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:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This is a continuation of commonly owned U.S. patent application Ser. No. 11/112,138, filed on Apr. 22, 2005, which is hereby incorporated by reference in its entirety for all purposes. 
     
    
     BACKGROUND 
       [0002]    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. 
         [0003]    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. 
         [0004]    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. 
         [0005]    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. 
         [0006]    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. 
         [0007]    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. 
         [0008]    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. 
         [0009]    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. 
         [0010]    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 
       [0011]    The present invention is directed towards a method and treatment that meets these needs. 
         [0012]    This invention provides a method of treating and preventing mucosal diseases, diseases associated with neuraminidase dependent bacteria and superinfections with a neuraminidase inhibitor. 
         [0013]    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. 
         [0014]    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. 
         [0015]    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. 
         [0016]    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. 
         [0017]    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. 
         [0018]    In some preferred embodiment, the compound comprising a neuraminidase inhibitor is oseltamivir (TAMIFLU®, hereinafter referred to as TAMIFLU). 
         [0019]    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. 
         [0020]    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. 
         [0021]    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). 
         [0022]    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. 
         [0023]    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. 
         [0024]    Finally, the present invention provides the use of a neuraminidase inhibitor to treat diseases involving neuraminidase dependent bacteria. 
         [0025]    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 
       [0026]    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. 
       Neuraminidase 
       [0027]    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. 
         [0028]    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., hereinafter referred to an RELENZA). 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 oseltamivir 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. 
         [0029]    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. 
         [0030]    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). 
         [0031]    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. 
         [0032]    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  Combreturn 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 neuraminidase 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. 
         [0033]    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. 
         [0034]    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. 
         [0035]    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. 
         [0036]    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. 
         [0037]    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. 
         [0038]    As used herein, “neuraminidase dependent bacteria” includes “neuraminidase producing bacteria.” 
         [0039]    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. 
         [0040]    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. 
         [0041]    “Coinfection”, as used herein, means two or more different bacterial strains together to produce pathology of a disease more severe than either can alone. 
         [0042]    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. 
         [0043]    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. 
         [0044]    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. 
       Treatment 
       [0045]    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. 
         [0046]    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. 
         [0047]    Most preferably, the neuraminidase inhibitor is administered within 48 hours of onset of first clinical signs. 
         [0048]    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. 
         [0049]    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. 
         [0050]    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. 
         [0051]    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. 
         [0052]    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®, Glaxo Wellcome 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. 
         [0053]    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. 
         [0054]    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 
       [0055]    The following examples show the importance of neuraminidase dependent bacteria in mucosal infections in several animal species. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 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 
                 
                 + 
                 + 
                 + 
                 + 
                   
                   
                 + 
               
               
                   
               
             
          
         
       
     
         [0056]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Superinfections in Veterinary Medicine 
               
             
          
           
               
                 Species: 
                 Disease 
                 Virus 
                 Bacteria 
                 Other 
               
               
                   
               
               
                   
                 Parvoviral Enteritis 
                 Canine Parvovirus 
                 
                   Clostridium 
                 
                 
                   Salmonella 
                 
               
               
                   
                   
                 CPV-2b &gt; CPV-2a 
                 
                   E. coli 
                 
                 
                   Peptostreptococcus 
                 
               
               
                   
                   
                   
                 
                   Streptococcus 
                 
               
               
                 Canine 
                   
                   
                 
                   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 
                 
               
               
                   
                 Feline Rhinotracheitis 
                 Feline Herpesvirus-1 
                 
                   Bordetella bronchiseptica 
                 
                 
                   Streptococcus 
                 
               
               
                 URI 
                   
                   
                   
                 
                   Pasturella 
                 
               
               
                 Complex 
                   
                   
                   
                 
                   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 
               
               
                   
               
             
          
         
       
     
         [0057]    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. 
         [0058]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 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 
               
               
                   
                 Changed Veterinarian 
               
               
                 10 
                   
                 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 
               
               
                   
                 Exposed - Preventive 
               
               
                 21 
                   
                 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 
               
               
                   
               
             
          
         
       
     
         [0059]    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. 
         [0060]    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. 
         [0061]    The exposed dogs received 1 mg/lb of TAMIFLU once a day for 5 days. Although exposed, these dogs remained healthy. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 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 
               
               
                   
                 Changed Veterinarian 
               
               
                 10 
                   
                 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 
               
               
                   
                 Exposed - Preventive 
               
               
                 22 
                   
                 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 
               
               
                   
               
             
          
         
       
     
         [0062]    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. 
         [0063]    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. 
         [0064]    The exposed dogs received 1 mg/lb of TAMIFLU once a day for 5 days and did not develop canine parvoviral enteritis. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 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 
                 Bedford, 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 
               
             
          
         
       
     
         [0065]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 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 
                 1 
                 wk/fem 
                 (+) 
                 SQ fluids 
                 AM/PM 
                 4 
               
               
                   
               
             
          
         
       
     
         [0066]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 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 
               
               
                   
               
             
          
         
       
     
         [0067]    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. 
         [0068]    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 neuraminidase 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. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 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 
                   
               
             
          
           
               
                  1-175 
                 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  
               
               
                   
               
             
          
         
       
     
         [0069]    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%. 
         [0070]    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. 
         [0071]    The Miami experiment was the basis for treatment during a similar ICT outbreak at a Kansas City track. 
         [0072]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 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 
                 
               
               
                   
               
             
          
         
       
     
         [0073]    Table 9 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the dog. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 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 
                 
               
               
                   
               
             
          
         
       
     
         [0074]    Table 10 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the cat. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 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 
               
               
                   
                   
                   
                   
                 Dry Gangrene 
               
               
                 
                   Serratia 
                 
                   
                 Mastitis 
                   
                 in Calves 
               
               
                 
                   Staphlococci 
                 
                   
                 Mastitis 
               
               
                   
                   
                 Udder impetigo 
               
               
                 
                   Streptococci 
                 
                   
                 Mastitis/Metritis 
               
               
                 
                   Haemophilus 
                 
                 Pneumonia 
               
               
                 
                   Arcanobacterium 
                 
                 Pneumonia 
                 Mastitis 
                 Liver Abscess 
                 Foot Rot 
               
               
                   
               
             
          
         
       
     
         [0075]    Table 11 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the cow. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 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 
               
               
                 
                   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 
                   
                   
                 Arthritis 
               
               
                   
                 and Respiratory Syndrome 
               
               
                 
                   Haemophilus influenzae 
                 
                 Porcine Reproductive and 
               
               
                   
                 Respiratory Syndrome 
               
               
                 
                   Arcanobacterium 
                 
                 Pneumonia 
               
               
                   
               
             
          
         
       
     
         [0076]    Table 12 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the pig. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 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 
                 
               
               
                   
               
             
          
         
       
     
         [0077]    Table 13 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the horse. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 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 
                 
               
               
                   
               
             
          
         
       
     
         [0078]    Table 14 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in chickens, turkeys, ducks. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 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 
               
               
                   
               
             
          
         
       
     
         [0079]    Table 15 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated in sheep, goats, rabbits. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
             
               
               
             
               
             
               
               
               
             
           
               
                 TABLE 16 
               
               
                   
               
               
                 Clinical Trial: Tamiflu and  E. coli   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Veterinarian or Clinic: 
                   
                 
                   Cat Health Clinic       
                 
                 Phone: 
                 
                   (910) 295-2287   
                 
               
             
          
           
               
                   
                 Address: 
                 
                   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 11/22/04 for vomiting beginning on 11/19/04. 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 11/24/04, 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 
               
               
                   
               
             
          
           
               
                   
                 Drugs/Fluids 
                 Observations 
               
               
                   
               
               
                 Treatment 
                 Dissolved 12.5 mg Zeiniquin in 12 cc of 
                 Can not sit or stand, urinated in bed this 
               
               
                 1st. 
                 Rebound and gave PO 
                 morning . . . urine was blood tinged.  E. coli   
               
               
                 Date: 11/24/04 
                 Gave 12 mg Tamiflu (1 cc)/PO at 2:00 PM 
                 cultured . . . sensitivity pending. 
               
               
                 Temp: 99.8 F. 
               
               
                 Treatment 
                 Gave 12 mg Tamiflu (1 cc) at 5:35 PM 
                 Pinga is more alert and has not vomited 
               
               
                 2nd. 
                   
                 since receiving Tamiflu. Can not stand, 
               
               
                 Date: 11/24/04 
                   
                 but can sit upright. 
               
               
                 Treatment 
                 Dissolved 12.5 mg Zeniquin in 12 cc of 
                 No vomiting since starting Tamiflu . . . is 
               
               
                 3rd. 
                 Rebound and gave PO 
                 drinking water . . . walked 20 feet and urinated 
               
               
                 Date: 11/25/04 
                 Gave 12 mg Tamiflu/PO at 10:15 AM 
                 a clear yellow colored urine next to litter box. 
               
               
                 Temp: 99.5 F. 
                   
                 About 1:30 AM, left bed, walked to owner&#39;s 
               
               
                   
                   
                 bed, jumped up and began to purr 
               
               
                 Treatment 
                 Tamiflu and Parvo Clinical Trial 
                 Urinated, was normal yellow color . . . has 
               
               
                 4th. 
                 Gave 12 mg Tamiflu/PO at 5:30 PM 
                 begun to walk around house . . . jumped 
               
               
                 Date: 11/25/04 
                   
                 and ran when attempted to brush . . . Pinga 
               
               
                 Temp: 98.9 F. 
                   
                 is more alert in clinic 
               
               
                 Treatment 
                 Dissolved 12.5 mg Zeniquin in 15 cc 
                 Pinga is walking around house . . . slept in 
               
               
                 5th. 
                 Rebound and gave PO at 10:30 AM 
                 owner&#39;s bed . . . refused being given Rebound 
               
               
                 Date: 11/26/04 
                 Gave 12 mg Tamiflu/PO 
                 by syringe . . . comes when called . . . Physical 
               
               
                 Temp: 98 8 F. 
                   
                 exam is normal 
               
               
                 Treatment 
                 Gave 12 mg Tamiflu/PO at 5 PM 
                 Urinated normal urine . . . passed 3 small 
               
               
                 6th. 
                   
                 firm BMs . . . jumped up to help iron clothes, 
               
               
                 Date: 11/26/2004 
                   
                 vocal . . . First time temperature has been 
               
               
                 Temp: 100.6 F. 
                   
                 above 100 F. 
               
               
                 Treatment 
                 Dissolved 12.5 mg Zeniquin in 15 cc 
                 Beginning 3rd day of Tamiflu . . . Pinga is 
               
               
                 7th. 
                 Rebound 
                 more alert . . . began to eat Wellness dry 
               
               
                 Date: 11/27/04 
                 Gave 12 mg Tamiflu/PO at 10:30 AM 
                 cat food . . . had BM in litter box . . . continues 
               
               
                 Temp: 98.8 F. 
                   
                 to be given Rebound via syringe at home 
               
               
                 Treatment 
                 Gave 12 mg Tamiflu/PO at 5 PM 
                 Appears to be “normal”, alert, active and 
               
               
                 8th. 
                   
                 interested in surroundings . . . Dispensed 
               
               
                 Date: 11/27/04 
                   
                 CNM-EN as a semi-soft food to try at home 
               
               
                 Temp: Not Taken 
               
               
                 Treatment 
                 Dissolved 12.5 mg Zeniquin in 15 cc 
                 Ate CMN-EN last night, urinated normally, 
               
               
                 9th. 
                 Rebound 
                 almost “normal” . . . maybe weak in rear 
               
               
                 Date: 11/28/04 
                 Gave 12 mg Tamiflu/PO at 10:30 AM 
                 when playing with ball . . . shows interest 
               
               
                 Temp: 100.1 F. 
                   
                 when Jerry is tying shoe strings . . . this is 
               
               
                   
                   
                 a normal activity for Pinga 
               
               
                 Treatment 
                 Gave 12 mg Tamiflu/PO at 5:30 PM 
                 Pinga appears to be normal . . . this is his 
               
               
                 10th. 
                   
                 last treatment with Tamiflu. 
               
               
                 Date: 
               
               
                 Temp: Not Taken 
               
               
                   
               
             
          
         
       
     
         [0080]    In Table 16,  E. coli , a neuraminidase dependent bacteria, was cultured from Ping a&#39;s urine following an 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.