US20110144048A1 - Novel Uses of Neuraminidase Inhibitors in Infectious Diseasess - Google Patents

Novel Uses of Neuraminidase Inhibitors in Infectious Diseasess Download PDF

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US20110144048A1
US20110144048A1 US13/024,285 US201113024285A US2011144048A1 US 20110144048 A1 US20110144048 A1 US 20110144048A1 US 201113024285 A US201113024285 A US 201113024285A US 2011144048 A1 US2011144048 A1 US 2011144048A1
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neuraminidase
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infections
disease
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Jack J. Broadhurst, III
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Priority to US13/612,739 priority patent/US20130005804A1/en
Priority to US14/169,076 priority patent/US20140148511A1/en
Priority to US15/138,144 priority patent/US20160235703A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • viruses such as influenza
  • Canine parvovirus 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.
  • the disease from a parvovirus infection is costly, both monetarily and emotionally for the dog's caretakers.
  • canine parvovirus 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.
  • Vaccines have also been used to treat diseases caused by viruses.
  • the vaccines derived from whole killed or whole attenuated viruses may retain residual disease causing activity.
  • vaccines typically are reformulated each year in response to antigenic variation and are known to be ineffective against new viral variants.
  • compositions and methods of treatment should preferably not have the undesirable properties of promoting microbial resistance, or being toxic to the recipient.
  • treatment and prevention in diseases caused by microorganisms that are cost effective and do not take a long period of time.
  • the present invention is directed towards a method and treatment that meets these needs.
  • This invention provides a method of treating and preventing mucosal diseases, diseases associated with neuraminidase dependent bacteria and superinfections with a neuraminidase inhibitor.
  • 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.
  • neuraminidase inhibitors according to the present invention have been proven to be successful and predictable.
  • the results have been dramatic.
  • 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.
  • the present invention provides methods used for preventing disease or treating animals, including humans, exposed to pathogens or the threat of pathogens.
  • the present invention there is a method used for preventing animals, including humans, from getting a disease associated with the specific pathogen.
  • the animal is contacted with effective amounts of the compositions prior to exposure to pathogenic organisms.
  • the animal is contacted with effective amounts of the composition after exposure to pathogenic organisms.
  • 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.
  • the compound comprising a neuraminidase inhibitor is oseltamivir (TAMIFLU®, hereinafter referred to as TAMIFLU).
  • the composition can include additional compounds, such as antibiotics, for example, which can be used in addition to the compound comprising the neuraminidase inhibitor.
  • the method or treatment is performed for a sufficient amount of time to reduce the virulence factor of the pathogenic bacteria.
  • 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).
  • 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.
  • 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.
  • the present invention provides the use of a neuraminidase inhibitor to treat diseases involving neuraminidase dependent bacteria.
  • oseltamivir 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.
  • TAMIFLU® oseltamivir
  • feline and feline parvoviral enteritis have 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.
  • 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, avi
  • Neuraminidases 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • neuraminidase in order to provide sialic acid to use in their metabolic pathways.
  • 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.
  • neuraminidase can also displace epithelial cells' IgA.
  • 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'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.
  • 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.
  • 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.
  • parvoenteritis is not known as a viral disease, but that the pathobiology is due to excess neuraminidase.
  • neuraminidase inhibitor like TAMIFLU
  • TAMIFLU neuraminidase
  • neuroaminidase dependent bacteria includes “neuraminidase producing bacteria.”
  • the neuraminidase inhibitors can be used to target neuraminidase dependent bacterial infections, superinfections, and coinfections and not dependent on viral neuraminidase.
  • “superinfection”, as used herein, means that an infection requires both virus and bacteria combined together to produce pathology more severe than either can alone.
  • Coinfection means two or more different bacterial strains together to produce pathology of a disease more severe than either can alone.
  • 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.
  • animal 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.
  • 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's innate immunity.
  • Neu5Ac2en N-acetyl-2,3-didehydro-2-deoxyneuraminic acid
  • 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.
  • neuraminidase inhibitors which are similar in structure to Neu5Ac2en.
  • 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).
  • the neuraminidase inhibitors according to the present invention are those compounds that hydrolyze sialic acid.
  • an effective amount of compound preferably a neuraminidase inhibitor can be administered to an animal.
  • 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.
  • anti-emetics can be administered to help alleviate nausea and vomiting.
  • 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.
  • 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.
  • the neuraminidase inhibitor can be administered during the entire, or part of the length of a bacterial infection, a superinfection or a co-infection.
  • the neuraminidase inhibitor is administered within 48 hours of onset of first clinical signs.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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's health improves.
  • the neuraminidase inhibitor for prevention of a disease caused by a microorganism, can be administered once a day for 5 days.
  • 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.
  • 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.
  • the neuraminidase inhibitor can be selected from the group consisting of zanamivir (RELENZA®, Glaxo Wellcome Inc), oseltamivir (TAMIFLU®, F.
  • 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.
  • the compound is a neuraminidase inhibitor that is oseltamivir.
  • Oseltamivir (TAMIFLU®) is available from Roche PharmaTM AG (Switzerland).
  • 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.
  • 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.
  • a neuraminidase inhibitor could be co-administered with a treatment during the course of the neuraminidase dependent bacterial infection.
  • 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.
  • Neuraminidase dependent bacteria are those known to use sialiac acid (neuraminic acid) either as a source for carbon, nitrogen, energy and amino acids for cell wall synthesis. This microbial sialic acid metabolism is known to be a virulence factor in a number of infectious diseases. Tables (9-14) representing specific diseases in the various species are included.
  • Table 2 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.
  • one or more virus are associated with one or more neuraminidase dependent bacteria.
  • Feline Parvovirus and Upper Respiratory Complex and canine Parvoviral Enteritis and Tracheobronchitis have proven to be responsive to neuraminidase inhibitors. There is no reason, the other superinfections will not respond in the same manner.
  • Table 3 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.
  • 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.
  • the exposed dogs received 1 mg/lb of TAMIFLU once a day for 5 days. Although exposed, these dogs remained healthy.
  • 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.
  • 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's clinic and received IV therapy. Those puppies remaining at the kennel were treated by the kennel staff.
  • the exposed dogs received 1 mg/lb of TAMIFLU once a day for 5 days and did not develop canine parvoviral enteritis.
  • Table 5 represents 48 individual cases of Canine Parvoviral Enteritis treated with 1 mg/lb TAMIFLU AM/PM for 10 treatments. Cases posted VIN's Infectious Dz Board by 20 veterinarians practicing in 15 states.
  • Table 6 represents 5 cases of Feline Parvoviral Enteritis with TAMIFLU at 1 mg/lb AM/PM for 10 treatments. One kitten exposed, remained normal when given TAMIFLU at 1 mg/lb once a day for 5 days.
  • Table 7 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.
  • 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.
  • 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.
  • ICT Infectious Canine Tracheobronchitis
  • 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%.
  • the Miami experiment was the basis for treatment during a similar ICT outbreak at a Kansas City track.
  • Cost of TAMIFLU was a factor during an ITC outbreak in Mobil, Ala. They The DVM decided to give half the recommended dose (0.5 mg/lb). The results were better than conventional, but longer than when the recommended dose is used. This trial demonstrates that the response is dose related.
  • Table 9 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the dog.
  • Table 10 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the cat.
  • Table 11 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the cow.
  • Table 12 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the pig.
  • Table 13 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the horse.
  • Table 14 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in chickens, turkeys, ducks.
  • Table 15 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated in sheep, goats, rabbits.
  • 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.
  • Treatment Gave 12 mg Tamiflu (1 cc) at 5:35 PM Pinga is more alert and has not vomited 2nd. since receiving Tamiflu.
  • E. coli a neuraminidase dependent bacteria, was cultured from Ping a'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.

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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
  • 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
  • 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.
  • 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.
  • 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.
  • 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's caretakers.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • The present invention is directed towards a method and treatment that meets these needs.
  • This invention provides a method of treating and preventing mucosal diseases, diseases associated with neuraminidase dependent bacteria and superinfections with a neuraminidase inhibitor.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • In some preferred embodiment, the compound comprising a neuraminidase inhibitor is oseltamivir (TAMIFLU®, hereinafter referred to as TAMIFLU).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • Finally, the present invention provides the use of a neuraminidase inhibitor to treat diseases involving neuraminidase dependent bacteria.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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' IgA.
  • 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'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.
  • 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.
  • Thus, in a preferred embodiment of the present invention, canine and feline parvoviral enteritis is shown to be a superinfection (requiring a virus+neuraminidase dependent bacteria living on a mucous substrate). The pathology seen at necropsy is solely due to endo and exotoxins produced by the commensal bacteria turned pathogenic. In a preferred embodiment of the present invention, parvoenteritis is not known as a viral disease, but that the pathobiology is due to excess neuraminidase. Thus, when a neuraminidase inhibitor like TAMIFLU is administered early in the course of the disease or as a prophylactic, one can prevent the production of neuraminidase (sialidase) and one can prevent the commensal bacteria from becoming pathogenic.
  • As used herein, “neuraminidase dependent bacteria” includes “neuraminidase producing bacteria.”
  • 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.
  • 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.
  • “Coinfection”, as used herein, means two or more different bacterial strains together to produce pathology of a disease more severe than either can alone.
  • 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.
  • 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.
  • 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'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
  • 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.
  • 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.
  • Most preferably, the neuraminidase inhibitor is administered within 48 hours of onset of first clinical signs.
  • 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.
  • 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.
  • 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's health improves.
  • 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 2nd dose, the diarrhea will cease. By the 6th dose, most clinical signs of the infection will have ceased.
  • 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.
  • 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.
  • 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
  • The following examples show the importance of neuraminidase dependent bacteria in mucosal infections in several animal species.
  • TABLE 1
    Neuraminidase Dependent Bacteria and Veterinary Diseases
    Bacteria spp: Dog Cat Cow Pig Horse Avian Other
    Actinobacillus + + + + +
    Actinomyces + + + + + + +
    Aeromonas + + + + +
    Bacteroides + + + + + +
    Bordetella + + + + + +
    Brucella + + + + + +
    Campylobacter + + + + + + +
    Clostridium + + + + + + +
    Corynebacterium + + + + + + +
    Enterobacter + + + + +
    E. coli + + + + + + +
    Erysipelothrix + + + + + + +
    Fusobacterium + + + + + +
    Klebsiella + + + + +
    Pasturella + + + + + + +
    Mannheimia + +
    Peptostreptococcus + + + + + +
    Proteus + + + + + + +
    Pseudomonas + + + + + + +
    Rhodococcus + +
    Salmonella + + + + + + +
    Serratia + + + + + + +
    Shigella + + + + + +
    Staphlococcus + + + + + + +
    Streptococcus + + + + + + +
    Vibrio + +
    Haemophilus + + + + + + +
    Arcanobacterium + + + + +
  • Neuraminidase dependent bacteria are those known to use sialiac acid (neuraminic acid) either as a source for carbon, nitrogen, energy and amino acids for cell wall synthesis. This microbial sialic acid metabolism is known to be a virulence factor in a number of infectious diseases. Tables (9-14) representing specific diseases in the various species are included.
  • TABLE 2
    Superinfections in Veterinary Medicine
    Species: Disease Virus Bacteria Other
    Parvoviral Enteritis Canine Parvovirus Clostridium Salmonella
    CPV-2b > 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
  • 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.
  • Feline Parvovirus and Upper Respiratory Complex and canine Parvoviral Enteritis and Tracheobronchitis have proven to be responsive to neuraminidase inhibitors. There is no reason, the other superinfections will not respond in the same manner.
  • TABLE 3
    Parvo Cases at Chihuahua Kennel
    Case Parvo IV Tamiflu Days to
    Number Town State Breed Age Test Drugs 1 mg/lb Recover
    1 DC County Loving Chihuahua 6 wks (+) Yes None Died
    2 Kennel, Purdon, TX Chihuahua 6 wks No Yes None Died
    3 Chihuahua 6 wks No Yes None Died
    4 Chihuahua 6 wks No Yes None Died
    5 Chihuahua 6 wks No Yes None Died
    6 Chihuahua 6 wks No Yes None Died
    7 Chihuahua 6 wks No Yes None Died
    8 Chihuahua 6 wks No Yes None Died
    9 Chihuahua 6 wks No Yes None Died
    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
  • 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.
  • 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.
  • The exposed dogs received 1 mg/lb of TAMIFLU once a day for 5 days. Although exposed, these dogs remained healthy.
  • TABLE 4
    Canine Parvo Cases at Sandcastle Kennels
    Case Parvo IV Tamiflu Days to
    Number Town State Breed Age Test Drugs 1 mg/lb Recover
    1 Foyil Oklahoma Cocker 6 wk (+) Yes None Died
    2 Cocker 6 wk No Yes None Died
    3 Cocker 6 wk No Yes None Died
    4 Cocker 6 wk No Yes None Died
    5 Cocker 6 wk No Yes None Died
    6 Cocker 8 wk (+) Yes None Died
    7 Cocker 8 wk No Yes None Died
    8 Cocker 8 wk No Yes None Died
    9 Cocker 8 wk No Yes None Died
    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
  • 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.
  • 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's clinic and received IV therapy. Those puppies remaining at the kennel were treated by the kennel staff.
  • The exposed dogs received 1 mg/lb of TAMIFLU once a day for 5 days and did not develop canine parvoviral enteritis.
  • TABLE 5
    Canine Parvoviral Enteritis Treated With Tamiflu
    Case Parvo IV Tamiflu Days to
    Number Town State Breed Age Test Drugs 1 mg/lb Recover
     1-10 Pinehurst, NC Mix 6-12 wks (+) None AM/PM 3 to 5
    11 Griffin, GA Mix 11 wks (+) None AM/PM 3
    12 Mix 14 wks (+) Yes AM/PM 2
    13 Mix 14 wks (+) Yes AM/PM 2
    14 Rockford, IL GSH 8 wks (+) Yes AM/PM 3
    15 Clayton, NC JRT 7 months (+) Yes AM/PM 5
    16 Carthage, NC Mix 19 wks (+) None AM/PM 3
    17 Mix 20 wks (+) None AM/PM 4
    18 Apple Valley, CA Beagle Pup (+) Yes AM/PM 3
    19 Millington, TN GSH Pup (+) Yes AM/PM 2
    20 Douglas, GA Basset 12 wks (+) Yes AM/PM 2
    21 It. Greyh. 12 wks (+) Yes AM/PM 3
    22 Boxer 12 wks (+) Yes AM/PM 3
    23 Canton, OH Rotti-x 6 months (+) Yes AM/PM 2
    24 Griffin, GA Mix Pup (+) Yes AM/PM 3
    25 Mix Pup (+) Yes AM/PM 3
    26 Mix Pup (+) Yes AM/PM 2
    27 Salisbury, MD Pit Bull-x 6 wks (+) None AM/PM 2
    28 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
  • Table 5 represents 48 individual cases of Canine Parvoviral Enteritis treated with 1 mg/lb TAMIFLU AM/PM for 10 treatments. Cases posted VIN's Infectious Dz Board by 20 veterinarians practicing in 15 states.
  • TABLE 6
    Feline Parvoenteritis Treated with Tamiflu
    Case Parvo IV Tamiflu Days to
    Number Town State Breed AgeSex Test Drugs 1 mg/lb Recover
    1 Smithfield, NC Siamese 5 M/m (+) Yes AM/PM 2
    2 Siamese 5 M/fem (+) Yes AM/PM 3
    3 Alberta, Canada DSH 14 wk/m no WBCs Yes AM/PM 3
    4 (Exposed) DSH 20 wk/fem condomate None AM Normal
    5 Phoenix, AZ DSH 10 wk/fem (+) SQ fluids AM/PM 4
    6 DSH 1 wk/fem (+) SQ fluids AM/PM 4
  • Table 6 represents 5 cases of Feline Parvoviral Enteritis with TAMIFLU at 1 mg/lb AM/PM for 10 treatments. One kitten exposed, remained normal when given TAMIFLU at 1 mg/lb once a day for 5 days.
  • TABLE 7
    Raccoon Parvoenteritis/Distemper Treated with Tamiflu
    Case Parvo IV Tamiflu Days to
    Number Town State Breed Age Test Drugs 1 mg/lb Recover
    1 Hudson, IL Raccoon Adult/Male none none AM/PM 3
    2 Raccoon Adult/Fem none none AM/PM 3
    3 Chiefland, FL Raccoon Adult none none AM/PM 3
    4 Raccoon Adult none none AM/PM 3
    5 Raccoon Adult none none AM/PM 3
  • 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.
  • 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.
  • 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 
  • 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%.
  • 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's clinical course was unchanged after 5 days of conventional therapy. Started TAMIFLU, and dogs recovered in 3-5 days.
  • The Miami experiment was the basis for treatment during a similar ICT outbreak at a Kansas City track.
  • Cost of TAMIFLU was a factor during an ITC outbreak in Mobil, Ala. They The DVM decided to give half the recommended dose (0.5 mg/lb). The results were better than conventional, but longer than when the recommended dose is used. This trial demonstrates that the response is dose related.
  • TABLE 9
    Neuraminidase Dependent Bacteria and Canine Diseases
    Bacteria spp: Respiratory Urogenital Gastrointestinal Other
    Actinomyces Pyothorax Deep Wounds
    Peritonitis
    Aeromonas Septicemia
    Bacteroides Bone Infect.
    Bordetella Kennel Cough
    Distemper
    Upper Resp. Infect.
    Brucella Abortion
    Infertility
    Campylobacter Gastroenteritis
    Clostridium Gastroenteritis Tetnus
    Parvoenteritis Botulism
    Corynebacterium
    Enterobacter
    E. coli Upper Respiratory Pyometra Colibacillosis
    Pneumonia Mastitis Parvoenteritis
    Renal Infections
    Cystitis
    Erysipelothrix Endocarditis
    Fusobacterium
    Klebsiella Upper Respiratory
    Pneumonia
    Cystitis
    Pasturella Upper Respiratory
    Pneumonia
    Peptostreptococcus Abscesses
    Proteus Upper and Lower Gastroenteritis Otitis
    Urinary Tract
    Pseudomonas Upper Respiratory Pyometra Otitis
    Pneumonia Cystitis Dermatitis
    Rhodococcus
    Salmonella Gastroenteritis
    Serratia
    Shigella Gastroenteritis
    Staphlococci Upper Respiratory Pyometra Otitis
    Pneumonia Mastitis Dermatitis
    Cystitis
    Streptococci Pneumonia Pyometra Parvoenteritis Septicemia
    Mastitis Puppy Strangles
    Cystitis
    Haemophilus
    Arcanobacterium
  • Table 9 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the dog.
  • TABLE 10
    Neuraminidase Dependent Bacteria and Feline Diseases
    Bacteria spp: Respiratory Urogenital Gastrointestinal Other
    Actinomyces Pyothorax Abscess
    Peritonitis
    Aeromonas
    Bacteroides Emphyema Abscess
    Bordetella Upper Respiratory
    Pneumonia
    Brucella
    Campylobacter Gastroenteritis
    Clostridium Gastroenteritis Tetnus
    Panleukopenia
    Corynebacterium
    Enterobacter
    E. coli Pyometra Colibacillosis
    Mastitis Panleukopenia
    Renal Infections
    Cystitis
    Erysipelothrix
    Fusobacterium
    Klebsiella Upper Respiratory
    Pneumonia
    Cystitis
    Pasturella Upper Respiratory
    Pneumonia
    Peptostreptococcus
    Proteus Otitis
    Pseudomonas Upper Respiratory Pyometra Otitis
    Pneumonia Cystitis Abscess
    Rhodococcus Pyothorax Abscess
    Salmonella Gastroenteritis
    Serratia
    Shigella Gastroenteritis
    Staphlococci Upper Respiratory Pyometra Otitis
    Pneumonia Mastitis Dermatitis
    Cystitis
    Streptococci Pneumonia Pyometra Panleukopenia Septicemia
    Mastitis
    Cystitis
    Haemophilus
    Arcanobacterium
  • Table 10 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the cat.
  • TABLE 11
    Neuraminidase Dependent Bacteria and Bovine Diseases
    Bacteria spp: Respiratory Urogenital Gastrointestinal Other
    Actinomyces Pneumonia Mastitis “Lumpy Jaw”
    Endometritis Arthritis
    Umbilical Infections Endocarditis
    Seminal Vesiculitis Abscess
    Aeromonas Mastitis
    Bacteroides Mastitis Gastroenteritis Foot Rot
    Osteomyelitis
    Brucella Abortion
    Orchitis
    Campylobacter Epizootic Infertility
    Embryonic Death
    Abortion
    Clostridium Gangrenous Mastitis Enterotoxaemia Tetanus
    Botulism
    Blackleg
    Maligant Edema
    Gas Gangrene
    Bacillary Haemoglobinuria
    Corynebacterium Pyelonephritis
    Cystitis
    Mastitis
    Enterobacter Coliform Mastitis
    E. coli Mastitis “White Scours” Septicemia
    Colibacillosis Joint III
    Fusobacterium Calf Diphtheria Mastitis Liver Abscess in Feedlot
    Metritis Hepatic Necrobacillosis
    Klebsiella Mastitis
    Pasturella “Shipping Fever” Hemorrhagic
    “Enzootic Pneumonia” Septicemia
    Fibrogranulomatous Disease
    Peptostreptococcus Summer Mastitis
    Proteus Enteritis
    Pseudomonas Focal Pneumonia Mastitis Enteritis Dermatitis
    Uterine Infections Abscess
    Arthritis
    Salmonella Abortion Enteritis Septicaemia
    Meningitis
    Joint III
    Dry Gangrene
    Serratia Mastitis in Calves
    Staphlococci Mastitis
    Udder impetigo
    Streptococci Mastitis/Metritis
    Haemophilus Pneumonia
    Arcanobacterium Pneumonia Mastitis Liver Abscess Foot Rot
  • Table 11 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the cow.
  • TABLE 12
    Neuraminidase Dependent Bacteria and Porcine Diseases
    Bacteria spp: Respiratory Urogenital Gastrointestinal Other
    Actinomyces Pneumonia Pyogranulomatous Arthritis
    Mastitis Lymphadenitis
    Endometritis
    Umbilical Infections
    Seminal Vesiculitis
    Aeromonas Diarrhea
    Bacteroides Diarrhea in Piglets Abscess
    Bordetella Atrophic Rhinitis
    Bronchopneumonia in Young Piglets
    Brucella Abortion Arthritis
    Orchitis Spondylitis
    Infertility
    Campylobacter Intestinal Adenomatosis Diarrhea
    Clostridium Tetnus
    Botulinum
    Black Leg
    Maligant Edema
    Hemorrhagic Enterotoxemia
    Corynebacterium Pyelonephritis
    Enterobacter Mastitis-Metritis
    Agalactia Complex(MMA)
    E. coli Associated with PRRSV Mastitis Neonatal Diarrhea Piglet
    Mastitis-Metritis Colisepticemia Meningitis
    Agalactia Complex(MMA) Weaning Enteritis Sudden
    Edema/death
    Erysipelothrix Acute Abortion “Diamond Skin Disease”
    Vegetative Endocarditis
    Polyarthritis
    Fusobacterium “Bull-Nose” Necrotic Enteritis Liver Abscess
    Pasturella Pneumonia Assoc. w/PRRSV
    Atrophic Rhinitis
    Peptostreptococcus
    Pseudomonas Respiratory Infections Abortion Enteritis Otitis
    Arthritis
    Rhodococcus Cervical Lymphadenitis
    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
  • Table 12 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the pig.
  • TABLE 13
    Neuraminidase Dependent Bacteria and Equine Diseases
    Bacteria spp: Respiratory Urogenital Gastrointestinal Other
    Actinomyces Poll Evil
    Fistulous Withers
    Aeromonas
    Bacteroides Diarrhea in Foals Osteomylitis
    Buccal Cavity Lesions
    Bordetella Respiratory Infections
    Brucella Poll Evil
    Fistulous Withers
    Campylobacter
    Clostridium Enteritis Tetanus
    Botulism
    Corynebacterium Ulcerative Lymphangitis
    Enterobacter Metritis
    E. coli Enteritis
    Erysipelothrix
    Fusobacterium “Thrush” involving the frog
    Klebsiella Pneumonia in Foals Metritis Abscess
    Cervicitis
    Pasturella Respiratory Infections
    Pneumonia
    Peptostreptococcus
    Proteus Kidney infections
    Cystitis
    Pseudomonas Lung Abscesses Metritis Eye Infections
    Glanders Lymphangitis with ulcers
    along lymphatics(Farcy)
    Rhodococcus Bronchopneumonia
    Salmonella Abortion Sever Enteritis Septicemia
    Serratia
    Shigella
    Staphlococci Mastitis
    Botryomycosis after
    Castration
    Streptococci Pneumonia Endometritis Foal Lymphangitis
    Mastitis Abscess
    Abortion Strangles
    Navel Infections Purpura Hemorrhagica
    Genital Infections
    Haemophilus
    Arcanobacterium
  • Table 13 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in the horse.
  • TABLE 14
    Neuraminidase Dependent Bacteria and Avian Diseases
    Bacteria spp: Respiratory Urogenital Gastrointestinal Other
    Actinobacillus
    Actinomyese
    Aeromonas Septicemia
    Bacteroides
    Bordetella Turkey Coryza
    Rhinotracheitis
    Sinusitis
    Campylobacter Avian Vibrionic Hepatitis
    Clostridium Necrotic Enteritis Tetanus
    Ulcerative Enteritis Botulism
    Necrotic Dermatitis
    “Struck”
    Corynebacterium
    Enterobacter
    E. coli Airsacculitis Ovarian Infection Peritonitis Omphalitis
    Infectious Bronchitis Hemorrhagic Enteritis
    Turkey Poult Enteritis
    Colibacillosis
    Coligranuloma in liver
    and intestines
    Erysipelothrix Spleenitis
    Endocarditis
    Arthritis
    Fusobacterium Avian Diphtheria secondary to Fowl Pox
    Klebsiella
    Pasturella Fowl Plague Fowl Cholera Fibrinous
    Pasteurellosis Polyserositis
    Peptostreptococcus
    Proteus
    Pseudomonas
    Rhodococcus
    Salmonella Pullorum Disease Fowl
    White Diarrhea Typhoid
    Paratyphoid
    Serratia Septicemia
    Staphlococci Bumble-Foot
    Arthritis
    Breast Blister
    Streptococci Septisemia
    Endocarditis
    Vibrio Cholera-like Enteric Disease
    Haemophilus Infectious Coryza
    Arcanobacterium
  • Table 14 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated with them in chickens, turkeys, ducks.
  • TABLE 15
    Neuraminidase Dependent Bacteria and Other Species' 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
  • Table 15 is a partial listing of known neuraminidase dependent bacteria and the infectious diseases associated in sheep, goats, rabbits.
  • TABLE 16
    Clinical Trial: Tamiflu and E. coli
    Veterinarian or Clinic: Cat Health Clinic       Phone: (910) 295-2287  
    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'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'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
  • In Table 16, E. coli, a neuraminidase dependent bacteria, was cultured from Ping a'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.
  • 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.

Claims (8)

1. A method for inhibiting neuraminidase dependent bacterial infections that are not viral generated dependent infections, from a disease-causing microorganism dependent on sialic acid metabolism, comprising administering to an animal in need thereof a therapeutically effective amount of a composition comprising one or more compounds, wherein one of the compounds comprises neuraminidase inhibitors.
2. The method of claim 1, wherein the neuraminidase inhibitor is selected from the group consisting of zanamivir, oseltamivir, 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.
3. The method of claim 1, wherein the disease-causing microorganism causes infectious diseases selected from the group consisting of parvoviral enteritis, canine kennel cough, feline upper respiratory infections, and feline nephritis secondary to E. coli.
4. A method for treating neuraminidase dependent bacterial infections that are not viral generated dependent infections, from a disease-causing microorganism dependent on sialic acid metabolism, comprising administering to an animal in need thereof a therapeutically effective amount of a composition comprising one or more compounds, wherein one of the compounds comprises neuraminidase inhibitors.
5. The method of claim 4, wherein the neuraminidase inhibitor is selected from the group consisting of zanamivir, oseltamivir, 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.
6. The method of claim 4, wherein the disease-causing microorganism causes infectious diseases selected from the group consisting of parvoviral enteritis, canine kennel cough, feline upper respiratory infections, and feline nephritis secondary to E. coli.
7. A method of using an antiviral drug for human influenza to treat neuraminidase dependent bacterial infections, that are not viral generated dependent infections, superinfections and coinfections which do not involve the human influenza virus A and/or B, in clinical veterinary medicine, comprising administering to an animal in need thereof a therapeutically effective amount of a composition comprising one or more compounds, wherein one of the compounds comprises neuraminidase inhibitors.
8. The method of claim 7, wherein the neuraminidase inhibitor is selected from the group consisting of zanamivir, oseltamivir, 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.
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