Sunday, 26 August 2012

Familiarity with the benefits, risks, resistance and judicious application of antimicrobials with special reference to Animal Science



Familiarity with the benefits, risks, resistance and judicious application   of     antimicrobials with special reference to Animal Science
 Ramesh Pandey *, Rajesh Pandey ** and Neeraj***
*   Associate Professor, F/o Animal Husbandry and Dairying, SHIATS, Allahabad-211007
** Ex. State Coordinator for NLEP in India , World Health Organization
***Professor, F/o Animal Husbandry and Dairying, SHIATS, Allahabad-211007
                        Any substance (natural, semi synthetic, or synthetic) that kills or inhibits the growth of a microorganism, but causes little or no host damage is termed as an antimicrobial whereas a substance produced by a microorganism that, at low concentrations, inhibits or kills other microorganisms is called antibiotic. So all antibiotics are antimicrobials but all antimicrobials may not necessarily be always considered as antibiotics. There is little reason to care about the distinction except that bacteria have been developing means to resist antibiotics for millennia. The term “antimicrobial” refers broadly to drugs with activity against a variety of microorganisms including bacteria, viruses, fungi, and parasites. Antimicrobial drugs that have specific activity against bacteria are referred to as antibacterial or antibiotic drugs. However, the broader term “antimicrobial,” commonly used in reference to drugs with activity against bacteria, is used in this document interchangeably with the terms antibacterial or antibiotic.
Table 1.                    Activity (range) of various antimicrobial classes

Bacteria
Mycoplasma
Rickettsia
Chlamydia
Protozoa
Aminoglycosides
+
+



Beta-lactams
+




Chloramphenicol
+
+
+
+

Lincosamides
+
+


+
Macrolides
+
+

+

Pleuromutilins
+
+

+

Tetracyclines
+
+
+
+

Quinolones
+
+
+
+

Sulfonamides
+
+

+
+
Trimethoprim
+



+
Spectrum: It describes the general activity of an antimicrobial mostly against bacteria. Narrow spectrum is usually taken to imply activity against some limited subset of bacteria. Broad Spectrum usually implies activity against a wide range of bacteria (perhaps even all genre) and may imply activity against mycoplasma, rickettsia, and chlamydia. Individual isolates of bacteria may be resistant to an antimicrobial even though they are part of its spectrum1.
Table 2. Antimicrobial spectrum (4 quadrants of "coverage")

Aerobic bacteria
Anaerobic bacteria

Spectrum
Gram
(+)
Gram
(-)
Gram
(+)
Gram
(-)
Examples
Broad
+
+
+
+
cefoxitin, chloramphenicol, imipenam, tetracyclines
Intermediate
+
+
+
±
carbenicillin, ticarcillin, ceftiofur, penicillin/clavulanic acid, cephalosporins
+
±
+
±
ampicillin, amoxicillin
Narrow

+


aztreonam, polymyxin
+
±
+
±
benzyl penicillin G
+
+


aminoglycosides, spectinomycin, sulfonamides, trimethoprim
+
+


enrofloxacin
+

+
+
lincosamides, macrolides, pleuromutilins, vancomycin
+

+

bacitracin


+
+
nitroimidazoles
± – variable activity


Benefits of antibiotics:
Antimicrobial drugs have been widely used in human and veterinary medicine for more than 50 years, with tremendous benefits to both human and animal health.
Ø  Antibiotics are an important set of tools available to fight against bacterial infections. They help to prevent clinical signs of selected infections/diseases .
Ø  Healthier animals:
·          Restore sick animals to health
·         Prevent more animals getting sick
·         When a herd is infected
Ø  Healthier people
·         Prevent transmission of zoonotic bacteria
·         Provide the basis for healthy food to humans
·         In many parts of the world livestock does not only equate a reliable source of food, but also a source of economic security.
Ø  Healthier world and other considerations
·         25% production losses due to disease are counteracted.
·         More efficient resource use better feed conversion rates and reduced waste production in healthy animals resulting in more efficient use of resources and reduced impact on the environment for the same amount of food.
·          May be more executable and economical than other methods of disease control2.
Risks associated with non-judicious use of antibiotics:
General risks
·         Exposure of bacteria to antibiotic agents results in resistance development.
·         All kinds of exposure have the potential to cause resistance
         - Natural exposure or intentional use
         - Use in humans, in animals, on plants or elsewhere in the environment
·           But: not all resistance and not all bacteria and not all antibiotics are alike
                          - Different mechanisms of resistance
                          - Different resistance in different bacteria
                          - Different modes of resistance dissemination
                          - Different types of resistance for different antibiotics
                          - Different hosts that can influence bacterial behavior
Risks at the animals-human interface
·         Treatment failure in animals through resistance development in target pathogens
·         Treatment failure in humans through transfer of resistance from animals to humans
·         Transfer through food
                 -showing little risk or none
·         Transfer through the environment
              -lots of unknowns
·         Transfer through contact with animal
      -up to now no major risk shown but concern at development of pools of
                            human strains in animal reservoirs2
Antimicrobial Resistance (AMR): A public health concern
Antimicrobial resistance is the ability of bacteria or other microbes to resist the effects of a drug. Antimicrobial resistance, as it relates to bacterial organisms, occurs when bacteria       change in some way that reduces or eliminates the effectiveness of drugs, chemicals, or other agents designed to treat bacterial infections3. There are differences in the use of the term “antimicrobial resistance”. Natural resistance implies an intrinsic property in an organism that confers resistance, whereas acquired resistance suggests that an organism has obtained, by one mechanism or another, the means to survive exposure to an antimicrobial agent. Chromosomal, extra chromosomal and transpositional resistances are terms used when the genetic determinants are on chromosomes, plasmids, or transposons, respectively. Phenotypic resistance, due to differences in physical and functional characteristics, is best exemplified by bacterial wall- defective variants( such as L-forms, spheroblasts and protoplasts) and by the impermeability of the cell walls of some gram negative bacteria due to very narrow conduits or porins. Microbiologic resistance implies an increase in the usual MIC range to levels that are too high to be reached at standard therapeutic rates. Clinical resistance, for which there may be many causes, is a general term used to describe unexpected lack of response to treatment in a clinical case. The development of resistance to this important class of drugs and the resulting loss of their effectiveness as antimicrobial therapies, poses a serious public health threat. Misuse and overuse of antimicrobial drugs creates selective evolutionary pressure that enables antimicrobial resistant bacteria to increase in numbers more rapidly than antimicrobial susceptible bacteria and thus increases the opportunity for individuals to become infected by resistant bacteria4. As antimicrobial drug use contributes to the emergence of drug resistant organisms, these important drugs must be used judiciously in both animal and human medicine to slow the development of resistance. Efforts have been made to promote the judicious use of these drugs in humans as well as in animals. Using these drugs judiciously means that unnecessary or inappropriate use should be avoided. The focus should be on the use of medically important antimicrobial drugs in food-producing animals. Based on a consideration of the available scientific information, Food and drug Administration (FDA), Centre for Veterinary Medicine, U.S.A. is providing a framework for the voluntary adoption of practices to ensure the appropriate or judicious use of medically important antimicrobial drugs in food-producing animals5.
Many patients around the world suffer harm due to AMR because infections caused by viruses, bacteria, fungi, protozoa or helminths are no longer susceptible to the common medicines used to treat them. Reports on AMR are most often generated on the basis of laboratory results on microbes obtained from human patients. These reports are used to take decisions on the treatment of individual patients, and also as evidence for policies at local, national, and international levels. Data from around the world confirm that AMR, including multidrug resistance, is increasing among many pathogens responsible for infections in health-care facilities and in the community.AMR makes it difficult and more expensive to treat a variety of common infections, causing delays in effective treatment, or in worst cases, inability to provide appropriate therapy. Many of the medical advances in recent years, such as chemotherapy for cancer treatment and organ transplantation, are dependent on the availability of anti-infective drugs. The predictable consequence of resistance is increased morbidity, prolonged illness, a greater risk of complications, and higher mortality rates. The economic burden includes loss of productivity (loss in income, diminished worker productivity, time spent by family) and increased cost of diagnostics and treatment (consultation, infrastructure, screening, cost of equipment, drugs). Both the health and economic consequences of AMR are considerable and costly but difficult to quantify precisely as the available data are incomplete in many countries. The additional human burden associated with it (pain, change in daily activities, psychosocial costs) is also significant, but even more difficult to quantify .Available quantitative evidence on excess harm caused to patients through drug resistance comes mainly from experiences with malaria, tuberculosis, and to some extent Human Immune deficiency Virus (HIV) also .There is a growing body of evidence that AMR is also increasingly important in many of the common bacterial diseases, but there are much less systematic data on its extent and the consequences for patients. Resistance to antimalarials medicines has been documented for all classes of antimalarials, including the artemisinin derivatives, and is a major threat to malaria control. The therapeutic efficacy of medicines is directly monitored by clinical and parasitological outcomes of treatment over at least 28 days. A change of national antimalarials treatment policy is recommended when the overall treatment failure rate exceeds 10%. Changes in policy have been necessary in many countries due to the emergence of chloroquine resistance, which has become so widespread that a combination of medicines including artemisinin (artemisinin based combination therapy) is now the recommended first line treatment for uncomplicated falciparum malaria 6.
Developing strategies for reducing antimicrobial resistance is critically important for protecting both public and animal health. Collaboration involving the public, the public health, animal health, and animal agriculture communities on the development and implementation of such strategies is needed to assure that the public health is protected while also assuring that such strategies are feasible and that the health needs of animals are taken care of. Antimicrobial resistance and the resulting failure of antimicrobial therapies in humans, is a mounting public health problem of global significance. This phenomenon is driven by many factors including the use of antimicrobial drugs in both humans and animals. In regard to animal use, the FDA addresses the use of medically important antimicrobial drugs in food-producing animals for production or growth-enhancing purposes. These uses, referred to as production uses throughout  are typically administered through the feed or water on a herd or flock wide basis and are approved for such uses as increasing rate of weight gain or improving feed efficiency. Unlike other uses of these drugs in animals (e.g., for the treatment, control, and prevention of disease), these “production uses” are not intended to manage a specific disease that may be ongoing or at risk of occurring, but rather are expressly indicated and used for the purpose of enhancing the production of animal-derived products (e.g., increasing rate of weight gain or improving feed efficiency).
The continued availability of effective antimicrobial drugs is critically important for combating infectious disease in both humans and animals. This includes the continued availability of feed and water uses of such drugs for managing disease in animal agriculture.
Therefore, it is in the interest of both human and animal health that we take a more proactive approach to consider as how antimicrobial drugs are being used, and take steps to assure that such uses are appropriate and necessary for maintaining the health of humans and animals. Using medically important antimicrobial drugs as judiciously as possible is key to minimize resistance development and preserve the effectiveness of these drugs as therapies for humans and animals. Although FDA applauds the efforts to date by various veterinary and animal producer organizations to institute guidelines for the judicious use of antimicrobial drugs, the agency believes that additional voluntary steps are yet to be taken.
To further address this public and animal health concern, FDA is recommending two additional principles about the appropriate or judicious use of medically important antimicrobial drugs in food-producing animals. These principles are consistent with the recommendations of a number of recent scientific panels or committees referenced earlier in this document including the 1997, 2000, and 2011 reports of the WHO, the 2003 IOM Report, and the 2005 Codex Code of Practice.
FDA recognizes the need to collaborate with the animal health and animal producer communities on strategies for minimizing animal health impacts or industry disruption that may be associated with the implementation of changes by animal drug sponsors to voluntarily align the use conditions of affected drug products with the principles outlined below. Furthermore, it intends to consult with the United States Department of Agriculture (USDA) on implementation strategies including the development of a framework for veterinary oversight and consultation requirements. FDA is committed to assure that the public health is protected while also assuring that the health needs of animals are properly addressed through adoption of following two fundamental principles:
Principle 1: The use of medically important antimicrobial drugs in food-producing animals should be limited to those uses that are considered necessary for assuring animal health.
In light of the risk that antimicrobial resistance poses to public health, it is believed that the use of medically important antimicrobial drugs in food-producing animals for production purposes (e.g., to promote growth or improve feed efficiency) represents an injudicious use of these important drugs. Production uses are not directed at any specifically identified disease, but rather are expressly indicated and used for the purpose of enhancing the production of animal-derived products. In contrast, FDA considers uses that are associated with the treatment, control, or prevention of specific diseases, including administration through feed or water, to be used if they are necessary for assuring the health of food-producing animals.
Some may have concerns that the use of medically important antimicrobial drugs in food-producing animals for disease prevention purposes is not an appropriate or judicious use. However, some indications for prevention use are necessary and judicious as long as such use includes professional veterinary involvement. Veterinary involvement in the decision-making process associated with the use of medically important antimicrobial drugs is an important aspect of assuring appropriate use, including judicious prevention use. When determining the appropriateness of a prevention use, veterinarians consider several important factors such as determining the medical rationale for such use, and that such use is appropriately targeted at a specific etiologic agent and appropriately timed relative to the disease. For example, if a veterinarian determines, based on the client’s production practices and herd health history, that cattle being transported or otherwise stressed are more likely to develop a certain bacterial infection, preventively treating these cattle with an antimicrobial approved for prevention of that bacterial infection would be considered a judicious use. Another example would be the prevention of necrotic enteritis in broiler chickens. In this case, the prevention use of an antimicrobial is important to manage this disease in certain flocks in the face of concurrent coccidiosis, a significant parasitic disease in poultry. On the other hand, FDA would not consider the administration of a drug to apparently healthy animals in the absence of any information .Disease prevention involves the administration of an antimicrobial drug to animals, none of which are exhibiting clinical signs of disease, in a situation where disease is likely to occur if the drug is not administered.
Principle 2: The use of medically important antimicrobial drugs in food-producing animals should be limited to those uses that include veterinary oversight or consultation.
Most of the feed-use antimicrobial drugs are currently approved for over-the-counter use in food-producing animals for purposes that include the treatment, control, and prevention of disease as well as for production purposes (i.e., for growth promotion uses such as increased rate of weight gain). In addition to instituting voluntary measures that would limit use of medically important antimicrobial drugs in food-producing animals to uses that are considered necessary to assure the animals’ health, it is important to phase-in the voluntary practice of including veterinary oversight or consultation in the use of these drugs. This practice is an important mechanism for helping to assure appropriate use. Veterinarians can play a critical role in the diagnosis of disease and in the decision-making process related to instituting measures to treat, control, or prevent disease. It is therefore apparent that the nature of veterinary involvement can vary due to numerous factors such as geographic location and animal production setting. In fact, there are limited numbers of large animal veterinarians, which can make consultation or oversight challenging in certain situations. For example, some animal disease events require immediate attention. In some cases, veterinarians may be directly diagnosing and administering therapies, while in other cases they are visiting and consulting with producers periodically to establish customized disease management protocols for that producer’s herd or flock. It is therefore well established that increasing veterinary involvement in the use of antimicrobial drugs has significant practical implications for animal producers, veterinary practitioners, and the veterinary profession as whole 7.
Reducing antimicrobial use in animal husbandry to reduce AMR
As in medical care for people, the introduction of antimicrobials was a significant milestone in veterinary practice. As in humans, these medicines are used for the treatment of infectious diseases in individual domestic pets and in farm and food-producing animals to ensure animal welfare and global food production .The development and spread of AMR is therefore also of concern in veterinary medicine. Furthermore, resistant bacteria carried by food-producing animals can spread to people, mainly via the consumption of inadequately cooked food, handling of raw food or by cross-contamination with other foods, but also through the environment (e.g. contaminated water) and through direct animal contact .Use is the main driver for resistance in all of these situations. For companion animals such as cats, dogs and horses, the use is similar to that in general human medical practice, with individual animal treatment being the norm. The main difference between antibiotic use in humans and animals is seen in the context of food production, where there is mass administration of antimicrobials to many animals at the same time for the purposes of disease prevention and growth promotion. Such practices provide favourable conditions for the emergence, spread and persistence of AMR bacteria capable of causing infections not only in animals, but also in people. The antimicrobial agents used for food producing animals are frequently the same, or belong to the same classes, as those used in human medicine. The total amount used in animals accounts for well over 50% of total antibiotic use, according to the available evidences.The importance of food animals as reservoirs of AMR bacteria which are pathogenic for humans is well documented for zoonotic bacteria such as non-typhoidal Salmonella enterica serovars110 and Campylobacter spp.111. It has been frequently demonstrated that the use of antimicrobial agents in food animals favours the development of resistance among bacteria which can then be transmitted to people, and may cause infections and illness. Bacteria and resistance to critically important antimicrobial agents associated with food animals include:
Escherichia coli and Salmonella spp resistant to 3rd and 4th generation cephalosporins and to fluoroquinolones; Campylobacter spp resistant to macrolides and fluoroquinolones; Staphylococcus aureus resistant to all beta-lactam-type drugs (i.e. MRSA); enterococci resistant to vancomycin (VRE) and C. difficile. There are significant direct and indirect effects of antimicrobial use in animals on AMR in human pathogens, as several lines of evidence have indicated. Data are as yet insufficient to allow this relationship to be fully evaluated, but it is clear that action is needed to reduce the use of antibiotics in food animals, and to obtain further information on the impact on AMR 8.
WHO guidance on reducing antimicrobial use in animal husbandry
The 2001 WHO Global Strategy for Containment of AMR includes specific recommendations on the use of antimicrobials in animal husbandry which are based on WHO global principles for the containment of antimicrobial resistance in animals intended for food .The recommendations include phasing out the use in food animals of antimicrobials which are used in human medicine, improving their use through regulation, education and guidelines, and monitoring use and resistance in this sector 9.
WHO principles for the containment of AMR in animals intended for food
The importance of the problem and the urgent need to take action were again stressed during the 2011 World Health Day. The core actions called for in the WHD policy briefs include the creation and enforcement of an enabling regulatory framework, strengthening surveillance and monitoring, promoting education and training on antimicrobial use in food-producing animals and reducing the need for antimicrobials through better animal husbandry. The needs for national leadership and inter-sectoral collaboration are also emphasized and WHO principles for the containment of AMR in animals intended for food includes the following:
• Introduce pre-licensing safety evaluation of antimicrobials with consideration of potential   
   resistance to human drugs.
• Monitor resistance to identify emerging health problems and take timely corrective action to
   protect human health.
• Develop guidelines for veterinarians to reduce the overuse and misuse of antimicrobials in
   food animals.
• Require obligatory prescriptions for all antimicrobials used for disease control in food                                  
  animals.
• In the absence of a public health safety evaluation, terminate or rapidly phase out the use of
  antimicrobials for growth promotion if they are also used for the treatment of humans.
• Create national systems to monitor antimicrobial use in food animals9.
Role of Veterinarians/Animal Scientists in Antimicrobial Resistance:
Two major aspects of antimicrobial use concerning veterinarians viz. the likelihood of causing a pathogenic organism to become resistant to current antimicrobial therapy and the likelihood of commensal organisms (generally GI) becoming resistant to future antimicrobial therapy. The former largely can be prevented by assuring that adequate concentrations of the appropriate drug reach the targeted site. The latter concern is less problematic in small animals because the risk of transfer of resistant commesal organisms to humans is not obvious as with the use of antibiotics in food production. However  the latter risk is difficult to quantitate . The use of antibiotics in food animals, including use as growth promotants, may contribute to the transfer of resistant genes among bacteria and ultimately from food animals to humans, where the organisms become pathogenic. Additionally, contamination of food with resistant pathogenic bacteria during the processing of food is a concern.  Carcasses may be contaminated at slaughter and processing, and subsequent improper handling or cooking of the product may lead to infection in people. The development of resistant pathogenic bacteria in poultry treated with fluoroquinolones has been documented. Infection of the human population is of particular concern because  the bacterial resistance created in the animal following veterinary use of a drug or drug class may result in resistance to human drugs of the same class whereas the organism developing resistance might be non pathogenic organism becoming resistant and ultimately in therapeutic failure in human patient. When selecting drug therapies for food animals, veterinarians must be aware of the potential for resistance. Use of antimicrobial drugs should be in the context of a valid Veterinarian-client-patient relationship. Selection should be based on all information available viz. clinical signs, experience, laboratory, data, physical examination findings, culture and sensitivity data etc. Pathogens should be identified and drugs with the narrowest spectrum of activity with known effectiveness against the pathogen should be used. Client education is important in preventing unnecessary use of antibacterial agents such as using leftover antibacterial drugs to treat a new occurrence of disease. In addition to judicious use, veterinarians/ animal scientists should be proactive in the education of their clients, including proper withdrawal guidelines of nay prescribed drugs and should administer drugs in proper class, at proper doses and through appropriate routes10.

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