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.