Understanding Antimicrobial Resistance

While man and animals have shared the benefits of antimicrobials for more than 50 years, this may not be the case in the future. Recent identification of human pathogens which are resistant to multiple antimicrobials has been a source of alarm for public health officials.These findings have raised concerns about the improper use of antimicrobials both in human and animal medicine. New discoveries

While man and animals have shared the benefits of antimicrobials for more than 50 years, this may not be the case in the future. Recent identification of human pathogens which are resistant to multiple antimicrobials has been a source of alarm for public health officials.

These findings have raised concerns about the improper use of antimicrobials both in human and animal medicine. New discoveries about the mechanisms of antimicrobial resistance transfer between bacteria have further fueled this concern.

As a result, there has been a call for more judicious use of antimicrobials in human medicine and greater regulatory restriction on the use of antimicrobials cleared for use in all animals, including hogs. If proposed regulatory changes are fully implemented, they will greatly alter pork producer and veterinary access to antimicrobials.

It is clear the use of antimicrobials in animals can no longer be taken for granted and must be carefully guarded by judicious use. It is also becoming increasingly apparent that public officials will require producers and veterinarians to partner to assure proper application and administration of antimicrobials. This includes creditable consideration of the risk of resistance development and resistance transfer whenever antimicrobials are used.

The Principle Of Selective Pressure Bacteria compete with each other for nutrients and space. Because vital resources are inherently limited, survival and growth of bacteria depends on each individual bacteria's ability to exclude other bacteria. Whenever antimicrobials are used, sensitive bacteria are either killed or their replication is slowed.

However, resistant bacteria are not affected and are given a competitive edge not only for survival, but also for growth. If surviving bacteria also happen to be either human or animal pathogens, then the significance of this event becomes critical.

It should be noted that selective pressure is not limited to pharmaceuticals. Disinfectants and even heavy metals may also result in selection based on resistance.

How Antimicrobial Agents Work Antimicrobials work in conjunction with the animal's immune system to eliminate pathogenic bacteria. Antimicrobials either kill bacteria by altering essential cellular functions or by slowing bacterial growth and replication. Antimicrobials which kill bacteria are classified as bactericidal agents. Those which hinder normal bacterial cellular functions are classified as bacteriostatic agents.

By altering cellular functions such as cell wall (cytoplasmic membrane) synthesis, protein synthesis, DNA replication or inhibition of vital metabolic processes, antimicrobials negatively impact bacteria.

For example, beta-lactam antibiotics such as penicillin or penicillin derivatives affect the enzymatic controls which keep cell wall (peptidoglycan) degradation and synthesis in balance. By adversely altering the ratio of peptidoglycan synthesis and degradation, beta-lactam antimicrobials cause cell wall breakdown. Veterinarians use pharmacokinetic (how drugs effect bacteria) information such as this, along witha working knowledge of pharmacodynamics (how drugs act in the body) and microbiology, when deciding which antimicrobial to use. Obviously, the age and number of pigs in the group must also be considered with each decision.

How Bacteria Resist Antimicrobials To survive an antimicrobial challenge, bacteria adapt so as to avoid the harmful effects of the antimicrobial. It is this adaptation which results in resistance. In a broad sense, resistance occurs either by alteration of cell structure or cell metabolism. The mechanism of resistance is generally distinctive based on the type of bacteria and the antimicrobial.

Specifically, bacteria block antimicrobial effects by:

Altering cell wall integrity,

Use of enzymes to inactivate the antimicrobial,

Using enzymes to stop the antimicrobial from moving across the cell wall,

Active removal (efflux) of the antimicrobial from the cell,

Altering the site in the bacteria destined for the antimicrobial,

Altering the affinity of the site in the bacteria for the antimicrobial, or

Creating metabolic processes which bypass the effect of the antimicrobial.

In some cases, bacteria develop resistance to one antimicrobial and, at the same time, become resistant to another antimicrobial. This "cross-resistance" occurs in select cases, particularly when two antimicrobials are in the same class of compounds or the antimicrobials have a similar mode of action.

Resistance Memory The information necessary to avoid the effect of antimicrobial treatment is embedded in the genetic material of the bacteria. This genetic material is the resident memory of the cell which drives all cell functions.

Early work on resistance suggested that resistance is primarily encoded on plasmids. More recent work has demonstrated that resistance may also be encoded on the chromosome. Within the chromosome, there are specific islands of genes which direct resistance expression. Within these islands are operons, promoters and repressors. It is the operon which codes for resistance. The operon, when acted upon by the promoter, activates resistance genes. In the case of tetracycline exposure, a repressor is present which stops transcription of the gene, thus preventing its resistance expression.

As these mechanisms of control are better understood, it is hoped they can be managed to prolong antimicrobial effectiveness.

Bacteria may be encoded with genes which make them resistant to more than one antimicrobial. Bacteria eliciting resistance to multiple antimicrobials are of great concern, particularly in human medicine, because they limit the therapeutic options for physicians.

The Origin Of Resistance Even though bacterial resistance was recognized shortly after the discovery of antimicrobials, its origin and evolution are still poorly understood.

It is generally accepted, however, that resistance is a natural phenomena and that it originated with a point mutation within the bacteria. Point mutations are thought to be rare, however, the odds of mutation increase when selective pressure is applied. Even when mutations do occur, survival of the mutated organism is generally not good.

However, whenever a viable, mutated bacteria does survive, it can have a major impact, particularly in light of recent discoveries about resistance transfer.

The Transfer Of Resistance Since the late 1980s, there have been several new discoveries which have revolutionized scientific thinking about resistance transfer. It is now recognized that genetic material can be mobilized and transferred between bacteria by conjugation.

Further, it is generally accepted that resistance is mainly acquired from other bacteria. There is considerable debate within the scientific community about the frequency of this passive occurrence. It has been suggested that the odds of resistance transfer increase the more closely related the bacteria.

In short, it is the chance of resistance transfer which is particularly alarming to public health officials. They are concerned that genes encoded for resistance may be transferred to multiple species of bacteria and result in a significant risk to human health.

Characterization Of Resistance Most farm managers at one time or another have received laboratory reports indicating the degree to which animal pathogens are sensitive or resistant to specific antimicrobial agents. These measures are an assessment of a particular bacteria's ability to grow in the presence of specific antimicrobials on artificial media in a laboratory. Sensitivity tests have been valuable in selecting proper antimicrobials for treatment of disease.

However, caution must used in interpreting this data as it may not necessarily reflect what happens in the animal in every instance.

Molecular scientists characterize resistance using sophisticated methods which map gene sequences common to resistant bacteria. Mapping specific gene sequences allows for the grouping of bacteria based upon not only their actual expression of resistance but also on their potential for resistance expression. Further, it gives scientists a tool to trace these bacterial clones throughout animal populations.

Most of the epidemiologic studies of resistance prevalence consists of measures of phenotypic resistance. Little is currently known about the dynamics of resistance transfer between animals, the environment and human populations.

More importantly for the food animal industries, little is known about the relative risk of resistance transfer by bacteria which are able to survive meat processing and cooking. This information is critical for the pork industry to justify its continued access to antimicrobials.

Proactive Prevalence Monitoring To get a handle on the prevalence of resistance that exists within important bacterial pathogens, resistance monitoring systems are being established in many developed countries.

In the U.S., two monitoring systems have recently been established. One, measuring resistance in human pathogens, is at the Centers for Disease Control and Prevention (CDC). The second is a monitoring program which examines resistance in bacterial isolates from animals. This program is NARMS (National Antimicrobial Resistance Monitoring System) and is ongoing at USDA-Agricultural Research Service (see Tables 1 and 2).

NARMS measures resistance in clinical, farm level and slaughter bacterial isolates. These monitoring systems, while limited, are giving us a glimpse at the patterns of resistance that exist throughout the U.S.

Further, they will be able to demonstrate changing trends in resistance. The information gathered from these studies will be important in regulatory decisions that will affect the producer's and veterinarian's access to antimicrobials.