.  
     
     
         30 . The composition of    claim 10    wherein the inert support is silica.  
     
     
         31 . The method of    claim 20    wherein the inert support is silica.  
     
     
         32 . The method of    claim 1    wherein the administration to the patient is performed prior to organ involvement other than intestinal involvement.  
     
     
         33 . The composition of    claim 10    wherein the composition is administered to the patient prior to organ involvement other than intestinal involvement.  
     
     
         34 . The method of    claim 20    wherein the administration to the patient is performed prior to organ involvement other than intestinal involvement.