From the Veterinarians

Judicious Use of Antimicrobials for Dairy Cattle Veterinarians 

Some material maybe duplicated or out of sequence. Sorry but info better than nothing. 

The material contained in this brochure was developed in cooperation with the American Veterinary Medical Association. The Food and Drug Administration Center for Veterinary Medicine1 Antimicrobials are needed for the relief of pain and suffering in animals. For food animals, the gains that have been made in food production capacity would not have been possible without the ability of safe and effective drugs to contain the threat of disease to animals.  The increased capacity of the United States livestock and poultry producer has kept high quality protein available and affordable for the majority of consumers in the U.S. and other countries.  The World Health Organization stated, “Antimicrobials are vital medicines for the treatment of bacterial infections in both humans and animals. Antimicrobials have also proved to be important for sustainable livestock production and for the control of animal infections that could be passed on to humans.”  The report by the National Research Council and Institute of Medicine states: “The benefit to human health in the proper use of antibiotics in food animals is related to the ability for these drugs to combat infectious bacteria that can be transferred to humans by either direct contact with the sick animal, consumption of food contaminated with pathogens from animals, or proliferation into the environment.”  However, the use of antimicrobials in food animals is not without risk.

In recent years, concerns about the use of antimicrobial products in food-producing animals have focused on human food safety because foods of animal origin are sometimes identified as the vehicles of food borne disease in humans and, therefore, also vehicles of resistant food borne pathogens and resistant genetic material.  The major zoonotic pathogens of concern for the development of antimicrobial resistance are Salmonella spp. and Campylobacter jejuni.  A recent report estimated that 80% of the estimated 2.5 million annual human cases in the United States of campylobacteriosis are food borne and that 95% of the 1.4 million annual human cases of nontyphoidal salmonellosis are food borne.  This equates to 1.96 million cases of food borne campylobacteriosis and 1.34 million cases of food borne salmonellosis per year in the United States.

If a significant percentage of Salmonella or Campylobacter become resistant to the antibiotics used to treat those infections in humans, there could be a significant impact on human health. Resistance to antimicrobials existed even before antimicrobials were used. However, this intrinsic form of resistance is not a major source of concern for human and animal health.  The vast majority of drug-resistant organisms have instead emerged as a result of genetic changes, acquired through mutation or Judicious Use of Antimicrobials for Dairy Cattle Veterinarians INTRODUCTION2 transfer of genetic material during the life of the microorganisms, and subsequent selection processes.  Mutational resistance develops as a result of spontaneous mutation in a locus on the microbial chromosome that controls susceptibility to a given antimicrobial.  The presence of the drug serves as a selecting mechanism to suppress susceptible microorganisms and promote the growth of resistant mutants.  Spontaneous mutations are transmissible vertically.  Resistance can also develop as a result of transfer of genetic material between bacteria.  Plasmids, which are small extra-chromosomal DNA molecules, transposons and integrons, which are short DNA sequences, can be transmitted both vertically and horizontally and can code for multi-resistance.  It is believed that a major portion of acquired resistance is plasmid-mediated, although the method of resistance transfer varies for specific drug /bacteria combinations. Resistance depends on different mechanisms and more than one mechanism may operate for the same antimicrobial.  Microorganisms resistant to a certain antimicrobial may also be resistant to other antimicrobials that share a mechanism of action or attachment.  Such relationships, known as cross-resistance, exist mainly between agents that are closely related chemically (e.g.  neomycin-kanamycin), but may also exist between structurally unrelated chemicals with similar mechanisms of action (e.g. erythromycin- lincomycin).  Microorganisms may also be resistant to several unrelated antimicrobials at the same time, even though the mechanisms of resistance may be very different.  Use of one such antimicrobial may therefore also select for resistance to the other antimicrobials. Definitive answers about the safety of antimicrobial use in animals remain scientifically challenging, but more information is accumulating that raises concerns about food safety.  As a result of treating animals with antibiotics, food borne microbes may become resistant to the antibiotics used to treat human disease.  When an animal is treated with an antimicrobial drug, a selective pressure is applied to all bacteria exposed to the drug.  Bacteria that are susceptible to the antimicrobial are killed or put at a competitive disadvantage, while bacteria that have the ability to resist the antimicrobial have an advantage and are able to grow more rapidly than more susceptible bacteria.  In addition, bacteria can become resistant when resistance genes are passed from a resistant bacterium to a sensitive one.  Thus, antimicrobial agents may increase the prevalence of resistant bacteria among both target pathogens and normal bacterial flora. For example, despite several restrictions placed on the use of the two approved poultry fluoroquinolone products in the U.S., ciprofloxacin-resistant Campylobacter were recently isolated from 20% of domestic retail chicken products sampled.   Molecular subtyping revealed an association between resistant C. jejuni strains from chicken products and C. jejuni strains from domestically acquired human cases of campylobacteriosis.   The 1998 Annual Report of the National Antimicrobial Resistance Monitoring System-Enteric Bacteria (NARMS) reported 13.3% of the human Campylobacter isolates were resistant to Ciprofloxacin.  Preliminary data from 1999 reveal an increase to 21% resistance. Temporal relationships between ciprofloxacin-resistant Campylobacter and approval of fluoroquinolones for food-producing animals have also been noted in the Netherlands, the United Kingdom, and Spain.3 Similarly, a temporal association has been noted between lessened susceptibility to fluoroquinolones among Salmonella enteric a serotype Typhimurium Definitive Type 104 (DT104) and the approval and use of a fluoroquinolone for veterinary therapeutic use in the United Kingdom.  This organism has also been identified in livestock and poultry in the U.S.  Human disease caused by DT104 in the U.S. has been associated with consumption of unpasteurized beef products and direct contact with livestock.  NARMS has identified small numbers of human Salmonella isolates in the U.S. with reduced susceptibility to ciprofloxacin.  Although the numbers are small, there is a trend towards reduced susceptibility to ciprofloxacin as measured by the percentage of Salmonella isolates with a minimum inhibitory concentration equal to or greater than 0.25 mg/ml.  The percentages were 0.4% of the Salmonella isolates in 1996 to 0.6% in 1997, 0.7% in 1998, and 1.3% in 1999 (preliminary data as of October 1, 1999). NARMS also tests Salmonella and Campylobacter isolates obtained from several species of animals.  The isolates come from diagnostic laboratories, healthy animals on farms, and raw products collected at slaughter or processing plants.  The Salmonella isolates are tested for susceptibility to 17 antimicrobials and the Campylobacter isolates are tested for susceptibility to eight antimicrobials.  In 1998, resistance of the Salmonella isolates was most common to tetracycline (38% of the isolates), sulfamethoxazole (32%), streptomycin (35%), ampicillin (18%), ticarcillin (17%), kanamycin (15%), and gentamicin (11%). Resistance of the Campylobacter isolates was most common to tetracycline (60%), nalidixic acid (16%), ciprofloxacin (11%), clindamycin (7%), and azithromycin and erythromycin (6%) each.  Resistance to multiple antimicrobials is a concern. As organisms become resistant to more antimicrobials, the problem of therapy is compounded.  In 1998, 40% of the animal Salmonella isolates were resistant to 2 or more antimicrobials.  This is an increase from 25% in 1997.  In 1998, 18% were resistant to 5 or more antimicrobials compared to 11% in 1997.

Unfortunately there is not a national monitoring system that tests for resistance in animal pathogens so we are unable to track and report trends. This document has been prepared to help dairy cattle practitioners in their efforts to use antimicrobials judiciously to minimize the development of resistance in human and animal pathogens while maintaining effectiveness to treat and prevent diseases of food animals.

JUDICIOUS USE

Whenever an animal or human host is exposed to antimicrobials, there will be some degree of selection for a resistant bacterial population.  Selection will depend upon the type of antimicrobial used, the number of individuals treated, the dosage regimen, and the duration of treatment.  Therefore, it is vital to limit therapeutic antimicrobial use in animals and humans to those situations where they are needed.

The veterinary profession shares the concerns of the public, governmental agencies, and public health community regarding the broad issue of antimicrobial resistance and specifically the potential risk of resistance developing in animals with subsequent transfer to humans.  Because of those concerns, to maintain the long-term effectiveness of antimicrobials for animal and human use and to increase the possibility of  future antimicrobial drug approvals for the treatment of  animals, the American Veterinary Medical Association and the American Association of  Bovine Practitioners  are committed to judicious and prudent use of  antimicrobials by veterinarians for the prevention, control, and treatment of  animal diseases.

The AVMA started a profession-wide initiative, including companion and food animal practitioner groups, to develop and implement judicious use principles for the therapeutic use of antimicrobials by veterinarians.  The AVMA Executive Board approved a general set of judicious use principles in November 1998.

Concurrent with the AVMA initiative, the AABP was addressing antimicrobial use in cattle through articles in the Bovine Practitioner, presentations at annual meetings, in discussions on AABP-l (an internet list server forum for AABP members) and a committee charged with developing guidelines for the use of antimicrobials in cattle.  The AABP Board of Directors approved Prudent Drug Use Guidelines in March 1999.  In the following pages, both the general AVMA judicious therapeutic antimicrobial use principles and the AABP guidelines for prudent use of drugs, with more specific examples, will be presented.

The overarching position of the AVMA is, “When the decision is reached to use antimicrobials for therapy, veterinarians should strive to optimize therapeutic efficacy and minimize resistance to antimicrobials to protect public and animal health.”  The objectives of the AVMA are to:

  • support development of a scientific knowledge base that provides the basis for judicious therapeutic antimicrobial use,
  • support educational efforts that promote judicious therapeutic antimicrobial use,
  • preserve therapeutic efficacy of antimicrobials, and
  • ensure current and future availability of veterinary antimicrobials.

Judicious use of antimicrobials is an integral part of good veterinary practice. It is an attitude to maximize therapeutic efficacy and minimize selection of resistant microorganisms.  Judicious use principles are a guide for optimal use of antimicrobials.  They should not be interpreted so restrictively as to replace the professional judgment of practitioners or to compromise animal health or welfare.  In all cases, animals should receive prompt and effective treatment as deemed necessary by the prescribing or supervising veterinarian.

There are fifteen general principles which emphasize preventive actions to avoid disease, suggest other options before choosing to use antimicrobials, or the use of drugs, when possible, that are less important to human and animal needs.

The principles with explanatory notes are:

1) Preventive strategies, such as appropriate husbandry and hygiene, routine health monitoring, and immunizations, should be emphasized.5 Antimicrobial use should not be viewed in isolation from the disciplines of animal management, animal welfare, husbandry, hygiene, nutrition, immunology and vaccination.  Diseases must be controlled to reduce the need for antimicrobial use and they can only be controlled successfully by preventive medicine.  The objective is to prevent disease to the greatest extent possible so that antimicrobial treatment is not required.  In food animals, antimicrobial use should always be part of, and not a replacement for, integrated disease control programs.  These programs are likely to involve hygiene and disinfection procedures, biosecurity measures, management alterations, changes in stocking rates, vaccination, and other measures.  These examples of preventive strategies are not exhaustive. Continued antimicrobial use in such control programs should be regularly assessed regarding effectiveness and whether such use can be reduced or stopped. Additional research is needed on economical and efficacious alternatives to the use of antimicrobials and to evaluate their effects on selection of resistant bacteria.  Evaluation is needed of vaccines, probiotics, and competitive exclusion principles and products, nutrition, and new health technologies and strategies.

2) Other therapeutic options should be considered prior to antimicrobial therapy. Cases of lameness may be due to trauma and not accompanied by infection that would require antimicrobial treatment.  Calf scours may only need to be treated with fluid replacement, not with antimicrobials.  Animals experiencing viral-induced disease may be supported through good nutrition and administration of drugs such as non-steroidal anti-inflammatory drugs with anti-pyretic properties.

3) Judicious use of antimicrobials, when under the direction of a veterinarian, should meet all the requirements of a valid veterinarian-client-patient relationship. A veterinarian is required to direct the use of prescription antimicrobials or antimicrobials being used in an extralabel manner.  This direction may only take place within the context of a valid veterinary-client-patient relationship (VCPR).

A valid VCPR exists when all of the following conditions have been met:

a) The veterinarian has assumed the responsibility for making clinical judgments regarding the health of the animal(s) and the need for medical treatment, and the client has agreed to follow the veterinarian’s instructions.

b) The veterinarian has sufficient knowledge of the animal(s) to initiate at least a general or preliminary diagnosis of the medical condition of the animal(s). Judicious Use of Antimicrobials for Dairy Cattle        Veterinarians the material contained in this brochure was developed in cooperation with the American Veterinary Medical Association.

The Food and Drug Administration Center for Veterinary Medicine1 Antimicrobials are needed for the relief of pain and suffering in animals. For food animals, the gains that have been made in food production capacity would not have been possible without the ability of safe and effective drugs to contain the threat of disease to animals.  The increased capacity of the United States livestock and poultry producer has kept high quality protein available and affordable for the majority of consumers in the U.S. and other countries.  The World Health Organization stated, “Antimicrobials are vital medicines for the treatment of bacterial infections in both humans and animals. Antimicrobials have also proved to be important for sustainable livestock production and for the control of animal infections that could be passed on to humans.”  The report by the National Research Council and Institute of Medicine states: “The benefit to human health in the proper use of antibiotics in food animals is related to the ability for these drugs to combat infectious bacteria that can be transferred to humans by either direct contact with the sick animal, consumption of food contaminated with pathogens from animals, or proliferation into the environment.”  However, the use of antimicrobials in food animals is not without risk.

In recent years, concerns about the use of antimicrobial products in food-producing animals have focused on human food safety because foods of animal origin are sometimes identified as the vehicles of food borne disease in humans and, therefore, also vehicles of resistant food borne pathogens and resistant genetic material.  The major zoonotic pathogens of concern for the development of antimicrobial resistance are Salmonella spp. and Campylobacter jejuni.  A recent report estimated that 80% of the estimated 2.5 million annual human cases in the United States of campylobacteriosis are food borne and that 95% of  the 1.4 million annual human cases of  nontyphoidal salmonellosis are food borne.  This equates to 1.96 million cases of food borne campylobacteriosis and 1.34 million cases of food borne salmonellosis per year in the United States.

Dairy Cattle Veterinarians INTRODUCTION 2

If a significant percentage of Salmonella or Campylobacter become resistant to the antibiotics used to treat those infections in humans, there could be a significant impact on human health. Resistance to antimicrobials existed even before antimicrobials were used. However, this intrinsic form of resistance is not a major source of concern for human and animal health.  The vast majority of drug-resistant organisms have instead emerged as a result of genetic changes, acquired through mutation or Judicious Use of Antimicrobials for transfer of genetic material during the life of the microorganisms, and subsequent selection processes.  Mutational resistance develops as a result of spontaneous mutation in a locus on the microbial chromosome that controls susceptibility to a given antimicrobial.  The presence of the drug serves as a selecting mechanism to suppress susceptible microorganisms and promote the growth of resistant mutants.  Spontaneous mutations are transmissible vertically.  Resistance can also develop as a result of transfer of genetic material between bacteria.  Plasmids, which are small extra-chromosomal DNA molecules, transposons and integrons, which are short DNA sequences, can be transmitted both vertically and horizontally and can code for multi-resistance.  It is believed that a major portion of acquired resistance is plasmid-mediated, although the method of resistance transfer varies for specific drug /bacteria combinations.

Resistance depends on different mechanisms and more than one mechanism may operate for the same antimicrobial.  Microorganisms resistant to a certain antimicrobial may also be resistant to other antimicrobials that share a mechanism of action or attachment.  Such relationships, known as cross-resistance, exist mainly between agents that are closely related chemically (e.g.  neomycin-kanamycin), but may also exist between structurally unrelated chemicals with similar mechanisms of action (e.g. erythromycin- lincomycin).  Microorganisms may also be resistant to several unrelated antimicrobials at the same time, even though the mechanisms of resistance may be very different.  Use of one such antimicrobial may therefore also select for resistance to the other antimicrobials. Definitive answers about the safety of antimicrobial use in animals remain scientifically challenging, but more information is accumulating that raises concerns about food safety.  As a result of treating animals with antibiotics, food borne microbes may become resistant to the antibiotics used to treat human disease.  When an animal is treated with an antimicrobial drug, a selective pressure is applied to all bacteria exposed to the drug.  Bacteria that are susceptible to the antimicrobial are killed or put at a competitive disadvantage, while bacteria that have the ability to resist the antimicrobial have an advantage and are able to grow more rapidly than more susceptible bacteria.  In addition, bacteria can become resistant when resistance genes are passed from a resistant bacterium to a sensitive one.  Thus, antimicrobial agents may increase the prevalence of resistant bacteria among both target pathogens and normal bacterial flora.

For example, despite several restrictions placed on the use of the two approved poultry fluoroquinolone products in the U.S., ciprofloxacin-resistant Campylobacter were recently isolated from 20% of domestic retail chicken products sampled.   Molecular subtyping revealed an association between resistant C. jejuni strains from chicken products and C. jejuni strains from domestically acquired human cases of campylobacteriosis.   The 1998 Annual Report of the National Antimicrobial Resistance Monitoring System-Enteric Bacteria (NARMS) reported 13.3% of  the human Campylobacter isolates were resistant to ciprofloxacin.  Preliminary data from 1999 reveal an increase to 21% resistance.

Temporal relationships between ciprofloxacin-resistant Campylobacter and approval of fluoroquinolones for food-producing animals have also been noted in the Netherlands, the United Kingdom, and Spain.

3 Similarly, a temporal association has been noted between lessened susceptibility to fluoroquinolones among Salmonella enteric a serotype Typhimurium Definitive Type 104 (DT104) and the approval and use of a fluoroquinolone for veterinary therapeutic use in the United Kingdom.  This organism has also been identified in livestock and poultry in the U.S.  Human disease caused by DT104 in the U.S. has been associated with consumption of unpasteurized beef products and direct contact with livestock.  NARMS has identified small numbers of human Salmonella isolates in the U.S. with reduced susceptibility to ciprofloxacin.  Although the numbers are small, there is a trend towards reduced susceptibility to ciprofloxacin as measured by the percentage of Salmonella isolates with a minimum inhibitory concentration equal to or greater than 0.25 mg/ml.  The percentages were 0.4% of the Salmonella isolates in 1996 to 0.6% in 1997, 0.7% in 1998, and 1.3% in 1999 (preliminary data as of October 1, 1999).

NARMS also tests Salmonella and Campylobacter isolates obtained from several species of animals.  The isolates come from diagnostic laboratories, healthy animals on farms, and raw products collected at slaughter or processing plants.  The Salmonella isolates are tested for susceptibility to 17 antimicrobials and the Campylobacter isolates are tested for susceptibility to eight antimicrobials.  In 1998, resistance of the Salmonella isolates was most common to tetracycline (38% of the isolates), sulfamethoxazole (32%), streptomycin (35%), ampicillin (18%), ticarcillin (17%), kanamycin (15%), and gentamicin (11%).

Resistance of the Campylobacter isolates was most common to tetracycline (60%), nalidixic acid (16%), ciprofloxacin (11%), clindamycin (7%), and azithromycin and erythromycin (6%) each.  Resistance to multiple antimicrobials is a concern. As organisms become resistant to more antimicrobials, the problem of therapy is compounded.  In 1998, 40% of the animal Salmonella isolates were resistant to 2 or more antimicrobials.  This is an increase from 25% in 1997.  In 1998, 18% were resistant to 5 or more antimicrobials compared to 11% in 1997.

Unfortunately there is not a national monitoring system that tests for resistance in animal pathogens so we are unable to track and report trends. This document has been prepared to help dairy cattle practitioners in their efforts to use antimicrobials judiciously to minimize the development of resistance in human and animal pathogens while maintaining effectiveness to treat and prevent diseases of  food animals.

JUDICIOUS USE

Whenever an animal or human host is exposed to antimicrobials, there will be some degree of selection for a resistant bacterial population.  Selection will depend upon the type of antimicrobial used, the number of individuals treated, the dosage regimen, and the duration of treatment.  Therefore, it is vital to limit therapeutic antimicrobial use in animals and humans to those situations where they are needed.

The veterinary profession shares the concerns of the public, governmental agencies, and public health community regarding the broad issue of antimicrobial resistance and specifically the potential risk of resistance developing in animals with subsequent transfer to humans.  Because of those concerns, to maintain the long-term effectiveness of antimicrobials for animal and human use and to increase the possibility of future antimicrobial drug approvals for the treatment of animals, the American Veterinary Medical Association and the American Association of Bovine Practitioners are committed to judicious and prudent use of antimicrobials by veterinarians for the prevention, control, and treatment of animal diseases. The AVMA started a profession-wide initiative, including companion and food animal practitioner groups, to develop and implement judicious use principles for the therapeutic use of antimicrobials by veterinarians.  The AVMA Executive Board approved a general set of judicious use principles in November 1998. Concurrent with the AVMA initiative, the AABP was addressing antimicrobial use in cattle through articles in the Bovine Practitioner, presentations at annual meetings, in discussions on AABP-l (an internet list server forum for AABP members) and a committee charged with developing guidelines for the use of antimicrobials in cattle.  The AABP Board of Directors approved Prudent Drug Use Guidelines in March 1999.  In the following pages, both the general AVMA judicious therapeutic antimicrobial use principles and the AABP guidelines for prudent use of drugs, with more specific examples, will be presented.

The overarching position of the AVMA is, “When the decision is reached to use antimicrobials for therapy, veterinarians should strive to optimize therapeutic efficacy and minimize resistance to antimicrobials to protect public and animal health.”  The objectives of the AVMA are to:

  • support development of a scientific knowledge base that provides the basis for judicious therapeutic antimicrobial use,
  • support educational efforts that promote judicious therapeutic antimicrobial use,
  • preserve therapeutic efficacy of antimicrobials, and
  • ensure current and future availability of veterinary antimicrobials.

Judicious use of antimicrobials is an integral part of good veterinary practice. It is an attitude to maximize therapeutic efficacy and minimize selection of resistant microorganisms.  Judicious use principles are a guide for optimal use of antimicrobials.  They should not be interpreted so restrictively as to replace the professional judgment of practitioners or to compromise animal health or welfare.  In all cases, animals should receive prompt and effective treatment as deemed necessary by the prescribing or supervising veterinarian. There are fifteen general principles which emphasize preventive actions to avoid disease, suggest other options before choosing to use antimicrobials, or the use of  drugs, when possible, that are less important to human and animal needs.

The principles with explanatory notes are:

1) Preventive strategies, such as appropriate husbandry and hygiene, routine health monitoring, and immunizations, should be emphasized. Antimicrobial use should not be viewed in isolation from the disciplines of animal management, animal welfare, husbandry, hygiene, nutrition, immunology and vaccination.  Diseases must be controlled to reduce the need for antimicrobial use and they can only be controlled successfully by preventive medicine.  The objective is to prevent disease to the greatest extent possible so that antimicrobial treatment is not required.  In food animals, antimicrobial use should always be part of, and not a replacement for, integrated disease control programs.  These programs are likely to involve hygiene and disinfection procedures, biosecurity measures, management alterations, changes in stocking rates, vaccination, and other measures.  These examples of preventive strategies are not exhaustive. Continued antimicrobial use in such control programs should be regularly assessed regarding effectiveness and whether such use can be reduced or stopped. Additional research is needed on economical and efficacious alternatives to the use of antimicrobials and to evaluate their effects on selection of resistant bacteria.  Evaluation is needed of vaccines, probiotics, competitive exclusion principles and products, nutrition, and new health technologies and strategies.

2) Other therapeutic options should be considered prior to antimicrobial therapy. Cases of lameness may be due to trauma and not accompanied by infection that would require antimicrobial treatment.  Calf scours may only need to be treated with fluid replacement, not with antimicrobials.  Animals experiencing viral-induced disease may be supported through good nutrition and administration of drugs such as non-steroidal anti-inflammatory drugs with anti-pyretic properties.

3) Judicious use of antimicrobials, when under the direction of a veterinarian, should meet all the requirements of a valid veterinarian-client-patient relationship. A veterinarian is required to direct the use of prescription antimicrobials or antimicrobials being used in an extralabel manner.  This direction may only take place within the context of  a valid veterinary-client-patient relationship (VCPR). A valid VCPR exists when all of  the following conditions have been met:

a) The veterinarian has assumed the responsibility for making clinical judgments regarding the health of  the animal(s) and the need for medical treatment, and the client has agreed to follow the veterinarian’s instructions.

b) The veterinarian has sufficient knowledge of  the animal(s) to initiate at least a general or preliminary diagnosis of  the medical condition of  the animal(s). This means that the veterinarian has recently seen and is personally acquainted with the keeping and care of  the animal(s) by virtue of  an examination of  the animal(s) or by medically appropriate and timely visits to the premises where the animal(s) are kept.

c) The veterinarian is readily available for follow-up evaluation, or has arranged for emergency coverage, in the event of  adverse reactions or failure of  the treatment regimen. When it is not possible to make a direct clinical evaluation, the diagnosis should be based on past experience, on knowledge of  the farm epidemiological status, and  historical and/or on-going susceptibility testing.

4) Prescription, Veterinary Feed Directive, and extralabel use of antimicrobials must meet all the requirements of a valid veterinarian-client-patient relationship. Federal regulations mandate a valid VCPR for the dispensing and use of prescription and VFD drugs and for extralabel use of drugs.  Extralabel use of antimicrobials in or on animal feeds is prohibited.

5) Extralabel antimicrobial therapy must be prescribed only in accordance with the Animal Medicinal Drug Use Clarification Act amendments to the Food, Drug, and Cosmetic Act and its regulations.

No drug can be marketed unless its quality, safety, and efficacy have been demonstrated.  Therefore, the first line of choice should be based on the products approved for the species and the indication concerned.  When no suitable product is approved for a specific condition or species, or the approved product is considered to be clinically ineffective, the choice of  an alternative product should be based, whenever possible, on the results of  valid scientific studies and a proven efficacy for the condition and species concerned.

a) For food animals, extralabel drug use (ELDU) is not permitted if  a drug exists that is labeled for the food animal species and contains the needed ingredient, is in the proper dosage form, is labeled for the indication, and is clinically effective.

b) ELDU is permitted only by or under the supervision of a veterinarian.

c) ELDU is allowed only for FDA approved animal and human drugs.

d) ELDU is permitted for therapeutic purposes only when an animal’s health is suffering or threatened.     ELDU is not permitted for production drugs (e.g., growth promotion).

e) ELDU in feed is prohibited.

f) ELDU is permitted for preventative purposes when an animal’s health is threatened.

g) ELDU is not permitted if  it results in a violative food residue, or any residue that may present a risk to public health.

h) ELDU requires scientifically based drug withdrawal times to ensure food safety.

i) The record and labeling requirements must be met.

j) The FDA prohibits specific ELDU.  For example, the following drugs are prohibited for extralabel use in food animals: chloramphenicol, clenbuterol,

diethylstilbestrol, dimetridazole, ipronidazole, other nitroimidazoles, furazolidone (except for approved topical use), nitrofurazone (except for approved topical use), sulfonamide drugs in lactating dairy cows (except approved use of  sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine), fluoroquinolones, and glycopeptides (example is vancomycin).

6) Veterinarians should work with those responsible for the care of animals to use antimicrobials judiciously regardless of the distribution system through which the antimicrobial was obtained.  Since 1988, FDA has approved new therapeutic antimicrobials for use in animals as prescription-only products.  The prescription-only policy is based on the need to assure the proper use of antimicrobials through precise diagnosis and 7 correct treatment of disease to minimize animal suffering and to avoid drug residues in food.  However, many of the older antimicrobials are available for over-the-counter sale to producers.  For these drugs, the FDA has determined that the producers can use the antimicrobials, safely and effectively, as directed on the label.  Regular, close veterinary involvement can assist the producers by providing informed advice and guidance on judicious use.  Extralabel use of over-the-counter antimicrobials would require that a veterinarian and the producer follow the constraints of AMDUCA, including the establishment of a valid veterinary client-patient relationship. Quality assurance programs also provide guidance to  producers and veterinarians on proper use of  drugs.  The Nebraska Beef Quality Assurance Program and the Wisconsin VMA  AMDUCA Task Force are outstanding examples.

7) Regimens for therapeutic antimicrobial use should be optimized using current pharmacological information and principles. For labeled use of  an antimicrobial, the most accessible source of  information is the label, which includes the package insert.  For extralabel use, the Food Animal Residue Avoidance Databank can assist with determinations of withdrawal times.  To assist with determinations of possible alternatives to antimicrobial therapy and with drug use regimens when using antimicrobials, several veterinary organizations and two producer organization are funding the development of  the Veterinary Antimicrobial Decision Support System (VADS). The objective of  VADS is to provide veterinarians with a source of  easily accessible information on the therapy of  specific diseases to help them make informed treatment decisions.  The new decision support system will allow veterinarians to access current, peer-reviewed information when selecting treatment regimens.  The available information will include a full-range of therapeutic options, and the supporting data for each antimicrobial available to treat a disease.  The pathogen data will include susceptibility profile information, when available, as well as an interpretation of susceptibility breakpoints as related to clinical efficacy.

The choice of the right antimicrobial needs to take into account pharmacokinetic parameters, such as bioavailability, tissue distribution, apparent elimination half-life, and tissue kinetics to ensure the selected therapeutic agent reaches the site of infection.  Duration of withdrawal times may be a factor in choosing suitable products.  Consideration must also be given to the available pharmaceutical forms and to the route of  administration. Prolonged oral use should be avoided, as most of the concerns with regard to resistance are associated with the selection and transfer of resistant, zoonotic bacteria that inhabit the gut.

8) Antimicrobials considered important in treating refractory infections in human or veterinary medicine should be used in animals only after careful review and reasonable justification.  Consider using other antimicrobials for initial therapy.

In this context, this principle takes into account development of resistance or cross-resistance to important antimicrobials.  In December 1998, the FDA made available  “A Proposed Framework for Evaluating and Assessing the Human Safety of  the Microbial Effects of  Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals”8 (Framework Document).  A concept introduced by the Framework Document is the categorization of antimicrobials based on their unique or relative importance to human medicine and their likelihood of affecting human exposure to food-borne pathogens..  While the criteria for categorization remain under discussion, it is expected that antimicrobials such as the fluoroquinolones and third generation cephalosporins will probably be classified in the most important category.  The fluoroquinolones are also very important for the treatment of colibacillosis in poultry.

9) Use narrow spectrum antimicrobials whenever appropriate. To minimize the likelihood of  broad antimicrobial resistance development, where an appropriate narrow spectrum agent is available, it should be selected in preference to a broad spectrum agent.

10) Utilize culture and susceptibility results to aid in the selection of antimicrobials when clinically relevant.

Susceptibility profiles can vary between herds and flocks.  Periodic culture and susceptibility testing can provide historical data on which to base future empirical treatment as well as assist in selecting a treatment for refractory infections.  Ideally, the susceptibility profile of the causal organism should be determined before therapy is started.  The veterinarian has a responsibility to determine the applicability of the breakpoints used by the lab for the specific disease indication being considered.  In disease outbreaks involving high mortality or where there are signs of  rapid spread of disease, treatment may be started on the basis of  a clinical diagnosis and previous applicable susceptibility results before current samples are submitted for susceptibility evaluation or results are obtained.   Even so, the susceptibility of the suspected causal organism should, where possible, be determined so that if treatment fails it can be changed in the light of the results of susceptibility testing.   Antimicrobial susceptibility trends should be monitored over time and such monitoring used to guide clinical judgment on antibiotic usage. Susceptibility tests are intended to be a guide for the practitioner, not a guarantee, that an antimicrobial will be effective in therapy.  Susceptibility testing can only give an indication of what the clinical activity of the drug will be.  The projection of clinical efficacy from an in vitro MIC determination is much more accurate for antimicrobials with validated breakpoints for the specific indication.  The effect of the drug in vivo depends on its ability to reach the site of infection in a high enough concentration, the nature of  the pathological process, and the immune responses of  the host.

11) Therapeutic antimicrobial use should be confined to appropriate clinical indications.   Inappropriate uses such as for uncomplicated viral infections should be avoided. Veterinarians should use their professional knowledge and clinical judgment to decide whether viral infections may involve or predispose to  a superimposed bacterial infection.

12) Therapeutic exposure to antimicrobials should be minimized by treating only for as long as needed for the desired clinical response. Theoretically, infections should be treated with antimicrobials only until the host’s defense system is adequate to resolve the infection.  While it may be difficult to judge optimal treatment duration, limiting the duration of use to only that required for therapeutic effect will minimize the exposure of the bacterial population to the antimicrobial.  The adverse effects on the surviving commensal microflora are minimized and the medical impact on the remaining zoonotic organisms is reduced.  However, treatment for too short a period can also be problematic because it can lead to recrudescence of the infection.  It is then possible that a higher percentage of the pathogens involved in the recrudescence episode have reduced susceptibility to the antimicrobial.

13) Limit therapeutic antimicrobial treatment to ill or at risk animals, treating the fewest animals indicated. In some classes of livestock, if a number of animals in a group have overt signs of disease, both sick and healthy animals may be treated with therapeutic levels of an antimicrobial.  This is intended to cure the clinically affected animals, reduce the spread of the disease, and arrest disease development in animals not yet showing clinical signs. It is recognized that strategic, metaphylactic medication of a specific group of animals may be appropriate in certain precisely defined circumstances.  However, this should be part of an integrated disease control program and the need for such education should be regularly re-evaluated.  The use of antimicrobials in the absence of clinical disease or pathogenic infections should be restricted to situations where past experience indicates that the risk is high that a group of animals may develop disease if  not treated.  In addition, long-term administration to prevent disease should not be practiced without a clear medical justification.

14) Minimize environmental contamination with antimicrobials whenever possible. Unused antimicrobials should be properly disposed.  Also some antimicrobials may be environmentally stable in manure.  If the antimicrobials are not bound in an inactive form, environmental exposure could contribute to resistance development.  Consideration may need to be given to disposal methods that will not recycle resistant organisms to humans or animals.

15) Accurate records of treatment and outcome should be used to evaluate therapeutic regimens. Outcome records can greatly assist with design of future empiric treatment regimens. The implementation of these general judicious use principles, and the more specific examples in the prudent antimicrobial use guidelines  given in the following sections,  will reduce the development of  resistant zoonotic pathogens and commensals in animals and will lessen the risk of a human health impact related to the therapeutic use of  antimicrobials in animals. Application of Judicious and Prudent Microbial Use Principles by Dairy Cattle Practitioners Veterinarians treating cattle with antimicrobials have always had three responsibilities: first, to diagnose, prevent and, when necessary, treat disease in their patients; second, to optimize the production and health maintenance resources of those who own and care for their patients; and third, to meet the expectations regarding the safety of food animal production of those who choose to consume food products derived from their clients’ cattle.  Consumers should expect that veterinarians have prudently and judiciously used antimicrobials in order to minimize the emergence or development of antimicrobial resistance.

There has never been a time when veterinarians did not have all three responsibilities.  In the past, some veterinarians may have chosen treatment options based on perceived  success in treating an individual patient or patients on an individual farm, as being the only important responsibility. To diminish the importance of the other two responsibilities is poor medical and business decision management.

Conservation of available antimicrobials requires that veterinarians select and use them appropriately.  If veterinarians do not, the FDA Center for Veterinary Medicine will have to respond as the laws and regulations require. The result will be an impression by consumers of food animal products and by groups advocating positions of food safety that cattle-derived food products are not produced with sound practices.  While the magnitude of the impact of antimicrobial use in cattle on the development of antibiotic resistance for human pathogens may continue to be discussed, the importance of prudent and judicious antimicrobial use has never been greater.

It is false economic benefit to choose an inappropriate antimicrobial regimen if it undermines the veterinary profession’s credibility with consumers or those who implement our national food animal drug laws and regulations.  When antimicrobial choices are diminished, veterinarians’  ability to enhance productivity and to treat disease will also be diminished. The focus of  both veterinarians and producers should be on the safety and of  the consumer.

The production of  safe and wholesome animal products for human consumption should be a primary goal of  veterinarians caring for dairy cattle.  In reachingthat goal, as mentioned in the general principles, emphasis should be placed on practitioners being committed to preventive immune system management throughthe use of  vaccines, parasiticides, stress reduction, and proper nutritional management. Proper and timely management practices can reduce the incidence of  disease and therefore reduce the need for antimicrobials.  Nevertheless, antimicrobials will remain a necessary tool to manage infectious diseases in dairy To reemphasize the points made earlier, prudent and judicious use of antimicrobials is necessary to reduce animal pain and suffering, to protect the 11 economic livelihood of  dairy producers, to ensure the continued production of foods of  animal origin, and to minimize the shedding of  zoonotic bacteria into the environment and potentially the food chain. Editors Note: The following was made for smaller width so paragraphs should not be trusted for length.

The following are specific recommendations for the prudent and judicious use of  antimicrobials in dairy cattle and are provided for each of  the prudent antimicrobial use guidelines adopted by theAABP. The veterinarian should accept responsibility for helping clients design management, immunization, housing, and nutritional programs that will reduce the incidence of  disease and the need for antimicrobials. Providing adequately ventilated housing, such as with calf  hutches, minimizes the potential for the development of  bovine respiratory disease. Colostrum management programs and their monitoring will enhance the health of  the young replacement Adequate selenium and vitamin E nutrition will enhance udder health and aid in mastitis prevention as well as minimizing the incidence of  retained placenta in the postpartum cow. Ensuring adequate pre-calving nutrition of  the cow, particularly protein, is of  paramount importance.  This will enhance the passive transfer of  antibodies from high quality colostrum to the neonatal calf, and has been proven to provide health benefits throughout the life of  the animal. When a poorly functioning immune system results in an increased level of respiratory disease, efforts to identify and correct  immunosuppresive factors should be

  1. The reduction in morbidity and mortality, and the related decrease in the need for antimicrobials, may be dramatic where levels of  nutrients such as copper, zinc and selenium are optimized. The use of antimicrobials only within the confines of  a valid veterinarianclient-patient relationship (see page 5), for both dispensing and the issuance of prescriptions, has been recommended by the American Association of  Bovine
  2. In addition, extra label usage should be within the provisions contained within the AMDUCA regulations (see page 6).  All veterinarians should carefully review their willingness to respond to producers’ requests for antimicrobial use recommendations.  If  a veterinarian is not the person responsible for diagnosis of  disease conditions on a dairy cattle operation, is not available for questions or concerns following treatment with antimicrobials or has not accepted the responsibility for health care of  the cattle on that operation, they will not be in position to optimize antimicrobial use or to minimize the development of  resistance to antimicrobials.  Veterinarians prescribing, dispensing, or administering antimicrobials to cattle should utilize the services of FARAD or other unbiased and reputable sources to provide scientifically sound withdrawal times for producers.

Veterinarians should properly select and use antimicrobial drugs. Veterinarians should participate in continuing education programs that include therapeutics and emergence and/or development of  antimicrobial resistance. Human food safety concerns are discussed at numerous regional, state and national meetings every year.  At least some portion of  required Continuing Education hours should be received on the topic of  antimicrobial susceptibility 12 of animal and potential zoonotic pathogens.  Material accessible from reliable sources such as the FDA/CVM, FARAD, and AABP home pages and from the list of  additional sources of  information given at the end of  this paper should be incorporated into treatment considerations and recommendations.

A dairy cattle veterinarian should have strong clinical evidence of  the identity of  the pathogen causing the disease, based upon clinical signs, history, necropsy examination, laboratory data and past experience before making a recommendation for antimicrobial use.  In addition, they should periodically monitor herd pathogen susceptibility and therapeutic response to detect changes in microbial susceptibility and to re-evaluate antimicrobial selections.  Records and observations on individual operations or within groups of cattle within a veterinarian’s area of  practice may be very helpful in making and modifying antimicrobial recommendations.  Historical diagnostic material obtained from post-mortem examinations, trans-tracheal washes and milk cultures may be utilized to allow the application of  narrow spectrum antimicrobials when necessary and only when necessary.  Although the susceptibility profiles of pathogens may be skewed in diagnostic data reports (due to prior therapy of some of  the animals), these reports are still a useful barometer of  changes in the populations of  pathogens encountered by food animal veterinarians.

The animal’s origin prior to their arrival should be considered when establishing a diagnosis in herd outbreaks and when developing treatment protocols, including therapeutic or metaphylactic antimicrobial use.  Implementation of applicable and proven biosecurity measures for purchased animals may reduce the need for antimicrobial therapy. Antimicrobials should be used at a dosage and duration appropriate for the condition treated.  The goals of  therapy should be to alleviate clinical signs and minimize recurrence of  clinical disease. Treatment of  subclinical mastitis caused by Streptococcus agalactiae should be directed by antimicrobial susceptibility information and should be administered so as to provide 24 hours of  therapeutic levels which will result in elimination of  the bacteria in 95% of  treated cases.  In the absence of data showing otherwise, practitioners should strive for the shortest duration of  therapy that results in satisfactory clinical response.

Product choices and regimens should be based on available laboratory and label (including  package insert) information, additional data in the literature and consideration of  the pharmacokinetics, spectrum, and pharmacodynamics of  the drug.  With this information, combined with the clinical and laboratory information previously mentioned, prudent and judicious antimicrobial use decisions are possible.  The label, dose, route, frequency, and duration should be followed whenever possible.

Antimicrobials should be used with specific clinical outcome(s) in mind, such as fever reduction, return of  mastitic milk to normal, to eliminate or reduce shedding, contagion, and recurrence of  disease. The use of  appropriately selected intramammary antimicrobials in cases of  mastitis caused by Gram positive bacteria will reduce the time to return to normal mammary secretion.13

The same does not hold true for Gram negative organisms.  Specific outcome criteria aid in preventing exceptionally long therapy and indicating when the current therapy is unsatisfactory. Periodically monitor herd pathogen susceptibility and therapeutic response, especially for routine therapy such as dry cow intramammary antibiotics, to detect changes in microbial susceptibility and to evaluateantimicrobial selections.  Susceptibility patterns for mastitis pathogens should be evaluated periodically to determine the appropriate class of  antimicrobials to Use products that have the narrowest spectrum of  activity and known efficacy in vivo against the pathogen causing the disease problem.   In clinical situations, the boundary between narrow and broad spectrum of  activity may be difficult to determine.  Narrow and broad spectrum levels of  activity will vary depending upon both the bacteria affected and the regimen chosen.  In spite of the difficulty in confining antimicrobial use to a narrow spectrum of  activity, resistance to antimicrobials should be minimized by selecting an antimicrobial with a narrow spectrum of  activity whenever possible. Utilizing  antimicrobials such as procaine penicillin G  for cases of  infection
with anaerobic bacteria, such as exist in infectious pododermatitis and toxic uterine infections, could be prudent  at labeled or some extralabel dosage, penicillin would be considered a narrow spectrum antimicrobial (see glossary). , even in the most ideal situation, the possibiltiy of  antimicrobial use affecting more than just the target pathogen exists. Antimicrobials should be used at a dosage appropriate for the condition treated and for as short a period of  time as reasonable. Therapy should be discontinued when it is apparent that the immune system can manage the disease, reduce pathogen shedding and minimize recurrence of  clinical disease or development of  the carrier state.  The National Mastitis Council recommends that intramammary antimicrobial therapy should provide for 72 hours of  levels at or above the MIC of  the pathogen causing a clinical mastitis to provide for the greatest chance of  microbiological cure in the affected quarter.  The veterinarian should rely on records and valid published information to justify their clinical judgement on the proper time to discontinue therapy. When possible, antimicrobials of  lesser importance in human medicine should be chosen before choosing a newer generation animal antimicrobial that may be in the same class as a human antimicrobial that may be used as the primary or sole treatment for a human infection.   An antimicrobial for which emergence of  resistance is expected to be in an advanced stage, should also not be chosen.   Products such as fluoroquinolones should be reserved for cases that can be predicted to be refractory to other therapies and should be used according to label directions or AMDUCA regulations.  No extralabel use of fluoroquinolones is provided for in the AMDUCA  regulations and this use is banned by law.  Therefore,  fluoroquinolones cannot be used in animals intended for dairy purposes.14 Antimicrobials labeled for use for treating the condition diagnosed should be used whenever possible.  The label, dose, route, frequency, and duration should be followed whenever possible. Antimicrobial therapy of  clinical mastitis, when indicated,  as with the Gram positive organisms, should provide adequate duration of  therapy. Combination antimicrobial therapy should be discouraged unless there is information to show increase in efficacy or suppression of  resistance development for the target organism.  Compounding of  antimicrobial formulations should be avoided.  There is little scientific information which supports the theories that either combinations of  antimicrobials or compounded antimicrobials are more effective than the use of  a solitary antimicrobial labeled for use in infections encountered in cattle.  We do know that combinations of  antimicrobials broaden the exposure of  pathogens and commensal bacteria in the animal. When appropriate, local therapy (e.g. intramammary, intrauterine, topical) is preferred over systemic therapy.  Labeled choices for local therapy may be very limited, but extralabel use would be appropriate if  the requirements for extralabel use  described on pages 5 and 6 were followed.  For example, an extralabel use of  a intrauterine antibacterial labeled for use in another animal species would be appropriate in cattle  if  no labeled antibacterial provided the efficacy or duration of  action needed.  An external wound dressing without a cattle label would be appropriate if  efficacious and if, as in all cases of  extralabel use, residues and contamination were prevented by the choice of  withdrawal Treatment of  chronic cases or those with a poor chance of  recovery should be avoided.  Chronic, non-responsive cases should be removed or isolated from the remainder of  the herd and use of  antimicrobials halted. Prophylactic or metaphylactic use of  antimicrobials should be based on a group, source or production unit evaluation rather than being utilized as standard practice.  The metaphylactic use of  lower than label doses of  antimicrobials to reduce expense should be actively discouraged. Veterinarians should endeavor to ensure proper on-farm drug use. Drug integrity should be protected through proper handling, storage and observation of  the expiration date.  Due to the potential for inspections of  drug storage facilities, the attending veterinarian should seek to perform periodic inspections of  the premises. Prescription or dispensed drug quantities should be appropriate to the production-unit size and expected need so that stockpiling of  antimicrobials on the farm is avoided.  The amount of  a particular pharmaceutical allowed for prescription from a drug distributor should be consistent with previous and expected disease incidence and treatment requirements.  If  the antimicrobials are not dispensed by the veterinarian, adequate lines of  communication between the veterinarian, animal producer, and pharmaceutical distributor, coupled with 15 appropriately scripted and labeled products, enhance proper drug usage.  The prescribing veterinarian should seek to review or receive copies of  invoices of scripted drug purchases to insure that appropriate quantities are being purchased for use. The veterinarian should train farm personnel who use antimicrobials on indications, dosages, withdrawal times, route of  administration, injection site precautions, storage, handling, record keeping, and accurate diagnosis of common diseases.  The veterinarian should ensure that labels are adequate to instruct farm personnel on the correct use of  antimicrobials. The veterinarian should be able to provide frequent inspections of  inventory and treatment Veterinarians are encouraged to provide written, updated protocols for diagnosis and treatment to clients whenever possible.  Those protocols should describe conditions and provide instructions for antimicrobial use at a farm or unit when a veterinarian is unavailable.

Additional Sources of Information Regarding Antimicrobial Use Apley, Mike: Respiratory disease therapeutics,  in Howard and Smith(eds): Current Veterinary Therapy-Food Animal Practice 4. Philadelphia, WB Saunders Co. 1999, pages 462-471. Apley, Mike: Feedlot therapeutics,  in Stokka GL (ed): Feedlot Medicine and Management. Veterinary Clinics of  North America, [Food Animal Practice],  July 1998, 291-311. Apley, Mike: Antimicrobial therapy of  bovine respiratory disease,  in St. Jean and Vestweber (eds): Update on Bovine Respiratory Disease. Veterinary Clinics of North America, [Food Animal Practice], November 1997, pages 549-574. Beef  Sessions on Antibiotic Resistance, in Proceedings of  32nd Annual Convention of  American Association of  Bovine Practitioners, September 1999, pages 71-122. Food Animal Residue Avoidance Databank Comprehensive Compendium of  Food Animal Drugs.  Available from Publications, University of  Florida, PO Box 110011, Gainsville, FL 32611-0011; or telephone 352-392-9861. General Sessions on Antibiotic Resistance, in Proceedings of  32nd Annual Convention of  American Association of  Bovine Practitioners,  September 1999, pages 10-23. Helpful Tips for Extra-Label Drug Use, in Journal of  American Veterinary Medical Association, vol 212, #5, March 1, 1998; #7, April 1, 1998; #9, May 1, 1998; #11, June 1, 1998. Langston, Vernon: Antimicrobial Use in Food Animals. in Howard and 16 Smith(eds): Current Veterinary Therapy-Food Animal Practice 4. Philadelphia, WB Saunders Co, 1999, pages17-32. Prudent Drug Usage Guidelines, in The Bovine Practitioner, January, 2000, vol 34, No. 1, p 73.

BIBLIOGRAPHY

1. Anonymous.  The Medical Impact of  the Use of  Antimicrobials in Food Animals—Report and  Proceedings of  a WHO Meeting, Berlin, Germany, 13-17 October 1997.  WHO,  p. 1, 1998.

2. Committee on Drug Use in Food Animals, NRC/IOM.  The Use of  Drugs in Food Animals: Benefits and  Risks. National Academy Press, p. 65, 1999.

3. Mead PS., et al, Food-Related Illness and Deaths in the United States.  Emerging Infectious  Diseases 5(5): September-October 1999.

4. Anonymous.  Risk Assessment on the Human Health Impact of  Fluoroquinolone Resistant Campylobacter  Associated with the Consumption of  Chicken.  FDA, December 1999. 

5. Smith K, et al.  The epidemiology of  quinolone-resistant Campylobacter infections in Minnesota,  1992-1998. N Engl J Med, 340(20):1525-1532, 1999.

  1. Anonymous. 1998 Annual Report – National Antimicrobial Resistance Monitoring System: Enteric Bacteria.  CDC, 1999.

GLOSSARY

Antibiotic—a chemical substance produced by a microorganism which has the capacity, in dilute solutions, to inhibit the growth of  or to kill other microorganisms.

Antimicrobial—an agent that kills bacteria or suppresses their multiplication or growth. This includes antibiotics and synthetic agents. This excludes ionophores and arsenicals. Narrow Spectrum Antimicrobial—an antimicrobial effective against a limited number of  bacterial genera often applied to an antimicrobial active against either Gram-positive or Gram-negative bacteria.

Broad Spectrum Antimicrobial—an antimicrobial effective against a large number of  bacterial genera; generally describes antibiotics effective against both Gram-positive and Gram-negative bacteria.

Antibiotic Resistance—a property of  bacteria that confers the capacity to inactivate or exclude antibiotics or a mechanism that blocks the inhibitory or killing effects of  antibiotics.

Extralabel—Extralabel use means actual use or intended use of  a drug in an 17 animal in a manner that is not in accordance with the approved labeling.  This includes, but is not limited to, use in species not listed in the labeling, use for

indications (disease or other conditions) not listed in the labeling, use at dosage levels, frequencies, or routes of  administration other than those stated in the labeling, and deviation from the labeled withdrawal time based on these different

Immunization—the process of  rendering a subject immune or of  becoming immune, either by conventional vaccination or exposure.

Monitoring—monitoring includes periodic health surveillance of  the population or individual animal examination.

Therapeutic—treatment, control, and prevention of  bacterial disease Veterinarian-Client-Patient Relationship (VCPR) — A VCPR exists when all of the following conditions have been met:

1. The veterinarian has assumed the responsibility for making clinical judgements regarding the health of  the animal(s) and the need for medical treatment, and the client has agreed to follow the veterinarian’s instructions.

2. The veterinarian has sufficient knowledge of  the animal(s) to initiate at least a general or preliminary diagnosis of  the medical condition of  the animal(s). This means that the veterinarian has recently seen and is personally acquainted with the keeping and care of  the animal(s) by virtue of  an examination of  the animal(s) or by medically appropriate and timely visits to the premises where the animal(s) are kept.

3. The veterinarian is readily available for follow-up evaluation, or has arranged for emergency coverage, in the event of  adverse reactions or failure of  the treatment regimen. Veterinary Feed Directive (VFD) Drug—The VFD category of  medicated feeds was created by the Animal Drug Availability Act of 1996 to provide an alternative to prescription status for certain therapeutic animal pharmaceuticals for use in feed. Any animal feed bearing or containing a VFD drug shall be fed to animals only by or upon a lawful VFD issued by a licensed veterinarian in the course of the veterinarian’s professional practice.DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration Center for Veterinary Medicine

This means that the veterinarian has recently seen and is personally acquainted with the keeping and care of  the animal(s) by virtue of  an examination of  the animal(s) or by medically appropriate and timely visits to the premises where t

he animal(s) are kept. c) The veterinarian is readily available for follow-up evaluation, or has arranged for emergency coverage, in the event of  adverse reactions or failure of  the treatment regimen. When it is not possible to make a direct clinical evaluation, the diagnosis should be based on past experience, on knowledge of  the farm epidemiological status, and  historical and/or on-going susceptibility testing.

4) Prescription, Veterinary Feed Directive, and extralabel use of  antimicrobials 6 must meet all the requirements of  a valid veterinarian-client-patient relationship.

Federal regulations mandate a valid VCPR for the dispensing and use of prescription and VFD drugs and for extralabel use of  drugs.  Extralabel use of antimicrobials in or on animal feeds is prohibited.

5) Extralabel antimicrobial therapy must be prescribed only in accordance with the Animal Medicinal Drug Use Clarification Act amendments to the Food, Drug, and Cosmetic Act and its regulations. No drug can be marketed unless its quality, safety, and efficacy have been

  1. Therefore, the first line of choice should be based on the products approved for the species and the indication concerned.  When no suitable product is approved for a specific condition or species, or the approved product is considered to be clinically ineffective, the choice of  an alternative product should be based, whenever possible, on the results of  valid scientific studies and a proven efficacy for the condition and species concerned.

a) For food animals, extralabel drug use (ELDU) is not permitted if  a drug exists that is labeled for the food animal species and contains the needed ingredient, is in the proper dosage form, is labeled for the indication, and is clinically effective.

b) ELDU is permitted only by or under the supervision of  a veterinarian.

c) ELDU is allowed only for FDA approved animal and human drugs.

d) ELDU is permitted for therapeutic purposes only when an animal’s health is suffering or threatened.  ELDU is not permitted for production drugs (e.g., growth promotion).

e) ELDU in feed is prohibited.

f) ELDU is permitted for preventative purposes when an animal’s health is

g) ELDU is not permitted if  it results in a violative food residue, or any residue that may present a risk to public health.

h) ELDU requires scientifically based drug withdrawal times to ensure food

i) The record and labeling requirements must be met.

j) The FDA prohibits specific ELDU.  For example, the following drugs are prohibited for extralabel use in food animals: chloramphenicol, clenbuterol, diethylstilbestrol, dimetridazole, ipronidazole, other nitroimidazoles, furazolidone (except for approved topical use), nitrofurazone (except for approved topical use), sulfonamide drugs in lactating dairy cows (except approved use of  sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine), fluoroquinolones, and glycopeptides (example is

vancomycin).

6) Veterinarians should work with those responsible for the care of  animals to use antimicrobials judiciously regardless of  the distribution system through which the antimicrobial was obtained. Since 1988, FDA has approved new therapeutic antimicrobials for use in animals as prescription-only products.  The prescription-only policy is based on the need to assure the proper use of  antimicrobials through precise diagnosis and7 correct treatment of  disease to minimize animal suffering and to avoid drug residues in food.  However, many of  the older antimicrobials are available for over-the-counter sale to producers.  For these drugs, the FDA has determined that the producers can use the antimicrobials, safely and effectively, as directed on the 1. Regular, close veterinary involvement can assist the producers by providing informed advice and guidance on judicious use.  Extralabel use of  over-thecounter antimicrobials would require that a veterinarian and the producer follow the constraints of  AMDUCA, including the establishment of  a valid veterinaryclient-patient relationship. Quality assurance programs also provide guidance to  producers and veterinarians on proper use of  drugs.  The Nebraska Beef  Quality Assurance Program and the Wisconsin  VMA  AMDUCA Task Force are outstanding examples.

7) Regimens for therapeutic antimicrobial use should be optimized using current pharmacological information and principles. For labeled use of  an antimicrobial, the most accessible source of  information is the label, which includes the package insert.  For extralabel use, the Food Animal Residue Avoidance Databank can assist with determinations of  withdrawal times.  To assist with determinations of  possible alternatives to antimicrobial therapy and with drug use regimens when using antimicrobials, several veterinary organizations and two producer organization are funding the development of  the Veterinary Antimicrobial Decision Support System (VADS).

The objective of VADS is to provide veterinarians with a source of  easily accessible information on the therapy of  specific diseases to help them make informed treatment decisions.  The new decision support system will allow veterinarians to access current, peer-reviewed information when selecting treatment regimens.  The available information will include a full-range of therapeutic options, and the supporting data for each antimicrobial available to treat a disease.  The pathogen data will include susceptibility profile information, when available, as well as an interpretation of  susceptibility breakpoints as related to clinical efficacy.

The choice of the right antimicrobial needs to take into account pharmacokinetic parameters, such as bioavailability, tissue distribution,  apparent elimination half-life, and tissue kinetics to ensure the selected therapeutic agent reaches the site of

  1. Duration of withdrawal times may be a factor in choosing suitable
  2. Consideration must also be given to the available pharmaceutical forms and to the route of  administration.  Prolonged oral use should be avoided, as most of  the concerns with regard to resistance are associated with the selection and transfer of resistant, zoonotic bacteria that inhabit the gut.

8) Antimicrobials considered important in treating refractory infections in human or veterinary medicine should be used in animals only after careful review and reasonable justification.  Consider using other antimicrobials for initial therapy.

In this context, this principle takes into account development of  resistance or cross-resistance to important antimicrobials.  In December 1998, the FDA made available  “A Proposed Framework for Evaluating and Assessing the Human Safety of  the Microbial Effects of  Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals”8 (Framework Document).  A concept introduced by the Framework Document is the categorization of  antimicrobials based on their unique or relative importance to human medicine and their likelihood of  affecting human exposure to food-borne pathogens..  While the criteria for categorization remain under discussion, it is expected that antimicrobials such as the fluoroquinolones and third generation cephalosporins will probably be classified in the most important category. The fluoroquinolones are also very important for the treatment of colibacillosis in poultry.

9) Use narrow spectrum antimicrobials whenever appropriate. To minimize the likelihood of  broad antimicrobial resistance development, where an appropriate narrow spectrum agent is available, it should be selected in preference to a broad spectrum agent.

10) Utilize culture and susceptibility results to aid in the selection of antimicrobials when clinically relevant.

Susceptibility profiles can vary between herds and flocks.  Periodic culture and susceptibility  testing can provide historical data on which to base future empirical treatment as well as assist in selecting a treatment for refractory infections.  Ideally, the

susceptibility profile of  the causal organism should be determined before therapy is

  1. The veterinarian has a responsibility to determine the applicability of the breakpoints used by the lab for the specific disease indication  being considered.  In disease outbreaks involving high mortality or where there are signs of  rapid spread of

disease, treatment may be started on the basis of  a clinical diagnosis and previous applicable susceptibility results before current samples are submitted for susceptibility evaluation or results are obtained.   Even so, the susceptibility of  the suspected causal organism should, where possible, be determined so that if  treatment fails it can be changed in the light of  the results of  susceptibility testing.   Antimicrobial susceptibility trends should be monitored over time, and such monitoring used to guide clinical judgement on antibiotic usage.

Susceptibility tests are intended to be a guide for the practitioner, not a guarantee, that an antimicrobial will be effective in therapy.  Susceptibility testing can only give an indication of  what the clinical activity of  the drug will

  1. The projection of clinical efficacy from an in vitro MIC determination is much more accurate for antimicrobials with validated breakpoints for the specific The effect of the drug in vivo depends on its ability to reach the site of  infection in a high enough concentration, the nature of  the pathological process, and the immune responses of  the host.

11) Therapeutic antimicrobial use should be confined to appropriate clinical

  1. Inappropriate uses such as for uncomplicated viral infections should be avoided. Veterinarians should use their professional knowledge and clinical judgment to decide whether viral infections may involve or predispose to  a superimposed

bacterial infection.

12) Therapeutic exposure to antimicrobials should be minimized by treating only for as long as needed for the desired clinical response. 9 Theoretically, infections should be treated with antimicrobials only until the host’s defense system is adequate to resolve the infection.  While it may be difficult to judge optimal treatment duration, limiting the duration of  use to only that required for therapeutic effect will minimize the exposure of  the bacterial population to the antimicrobial.  The adverse effects on the surviving commensal microflora are minimized and the medical impact on the remaining zoonotic organisms is reduced.  However, treatment for too short a period can also be problematic because it can lead to recrudescence of  the infection.  It is then possible that a higher percentage of  the pathogens involved in the recrudescence episode have reduced susceptibility to the antimicrobial.

13) Limit therapeutic antimicrobial treatment to ill or at risk animals, treating the fewest animals indicated. In some classes of  livestock, if  a number of  animals in a group have overt signs of  disease, both sick and healthy animals may be treated with therapeutic levels of an antimicrobial.  This is intended to cure the clinically affected animals, reduce the spread of  the disease, and arrest disease development in animals not yet showing clincial signs.

It is recognized that strategic, metaphylactic  medication of  a specific group of animals may be appropriate in certain precisely defined circumstances.  However, this should be part of  an integrated disease control program and the need for such

medication should be regularly re-evaluated.  The use of  antimicrobials in the absence of  clinical disease or pathogenic infections should be restricted to situations where past experience indicates that the risk is high that a group of animals may develop disease if  not treated.  In addition, long-term administration to prevent disease should not be practiced without a clear medical justification.

14) Minimize environmental contamination with antimicrobials whenever Unused antimicrobials should be properly disposed.  Also some antimicrobials may be environmentally stable in manure.  If  the antimicrobials are not bound in an inactive form, environmental exposure could contribute to resistance development.  Consideration may need to be given to disposal methods that will not recycle resistant organisms to humans or animals.

15) Accurate records of  treatment and outcome should be used to evaluate therapeutic regimens. Outcome records can greatly assist with design of  future empiric treatment The implementation of  these general judicious use principles, and the more

specific examples in the prudent antimicrobial use guidelines  given in the following sections,  will reduce the development of  resistant zoonotic pathogens and commensals in animals and will lessen the risk of a human health impact related to the therapeutic use of  antimicrobials in animals.

10 Application of Judicious and Prudent Microbial Use Principles by Dairy Cattle Practitioners 

Veterinarians treating cattle with antimicrobials have always had three responsibilities: first, to diagnose, prevent and, when necessary, treat disease in their patients; second, to optimize the production and health maintenance resources of  those who own and care for their patients; and third, to meet the expectations regarding the safety of  food animal production of  those who choose to consume food products derived from their clients’ cattle.  Consumers should expect that veterinarians have prudently and judiciously used antimicrobials in order to minimize the emergence or development of  antimicrobial resistance.

There has never been a time when veterinarians did not have all three

  1. In the past, some veterinarians may have chosen treatment options based on perceived  success in treating an individual patient or patients on an individual farm, as being the only important responsibility. To diminish the importance of  the other two responsibilities is poor medical and business decision Conservation of  available antimicrobials requires that veterinarians select and use  them appropriately.  If  veterinarians do not, the FDA Center for Veterinary Medicine will have to respond as the laws and regulations require. The result will be an impression by consumers of  food animal products and by groups advocating positions of  food safety that cattle-derived food products are not produced with sound practices.  While the magnitude of  the impact of  antimicrobial use in cattle on the development of  antibiotic resistance for human pathogens may continue to be discussed, the importance of  prudent and judicious antimicrobial use has never been greater. It is false economic benefit to choose an inappropriate antimicrobial regimen if  it undermines the veterinary profession’s credibility with consumers or those who implement our national food animal drug laws and regulations.  When antimicrobial choices are diminished, veterinarians’  ability to enhance productivity and to treat disease will also be diminished.  The focus of  both veterinarians and producers should be on the safety and needs of  the consumer.

The production of  safe and wholesome animal products for human consumption should be a primary goal of  veterinarians caring for dairy cattle.  In reaching that goal, as mentioned in the general principles, emphasis should be placed on practitioners being committed to preventive immune system management through the use of  vaccines, parasiticides, stress reduction, and proper nutritional management. Proper and timely management practices can reduce the incidence of  disease and therefore reduce the need for antimicrobials.  Nevertheless, antimicrobials will remain a necessary tool to manage infectious diseases in dairy To reemphasize the points made earlier, prudent and judicious use of antimicrobials is necessary to reduce animal pain and suffering, to protect the11 economic livelihood of  dairy producers, to ensure the continued production of foods of  animal origin, and to minimize the shedding of  zoonotic bacteria into the environment and potentially the food chain.   The following are specific recommendations for the prudent and judicious use of  antimicrobials in dairy cattle and are provided for each of  the prudent antimicrobial use guidelines adopted by theAABP.

The veterinarian should accept responsibility for helping clients design management, immunization, housing, and nutritional programs that will reduce the incidence of  disease and the need for antimicrobials. Providing adequately ventilated housing, such as with calf  hutches, minimizes the potential for the development of  bovine respiratory disease.  Colostrum management programs and their monitoring will enhance the health of  the young replacement Adequate selenium and vitamin E nutrition will enhance udder health and aid in mastitis prevention as well as minimizing the incidence of  retained placenta in the postpartum cow. Ensuring adequate pre-calving nutrition of  the cow, particularly protein, is of  paramount importance.  This will enhance the passive transfer of antibodies from high quality colostrum to the neonatal calf, and has been proven to provide health benefits throughout the life of  the animal. When a poorly functioning immune system results in an increased level of  respiratory disease, efforts to identify and correct  immunosuppresive factors should be

  1. The reduction in morbidity and mortality, and the related decrease in the need for antimicrobials, may be dramatic where levels of  nutrients such as copper, zinc and selenium are optimized.

The use of  antimicrobials only within the confines of  a valid veterinarianclient-patient relationship (see page 5), for both dispensing and the issuance of prescriptions, has been recommended by the American Association of  Bovine

  1. In addition, extralabel usage should be within the provisions contained within the AMDUCA regulations (see page 6).  All veterinarians should carefully review their willingness to respond to producers’ requests for antimicrobial use recommendations.  If  a veterinarian is not the person responsible for diagnosis of  disease conditions on a dairy cattle operation, is not available for questions or concerns following treatment with antimicrobials or has not accepted the responsibility for health care of  the cattle on that operation, they will not be in position to optimize antimicrobial use or to minimize the development of  resistance to antimicrobials.  Veterinarians prescribing, dispensing, or administering antimicrobials to cattle should utilize the services of FARAD or other unbiased and reputable sources to provide scientifically sound withdrawal times for producers. Veterinarians should properly select and use antimicrobial drugs. Veterinarians should participate in continuing education programs that include therapeutics and emergence and/or development of  antimicrobial resistance.

Human food safety concerns are discussed at numerous regional, state and national meetings every year.  At least some portion of  required Continuing Education hours should be received on the topic of  antimicrobial susceptibility12 of  animal and potential zoonotic pathogens.  Material accessible from reliable sources such as the FDA/CVM, FARAD, and AABP home pages and from the list of  additional sources of  information given at the end of  this paper should be incorporated into treatment considerations and recommendations.

A dairy cattle veterinarian should have strong clinical evidence of  the identity of  the pathogen causing the disease, based upon clinical signs, history, necropsy examination, laboratory data and past experience before making a recommendation for antimicrobial use.  In addition, they should periodically monitor herd pathogen susceptibility and therapeutic response to detect changes in microbial susceptibility and to re-evaluate antimicrobial selections.  Records and observations on individual operations or within groups of  cattle within a veterinarian’s area of  practice may be very helpful in making and modifying antimicrobial recommendations.  Historical diagnostic material obtained from post mortem examinations, trans-tracheal washes and milk cultures may be utilized to allow the application of  narrow spectrum antimicroials when necessary and only when necessary.  Although the susceptibility profiles of pathogens may be skewed in diagnostic data reports (due to prior therapy of  some of  the animals), these reports are still a useful barometer of  changes in the populations of  pathogens encountered by food animal veterinarians.

The animal’s origin prior to their arrival should be considered when establishing a diagnosis in herd outbreaks and when developing treatment protocols, including therapeutic or metaphylactic antimicrobial use.  Implementation of applicable and proven biosecurity measures for purchased animals may reduce the need for antimicrobial therapy.

Antimicrobials should be used at a dosage and duration appropriate for the condition treated.  The goals of  therapy should be to alleviate clinical signs and minimize recurrence of  clinical disease. Treatment of  subclinical mastitis caused by Streptococcus agalactiae should be directed by antimicrobial susceptibility information and should be administered so as to provide 24 hours of  therapeutic levels which will result in elimination of  the bacteria in 95% of  treated cases.  In the absence of  data showing otherwise, practitioners should strive for the shortest duration of  therapy that results in satisfactory clinical response. Product choices and regimens should be based on available laboratory and label (including  package insert) information, additional data in the literature and consideration of  the pharmacokinetics, spectrum, and pharmacodynamics of  the drug.  With this information, combined with the clinical and laboratory information previously mentioned, prudent and judicious antimicrobial use decisions are possible.  The label, dose, route, frequency, and duration should be followed whenever possible.

Antimicrobials should be used with specific clinical outcome(s) in mind, such as fever reduction, return of  mastitic milk to normal, to eliminate or reduce shedding, contagion, and recurrence of  disease. The use of  appropriately selected intramammary antimicrobials in cases of  mastitis caused by Gram positive bacteria will reduce the time to return to normal mammary secretion.13 

The same does not hold true for Gram negative organisms.  Specific outcome criteria aid in preventing exceptionally long therapy and indicating when the current therapy is unsatisfactory. Periodically monitor herd pathogen susceptibility and therapeutic

response, especially for routine therapy such as dry cow intramammary antibiotics, to detect changes in microbial susceptibility and to evaluate antimicrobial selections.  Susceptibility patterns for mastitis pathogens should be evaluated periodically to determine the appropriate class of  antimicrobials to Use products that have the narrowest spectrum of  activity and known efficacy in vivo against the pathogen causing the disease problem.   In clinical situations, the boundary between narrow and broad spectrum of  activity may be difficult to determine.  Narrow and broad spectrum levels of  activity will vary depending upon both the bacteria affected and the regimen chosen.  In spite of the difficulty in confining antimicrobial use to a narrow spectrum of  activity, resistance to antimicrobials should be minimized by selecting an antimicrobial with a narrow spectrum of  activity whenever possible.

Utilizing  antimicrobials such as procaine penicillin G  for cases of  infection with anaerobic bacteria, such as exist in infectious pododermatitis and toxic uterine infections, could be prudent  at labeled or some extralabel dosage, penicillin would be considered a narrow spectrum antimicrobial (see glossary).

However, even in the most ideal situation, the possibiltiy of  antimicrobial use affecting more than just the target pathogen exists. Antimicrobials should be used at a dosage appropriate for the condition treated and for as short a period of  time as reasonable. Therapy should be discontinued when it is apparent that the immune system can manage the disease, reduce pathogen shedding and minimize recurrence of  clinical disease or development of  the carrier state.  The National Mastitis Council recommends that intramammary antimicrobial therapy should provide for 72 hours of  levels at or above the MIC of  the pathogen causing a clinical mastitis to provide for the greatest chance of  microbiological cure in the affected quarter.  The veterinarian should rely on records and valid published information to justify their clinical judgement on the proper time to discontinue therapy.

When possible, antimicrobials of  lesser importance in human medicine should be chosen before choosing a newer generation animal antimicrobial that may be in the same class as a human antimicrobial that may be used as the primary or sole treatment for a human infection.   An antimicrobial for which emergence of  resistance is expected to be in an advanced stage, should also not be chosen.   Products such as fluoroquinolones should be reserved for cases that can be predicted to be refractory to other therapies and should be used according to label directions or AMDUCA regulations.  No extralabel use of fluoroquinolones is provided for in the AMDUCA  regulations and this use is banned by law.  Therefore,  fluoroquinolones cannot be used in animals intended for dairy purposes.14

Antimicrobials labeled for use for treating the condition diagnosed should be used whenever possible.  The label, dose, route, frequency, and duration should be followed whenever possible. Antimicrobial therapy of  clinical mastitis, when indicated,  as with the Gram positive organisms, should provide adequate duration of  therapy. Combination antimicrobial therapy should be discouraged unless there is information to show increase in efficacy or suppression of  resistance development for the target organism.  Compounding of  antimicrobial formulations should be avoided.  There is little scientific information which supports the theories that either combinations of  antimicrobials or compounded antimicrobials are more effective than the use of  a solitary antimicrobial labeled for use in infections encountered in cattle.  We do know that combinations of  antimicrobials broaden the exposure of  pathogens and commensal bacteria in the animal.

When appropriate, local therapy (e.g. intramammary, intrauterine, topical) is preferred over systemic therapy.  Labeled choices for local therapy may be very limited, but extralabel use would be appropriate if  the requirements for extralabel use  described on pages 5 and 6 were followed.  For example, an extralabel use of  a intrauterine antibacterial labeled for use in another animal species would be appropriate in cattle  if  no labeled antibacterial provided the efficacy or duration of  action needed.  An external wound dressing without a cattle label would be appropriate if  efficacious and if, as in all cases of  extralabel use, residues and contamination were prevented by the choice of  withdrawal Treatment of  chronic cases or those with a poor chance of  recovery should be avoided.  Chronic, non-responsive cases should be removed or isolated from the remainder of  the herd and use of  antimicrobials halted.

Prophylactic or metaphylactic use of  antimicrobials should be based on a group, source or production unit evaluation rather than being utilized as standard practice.  The metaphylactic use of  lower than label doses of  antimicrobials to reduce expense should be actively discouraged. Veterinarians should endeavor to ensure proper on-farm drug use. Drug integrity should be protected through proper handling, storage and observation of  the expiration date.  Due to the potential for inspections of  drug storage facilities, the attending veterinarian should seek to perform periodic inspections of  the premises.

Prescription or dispensed drug quantities should be appropriate to the production-unit size and expected need so that stockpiling of  antimicrobials on the farm is avoided.  The amount of  a particular pharmaceutical allowed for prescription from a drug distributor should be consistent with previous and expected disease incidence and treatment requirements.  If  the antimicrobials are not dispensed by the veterinarian, adequate lines of  communication between the veterinarian, animal producer, and pharmaceutical distributor, coupled with15 appropriately scripted and labeled products, enhance proper drug usage.  The prescribing veterinarian should seek to review or receive copies of  invoices of scripted drug purchases to insure that appropriate quantities are being purchased for use.

The veterinarian should train farm personnel who use antimicrobials on indications, dosages, withdrawal times, route of  administration, injection site precautions, storage, handling, record keeping, and accurate diagnosis of common diseases.  The veterinarian should ensure that labels are adequate to instruct farm personnel on the correct use of  antimicrobials. The veterinarian should be able to provide frequent inspections of  inventory and treatment Veterinarians are encouraged to provide written, updated protocols for diagnosis and treatment to clients whenever possible.  Those protocols should describe conditions and provide instructions for antimicrobial use at a farm or unit when a veterinarian is unavailable.

Additional Sources of Information Regarding Antimicrobial Use Apley, Mike: Respiratory disease therapeutics,  in Howard and Smith(eds): Current Veterinary Therapy-Food Animal Practice 4. Philadelphia, WB Saunders Co. 1999, pages 462-471.

Apley, Mike: Feedlot therapeutics,  in Stokka GL (ed): Feedlot Medicine and Management. Veterinary Clinics of  North America, [Food Animal Practice],  July 1998, 291-311.

Apley, Mike: Antimicrobial therapy of  bovine respiratory disease,  in St. Jean and Vestweber (eds): Update on Bovine Respiratory Disease. Veterinary Clinics of North America, [Food Animal Practice], November 1997, pages 549-574.

Beef  Sessions on Antibiotic Resistance, in Proceedings of  32nd Annual Convention of  American Association of  Bovine Practitioners, September 1999, pages 71-122.

Food Animal Residue Avoidance Databank Comprehensive Compendium of  Food Animal Drugs.  Available from Publications, University of  Florida, PO Box 110011, Gainsville, FL 32611-0011; or telephone 352-392-9861.

General Sessions on Antibiotic Resistance, in Proceedings of  32nd Annual Convention of  American Association of  Bovine Practitioners,  September 1999, pages 10-23. Helpful Tips for Extra-Label Drug Use, in Journal of  American Veterinary Medical Association, vol 212, #5, March 1, 1998; #7, April 1, 1998; #9, May 1, 1998; #11, June 1, 1998.

Langston, Vernon: Antimicrobial Use in Food Animals. in Howard and16 Smith(eds): Current Veterinary Therapy-Food Animal Practice 4. Philadelphia, WB Saunders Co, 1999, pages17-32. Prudent Drug Usage Guidelines, in The Bovine Practitioner, anuary, 2000, vol 34, No. 1, p 73.

 

Monsanto vs Alkalized Water on Cows!

With the advent of electrolysis water treatment in the Japanese marketplace, Electrolysis alkaline water was introduced into the dairy farms. Knowing the positive health benefits and results that were acquired through human consumption, alkali water was used in place of tap water as the sole source of water for dairy cows. The result of this water usage is reported in the subsequent findings. The information was obtained through 27 dairy farms along with a report from a group of veterinarians. The source of each report is identified at the beginning of each report. The SD501 pumps 60 gallons an hour at $3980+tax and has 7 solid plates. The K8 pumps 90 gallons an hour at $4980+tax and has 8 solid plates and we have financing! Machine last 20 to 25 years and can be rebuilt for $750 for 20 more years. After you read this see this video 

See the purchasing of multiple SD501 units. This water has been used in hundreds of Japanese Hospitals and treatment centers for 40 years and the SD501 has had over 20 years in homes and last 20 to 25 years, can be rebuilt for $750 for decades more and in 36 countries. They will celebrate their 1 millionth machine sold in 6 months. So with the declining costs when purchasing more than 1 machine, with the end of costs basically at purchase, reduced sterilization costs and the Japanese drink the most alkaline water per person in the world and live the longest how can you deny your cows and cattle this water. Now the report.

In general, the following measurable conditions were noted:

1. An increase in milk output by 18~28%

2. A notable improvement in the quality of milk.

3. Elimination of strong feces and urine odors.

4. Healthier skin condition.

5. Minimized injury to the udder.

6. Decrease in diarrhea cases.

7. Strengthening of the legs.

8. Increased appetite.

9. Able to reduce mineral supplements normally added to the feed.

10. Due to an improved health condition coupled with stronger legs. Extended the productive life span of the cows.

11. Improved the fertility rate and reduced still births in new-born calves.

Aside from the above, the following opinions were noted by the veterinarians:

 

1. A noticeably increased appetite; no new supplements were added to their diet. Increase in appetite noted in older cows also.

2. Well digested foods.

3. A beautiful sheen on the cow’s hair.

4. Higher fertility rate; higher pregnancy rate.

5. A new-born calf exposed to alkali water matures quicker.

6. A dramatic increase in milk production.

7. Improved liver condition.

8. Strengthened legs.

9. Minimizing of sicknesses; tremendously improved health condition. .

10. No adverse conditions noted with the consumption of alkali water. Lesser visits made by veterinarians.

The following are individual findings that have been noted by each dairy farmer that have replaced tap water with alkali water.

A. Dairy Farm: Kasahara Ranch
Location: Nomura, Hokkaido
Spokesperson: Mr. G. Kasahara

1. The milk output had increase from 7,OOOkg to 8,9OOkg or an increase of 27%.
2. The use of the alkali water had instilled a preventive approach to the overall health condition of the dairy cow in lieu of reactive medical means. The overall health condition of the herd had improved dramatically.

B. Dairy Farm:Shikawa Ranch
Location: Momembetsu, Hokkaido .
Spokesperson: Mr. T Shikawa

1. There was a noticeable improvement in the quality of the milk.
2. Despite the high temperature during the Summer months, the milk output had increased dramatically. During the previous Summer months, milk output had declined.

c. Dairy Farm: Sudo Ranch
Location: Munetani, Hokkaido
Spokesperson: Mr. M. Sudo

NOTE: Unlike other dairy farms. this farmer had discontinued the use of alkali water to measure the effects of returning to normal tap water. The following were the effects that were noted:

1. The strong odors associated with cow excrements had returned after a period of time when the foul odor had been eliminated through the consumption of alkali water.
2. The sheen that was once present on the cows had disappeared and the hair had returned to a lackluster condition.
3. The frequency of diarrhea had increased.
4. Weakness was noticed in the cows legs as opposed to the strengthening of the cows legs during the use of alkali water.

D. Dairy Farm: Takahashi Ranch
Location: Notsuke. Hokkaido.
Spokesperson: Mr. 1. Takahashi

1. The sickness rate was considerably reduced.

E. Dairy Farm: Hamanasu Ranch
Location: Mombetsu. Hokkaido
Spokesperson: Mr. S. Nakagawa

1. The coloring of the udder became extremely healthy.
2. Due to the alkali consumption and it’s natural healing ability. the amount of injury to the udder had diminished.
3. The milk output has increased by 8OO kg per cow. (NOTE: since there was no “before and after” numbers provided the percentage of increase could not be determined.)

F. Dairy Farm: Karita Ranch
Location: Notsuke, Hokkaido
Spokesperson: Mr. H. Karita

1. The results were excellent in every manner. Milk production was considerably higher. the sickness rate
2. was down, problems associated with diarrhea were minimized, the foul odor from the excrement was
gone, the cow’s appetite was up, the sheen on the cow’s hair was considerably higher and the overall quality of the milk was up.

G. Dairy Farm: Takada Ranch
Location: Hokkaido. Takigawa
Spokesperson: Mr. K. Takagawa

1.The farmer was having a very difficult time to get their cows to drink tap water. With the introduction of alkali water, this concern was eliminated. The cows had taken a liking to the alkali water and had started to drink it on a consistent manner.

H. Dairy Farm: No Name Provided
Location: Kamikawa. Hokkaido
Spokesperson: Mr. N. Kushida

1. The consumption of the alkali water has stabilized the appetites of the cow. The cows have developed a steady and strong appetite.

I. Dairy Farm: Mori Ranch
Location: Kamikawa. Hokkaido
Spokesperson: Mr. S. Mori

1. The rate of diarrhea has decreased considerably.
2. The cows had developed an increased and consistent appetite.
3. The farmer was able to reduce the amount of mineral supplements that were being added to the diet on account of the alkali water.

J. Dairy Farm: No Name Given
Location: Notsuke, Hokkaido
Spokesperson: Mr. K. Noya

1. Due to the increase in calcium intake the legs were strengthened on the cow resulting in a longer life span for the cow as a milk producer.
2. It became known that water was the most important element in the cow’s diet and overall health condition.
3. The effects of the fortified minerals. through alkali water were positive and conclusive.

K. Dairy Farm: Nozawa Ranch
Location: Kamikawa, Hokkaido
Spokesperson: Mr. T. Nozawa

1. The dramatically improved health condition, stamina level and the improved strength in the legs of the cows have added longevity to the cows. This has reduced the frequency of having to procure new dairy
cows.

2. The appetite level of a cow giving birth generally declined after it’s pregnancy. This condition was overcome by the use of alkali water which rejuvenated their appetite immediately after delivery.

L. Dairy Farm: Sunnydale Ranch
Location: Hyotsu, Hokkaido
Spokesperson: Mr. M. Danshora

1. In prior years, in an effort to increase milk production, increased feed was given to cows. With the use of alkali water, the need of increasing feed was minimized.
2. Despite the pregnancy of the cow, the amount of milk production has not decreased. In prior pregnancies, the amount of milk production had decreased. This was noted in 9 out of 1 0 cows.
3. The improved health condition of the cows along with the stronger legs have reduced the turnover of cows. This has considerably improved the productivity life span of each cow.

K. Dairy Farm: No Name Given
Location: Mombetsu, Hokkaido
Spokesperson: Mr. T Yamaguchi

1. The overall skin condition of each cow had improved dramatically.
2. The foul odors associated with excrements and urine were eliminated with the consumption of alkali water.
3. The farm was able to reduce the amount of mineral supplements that were being added to the diet on account of the alkali water.
4. The newly born calves have experienced no diarrhea.

L. Dairy Farm: Koizumi Ranch
Location: Kamikawa, Hokkaido
Spokesperson: Mr. T. Koizumi

1. The recovery period for cows giving birth had improved noticeably with the consumption of alkali water.
2. The cows have experienced increased appetite.
3. Despite the higher temperature during the Summer months, the milk output had increased dramatically.
4. The consumption of alkali water had stabilized the pH factor for each cow.

M. Dairy Farm: Honami MBB Ranch

Location : Joro, Hokkaido
Spokesperson: Mr. Y. Takigawa

1. There was a remarkable improvement in the quality of milk.
2. The cows increased their water intake which resulted in increased milk production.
3. The cows experienced reduced diarrhea conditions.
4. There was a remarkable improvement in the hair and skin texture of every cow.

N. Dairy Farm: Aneshi Ranch
Location: Esachi . Hokkaido
Spokesperson: Mr. K. Aneshi

1. Due to the consumption of alkali water and the improved immunity levels, there was lesser injuries to the cow’s udder during the milking process.
2. The milk output had increased from 282 tons to 360 tons or a 28% increase.
3. It was a financially and economically wise decision to use electrolysis alkali water.

O. Dairy Farm: Royal Farm
Location: Kamikawa, Hokkaido
Spokesperson: Mr. T. Sawamoto

1. The milk output had increased from a range of 7.000 to 7 300 kg to a higher output of 9,OOO kg or a 28% increase.
2. Due to the unstable water condition, the farm had gone to electrolysis water. This decision ended up being a financially-wise decision.

P. Dairy Farm: Nogyo Kyosai Dairy Association
Location: Kushiro. Hokkaido
Spokesperson: Mr. M. Sugiyama

1. The use of alkali water has considerably reduced the number of sick cows and dramatically improved the health condition.
2. The farm has not measured all the positive effects brought about by the alkali water but on the other hand have not experienced any negative effects.
3. One noticeable difference was their improved digestion.

Q. Dairy Farm: Okura Ranch
Location: Asahi-kawa, Hokkaido
Spokesperson: Mr. Y. Okura

1. The alkali water has produced healthier cows. There were no changes to the diet or the environment but the cows became healthier. Increased their monthly sales by $20.000.00through increased milk . output. (NOTE: There were no other comparative numbers provided to determine the actual increase in productivity levels.

R. Dairy Farm: Aikawa Ranch

Location: Akan, Hokkaido

Spokesperson: Mr. M. Aikawa

1. The odors th at are normally present in the urine and excrements were dramatically reduced.
2. The birthrate was considerably increased by the increase in fertility rate and the minimizing of stillborn calves.
3.There was a dramatic increase in mill production. .
4.This farm is utilized as a model ranch in the use of alkali water

S. Dairy Farm: Mitani Ranch
Location: Yubari, Hokkaido
Spokesperson: Mr. K. Mitani

1. Experienced 1 00 % fertility and birth rates through artificial insemination.

T. Dairy Farm: Ueda Ranch
Location: Akan, Hokkaido
Spokesperson: Mr. T. Ueda

1. The fortified calcium through the electrolysis water has strengthened the legs of the cows.
2. Due to the dramatically-improved health conditions, the quality of the milk has improved.
2. In the long run, the use of alkali water is a totally economical approach to the dairy industry.

U. Dairy Farm: Yamatani Ranch

Location: Kamikawa, Hokkaido

Spokesperson: Mr. M. Yamatani

1. The quality and quantity of the milk has improved considerably.
2. Considerably minimized the sickness rate of each cow.
3. Minimized diarrhea conditions.
4. An overall improvement was noted in every aspect of the dairy cow equating to better economic conditions.

V. Dairy Farm: Yamamoto Ranch
Location: Amashio, Hokkaido
Spokesperson: Mr. M. Yamatani

1. The milk output had increased from 317 tons to 393 tons or an increase of 24.0%
2. The cow became fertile with one month of giving birth.
3. There was a substantial reduction to the number of veterinary visits.
4. There was a noticeable increase in their appetites. .

W. Dairy Farm: Saida Ranch
Location: Shirahata, Hokkaido
Spokesperson: Mr. K. Saida

The milk output had increased from 8.641kg to 10,177kg or an increase of 17.8%

X. Dairy Farm: Fukagawa Ranch
Location: Joro, Hokkaido
Spokesperson: Mr. E. Fukagawa

1. There was a substantial reduction to the number of veterinary visits.
2. Reduced the swelling rate of the cow’s legs.
3. Reduced the rate of external wounds caused by suction cups.

CONCLUSION:

An increase in milk output by 18~28% – A notable improvement in the quality of milk – Elimination of strong feces and urine odors – Healthier skin condition – Minimized injury to the udder – Decrease in diarrhea cases – Strengthening of the legs – Increased appetite – Able to reduce mineral supplements normally added to the feed – Due to an improved health condition coupled with stronger legs – Extended the productive life span of the cows – Improved the fertility rate and reduced still births in new-born calves – Aside from the above, the following opinions were noted by the veterinarians: A noticeably increased appetite; no new supplements were added to their diet. Increase in appetite noted in older cows also – Well digested foods – A beautiful sheen on the cow’s hair – Higher fertility rate; higher

pregnancy rate – A new-born calf exposed to alkali water matures quicker – A dramatic increase in milk production – Improved liver condition – Strengthened legs – Minimizing of sicknesses; tremendously improved health condition – No adverse conditions noted with the consumption of alkali water – Lesser visits made by veterinarians.

IONIZED ALKALINE WATER SAFELY INCREASES MILK PRODUCTION AND MILK QUALITY

The most important animal supplement but least recognized is water. To maximize milk production, the cow must have energy and be completely hydrated. Energy is a result of proper feed conversion. Hydration is a result of water absorption.

All water is not equal. A little known fact is water carries an electrical charge. The higher the electrical charge the less it will absorb. Therefore, a very hydrating water has no electrical charge. This is called negative water, functional water or ionized alkaline water. The Japanese recognized the value of this water more than 20 years ago and has been using it to increase milk production. The Japanese report up to 28% increase in milk production with ionized alkaline water compared to well water.

Ionized alkaline water is the best method for organic dairies to improve profits. Our organic dairies report 15% to 20% increase in milk production after 6 weeks of use. It is well known high somatic cell counts lowers milk production and quality. BioChem Solutions combines ionized alkaline water with a complimentary fermenting biology that assists in hydration, reduces mastitis and other infections including sub-clinical infections resulting in drastically lower somatic cell counts. The combination of these products has proven to eliminate scours within 24 hours; boost the animal’s immune system thereby reducing or eliminating antibiotics and veterinary costs.

Ionized alkaline water with the fermentive biology is the best method for dairies that are phasing out rBST. This combination keeps milk production high, improves the herd’s health, lower infections and somatic cell counts. Compared to rBST, ionized alkaline water is very inexpensive. A 14-day rBST cycle averages 45 cents per day. Ionized alkaline water with fermentive biology cost less than 7 cents per day. In addition rBST only provides 6% to 8% milk increase while ionized alkaline water can increase milk production up to 28%.

Ionized alkaline water is beginning to be recognized for its dairy benefits. Recently, the University of Pennsylvania’s New Bolton Veterinary Center completed a 12-week study that confirmed the Japanese results of higher milk yields and quality. The study concluded ionized alkaline water increased milk production, milk butterfat and lowered MUN (milk urea nitrogen). This study helps validate the technology and proves that ionized alkaline water is the modern method to safely increase milk production, milk quality and animal health.

For articles, videos and clinical studies by International Doctors and Hospitals say about the water in Humans.

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