Abstract:
The present invention relates to methods of decreasing the infectivity, morbidity and rate of mortality, in treating diseases associated with a variety of pathogenic organisms, specifically diseases involving one or more pathogens that require neuraminidase as a virulence factor. In addition, the present invention uses biology based therapy to treat neuraminidase dependent infections or diseases dependent on sialic acid metabolism.

Description:
BACKGROUND  
       [0001]     Many disease causing microorganisms, such as bacteria, fungi, and viruses, play a significant role in producing a myriad of diseases and conditions in humans and animals. Due to their widespread capability of pathogenic infectivity, morbidity and mortality, considerable activity has been devoted towards developing convenient effective methods to help prevent or treat these diseases caused by these pathogens.  
         [0002]     For example, viruses such as influenza, have a high mortality rate in humans and are devastating to man and animals. It is estimated that more than $1 billion per year is lost in productivity from absence due to sickness from an influenza virus infection.  
         [0003]     With respect to clinical veterinary medicine, there are many diseases, viral and bacterial, that are detrimental to animals. Viruses or bacteria that cause diseases that effect animals in the food industry, for example, cattle, pigs and chickens can be quite costly and result in billions of dollars lost in the food industry. These same microorganisms can wipe out large masses of domestic animals, such as cats and dogs, since they can be highly contagious and spread quickly, thus being detrimental to veterinary hospitals, kennels, and breeding facilities, resulting in both emotional and monetary loss. Recently, there have been several disease causing microorganisms that have jumped the species barrier, resulting in new variant diseases that are fatal to man.  
         [0004]     Canine parvovirus (CPV), for example, has a high morbidity and mortality rate and is a life threatening infection that has been estimate to affect up to 1 million dogs per year in the United States. The disease resulting from parvovirus is typically almost always fatal, and there have been very few major advances in the way that dogs with canine parvovirus are treated. As a result, the disease is typically associated with a significant mortality rate. Most of the untreated dogs succumb to the diseases, and even with care, for example, in private practice, mortality rate still is quite high. In addition, the disease from a parvovirus infection is costly, both monetarily and emotionally for the dog&#39;s caretakers.  
         [0005]     With canine parvovirus, the clinical disease is often characterized by fever, acute gastroenteritis, which can progress rapidly to shock and death. Septicemia and endotoxemia can play an important role in the pathogenesis of canine parvovirus. It has been found that when gnotobiotic (germ free) dogs were infected with canine parvovirus, they did not develop any signs of the illness. Similar findings were made with germ-free cats when exposed with highly pathogenic feline parvovirus. Thus, attempts have been directed to utilize treatments aimed at preventing or treating septicemia and endotoxemia. Unfortunately, these treatments have shown little or no benefit on survival of these animals.  
         [0006]     Conventional methods towards the control of these disease causing microorganisms or pathogens, include vaccination, drug therapy and public health measures. Typically, one method of treatment of these types of diseases is antibiotic therapy, which has been found to be effective against diseases caused by bacteria. Although an invaluable advance, there are disadvantages of using antibiotic therapy, especially when strains of bacteria appear to be resistant to antibiotics.  
         [0007]     Vaccines have also been used to treat diseases caused by viruses. However, there can be disadvantages involved with the production of suitable vaccines. First, the vaccines derived from whole killed or whole attenuated viruses, may retain residual disease causing activity. Further, vaccines typically are reformulated each year in response to antigenic variation and are known to be ineffective against new viral variants.  
         [0008]     Additional disadvantages are that medications typically can be expensive, especially if animals are on antibiotics, for example, over a long course of time, eventually often resulting in an agonizing imminent death of these animals.  
         [0009]     As those skilled in the art would appreciate, there is a need for methods that can decrease the infectivity, morbidity and mortality associated with exposures to such pathogens. Such compositions and methods of treatment should preferably not have the undesirable properties of promoting microbial resistance, or being toxic to the recipient. Still further, there is a need for treatment and prevention in diseases caused by microorganisms that are cost effective and do not take a long period of time. In addition, there is a need to provide treatment of infectious diseases by developing biology based therapies.  
       SUMMARY  
       [0010]     The present invention is directed towards a method and treatment that meets these needs.  
         [0011]     This invention provides a method of treating and preventing mucosal diseases, diseases associated with neuraminidase dependent bacteria and superinfections with a neuraminidase inhibitor.  
         [0012]     In a preferred embodiment, the present invention uses biology based therapy to treat infectious diseases that have been previously treated with antibiotics or antivirals, alone or in combination, with limited success. Where there has been variable success in viruses with antiviral drugs, and antibiotics (conventional therapy), neuraminidase inhibitors according to the present invention have been proven to be successful and predictable. In a most preferred embodiment of the present invention, when neuraminidase inhibitors are used in these same diseases, the results have been dramatic.  
         [0013]     Further, this invention relates to a means for reducing the severity of or preventing a neuraminidase dependent bacterial infection of the mucousal membrane tract following a viral infection by administering an effective amount of a neuraminidase inhibitor alone or in combination with a pharmaceutically acceptable compound prior to or during the course of the neuraminidase dependent bacterial infection, during the course of the superinfection or during the course of the coinfection.  
         [0014]     In one embodiment, the present invention provides methods used for preventing disease or treating animals, including humans, exposed to pathogens or the threat of pathogens.  
         [0015]     In still a further embodiment of the present invention, there is a method used for preventing animals, including humans, from getting a disease associated with the specific pathogen. For example, the animal is contacted with effective amounts of the compositions prior to exposure to pathogenic organisms. In other embodiments, the animal is contacted with effective amounts of the composition after exposure to pathogenic organisms. Thus, the present invention provides a method of both prevention and treatment of microbial infections.  
         [0016]     In preferred embodiments, the present invention provides methods to decrease pathogenic organism infectivity, morbidity and mortality, by using an effective method of treatment where the composition comprises a compound that can include neuraminidase inhibitors.  
         [0017]     In some preferred embodiment, the compound comprising a neuraminidase inhibitor is oseltamivir (Tamiflu).  
         [0018]     In another aspect of the present invention, the composition can include additional compounds, such as antibiotics, for example, which can be used in addition to the compound comprising the neuraminidase inhibitor.  
         [0019]     In specific embodiments of the present invention, the method or treatment is performed for a sufficient amount of time to reduce the virulence factor of the pathogenic bacteria.  
         [0020]     In a most preferred embodiment, the current invention provides a method of using neuraminidase inhibitors to treat: 1) infections involving neuraminidase dependent bacteria other than mucosal surfaces (blackleg, necrotic dermatitis), 2) one or more bacteria involving mucosal surfaces (colibacillosis or enteriopathic  E. coli  in all species, respiratory, renal, uterine, and mammary gland infections involving neuraminidase producing bacteria, Salmonellosis in all species,  Bordetella  and  Pasturella  respiratory infection in all species) and 3) superinfections that do involve mucosal surfaces (gastrointestinal, respiratory in all species).  
         [0021]     In yet another preferred embodiment, the present invention provides a method of using an antiviral drug patented for human influenza to treat neuraminidase dependent bacterial infections, superinfections and coinfections which do not involve the human influenza virus A and/or B, for example, in clinical veterinary medicine.  
         [0022]     In still another preferred embodiment, the present invention provides unexpected results of almost 100% effectiveness when used at 1 mg/lb every 12 hours for 10 treatments for therapeutic use and every 24 hours for 5 treatments for prophylactic use.  
         [0023]     Finally, the present invention provides the use of a neuraminidase inhibitor to treat diseases involving neuraminidase dependent bacteria.  
         [0024]     In the most preferred embodiment of the present invention, oseltamivir (Tamiflu) has been used to treat canine and feline parvoviral enteritis, canine kennel cough, feline upper respiratory infections, feline nephritis secondary to  E. coli , and parvoviral enteritis in raccoons. Given the unique and universal role that sialic acid is known to play in infectious diseases involving neuraminidase dependent bacteria, the concept in the use of a neuraminidase inhibitor would be successful in treating all diseases involving these bacteria regardless of animal species is expected. Animal includes but is not limited to human beings, canine, feline, bovine, equine, avian, porcine and any other species known to those skilled in the art, for example, sheep goats and rabbits. 
     
    
     DESCRIPTION  
       [0025]     According to the present invention, there is provided novel uses of selective neuraminidase inhibitors effective in shortening or stopping the pathophysiology of diseases involving one or more pathogens that require neuraminidase as a virulence factor.  
         [0000]     Neuraminidase  
         [0026]     Neuraminidases, (also known as sialidases) are known to those skilled in the art as enzymes that have been identified in many viruses, bacteria and eukaryotes that cleave sialic acid moieties and can be involved in many functions in vivo. It has been shown that neuraminidases can play a significant role in the pathogenesis of infectious diseases, whose etiologic agents produce neuraminidase to cleave sialic acids in infected tissues to facilitate their ability to invade a host. It has been shown that there is a positive correlation between the level of production of sialidases and the virulence of various bacterial strains. This virulence is further enhanced by different bacteria being able to produce more than one sialidase. Thus, many disease causing microorganisms possess a neuraminidase.  
         [0027]     One example of a neuraminidase inhibitor that has been approved for the treatment of human influenza, is oseltamivir (Tamiflu, F. Hoffman-La Roche, Switzerland) and zanamivir (Relenza, Glaxo Wellcome, Inc). Oseltamivir is a synthetic sialic acid analog that has been modified at the C4 position. Synthetic sialic acid analogs, such as oseltamivir have been demonstrated to inhibit the action of neuraminidases. Since their introduction in 1999, zanamivir and oseltmivir have been used successfully to treat human influenza A and B viral infections. In humans, neither zanamivir nor oseltamivir has been demonstrated to be effective in preventing serious influenza-related complications, such as bacterial or viral pneumonia or exacerbation of chronic diseases. Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent.  
         [0028]     In some pathogens, including many enteric bacteria, neuraminidases typically are recognized as virulence factors. Neuraminidases cleave terminal sialic acid residues from cell surface molecules such as glycoproteins and glycolipids. As a result of this cleavage, internal sugar residues can be exposed that are normally protected and not available to pathogens. Neuraminidase activity can be particularly important for bacterial adhesion to mucosal surfaces. Mucous typically is highly sialylated and can be a major component of innate mucosal immunity. In mucosal diseases, commensal bacteria are separated from epithelial cells by a mucous barrier. Pathogenic bacteria have been shown to produce sialidases which can decrease the viscosity of the mucous and thus enable the bacteria to colonize on the epithelial cell membrane. Once in contact with the epithelial cell, a pathogen can become attached. With bacterial colonization and proliferation, there can be detachment and depletion of immunoglobin IgA. Bacterial endotoxins and exotoxins can be released resulting in local and distant tissue damage. Bacterial neuraminidases (sialidases) can cause the dissolution of the neuraminic acid located within the intercellular cement of the epithelial cells, allowing bacteria, their endotoxins, exotoxins and any environmental free sialic acid to enter the submucosa.  
         [0029]     According to the present invention, it is known to those skilled in the art, the mechanism of hydrolyses of sialic acid compound during neuraminidase inhibition and pathogens that use sialic acid, is fully described and incorporated herein by reference in its entirety (Vrim et al., Microbiology and Molecular Biology Reviews, March 2004, p. 132-153).  
         [0030]     A definitive role of neuraminidase activity in, for example, canine parvoviral infections, has not been established and it is thought that canine parvovirus does not have a neuraminidase in its genome. However, in one preferred embodiment of the present invention, it has been found that it is not essential for canine parvovirus to contain or utilize neuraminidases in order for them to enhance pathogenicity. Neuraminidases have been known to demonstrate enhanced pathogenicity in a synergistic fashion in several viral and bacterial superinfections involving mucosal surfaces. In some cases, for example, pneumococcal pneumonia secondary to influenza, viral neuraminidase activity enhanced the adhesion of the bacteria to the mucosal surface that resulted in increased bacterial invasion into tissues and resistant bacterial superinfection. Neuraminidases of bacterial origin alone are known as vitally important virulence factors.  
         [0031]     The present invention provides the use of neuraminidase inhibitor to treat diseases involving neuraminidase dependent bacteria. Evidence to support this theory includes the following. It is known that the Fulani Pastoralists of rural Nigeria prevented blackleg infections in their cattle by feeding them the stem bark from two plants ( Tamarindus indicus  and  Combretum fragrans ). These plants contained neuraminidase inhibitors in their stem bark. Blackleg is a lethal disease in cows caused by a neuraminidase dependent bacteria  Clostridium chauvoei . In one preferred embodiment of the present invention, it has been demonstrated that bacteria must be present in the disease causing microorganism, for example, parvovirus infection, to result in significant pathology. Typically, germ free animals do not demonstrate any of the clinical disease that is seen in normal animals when they are challenged with virulent parvovirus strains. The pathology is thought to be attributed to septicemia and endotoxemia and is believed to originate from enteric bacteria. Several enteric bacterial species are known to have neurminidase activity including  Escherichia coli, Campylobacterium, Salmonella, Shigella, Staphylococcus  and  Clostridium . From the list, at least two of these species,  E. coli  and  Clostridium , have been associated with morbidity and mortality in dogs with parvovirus.  
         [0032]     In addition, germ-free kittens and germ-free puppies when exposed to pathogenic strains of feline and canine parvovirus, did not develop any clinical signs. It is known to those skilled in the art that the commensal microflora of puppies contains neuraminidase dependent bacteria ( Strep., E. coli, Staph., Clostridium, peptostreptococci, lactobacilli ). According to the present invention, it has been shown that  E. coli  and  Clostridium  have been associated with morbidity and mortality in dogs with parvovirus. In addition, neuraminidases have been demonstrated to enhance pathogenicity in a synergistic fashion in some viral and bacterial superinfections involving mucosal surfaces. Still further, the role of sialic acid metabolism in commensal and pathogenic strains of neuraminidase dependent bacteria provides support for the methods used in accordance with the present invention. Further evidence supporting the role of neuraminidases in infectious diseases includes knowing that the histopathological lesions associated with canine parvoviral enteritis were typical of those created by bacterial septicemia and endotoxemia.  
         [0033]     In addition, most if not all of these commensal bacteria produce neuraminidase in order to provide sialic acid to use in their metabolic pathways. When canine parvovirus exits an infected gastrointestinal (GI) epithelial cell, sialic acid is released into the GI tract. The commensal bacteria begins to colonize and proliferate and produce their own neuraminidase. This excess neuraminidase can provide additional sialic acid and can also dissolve the neuraminic acid in intercellular cement providing a portal to submucosal tissue. In addition, neuraminidase can also displace epithelial cells&#39; IgA.  
         [0034]     Interleukin-8 is known as a cytokine produced by many cell types including endothelial cells, fibroblast, respiratory epithelial cells, macrophages and PMNs. With the release of IL-8, the PMNs can mobilize intracellular sialidases that move to their cell membrane and causes the release of sialic acid from the membrane surface. The removal of sialic acid residues from the PMN&#39;s cell membrane allows them to attach to the endotheial cell wall and move by diapedesis towards the tissues containing high levels of IL-8.  
         [0035]     High levels of neuraminidase can also stimulate dendritic cells to interact with macraphages. Both CD4 and CD8 lymphocytes can also be stimulated to produce Th1 and Th2 cytokines.  
         [0036]     Thus, in a preferred embodiment of the present invention, canine and feline parvoviral enteritis is shown to be a superinfection (requiring a virus+neuraminidase dependent bacteria living on a mucous substrate). The pathology seen at necropsy is solely due to endo and exotoxins produced by the commensal bacteria turned pathogenic. In a preferred embodiment of the present invention, parvoenteritis is not known as a viral disease, but that the pathobiology is due to excess neuraminidase. Thus, when a neuraminidase inhibitor like Tamiflu is administered early in the course of the disease or as a prophylactic, one can prevent the production of neuraminidase (sialidase) and one can prevent the commensal bacteria from becoming pathogenic. As used herein, “neuraminidase dependent bacteria” includes “neuraminidase producing bacteria.” 
         [0037]     In still yet another preferred embodiment of the present invention, the neuraminidase inhibitors can be used to target neuraminidase dependent bacterial infections, superinfections, and coinfections and not dependent on viral neuraminidase.  
         [0038]     In one preferred embodiment of the present infection, “superinfection”, as used herein, means that an infection requires both virus and bacteria combined together to produce pathology more severe than either can alone.  
         [0039]     “Coinfection”, as used herein, means two or more different bacterial strains together to produce pathology of a disease more severe than either can alone.  
         [0040]     As used herein, the term “pathogen” refers to a microbe producing one or more virulence factors of which neuraminidase is one of. According to the present invention, the difference between pathogen and commensal bacteria is that commensal bacteria are not producing neuraminidase as virulence factors.  
         [0041]     By the term “animal”, as used herein, can be any animal species, including a human being, who is infected with, or is likely to be infected with, microorganism producing disease, which are believed to be pathogenic. Animal includes but is not limited to human beings, canine, feline, bovine, equine, avian, porcine and any other species known to those skilled in the art, for example, sheep goats and rabbits.  
         [0042]     The inhibitors of interest in this invention are neuraminidase dependent bacteria inhibitors. Of particular interest are those which are specific for the neuraminidase enzyme. Since many commensal and pathogenic bacteria also used environmental (hosts) sialic acids as sources of carbon, nitrogen, energy and amino sugars for cell wall synthesis, microbial sialic acid metabolism has been established as a virulence determinant in a range of infectious diseases. Both commensal and pathogen bacteria have been known to modify their cell membranes with sialic acids in order to masquerade as “self” to avoid, obvert or inhibit host&#39;s innate immunity. Dehydration at the sialic acid reducing ends, leading to formation of a planar structure known as N-acetyl-2,3-didehydro-2-deoxyneuraminic acid (diddeoxyNeu5Ac [Neu5Ac2en]. The flattened Neu5Ac2en ring mimics the transition state during hydrolysis of sialoglycoconjugates (Sia-O-acceptors) by glycosylhydrolases designated sialidases (synonymous with neuraminidase). Neu5Ac2en is typically known as a sialidase or neuraminidase inhibitor. In particular, a preferred group of inhibitors are those neuraminidase inhibitors which are similar in structure to Neu5Ac2en. For example, Neu5Ac2en has been known to those skilled in the art, to serve as the lead compound for synthesis of one of the most well known sialidase inhibitor, zanamivir (Relenza). Most preferably, the neuraminidase inhibitors according to the present invention are those compounds that hydrolyze sialic acid.  
         [0000]     Treatment  
         [0043]     According to one embodiment of the present invention, an effective amount of compound, preferably a neuraminidase inhibitor can be administered to an animal. Typically, when a parvovirus infected animal presents symptoms such as vomiting/nausea and pain, traditional treatment involves administering fluids and cortisone for shock, antibiotics therapy and medicine for pain. In addition, anti-emetics can be administered to help alleviate nausea and vomiting.  
         [0044]     The neuraminidase inhibitor can be administered in several ways: i) at the start of or during the course of the neuraminidase dependent bacterial infection, or some part thereof; or ii) at the start of or during the course of a superinfection infection or some part thereof; or iii) at the start of or during the course of a coinfection or some part thereof. In addition, the inhibitor can be administered prior to the onset of a neuraminidase dependent bacterial infection, superinfection or coinfection, and preferably continued for some period during the course of the bacterial infection, superinfection or coinfection. In a most preferred embodiment of the present invention, the neuraminidase inhibitor can be administered during the entire, or part of the length of a bacterial infection, a superinfection or a co-infection.  
         [0045]     Most preferably, the neuraminidase inhibitor is administered within 48 hours of onset of first clinical signs.  
         [0046]     By the term “an effective amount” is meant an amount of the compound in question which will in a majority of animals have either the effect that the disease caused by the pathogenic bacteria is cured or, if the substance has been given prophylactically, the effect that the disease is prevented from manifesting itself. The term “an effective amount” also implies that the substance is given in an amount which only causes mild or no adverse effects in the animal to whom it has been administered, or that the adverse effects may be tolerated from a medical and pharmaceutical point of view in the light of the severity of the disease for which the substance has been given.  
         [0047]     For the purposes of this invention, it is preferred to administer an effective amount of the neuraminidase inhibitor in an amount from about 0.6 mg/lb to 12 mg/lb, more preferably 0.3 mg/lb to 10 mg/lb, and most preferably 1 mg/lb of the active ingredient. Too high a dose of neuraminidase inhibitor can be toxic. Too low of a dose may not be effective enough to treat or prevent the neuraminidase dependent disease.  
         [0048]     The neuraminidase inhibitor can be administered by any route. The route of administration of the substance could be any conventional route of administration, i.e. oral, intravenous, intramuscular, intradermal, subcutaneous etc. A preferred formulation will be the oral route; oral immediate release tablet or an oral controlled release tablet. For treatment of a disease caused by a microorganism, the neuraminidase inhibitor can be administered up to 6 times per day, though twice or once a day dosing regime is preferred. More preferably, 10 doses over a period of 5 days. Most preferably, 6 doses over a period of 3 days or until the animal&#39;s health improves.  
         [0049]     In yet another preferred embodiment of the present invention, for prevention of a disease caused by a microorganism, the neuraminidase inhibitor can be administered once a day for 5 days. Typically, with animals infected with parvovirus, administering the neuraminidase inhibitor with the first dose will stop the vomiting. After the 2 nd  dose, the diarrhea will cease. By the 6 th  dose, most clinical signs of the infection will have ceased.  
         [0050]     In one preferred embodiment, a composition can be administered to an animal, the composition comprising a compound. The compound preferably is a selective neuraminidase inhibitor. More preferably, the compound is a neuraminidase inhibitor which is selective towards neuraminidase dependent bacteria. Preferably, the neuraminidase inhibitor can be selected from the group consisting of zanamivir (Relenza, Claxo Wellcom Inc), oseltamivir (Tamiflu, F. Hoffmann La Roche, Switzerland), rimantadine, rimantadine hydrochloride, amantadine, ribavirin and the like and any drug that are synthetic sialic acid analogs that can inhibit action of viral, bacterial and eukaryotic neuraminidases. Most preferably, the compound is a neuraminidase inhibitor that is oseltamivir. Oseltamivir (Tamiflu®) is available from Roche Pharma™ AG (Switzerland). Alternatively, oseltamivir can be prepared according to the methods described in U.S. Pat. No. 5,763,483 to Bischofberger et al and U.S. Pat. No. 5,866,601 to Lew et al., the disclosures of which are hereby incorporated by reference.  
         [0051]     While the administration of neuraminidase inhibitor as the sole compound of the composition is most preferred, one or more of these neuraminidase inhibitors can be combined with other compounds for treating bacterial infections, superinfections and coinfections. For example, a neuraminidase inhibitor could be co-administered with a treatment during the course of the neuraminidase dependent bacterial infection. Examples of drugs that can also be used in combination with one or more other compounds without limitation, are anti-infective agents and/or other agents used to treat other acute or chronic ailments which include, antimicrobial compounds (such as antibiotics), antiviral compounds, anticancer compounds, vitamins, trace metal supplements, or ionic buffers designed to maintain or correct proper ionic balance in blood or other tissues, such drugs are alpha and beta interferon, Inosine pranobex, moroxydine hydrochloride and the like. If antibiotics are used, preferably, the antibiotic is selected from the group consisting of penicillins, benzylpenicillin, amoxycillin, ampicillin, cephalosporins, erythromycin and co-trimoxazole.  
         [0052]     Appropriate dose ratio between a compound of the present invention and a second therapeutic compound for co-administration to an animal will be readily appreciated by those skilled in the art. Clearly, the combination therapies described herein are merely exemplary and are not meant to limit possibilities for other combination treatments or co-administration regimens.  
       EXAMPLES  
       [0053]     The following examples show the importance of neuraminidase dependent bacteria in mucosal infections in several animal species.  
                                                 TABLE 1                           Neuraminidase Dependent Bacteria and Veterinary Diseases            Bacteria spp:   Dog   Cat   Cow   Pig   Horse   Avian   Other                 Actinobacillus     +   +   +   +   +                 Actinomyces     +   +   +   +   +   +   +         Aeromonas     +       +   +       +   +         Bacteroides     +   +   +   +   +       +         Bordetella     +   +       +   +   +   +         Brucella     +   +   +   +   +       +         Campylobacter     +   +   +   +   +   +   +         Clostridium     +   +   +   +   +   +   +         Corynebacterium     +   +   +   +   +   +   +         Enterobacter     +   +   +   +   +         E. coli     +   +   +   +   +   +   +         Erysipelothrix     +   +   +   +   +   +   +         Fusobacterium     +   +   +   +   +   +         Klebsiella     +   +   +   +   +         Pasturella     +   +   +   +   +   +   +         Mannheimia             +               +         Peptostreptococcus     +   +   +   +   +   +         Proteus     +   +   +   +   +   +   +         Pseudomonas     +   +   +   +   +   +   +         Rhodococcus         +           +         Salmonella     +   +   +   +   +   +   +         Serratia     +   +   +   +   +   +   +         Shigella     +   +   +   +   +       +         Staphlococcus     +   +   +   +   +   +   +         Streptococcus     +   +   +   +   +   +   +         Vibrio                         +   +         Haemophilus     +   +   +   +   +   +   +         Arcanobacterium     +   +   +   +           +                  
 
         [0054]     Neuraminidase dependent bacteria are those known to use sialiac acid (neuraminic acid) either as a source for carbon, nitrogen, energy and amino acids for cell wall synthesis. This microbial sialic acid metabolism is known to be a virulence factor in a number of infectious diseases. Tables (9-14) representing specific diseases in the various species are included.  
                                     TABLE 2                           Superinfections in Veterinary Medicine            Species:   Disease   Virus   Bacteria   Other                 Canine     Parvoviral Enteritis   Canine Parvovirus     Clostridium       Salmonella                 CPV-2b &gt; CPV-2a     E. coli       Peptostreptococcus                       Streptococcus                       Staphylococcus             Tracheobronchitis   Canine Adenovirus-1     Bordetella bronchiseptica       Streptococcus             (Kennel Cough)   Canine Adenovirus-2         Pasturella                 Canine Parainfluenza         Pseudomonas                           Klebsiella                           E. coli           Feline     Parvoviral Enteritis   Feline Parvovirus     Clostridium             (Panleukopenia)         E. coli                       Streptococcus                       Staphylococcus                       Peptostreptococcus         URI   Feline Rhinotracheitis   Feline Herpesvirus-1     Bordetella bronchiseptica       Streptococcus         Complex                 Pasturella                           Pseudomonas             Feline Calicivirus   Feline Calicivirus     Bordetella bronchiseptica       Klebsiella                           E. coli                           Chlamydia           Bovine     Enzootic Pneumonia   Parainfluenza-3 (Pi-3)     Pasturella multocida       Mycoplasma dispar                 Bovine Respiratory     Arcanobacterium       Mycoplasma bovis                 Syncytial Virus (BRSV)     pyognes       Ureaplasma                 Bovine Herpes-1     Haemophilus somnus       Chlamydia                 Reoviruses     E. coli                 Rhinoviruses           Shipping Fever or   Pi-3     Mannheimia haemolytica       Pasteurella multocida             Pneumonic pasteurellosis   BRSV               BHV-1           Infectious Bovine   Bovine Herpes-1     Mannheimia haemolytica       Pasteurella multocida             Rhinotracheitis (IBR)           Bovine Viral Diarrhea   BVD-1     Clostridium                 BVD-2     E. coli                       Streptococcus                       Staphylococcus                       Peptostreptococcus           Porcine     Swine Influenza   Swine Influenza-A     Pasturella multocida       Arcanobacterium                           pyogenes                           Haemophilus             Inclusion Body Rhinitis   Porcine Cytomegalovirus     Bordetella bronchiseptica             (Atrophic Rhinitis)   (PCMV)     Pasturella multocida             Porcine Reproductive   PRRSV     Streptococcus suis             and Respiratory Syndrome         Haemophilus parasuis             (PRRS)         Arcanobacterium suis                       E. coli             Transmissible   TGEV     E. coli       Streptococcus             Gastroenteritis (TGE)         Clostridium       Staphlococcus           Equine     Equine Influenza   EIV-1     Streptococcus                 EIV-2     zooepidermicis                       Staphlococcus aureus           Avian         Chicken   Infectious Bronchitis   IBV   Respiratory  E. coli         Turkey   Hemorrhagic Enteritis     Adenovirus     Enteropathic  E. coli                     Enteropathic  E. coli             Poult Enteritis   Coronavirus   Enteropathic  E. coli           Ovine     Pneumonic Pasturellosis   ORSV     Mannheimia haemolytica       Pasturella multocida                 Pi-3               Adenovirus               Reovirus                  
 
         [0055]     Table 2 represents a partial list of infectious diseases in veterinary medicine known to be superinfections. Superinfections are those diseases requiring at least 2 different infectious microbes, that together produce a disease that neither are capable of doing alone. In these cases, one or more virus are associated with one or more neuraminidase dependent bacteria.  
         [0056]     Feline Parvovirus and Upper Respiratory Complex and canine Parvoviral Enteritis and Tracheobronchitis have proven to be responsive to neuraminidase inhibitors. There is no reason, the other superinfections will not respond in the same manner.  
                                                                                   TABLE 3                           Parvo Cases at Chihuahua Kennel            Case               Parvo   IV   Tamiflu   Days to       Number   Town State   Breed   Age   Test   Drugs   1 mg/lb   Recover                    1   DC County Loving   Chihuahua   6 wks   (+)   Yes   None   Died       2   Kennel, Purdon, TX   Chihuahua   6 wks   No   Yes   None   Died       3       Chihuahua   6 wks   No   Yes   None   Died       4       Chihuahua   6 wks   No   Yes   None   Died       5       Chihuahua   6 wks   No   Yes   None   Died       6       Chihuahua   6 wks   No   Yes   None   Died       7       Chihuahua   6 wks   No   Yes   None   Died       8       Chihuahua   6 wks   No   Yes   None   Died       9       Chihuahua   6 wks   No   Yes   None   Died       10   Changed Veterinarian   Chihuahua   6 wks   (+)   None   AM/PM   5       11       Chihuahua   6 wks   No   None   AM/PM   3       12       Chihuahua   6 wks   No   None   AM/PM   3       13       Chihuahua   6 wks   No   None   AM/PM   3       14       Chihuahua   6 wks   No   None   AM/PM   3       15       Chihuahua   6 wks   No   None   AM/PM   3       16       Chihuahua   6 wks   No   None   AM/PM   3       17       Chihuahua   6 wks   No   None   AM/PM   3       18       Chihuahua   6 wks   No   None   AM/PM   3       19       Chihuahua   6 wks   No   None   AM/PM   3       20       Chihuahua   6 wks   No   None   AM/PM   3       21   Exposed - Preventive   Chihuahua   6 wks   No   None   AM   Healthy       22       Chihuahua   6 wks   No   None   AM   Healthy       23       Chihuahua   6 wks   No   None   AM   Healthy       24       Chihuahua   Adult   No   None   AM   Healthy       25       Chihuahua   Adult   No   None   AM   Healthy       26       Chihuahua   Adult   No   None   AM   Healthy       27       Chihuahua   Adult   No   None   AM   Healthy       28       Chihuahua   Adult   No   None   AM   Healthy                  
 
         [0057]     Table 3 represents 28 Chihuahua dogs and puppies that experienced an outbreak of canine parvoviral enteritis within their kennel. The initial treatment lasted one week and was consistent with traditional therapy. (IV fluids, antibiotics and antiemetics). During the first week, 9 puppies died and a second veterinarian was consulted.  
         [0058]     The second veterinarian removed all IV treatment and started oral Tamiflu and AmoxiDrops on 11 puppies. This treatment was administered by the kennel staff with the veterinarian consulting by phone. All puppies survived with the new protocol.  
         [0059]     The exposed dogs received 1 mg/lb of Tamiflu once a day for 5 days. Although exposed, these dogs remained healthy.  
                                                                                   TABLE 4                           Canine Parvo Cases at Sandcastle Kennels            Case               Parvo   IV   Tamiflu   Days to       Number   Town State   Breed   Age   Test   Drugs   1 mg/lb   Recover                    1   Foyil Oklahoma   Cocker    6 wk   (+)   Yes   None   Died       2       Cocker    6 wk   No   Yes   None   Died       3       Cocker    6 wk   No   Yes   None   Died       4       Cocker    6 wk   No   Yes   None   Died       5       Cocker    6 wk   No   Yes   None   Died       6       Cocker    8 wk   (+)   Yes   None   Died       7       Cocker    8 wk   No   Yes   None   Died       8       Cocker    8 wk   No   Yes   None   Died       9       Cocker    8 wk   No   Yes   None   Died       10   Changed Veterinarian   Cocker    6 wk   (+)   None   AM/PM   3       11       Cocker    6 wk   No   None   AM/PM   5       12       Cocker    8 wk   (+)   None   AM/PM   3       13       Cocker    8 wk   No   None   AM/PM   5       14       Cocker    8 wk   No   Yes   AM/PM   5       15       Cocker   10 wk   (+)   None   AM/PM   3       16       Cocker   11 wk   No   None   AM/PM   3       17       Cocker   12 wk   (+)   None   AM/PM   4       18       Cocker   12 wk   No   None   AM/PM   5       19       Cocker   12 wk   No   None   AM/PM   3       20       Cocker   12 wk   (+)   Yes   AM/PM   4       21       Cocker   14 wk   (+)   None   AM/PM   5       22   Exposed - Preventive   Cocker    7 month   No   None   AM   Healthy       23       Cocker    7 month   No   None   AM   Healthy       24       Cocker   10 month   No   None   AM   Healthy       25       Cocker   10 month   No   None   AM   Healthy                  
 
         [0060]     Table 4 represents of 25 cocker spaniel dogs and puppies that experienced an outbreak of canine parvoviral enteritis within their kennel. The initial treatment lasted one week and was consistent with traditional therapy consisting of IV fluids and antibiotics, antiemetics and steroids. During this period of time, 9 puppies died, and a second veterinarian was consulted.  
         [0061]     The second veterinarian removed all IV treatment and oral Tamiflu and sulfadimethoxine/ormetoprim (antibiotic) were the only drugs administered to 11 of the puppies. The 12th puppy was taken to the veterinarian&#39;s clinic and received IV therapy. Those puppies remaining at the kennel were treated by the kennel staff.  
         [0062]     The exposed dogs received 1 mg/lb of Tamiflu once a day for 5 days and did not develop canine parvoviral enteritis.  
                                                           TABLE 5                           Canine Parvoviral Enteritis Treated With Tamiflu            Case               Parvo   IV   Tamiflu   Days to       Number   Town State   Breed   Age   Test   Drugs   1 mg/lb   Recover               1-10   Pinehurst, NC   Mix   6-12 wks   (+)   None   AM/PM   3 to 5       11   Griffin, GA   Mix   11 wks   (+)   None   AM/PM   3       12       Mix   14 wks   (+)   Yes   AM/PM   2       13       Mix   14 wks   (+)   Yes   AM/PM   2       14   Rockford, IL   GSH    8 wks   (+)   Yes   AM/PM   3       15   Clayton, NC   JRT    7 months   (+)   Yes   AM/PM   5       16   Carthage, NC   Mix   19 wks   (+)   None   AM/PM   3       17       Mix   20 wks   (+)   None   AM/PM   4       18   Apple Valley, CA   Beagle   Pup   (+)   Yes   AM/PM   3       19   Millington, TN   GSH   Pup   (+)   Yes   AM/PM   2       20   Douglas, GA   Basset   12 wks   (+)   Yes   AM/PM   2       21       It. Greyh.   12 wks   (+)   Yes   AM/PM   3       22       Boxer   12 wks   (+)   Yes   AM/PM   3       23   Canton, OH   Rotti-x    6 months   (+)   Yes   AM/PM   2       24   Griffin, GA   Mix   Pup   (+)   Yes   AM/PM   3       25       Mix   Pup   (+)   Yes   AM/PM   3       26       Mix   Pup   (+)   Yes   AM/PM   2       27   Salisbury, MD   Pit Bull-x    6 wks   (+)   None   AM/PM   2       28   Redford, MI   Pit Bull    9 months   Corona   Yes   AM/PM   4       29   Grand Rapids, MI   Mix   Pup   (+)   Yes   AM/PM   3       30       Mix   Pup   (+)   Yes   AM/PM   3       31       Mix   Pup   (+)   Yes   AM/PM   3       32   Bend, OR   Bost. Terr.    6 months   (+)   Yes   AM/PM   2       33   Mishawaka, IN   Eng. Sett.   14 wks   None   Yes   AM/PM   4       34   Vancouver, WA   Rotti    8 wks   (+)   Yes   AM/PM   5       35   Atlanta, GA   Mix    7 wks   (+)   Yes   AM/PM   3       36   Jonesboro, AR   Min. Sch.    6 months   (+)   Yes   AM/PM   2       37       Beagle-x    5 months   (+)   Yes   AM/PM   4       38   Columbia, MO   Mix   Pup   (+)   Yes   AM/PM   3       39   Ocoee, FL   Shar Pei    4 months   (+)   None   AM/PM   2       40   Mishawaka, IN   Mix   14 wks   (weak)   Yes   AM/PM   4       41       Mix    4 months   (+)   Yes   AM/PM   3       42       Mix   12 wks   (+)   Yes   AM/PM   3       43   Atlanta, GA   Mix   10 wks   (+)   None   AM/PM   3       44       Gold. Ret.    8 wks   (+)   Yes   AM/PM   2       45   Los Angeles, CA   St. Ber.mix   10 wks   (+)   None   AM/PM   2       46-48   Garden City, KS   Lab    6 months   (+)   None   AM/PM   3           (exposed)   B. CollieX   12 weeks   (weak)   None   AM/PM   Normal               B. CollieX   12 weeks   (+)   None   AM/PM   4                 Summary:               States   15       DVMS   20       Puppies   48          
 
         [0063]     Table 5 represents 48 individual cases of Canine Parvoviral Enteritis treated with 1 mg/lb Tamiflu AM/PM for 10 treatments. Cases posted VIN&#39;s Infectious Dz Board by 20 veterinarians practicing in 15 states.  
                                                 TABLE 6                           Feline Parvoenteritis Treated with Tamiflu            Case               Parvo   IV   Tamiflu   Days to       Number   Town State   Breed   AgeSex   Test   Drugs   1 mg/lb   Recover               1   Smithfield, NC   Siamese    5 M/m   (+)   Yes   AM/PM   2       2       Siamese    5 M/fem   (+)   Yes   AM/PM   3       3   Alberta, Canada   DSH   14 wk/m   no WBCs   Yes   AM/PM   3       4   (Exposed)   DSH   20 wk/fem   condomate   None   AM   Normal       5   Phoenix, AZ   DSH   10 wk/fem   (+)   SQ fluids   AM/PM   4       6       DSH   10 wk/fem   (+)   SQ fluids   AM/PM   4                  
 
         [0064]     Table 6 represents 5 cases of Feline Parvoviral Enteritis with Tamiflu at 1 mg/lb AM/PM for 10 treatments. One kitten exposed, remained normal when given Tamiflu at 1 mg/lb once a day for 5 days.  
                                                 TABLE 7                           Raccoon Parvoenteritis/Distemper Treated with Tamiflu            Case               Parvo   IV   Tamiflu   Days to       Number   Town State   Breed   Age   Test   Drugs   1 mg/lb   Recover               1   Hudson, IL   Raccoon   Adult/Male   none   none   AM/PM   3       2       Raccoon   Adult/Fem   none   none   AM/PM   3       3   Chiefland, FL   Raccoon   Adult   none   none   AM/PM   3       4       Raccoon   Adult   none   none   AM/PM   3       5       Raccoon   Adult   none   none   AM/PM   3                  
 
         [0065]     Table 7 represents 5 raccoons treated with Tamiflu at 1 mg/lb given every 12 hrs for 10 treatments. Treatment administered by civilian rehabbers at their homes. Granules mixed with pancake syrup.  
         [0066]     Raccoons represent the 5th species (cow, dog, cat, mice) in which a neuraminidase inhibitor has been successful in treating or preventing a disease associated with neuramimidase dependent bacteria. Before using Tamiflu, the hemorrhagic gastroenteritis (Parvo) in raccoon was 100% fatal. While the numbers are small they are significant as they prove the pathobiology seen in hemorrhagic gastroenteritis of raccoon is neuraminidase driven. Treatment was administered by untrained lay personnel at the rehab centers.  
                                                                                                                                                                                                                                                 TABLE 8                           Canine Kennel Cough Cases Treated With Tamiflu            Case               Oral   Cough   Tamiflu   Days to       Number   Town State   Breed   Age   Antibiotic   Suppressant   AM/PM   Recover                    Holding Kennels for Pet Stores       1 mg/lb                11-175   Lynbrook, NY   Mixed    8-12 wks   Doxy   None   AM/PM   3-5 days       1-65   New Hyde Park, NY   Mixed    8-12 wks   Doxy   None   AM/PM   3-5 days       1-60   Lawrence, NY   Mixed    8-12 wks   Doxy   None   AM/PM   3-5 days            Racing Greyhounds at Race Tracks       1 mg/lb                1, 2, 3   Miami, Florida   Greyhound   1.5-4 yr.   None   None   AM/PM   3-5 days       1-46   Group A   Greyhound   1.5-4 yr.   Doxy   Dextromet   none   No Change       1-46   Group B   Greyhound   1.5-4 yr.   Cephalexin   Torbutrol   none   No Change       1-47   Group C   Greyhound   1.5-4 yr.   Clamamox   Hycodan   none   No Change            ***After 5 days, DVM stopped antibiotics and cough suppressants and started Tamiflu            1-46   Group A   Greyhound   1.5-4 yr.   None   None   AM/PM   3-5 days       1-46   Group B   Greyhound   1.5-4 yr.   None   None   AM/PM   3-5 days       1-47   Group C   Greyhound   1.5-4 yr.   None   None   AM/PM   3-5 days       1-70   Kan. City, Kansas   Greyhound   1.5-4 yr.   Doxy   None   AM/PM   3-5 days            ***Track Veterinarian had to use 0.5 mg/lb due to cost   0.5 mg/lb                1-72   Mobile, Alabama   Greyhound   1.5-4 yr.   Pen - G   None   (+)   5-10 days                  
 
         [0067]     Infectious Canine Tracheobronchitis (ICT) or Kennel Cough is a highly infectious superinfection spread by aerosol droplets. The 3 holding kennels represent the first attempt at a herd health plan. The sick dogs were given Tamiflu at 1 mg/lb AM/PM for 5 days. They recovered in 3-5 days. Those not showing clinical signs and any new puppy entering the kennel were given 1 mg/lb once a day for 5 days. This program reduced illness to below 5 percent, and cost of veterinary care by over 75%.  
         [0068]     Kennel Cough outbreaks at Greyhound racing tracks result in the tracks being closed. In Miami, a total of 142 dogs became infected with ICT. They were separated into 4 groups: Group A,B and C received a different combination of antibiotic/cough suppressant. Three dogs were given Tamiflu at 1 mg/lb AM/PM for 10 treatments. Groups A,B and C&#39;s clinical course was unchanged after 5 days of conventional therapy. Started Tamiflu, and dogs recovered in 3-5 days.  
         [0069]     The Miami experiment was the basis for treatment during a similar ICT outbreak at a Kansas City track.  
         [0070]     Cost of Tamiflu was a factor during an ITC outbreak in Mobil, Ala. They The DVM decided to give half the recommended dose (0.5 mg/lb). The results were better than conventional, but longer than when the recommended dose is used. This trial demonstrates that the response is dose related.  
                                     TABLE 9                           Neuraminidase Dependent Bacteria and  Canine  Diseases            Bacteria spp:   Respiratory   Urogenital   Gastrointestinal   Other                 Actinomyces     Pyothorax           Deep Wounds           Peritonitis         Aeromonas                 Septicemia         Bacteroides                 Bone Infect.         Bordetella     Kennel Cough           Distemper           Upper Resp. Infect.         Brucella         Abortion               Infertility         Campylobacter             Gastroenteritis         Clostridium             Gastroenteritis   Tetnus                   Parvoenteritis   Botulism         Corynebacterium           Enterobacter           E. coli     Upper Respiratory   Pyometra   Colibacillosis           Pneumonia   Mastitis   Parvoenteritis               Renal Infections               Cystitis         Erysipelothrix                 Endocarditis         Fusobacterium           Klebsiella     Upper Respiratory           Pneumonia               Cystitis         Pasturella     Upper Respiratory           Pneumonia         Peptostreptococcus                 Abscesses         Proteus         Upper and Lower   Gastroenteritis   Otitis               Urinary Tract         Pseudomonas     Upper Respiratory   Pyometra       Otitis           Pneumonia   Cystitis       Dermatitis         Rhodococcus           Salmonella             Gastroenteritis         Serratia           Shigella             Gastroenteritis         Staphlococci     Upper Respiratory   Pyometra       Otitis           Pneumonia   Mastitis       Dermatitis               Cystitis         Streptococci     Pneumonia   Pyometra   Parvoenteritis   Septicemia               Mastitis       Puppy Strangles               Cystitis         Haemophilus           Arcanobacterium                    
 
         [0071]     Table 9 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the dog.  
                                     TABLE 10                           Neuraminidase Dependent Bacteria and  Feline  Diseases            Bacteria spp:   Respiratory   Urogenital   Gastrointestinal   Other                 Actinomyces     Pyothorax           Abscess           Peritonitis         Aeromonas           Bacteroides     Emphyema           Abscess         Bordetella     Upper Respiratory           Pneumonia         Brucella           Campylobacter             Gastroenteritis         Clostridium             Gastroenteritis   Tetnus                   Panleukopenia       Corynebacterium         Enterobacter           E. coli         Pyometra   Colibacillosis               Mastitis   Panleukopenia               Renal Infections               Cystitis         Erysipelothrix           Fusobacterium           Klebsiella     Upper Respiratory           Pneumonia               Cystitis         Pasturella     Upper Respiratory           Pneumonia         Peptostreptococcus           Proteus                 Otitis         Pseudomonas     Upper Respiratory   Pyometra       Otitis           Pneumonia   Cystitis       Abscess         Rhodococcus     Pyothorax           Abscess         Salmonella             Gastroenteritis         Serratia           Shigella             Gastroenteritis         Staphlococci     Upper Respiratory   Pyometra       Otitis           Pneumonia   Mastitis       Dermatitis               Cystitis         Streptococci     Pneumonia   Pyometra   Panleukopenia   Septicemia               Mastitis               Cystitis         Haemophilus           Arcanobacterium                    
 
         [0072]     Table 10 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the cat.  
                                                                                                                             TABLE 11                           Neuraminidase Dependent Bacteria and  Bovine  Diseases            Bacteria spp:   Respiratory   Urogenital   Gastrointestinal   Other                 Actinomyces     Pneumonia   Mastitis       “Lumpy Jaw”               Endometritis       Arthritis               Umbilical Infections       Endocarditis               Seminal Vesiculitis       Abscess         Aeromonas         Mastitis         Bacteroides         Mastitis   Gastroenteritis   Foot Rot                       Osteomyelitis         Brucella         Abortion               Orchitis         Campylobacter         Epizootic Infertility               Embryonic Death               Abortion         Clostridium         Gangrenous Mastitis   Enterotoxaemia   Tetanus                       Botulism                       Blackleg                Maligant Edema                Gas   Gangrene                Bacillary Haemoglobinuria              Corynebacterium         Pyelonephritis                       Cystitis               Mastitis         Enterobacter         Coliform Mastitis         E. coli         Mastitis   “White Scours”   Septicemia                   Colibacillosis   Joint III         Fusobacterium     Calf Diphtheria   Mastitis   Liver Abscess in Feedlot               Metritis   Hepatic Necrobacillosis         Klebsiella         Mastitis         Pasturella     “Shipping Fever”           Hemorrhagic           “Enzootic Pneumonia”           Septicemia                Fibrogranulomatous Disease              Peptostreptococcus         Summer Mastitis                 Proteus             Enteritis         Pseudomonas     Focal Pneumonia   Mastitis   Enteritis   Dermatitis               Uterine Infections       Abscess                       Arthritis         Salmonella         Abortion   Enteritis   Septicaemia                       Meningitis                       Joint III         Serratia         Mastitis       Dry Gangrene                       in Calves         Staphlococci         Mastitis               Udder impetigo         Streptococci         Mastitis/Metritis         Haemophilus     Pneumonia         Arcanobacterium     Pneumonia   Mastitis   Liver Abscess   Foot Rot                  
 
         [0073]     Table 11 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the cow.  
                                                                                                                                                                                                                                                                                                                         TABLE 12                           Neuraminidase Dependent Bacteria and  Porcine  Diseases            Bacteria spp:   Respiratory   Urogenital   Gastrointestinal   Other                 Actinomyces     Pneumonia   Pyogranulomatous       Arthritis                Mastitis   Lymphadenitis                    Endometritis                       Umbilical Infections               Seminal Vesiculitis         Aeromonas             Diarrhea         Bacteroides             Diarrhea in Piglets   Abscess         Bordetella     Atrophic Rhinitis                Bronchopneumonia in Young Piglets                  Brucella         Abortion       Arthritis               Orchitis       Spondylitis               Infertility         Campylobacter         Intestinal Adenomatosis   Diarrhea         Clostridium                 Tetnus                       Botulinum                Black Leg           Maligant Edema           Hemorrhagic Enterotoxemia              Corynebacterium         Pyelonephritis                 Enterobacter         Mastitis-Metritis               Agalactia Complex(MMA)         E. coli     Associated with PRRSV   Mastitis   Neonatal Diarrhea   Piglet               Mastitis-Metritis   Colisepticemia   Meningitis               Agalactia Complex(MMA)   Weaning Enteritis   Sudden                       Edema/death              Erysipelothrix     Acute Abortion   “Diamond Skin Disease”               Vegetative Endocarditis               Polyarthritis              Fusobacterium     “Bull-Nose”   Necrotic Enteritis   Liver Abscess              Pasturella     Pneumonia Assoc. w/PRRSV                    Atrophic Rhinitis                     Peptostreptococcus           Pseudomonas     Respiratory Infections   Abortion   Enteritis   Otitis                       Arthritis              Rhodococcus     Cervical Lymphadenitis            1  Salmonella         Hog Cholera                   Chronic Enteritis   Septicemia         Serpulina         Swine Dysentery              Staphlococci     Mastitis   Exudative Epidermitis or           Endometritis   Greasy Pig Disease                Udder Impetigo              Streptococci     Rhinitis, Pneumonia   Lymphadenitis                assoc. w/Porcine Reproductive and Respiratory Syndrome   Arthritis              Haemophilus influenzae     Porcine Reproductive and Respiratory Syndrome                  Arcanobacterium     Pneumonia                  
 
         [0074]     Table 12 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the pig.  
                                                                                                                                                                                                                                                     TABLE 13                           Neuraminidase Dependent Bacteria and  Equine  Diseases            Bacteria spp:   Respiratory   Urogenital   Gastrointestinal   Other                 Actinomyces                 Poll Evil                   Fistulous Withers         Aeromonas           Bacteroides             Diarrhea in Foals   Osteomylitis                Buccal Cavity Lesions              Bordetella     Respiratory Infections             Brucella         Poll Evil                Fistulous Withers              Campylobacter                           Clostridium             Enteritis   Tetanus                       Botulism              Corynebacterium     Ulcerative Lymphangitis              Enterobacter         Metritis             E. coli             Enteritis         Erysipelothrix                Fusobacterium     “Thrush” involving the frog              Klebsiella     Pneumonia in Foals   Metritis   Abscess               Cervicitis         Pasturella     Respiratory Infections           Pneumonia         Peptostreptococcus           Proteus         Kidney infections               Cystitis              Pseudomonas     Lung Abscesses   Metritis   Eye Infections           Glanders       Lymphangitis with ulcers                   along lymphatics(Farcy)              Rhodococcus     Bronchopneumonia                     Salmonella         Abortion   Sever Enteritis   Septicemia         Serratia           Shigella           Staphlococci         Mastitis               Botryomycosis after               Castration              Streptococci     Pneumonia   Endometritis   Foal Lymphangitis                Mastitis   Abscess           Abortion   Strangles                Navel Infections   Purpura Hemorrhagica                Genital Infections         Haemophilus           Arcanobacterium                    
 
         [0075]     Table 13 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the horse.  
                                                                                                                                                                 TABLE 14                           Neuraminidase Dependent Bacteria and  Avian  Diseases            Bacteria spp:   Respiratory   Urogenital   Gastrointestinal   Other                 Actinobacillus                           Actinomyese           Aeromonas                 Septicemia         Bacteroides           Bordetella     Turkey Coryza           Rhinotracheitis           Sinusitis         Campylobacter             Avian Vibrionic Hepatitis         Clostridium             Necrotic Enteritis   Tetanus                   Ulcerative Enteritis   Botulism                Necrotic Dermatitis                            “Struck”         Corynebacterium           Enterobacter           E. coli     Airsacculitis   Ovarian Infection   Peritonitis   Omphalitis           Infectious Bronchitis       Hemorrhagic Enteritis                   Turkey Poult Enteritis                   Colibacillosis                   Coligranuloma in liver                   and intestines         Erysipelothrix                 Spleenitis                Endocarditis                Arthritis              Fusobacterium     Avian Diphtheria secondary to Fowl Pox             Klebsiella                Pasturella     Fowl Plague   Fowl Cholera   Fibrinous           Pasteurellosis       Polyserositis         Peptostreptococcus           Proteus           Pseudomonas           Rhodococcus           Salmonella         Pullorum Disease   Fowl               White Diarrhea   Typhoid                   Paratyphoid         Serratia             Septicemia              Staphlococci     Bumble-Foot                Arthritis           Breast Blister         Streptococci     Septisemia           Endocarditis              Vibrio     Cholera-like Enteric Disease              Haemophilus     Infectious Coryza         Arcanobacterium                    
 
         [0076]     Table 14 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in chickens, turkeys, ducks.  
                                                                                                                                                                                                                                                                                   TABLE 15                           Neuraminidase Dependent Bacteria and Other Species&#39; Diseases       Sheep, Goats and Rabbits            Bacteria spp:   Respiratory   Urogenital   Gastrointestinal   Other                      Actinomyces               Aeromonas           Bacteroides     Contagious Foot Rot                        Enterotoxic Diarrhea             Bordetella     “Snuffles” in Rabbits           Bronchopneumonia           Septicemia         Brucella         Abortion               Epididymitis         Campylobacter         Abortion                Ovine Genital Campylobacteriosis                  Clostridium     Pulpy Kidney Disease   Enterotoxemia   Tetanus           Gangrenous Mastitis   Mucoid Enteritis/Rabbits   Botulism                Maligant Edema                Braxy   Big Head                Hemorrhagic Enterotoxemia           Struck         Corynebacterium     Caseous Lymphadenitis         Enterobacter                E. coli     Mastitis   Colibacillosis               Colisepticemia                “Watery Mouth” in Nenatal Lambs              Erysipelothrix     Septicemia           Arthritis                Endocarditis         Fusobacterium     Foot Abscess           Necrobacillosis of lips and mouth              Klebsiella                           Pasturella     Pleuropneumonia   Mastitis       Septicemia         Peptostreptococcus           Proteus             Diarrhea in Goats. Lambs         Pseudomonas                 Arthritis                Lymphangitis              Rhodococcus                           Salmonella         Abortion in Ewes   Enteritis   Septicemia         Serratia           Shigella           Staphlococci         Mastitis       Dermatitis                       Abscess                Periorbital Eczema           Conjunctivitis              Streptococci     Pneumonia   Chronic Mastitis   Arthritis                   Pericarditis         Haemophilus                Arcanobacterium     Mastitis   Foot Abscess                  
 
         [0077]     Table 15 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated in sheep, goats, rabbits.  
                                                                                                                                     TABLE 16                       Clinical Trial: Tamiflu and  E. coli                                  Veterinarian or Clinic:   Cat Health Clinic   Phone:   (910) 295-2287                Addres:   2212 Midland Road       Pinehurst       NC   28374               Street       City       State   Zip       Patient:   Owner:   Vince and Peggy Meads           Name:   Pinga   Age:   Oct. 19, 1998       Breed:   Siamese                   Sex:   FS            Medical History:         Presented Nov. 22, 2004 for vomiting beginning on Nov. 19, 2004. Blood for CBC/Chem Profile submitted       along with urine for culture sensitivity. Started Zeniquin at 12.5 mg/day dissolved in Rebound electrolyte solution.       Reglan was given for nausea.         When seen on Nov. 24, 2004, was presented on a blanket in lateral recumbancy. Had urinated blood       tinged urine on bedding. Lab reported isolating  E. coli , sensitivity pending. Other abnormal values: BUN       (55 mg/dl), Phos (10.6 mg/dl), Sodium (162 mEq/L), Osm (340 mOs/L and WBC elevated at 19,100. Since Pinga       had gotten progressively worse over the course of antibiotic therapy, and now appeared to be approaching       endotoxic shock Tamiflu was begun at 2 PM.  E. coli  is a neuraminidase dependent bacteria.            Physical Exam:   Temp:   99.9 F.   Pulse:   140/min   Weight:   8.06 lbs.           Resp:       % Dehy:   Slight   Parvo Test:   Not Done                Pinga was presented laying on her side unable to sit or stand.           She had a decreased capillary refilling time and temperature was subnormal.            Tamiflu dose: 1 mg/lb . . . that dose given every 12 hours for a total of 10 treatments            Treatment   Drugs/Fluids   Observations               1st.       Date:   Dissolved 12.5 mg Zeiniquin in 12 cc of   Can not sit or stand, urinated in bed this       Nov. 24, 2004   Rebound and gave PO   morning . . . urine was blood tinged.  E. coli         Temp: 99.8 F.   Gave 12 mg Tamiflu (1 cc)/PO at 2:00 PM   cultured . . . sensitvity pending.       2nd.       Date:   Gave 12 mg Tamiflu (1 cc) at 5:35 PM   Pinga is more alert and has not vomited       Nov. 24, 2004       since receiving Tamiflu. Can not stand,               but can sit upright.       3rd.       Date:   Dissolved 12.5 mg Zeniquin in 12 cc of   No vomiting since starting Tamiflu . . . is       Nov. 25, 2004   Rebound and gave PO   drinking water . . . walked 20 feet and urinated       Temp:   Gave 12 mg Tamiflu/PO at 10:15 AM   a clear yellow colored urine next to litter box.       99.5 F.   Tamiflu and Parvo Clinical Trial   About 1:30 AM, left bed, walked to owne&#39;s               bed, jumped up and began to purr       4th.       Date:   Gave 12 mg Tamiflu/PO at 5:30 PM   Urinated, was normal yellow color . . . has       Nov. 25, 2004       begun to walk around house . . . jumped       Temp:       and ran when attempted to brush . . . Pinga       98.9 F.       is more alert in clinic       5th.       Date:   Dissolved 12.5 mg Zeniquin in 15 cc   Pinga is walking around house . . . slept in       Nov. 26, 2004   Rebound and gave PO at 10:30 AM   owner&#39;s bed . . . refused being given Rebound       Temp:   Gave 12 mg Tamiflu/PO   by syringe . . . comes when called . . . Physical       98.8 F.       exam is normal       6th.       Date:   Gave 12 mg Tamiflu/PO at 5 PM   Urinated normal urine . . . passed 3 small       Nov. 26, 2004       firm BMs . . . jumped up to help iron clothes,       Temp:       vocal . . . First time temperature has been       100.6 F.       above 100 F.       7th.       Date:   Dissolved 12.5 mg Zeniquin in 15 cc   Beginning 3rd day of Tamiflu . . . Pinga is       Nov. 27, 2004   Rebound   more alert . . . began to eat Wellness dry       Temp:   Gave 12 mg Tamiflu/PO at 10:30 AM   cat food . . . had BM in litter box . . . continues       98.8 F.       to be given Rebound via syringe at home       8th.       Date:   Gave 12 mg Tamiflu/PO at 5 PM   Appears to be “normal”, alert, active and       Nov. 27, 2004       interested in surroundings . . . Dispensed       Temp:       CNM-EN as a semi-soft food to try at home       Not Taken       9th.       Date:   Dissolved 12.5 mg Zeniquin in 15 cc   Ate CMN-EN last night, urinated normally,       Nov. 28, 2004   Rebound   almost “normal” . . . maybe weak in rear       Temp:   Gave 12 mg Tamiflu/PO at 10:30 AM   when playing with ball . . . shows interest       100.1 F.       when Jerry is tying shoe strings . . . this is               a normal activity for Pinga       10th.       Date:   Gave 12 mg Tamiflu/PO at 5:30 PM   Pinga appears to be normal . . . this is his       Temp:       last treatment with Tamiflu.       Not Taken                  
 
 Medical History: 
 
         [0078]     Presented Nov. 22, 2004 for vomiting beginning on Nov. 19, 2004. Blood for CBC/Chem Profile submitted along with urine for culture sensitivity. Started Zeniquin at 12.5 mg/day dissolved in Rebound electrolyte solution. Reglan was given for nausea.  
         [0079]     When seen on Nov. 24, 2004, was presented on a blanket in lateral recumbancy. Had urinated blood tinged urine on bedding. Lab reported isolating  E. coli , sensitivity pending. Other abnormal values: BUN (55 mg/dl), Phos (10.6 mg/dl), Sodium (162 mEq/L), Osm (340 mOs/L and WBC elevated at 19,100. Since Pinga had gotten progressively worse over the course of antibiotic therapy, and now appeared to be approaching endotoxic shock Tamiflu was begun at 2 PM.  E. coli  is a neuraminidase dependent bacteria.  
         [0000]     Tamiflu dose: 1 mg/lb . . . . that dose given every 12 hours for a total of 10 treatments  
         [0080]     In Table 16,  E. coli , a neuraminidase dependent bacteria, was cultured from Pinga&#39;s urine followingan acute onset of vomiting and hematuria. She failed to respond to Zeniquin, but had a dramatic reversal when Tamiflu was started on Nov. 24, 2005 when she presented in an endotoxic condition. This case demonstrates the success of Tamiflu in cases of  E. coli  enterotoxemia.  
         [0081]     The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.