Pharmacology

In order to understand the core principles underlying antimicrobial drug use and its relationship to the development of bacterial drug resistance, it is important to have a good foundation on some key pharmacological concepts. This module deals with (1) the birth and development of our antibiotic arsenal, (2) some basic concepts on how antibiotic/antimicrobial drugs work, how they are processed in animal patients, and how they are used in veterinary practice, and (3) how these important drugs should be best prescribed so as to reduce the incidence of drug resistance. These topics will serve as guidelines for chemotherapy, including appropriate drug selection and other measures for mitigating antibiotic resistance.

LEARNING OUTCOMES:

This module focuses on key pharmacologic concepts that are related to the medical use of antimicrobial drugs and microbial resistance to these drugs. By the end of the module, you will be able to:

  1. Outline how antibiotics were discovered and what drives the discovery of new antimicrobial drugs.
  2. Define and differentiate the following related terms: antibiotic, antimicrobial, anthelmintic, antiparasitic, and antifungal.
  3. Describe the different mechanisms of action for antimicrobial drugs, and associate these mechanisms with the common classes of antimicrobial drugs.
  4. Explain pharmacodynamic and pharmacokinetic factors that affect dose and duration of treatment needed to provide effective therapy for bacterial infections.
  5. Describe some important considerations in prescribing antimicrobial drugs to successfully treat infections in animals without promoting microbial drug resistance.

Quick Navigation Links:

The Pre-Antibiotic Era

First Treatments

Many ancient cultures used molds, soil, and plants to treat bacterial infections. Tetracycline has been found in human skeletal remains in Egypt and the Sudan that are some 1,500 years old; it is speculated that it was present in materials consumed in the diet (Aminov). In ancient Serbia, Greece, and China, moldy bread was pressed against wounds to prevent infection. In Egypt, crusts of moldy wheat bread were applied on pustular scalp infections and “medicinal earth” was dispensed for its curative properties (Keyes). These remedies were believed to influence the spirits or the gods responsible for illness and suffering. Today we know that the occasional efficacy of these early treatments was due to the active metabolites and chemicals present in these concoctions, such as antimicrobial substances produced by the molds on bread.

Patent Medicines and Chemical Weapons

People living before the antibiotic era depended mainly on their immune system to survive infectious disease. However, they often sought a variety of largely untested remedies to treat their illnesses. These concoctions were of highly variable efficacy and safety and sometimes had no connection with the cure or relief from disease conditions. They were nonetheless patented, sold, and utilized by desperate people with no suitable alternatives.

The widespread acceptance of the germ theory of disease in the second half of the 19th century sparked a revolutionary change in the understanding of the vital role that microbes play in infectious diseases. Specific bacterial, fungal, and viral pathogens were identified as the causative agents of many serious diseases, and a race immediately began to find effective means to attack these implicated microbes. Vaccines were deployed to prevent infectious disease by educating the host’s immune system with the attenuated or killed microbe of concern. However, they were not an effective remedy against acute infections. Chemical weaponry against bacterial diseases that could rapidly act alone or in concert with the host immune system to clear preexisting infections was discovered just before the turn of the 20th century. The German physician Paul Ehrlich investigated medicinal dyes that would specifically bind to and destroy pathogenic parasites and bacteria, but not harm the host. As the founder of modern chemotherapy, he sought after a “magic bullet” that could target the causative spirochete in syphilis, a devastating, widespread, and incurable disease, which was known since the Renaissance. In 1910, Ehrlich discovered the arsenic-containing chemical dye he eventually named Salvarsan. It was the first chemical compound shown to cure syphilis (Schwartz, Thoburn, Winau).

paul_ehrlichLearn more about Paul Ehrlich by watching this short documentary.

spacer image to break up text

spacer image to break up text

The Golden Age of Antibiotics and Synthetic Antibacterial Drugs

Fleming’s original culture plate 

Fleming culture plate

Photo credit: microbiologysociety.org

The Miracle Drug

As indicated above, it was long known that some molds possessed antibacterial activity but the substances contributing to this phenomenon were unknown. In 1928, the British physician-scientist Sir Alexander Fleming serendipitously discovered that the antibiotic substance he termed “penicillin” was produced by a Penicillium mold growing on agar plates impregnated with staphylococci.

Let's learn more by watching a video: The Discovery of Penicillin and Antibiotics.

The full impact of this discovery was realized during the Second World War when his colleagues Florey and Chain began working in great secrecy with the USDA and several American universities. This British-American collaboration generated quantities of penicillin sufficient to treat most battlefield infections of Allied military personnel during this conflict (Sneader). Penicillin was later hailed as the miracle drug of the 20th century.

Other Miracles
In the mid-1930s, Gerhard Domagk, a chemist at the Bayer Laboratories of IG Farben in Germany, made a breakthrough discovery of the first sulfonamide, a synthetic red dye more popularly known by its trade name of Prontosil (Otten). This was the first synthetic compound that effectively arrested the growth of streptococci and other bacteria, and its subsequent medical use resulted in a sharp decline in mortality from diseases such as meningitis, childbed fever, and pneumonia. Indeed, Domagk’s discovery of the sulfa drugs saved many lives, including those of his own daughter (the first patient) and some prominent figures such as Winston Churchill and Franklin D. Roosevelt, Jr., son of US President Roosevelt (Dixon). Inspired by the groundbreaking work of these Nobel Prize-winning scientists, several other classes of antimicrobial substances were soon discovered and deployed in medicine. Some were derived from antibiotics made by soil bacteria, such as Streptomyces (Hopwood). Although thousands of chemicals are capable of disabling bacteria, only a select few have desirable features that render them suitable for use in animal or human patients. The discovery of new antimicrobial molecules currently relies on the identification and effective screening of candidate drugs from new microbial and nonmicrobial sources and the application of modern chemical biology, imaging, and bioinformatics technologies.

light bulbNow it's time to Check Your Understanding of your comprehension of this section.

The Era of Antimicrobial Resistance

A Prescient Warning
Fleming predicted in 1945 that the misuse of penicillin could lead to the selection and propagation of mutant forms of bacteria resistant to the drug. He was particularly concerned that bacteria exposed to inadequate amounts of penicillin could develop resistance to this miracle cure. Nevertheless, the antibiotic was soon made freely available to the public, and various preparations of salves, lozenges, nasal ointments, and even cosmetic creams were sold without a prescription and with no attention to proper drug dosing. As Fleming predicted, widespread bacterial resistance to penicillin did develop, requiring most countries to restrict penicillin to prescription use only by 1955. The ability of bacteria to resist an antimicrobial drug soon after it is introduced into medicine has become a common theme in chemotherapy. Furthermore, the ability of bacteria to become resistant to several classes of antimicrobial drugs has become a major concern in humans and animals. Resistance to antimicrobial drugs has been an important driving force for the discovery and introduction of new drugs, although the rate of progress in identifying new antimicrobial compounds has slowed considerably in recent years due to a number of pharmaco-economic factors. The mechanisms by which bacteria and other organisms acquire drug resistance phenotypes are covered in the Microbiology Module.

Consensus and Moving Forward
The inappropriate use of antibiotics is now believed to be largely responsible for the development of antimicrobial resistance (Aaerstrup, Inglis, Luangtongkum, Mellon, US GAO). In response to this concern, national and international agencies have collaborated to combat the growing threat of antimicrobial resistance. In 2014, President Obama issued an Executive Order on Combating Antibiotic-Resistant Bacteria, which declared the issue a national security priority and charged a multiagency task force with devising a five-year National Action Plan to combat antimicrobial resistance (The White House). In addition, the Food and Drug Administration issued the Veterinary Feed Directive Final Rule in 2015, which strictly limits the use of antibiotics of medical importance in humans in food animals (US FDA). In May 2015, the World Health Assembly, led by the World Health Organization Secretariat, endorsed a Global Action Plan on Antimicrobial Resistance (WHO).

Review the timeline (click to enlarge) to learn more!CDC Resistance Timeline
Image source: https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf

Antimicrobial Drugs: An Introduction

First, Some Terminology
The adjective “antimicrobial” was derived from the Greek words anti (against), mikros (little) and bios (life) and refers to all agents that act against microbial organisms. This is not synonymous with an antibiotic, a neologism derived from the Greek word anti (against) and biotikos (concerning life).

By strict definition, the term “antibiotic” refers to a substance produced by a microorganism that acts to inhibit the multiplication or kill another microorganism. Thus, it does not apply to antimicrobial substances that are synthetic (sulfonamides and quinolones), semisynthetic (methicillin and amoxicillin), or originate from plants (quercetin and various alkaloids) or animals (lysozyme). The term “antimicrobial” refers to all agents that act against microorganisms, including bacteria (antibacterial), viruses (antiviral), fungi (antifungal), and protozoa (antiprotozoal). All antibiotics are antimicrobial agents, but not all antimicrobial drugs are antibiotics.

The term “antibacterial,” which refers to the most widely known and studied class of antimicrobial drugs, is often used interchangeably with the term “antimicrobial” and will be the major focus of this discussion.

Classification of Antimicrobial Drugs
Antimicrobial drugs are classified in several ways, on the basis of their mechanism of action, spectrum of activity, or effect on bacteria.

major targets of common antimicrobial agentsMechanism of Action 

Different classes of antimicrobial drugs have different mechanisms of action, owing to the nature of their chemical structure and specific affinities for target sites on or within bacterial cells.

spacer image to break up text

spacer image to break up text

  • Inhibitors of cell wall synthesis

While the cells of humans and animals do not have cell walls, this structure is critical for the life and survival of bacteria. Cell walls are constantly being produced and broken down by bacterial enzymes known as autolysins. A drug that targets cell walls can therefore selectively inhibit the growth or even kill a bacterial organism. The beta-lactam antibiotics (penicillins and cephalosporins), bacitracin and vancomycin, interrupt specific points in the synthesis pathway for bacterial cell walls and therefore inhibit cell wall production. However, the activity of autolysins is not affected, leading to unchecked cell wall breakdown and bacterial death.

  • Inhibitors of cell membrane function

Cell membranes segregate and regulate the intra- and extracellular flow of vital substances, and damage to this important barrier could result in leakage of important solutes essential for the cell’s survival. Because cell membranes are a feature of both prokaryotic and eukaryotic cells, drugs of this class are often poorly selective and could be toxic to the host if they gain access to the host’s bloodstream. Drugs that act through this mechanism, such as polymyxin B and colistin, are used to treat topical infections or, if poorly absorbed after oral administration, infections in the gastrointestinal tract.

  • Inhibitors of protein synthesis

Enzymes and cellular structures are primarily made of proteins. Protein synthesis is essential for the multiplication and survival of all bacterial cells. Several types of antibacterial agents—macrolides, lincosamides, streptogramins, chloramphenicol, and tetracyclines—target bacterial protein synthesis by binding to either the 30S or 50S subunits of bacterial ribosomes. These drugs usually arrest bacterial growth, e.g., they have a “bacteriostatic” effect. In the case of aminoglycosides, however, drug binding to the 30S ribosome produces incorrectly formed proteins resulting in bacterial death, a “bactericidal” effect.

  • Inhibitors of DNA transcription to RNA

DNA and RNA are the keys to the replication of all living forms, including bacteria. Some antimicrobial drugs work by binding and inhibiting molecules involved in DNA coiling or transcription to RNA, ultimately compromising bacterial multiplication and survival. Examples include drugs like the fluoroquinolones, metronidazole, and rifampin.

  • Inhibitors of vital metabolic processes

Some antibacterial drugs disrupt biochemical processes essential for bacterial survival. For example, both sulfonamides and trimethoprim disrupt the folic acid pathway, which is necessary for the production of nucleic acids, the precursors of DNA and RNA. They act as “antimetabolites,” false substrates for key enzymes that catalyze vital processes in cell metabolism. Sulfonamides target bacterial dihydropteroate synthase, and trimethoprim inhibits the next enzyme downstream, dihydrofolate reductase. Both of these enzymes are essential for the production of folic acid, a vitamin that has to be synthesized by most bacteria and protozoa, but is consumed in the diet by people and most animals. Because bacterial resistance to sulfonamides is widespread, trimethoprim is often given in combination with sulfonamides to inhibit two enzymes along the folate synthesis pathway and ensure that folate production is completely inhibited. The trimethoprim-sulfa (TMS) combination has a bacteriostatic effect superior to that produced by either drug alone. This practice embodies the concept of “sequential inhibition”.

antibiotics_mechanism_of_action Watch Antibiotics—Mechanism of Action to learn more.

Spectrum of Activity

Depending on the range of bacterial species that are sensitive to an antibacterial drug, the drug may be classified as broad spectrum, intermediate spectrum, or narrow spectrum. The activity a drug possesses against bacteria is dependent on factors such as intrinsic bacterial resistance and bacterial doubling time. This can be clinically challenging when dealing with bacterial pathogens that are naturally insensitive to a large number of antimicrobial drug classes, such as Mycobacterium tuberculosis or Pseudomonas aeruginosa, bacteria that have cellular barriers impermeable to many antimicrobial drugs and specialized mechanisms for drug inactivation and removal (Gellatly; Smith).

Antibacterial drug effectiveness may change if a bacterial strain forms a biofilm, goes into a state of slowed growth, or acquires a resistant phenotype to the drug, as discussed in the Microbiology module.

Broad-spectrum antibacterial drugs are effective against both Gram-positive and Gram-negative organisms. Examples include tetracyclines, amphenicols, newer fluoroquinolones, and third- and fourth-generation cephalosporins.

Narrow-spectrum antibacterial drugs have limited activity and are primarily only useful against particular species of microorganisms. For example, vancomycin and bacitracin are only active against Gram-positive bacteria. Aminoglycosides are only effective against aerobic (or facultative anaerobic) Gram-negative bacteria, whereas metronidazole is only effective on obligate anaerobes.

Antibacterial Quadrant

The table (left) illustrates the different categories into which bacteria are classified, depending on gram stain uptake and oxygen requirements. These categories may guide antimicrobial drug selection. Atypical bacteria, such as Mycoplasma, and other types of microbes, such as protozoans and fungi, fall outside of these classifications.

Drug Effects on Bacteria

Depending on their mechanism of action, antibacterial drugs either inhibit the growth or kill the bacteria that they target.

Static vs CidalBactericidal drugs are those that at normally effective concentrations kill and therefore reduce the population of target organisms. Examples of bactericidal drugs include aminoglycosides, cephalosporins, penicillins, and fluoroquinolones.

Bacteriostatic drugs at normally effective concentrations keep bacteria in the stationary phase of growth, thereby limiting their multiplication. Examples of such drugs include tetracyclines, sulfonamides, and macrolides. Bacteriostatic drugs depend on a working immune system for effective elimination of microorganisms by an infected host. Bacteriostatic drugs are therefore not advisable for immunocompromised animals or for those suffering from life-threatening acute infections.

Most antibacterial drugs can be potentially bacteriostatic and bactericidal, depending on the drug concentration achieved at sites of infection, the duration of drug action, and the state of the invading bacteria. In general, drugs that have bacteriostatic effects at low concentrations may produce bactericidal actions on susceptible bacterial strains when they achieve a sufficiently high concentration in vitro or in vivo. For example, trimethoprim-sulfa combinations that are normally bacteriostatic have bactericidal actions against common lower urinary tract pathogens because these drugs undergo renal excretion and therefore reach high concentrations in the urine. There are, of course, exceptions to this rule. Penicillin, for example, has bactericidal effects at low concentrations but can paradoxically slow bacterial growth and thus reduce bacterial killing at very high concentrations. Because of its high margin of safety, it is tempting to use penicillin at a higher-than-recommended dose. However, this practice could be counter-productive because it may make the drug less effective in killing pathogenic bacteria.

Alexander Fleming, the discoverer of penicillin, developed a method for measuring the bacteriostatic action of an antibiotic using the measurement parameter known as the “minimum inhibitory concentration” or MIC value. The MIC is the lowest drug concentration that inhibits the visible growth of a bacterial culture containing 105 organisms after an overnight incubation, and it remains the best estimate of antibacterial activity in vitro. In common practice, the effects of a drug on a bacterial strain are measured as a population-based MIC value, reflecting a range of MIC values obtained from drug interactions with over one hundred (often thousands) of bacterial isolates. Thus, a MIC90 value refers to the minimum drug concentration capable of inhibiting growth in 90% of the numerous isolates tested (Turnidge).

A brief discussion of MIC measurement is discussed in the Microbiology Module - Disk-diffusion section. MICTo get a more in-depth understanding, watch this lecture on minimum inhibitory concentration.

The MIC value is related to the action and residence time of an antibacterial drug in the body and to the clinical outcome of antibacterial drug therapy through the drug dosing regimen. See the table below for relevant definitions. Effective drug dosing is also guided by the post-antibiotic effect of an antimicrobial drug, i.e., whether the drug produces a short- or long-lasting suppression of bacterial growth after its concentration falls below the MIC value. Beta-lactam antimicrobial drugs, for example, have a relatively short post-antibiotic effect when compared to longer-lasting tetracyclines or aminoglycosides.

concentration_abbreviation_definition_tableThe assays used to determine MIC, MBC, and MPC values involve planktonic bacteria, microorganisms that exist as single cells or small colonies in an aqueous medium. However, many bacteria can adhere to tissues and form biofilms within the body that behave quite differently from planktonic bacteria. It is difficult for many drugs to penetrate biofilms, as indicated by the MBEC values. Read more about biofilms in the Microbiology section

Study Example: Planktonic E. coli K-99 from a calf enteritis case was sensitive to enrofloxacin, oxytetracycline, and TMS, but biofilms of this microbe were completely insensitive to these drugs. These same bacteria grown under planktonic or biofilm conditions were equally sensitive to gentamicin, however (Olson).

spacer image to break up text

Minimum Inhibitory Concentration (MIC): The MIC value can help clinical laboratories detect the emergence of drug resistance in specific bacterial strains over time. A bacterial strain that was once sensitive to low concentrations of an antibiotic will stop growing only at progressively higher antibiotic concentrations as it is becoming increasingly resistant to the drug; this phenomenon has been termed “relative resistance.” Eventually, the MIC for the bacteria-antimicrobial drug combination will become so high that the antimicrobial drug would produce unacceptable side effects or toxicity in the infected host, rendering the drug clinically unusable (“high-level resistance”).

Mutant Prevention Concentration (MPC): Bacterial exposure to an antimicrobial drug at concentrations below the MPC value has been associated with the emergence of drug-resistant bacterial phenotypes. The “mutant selection window” (MSW) is the range of drug concentrations between the MIC (lower limit) and MPC (upper limit) within which there is a good likelihood of selection for drug-resistant bacterial strains over time. Therefore, to prevent the development of microbial drug resistance, it has been recommended that drugs be prescribed to attain the MPC for the pathogen at the infection site over a short period of time (three days). In other words, if possible, “hit hard and hit fast with a short duration” (Martinez).

light bulbNow it's time to Check Your Understanding of your comprehension of this section.

The Action and Fate of an Antimicrobial Drug in the Body Can Determine Effective Drug Dosing

As indicated above, the ability of an antimicrobial drug to arrest the growth or kill bacteria is dependent upon its mechanism of action and the concentration that the drug attains at the infection site. When a drug is introduced into the body, it is rapidly carried through the bloodstream to the liver, kidneys, and other organs that can chemically change or reduce its antibacterial activity and promote its excretion.

These processes of drug (1) absorption from its site of administration, its subsequent (2) distribution throughout the body and its elimination by (3) biochemical metabolism, and (4) excretion through the urine, bile, or other routes are pharmacokinetic parameters collectively given the acronym “ADME.” These variables are dependent both on the patient and on the physicochemical features and other properties of the antimicrobial drug.

This chemical and physiological processing by the body as well as the lipid solubility and other chemical properties of the drug affect the ability of the drug to penetrate infected tissues and make contact with pathogens that reside in interstitial fluids or host cells. The early exposure of pathogenic bacteria to effective drug concentrations for an optimum period of time is directly associated with the clinical success of antimicrobial drug therapy.

Click the images in the table below to learn more about the veterinary importance of these antibiotics. The links provide additional drug information.

aminoglycosides

AMINOGLYCOSIDES

beta_lactam_antibiotics

BETA-LACTAM ANTIBIOTICS

chloramphenicol

CHLORAMPHENICOL

FLUOROQUINOLONES

FLUOROQUINOLONES

GLYCOPEPTIDES

GLYCOPEPTIDES

LINCOSAMIDES

LINCOSAMIDES

MACROLIDES

MACROLIDES

POLYMIXINS

POLYMYXINS

RIFAMPIN

RIFAMPIN

STREPTOGRAMINS

STREPTOGRAMINS

SULFONAMIDES

SULFONAMIDES

TETRACYCLINES

TETRACYCLINES

trimethoprim

  TRIMETHOPRIM

Usage of Antimicrobial Drugs in Animals

The use of antimicrobials in animals closely parallels their discovery and usage in humans. Sulfonamide was the first antimicrobial drug to be introduced to food animal medicine in the 1940s. The subsequent discovery of newer antibiotics, such as chlortetracycline in the early 1950s, quickly led to their widespread  use to treat a multitude of infectious diseases in virtually all food animal species. Antibiotics have also been given to healthy food animals to prevent disease or promote animal growth.

The appropriate medical use of antimicrobial drugs in animals harboring infections has brought major benefits to both animals and humans, including:

  1. Reduction of animal pain and suffering
  2. Protection of livelihood and animal resources
  3. Assurance of continuous production of foods of animal origin
  4. Prevention or minimizing shedding of zoonotic bacteria into the environment and the food chain
  5. Containment of potentially large-scale epidemics that could result in severe loss of animal and human lives

On the other hand, there are conflicting opinions regarding the use of antimicrobial drugs to prevent potential infections or promote growth in the production of poultry and livestock. While some people argued that former US regulatory policies were appropriate and that further restriction of antibiotic usage for food animals would be economically harmful to both consumers and producers, many stakeholders supported a reduction in overall use of antimicrobial drugs to limit the acquisition and spread of antimicrobial drug resistance in bacteria (as discussed in Era of Antimicrobial Resistance). Animals excrete these drugs and their metabolites into the environment, potentially bringing these foreign chemicals into contact with soil and water microorganisms, which in turn could develop drug resistance and pass it to other bacterial species.

Veterinary and human health care providers agree that deliberate efforts must be made to ensure that antimicrobial drugs are used judiciously in animals as well as in people.

You may be interested in this video Why Is Antimicrobial Stewardship Important?  Why is Antimicrobial Stewardship Important?

This fact sheet is a good companion to the video.

light bulbNow it's time to Check Your Understanding of your comprehension of this section.

Therapeutic Uses of Antimicrobial Drugs

According to the U.S. Food and Drug Administration, the therapeutic use of antibiotics refers to the treatment of clinically ill animals, as well as to the use of antibiotics to prevent and control disease. Although the importance of good management and preventive medicine should not be underestimated, there are many disease conditions in animals that can only be addressed by antimicrobial therapy. Given the variations between species and the reasons for which animals are owned and are being treated, the therapeutic use of antibiotics in veterinary medicine is more complex than in human medicine.

Antimicrobial drugs are administered to patients based on clinical signs of infection. Ideally, antimicrobial susceptibility testing is done to determine the available options for therapy. This is known as definitive therapy. It is important to note that bacterial susceptibility is not the only consideration when selecting an antibiotic. Aside from the susceptibility and species of the invading pathogen, factors to consider in the appropriate selection of antimicrobial therapies should include the drug’s attributes (such as pharmacodynamics, pharmacokinetics, toxicity, tissue distribution), the host characteristics (such as age, species, immune status), the treatment’s potential impact on public health, and other issues such as the cost-effectiveness of drug treatment.

Considerations when choosingOften the selection of an appropriate drug is made based on clinical experience and knowledge of common pathogens at common sites of infection and the probability that they are not highly resistant to the chosen drug. This approach is termed empirical therapy. For example, lower urinary tract infections in dogs are usually caused by Gram-negative intestinal bacilli that can be cured by treatment with trimethoprim-sulfamethoxazole or amoxicillin. These drugs target Gram-negative bacteria and are eliminated in the urine at high concentrations, which make them a good treatment option for this disease condition. It is best to treat an infection at its earliest stage, i.e., when the numbers of pathogenic bacteria are small, with an antimicrobial drug capable of targeting the suspected causative pathogen at an effective concentration and over a sufficient time period.

 

Some Points to Consider in Making Antibiotic Treatment Decisions

TO TREAT OR NOT TO TREAT: WHEN TREATMENT IS THE BEST OPTION:
  1. Does the condition necessitate treatment?
  2. Are there other options besides antibiotic treatment?
  3. Will the potential drawbacks outweigh the benefits of treatment?
  4. What is the host species involved? Does treatment make economic sense?
  5. Will treatment work against the pathogen involved?
  6. Are there any risks to public health with this treatment?
  1. Which drug would be best against the condition of interest?
  2. What is the optimal dosage, duration of action and route of administration for the drug of choice?
  3. What are the host’s attributes? Is the drug safe, given these?
  4. What are the pathogen’s attributes and where is the infection located? Will the drug achieve an effective concentration at the site of infection?
  5. Will the use of the drug negatively impact public health?
  6. Will the treatment be cost-effective?

Antimicrobial drugs and intestinal microbiota

E. G. Pamer, SCIENCE

Image is adapted from E. G. Pamer, SCIENCE 352:535 (2016). Reprinted with permission from AAAS. This figure may be used for personal and noncommercial classroom purposes only. Any other use requires the prior written permission from AAAS.

Many studies have illustrated the important influence of the intestinal microbiota on local and systemic immune systems (Becattini). The administration of antimicrobial drugs can severely impair the functions of the gut microbiome by inhibiting the downregulation of virulence factors and reducing colonization resistance. Studies in mice and humans have demonstrated that even a single dose of some antibacterial drugs can lead to lasting changes in intestinal bacterial flora, including the emergence of antimicrobial-resistant strains and the upregulation of antibiotic-resistant genes (ARGs). These ARGs may also impart tolerance to antimicrobial drugs other than those administered. In some animal species, e.g., rabbits and horses, changes in the gut microbial flora produced by certain antibiotic drugs can allow disease-causing bacterial species to flourish and lead to the death of the host.

Nontherapeutic Uses of Antimicrobial Drugs

The burgeoning global demand for animal protein has led to efficient intensive farming systems that maximize the amount of utilizable animal product at the least cost. High stocking densities and rapid animal growth, coupled with the reduction of available agricultural space, can facilitate the transmission of infectious agents and the susceptibility of the animals to infectious diseases. To improve production, food animal producers have utilized antibiotics for nontherapeutic purposes. These fall into two main categories:

  1. Use of antimicrobial drugs in animals for growth promotion
  2. Use of antimicrobial drugs in animals to improve feed efficiency.

Growth Promotion

chicken antibiotics poster from 1950'sThe growth promoting properties of antibiotics were discovered in the 1940s, when it was observed that the growth of chicks increased when they were fed bacterial shells of Streptomyces aureofaciens that contained chlortetracycline residues. Because the amount of antibiotic required for growth enhancement was extremely small, the effect was regarded as largely nutritional by producers and authorities in the food industry (Levy). In the years to follow, other countries also allowed the use of antibiotics in animal feeds. With the emergence of antibiotic resistance, however, the use of growth promoters has come under scrutiny and is now restricted to varying degrees in different countries, as discussed in the One Health module.

HOW DO SUBTHERAPEUTIC LEVELS OF ANTIBIOTICS PROMOTE GROWTH?

Although extensively studied, the mechanism by which antibiotics at subtherapeutic concentrations enhance growth remains unclear. Potential modes of action include (Holman & Chénier):

  1. Suppression of normal intestinal bacteria, leading to increased nutrient availability to the animal
  2. Decrease of harmful metabolites produced by intestinal bacteria
  3. Thinning of intestinal wall resulting in increased absorption of dietary nutrients
  4. Anti-inflammatory effects that are independent of the gut microbiota
  5. Inhibition of endemic subclinical disease

 

light bulbNow it's time to Check Your Understanding of your comprehension of this section.


Preemptive Use

prophylaxis and metaphylaxisIt is not uncommon for veterinarians to prescribe antibiotics for animals that are not exhibiting signs of an infection but are at high risk of acquiring an infection. In companion animal veterinary medicine, antibiotics are commonly used to control secondary bacterial infections that could occur in the course of surgical procedures, and for managing infection-promoting disease conditions, such as urolithiasis. For example, a dog may be prophylactically treated with antibiotics if it is at risk for infection having undergone surgery or injurious trauma. Livestock herds and avian flocks may be given antibiotics if they are vulnerable during an infectious disease outbreak due to exposure to disease agents or extremely unfavorable host or environmental conditions (metaphylaxis). In poultry and livestock, the mass administration of antibiotics is often practiced when transporting or moving young animals, during dry-cow therapy in dairy cows, and in preventing respiratory and intestinal maladies when animals have been subjected to highly stressful conditions.

The prophylactic or metaphylactic use of antibiotics can play an important role in the control and prevention of numerous diseases in both food and companion animals. However, this use of antimicrobials should never replace good management practices. As with the treatment of diseased animals with antimicrobial drugs, issues to be considered when deciding whether or not to use an antibiotic preemptively include a knowledge of the pathogen involved and of the drug’s properties, the species of animal, and the intended use of the drug.

The prudent use of antimicrobials, also referred to as “judicious use” or “antimicrobial stewardship,” encompasses the (1) optimal selection of a drug, (2) the careful consideration of drug dose and duration of antimicrobial treatment in the infected host, and (3) the reduction of inappropriate, inadequate or excessive drug use to meet the goal of slowing or halting the emergence of drug-resistant microbes (Shales, et al., 1997 as cited by Weese). In comparison to human medicine, the judicious use of antibiotics in veterinary medicine is complicated, due to the nature of antimicrobial use in animals and the influences of various stakeholders on animal husbandry standards. As they have a dual responsibility in protecting the health and well-being of animals and safeguarding public health, it is important that veterinarians are leaders in antimicrobial drug stewardship.

More details on antimicrobial practices and prudent use in particular animal species can be found in the modules on clinical applications.

light bulbNow it's time to Check Your Understanding of your comprehension of this section.

Module Summary

  • The discovery of the first antimicrobial drugs, the antibiotic penicillin and the synthetic antimicrobial “sulfa” drug Prontosil, was made between the First and Second World Wars in the 1930s. Poor antimicrobial drug stewardship has led to the rapid emergence of drug-resistant bacteria, a phenomenon that has been repeated since that time as newer antimicrobial drugs have been introduced. Drug resistance has been found to occur in pathogenic viruses, fungi, parasites as well as host cancer cells. Drug resistance has been a major driver of new drug development.
  • Antibacterial drugs act to target key cellular processes that are essential for bacterial survival, from microbial metabolism and ability to reproduce to cell wall maintenance. In addition, they may be as classified as broad spectrum or narrow spectrum, depending on how many different types of microorganisms are naturally susceptible to their action, and as bactericidal or bacteriostatic, depending on whether a drug kills or inhibits the growth of the targeted bacteria. When given to treat infections in a human or animal host, these drugs act in concert with the host immune system to eradicate offending pathogens. However, they must be able to reach bacteria in sites of infection at effective concentrations and over a sufficient period of time. As with any type of chemotherapeutic drug, the extent to which the pathogen is eliminated by the drug is determined by bacterial sensitivity to the drug, the physicochemical characteristics of the drug, the drug dosing regimen, and the processing and speed of elimination of the drug by the host.
  • The medical use of antimicrobial drugs is initiated upon the appearance of clinical signs of infection in an animal host. The practitioner may elect to prescribe empirical drug treatment, based on clinical judgment and knowledge of the disease and its etiology. Particularly for serious infections, definitive treatment is important. This involves submitting bacterial isolates for culture and drug sensitivity testing to ensure that an appropriate drug will be chosen that is targeted to the causative microbe. It has been common practice for many years to treat animals preemptively with antimicrobial drugs to prevent an infection, although this approach should be carefully weighed in terms of its known risks and potential benefit and after consideration of alternative strategies, like improvements in herd management. Moreover, antimicrobial drugs have been fed to animals in order to promote their growth. This practice is quickly being supplanted by other approaches, such as the use of probiotics and vaccines.
  • The advent of antibiotics has revolutionized the treatment of infectious diseases: common infections became easily curable, and outbreaks of infectious disease were readily controlled. However, the declaration of victory over bacterial pathogens was premature, as antimicrobial resistance quickly emerged in bacteria and reduced the clinical usefulness of these new drugs. Antibiotics are used therapeutically in animals for treating, preventing, and controlling bacterial diseases, and have been used non-therapeutically for growth promotion and feed efficiency purposes. It is a major public health responsibility of veterinarians to advocate the judicious use of antibiotics in order to ensure their effectiveness in treating both animals and people well into the future.

References

  1. Aarestrup, FM, AM Seyfarth, HD Emborg, K Pedersen, RS Hendriksen, and F Bager. 2001. Effect of abolishment of the use of antimicrobial agents for growth promotion on occurrence of antimicrobial resistance in fecal enterococci from food animals in Denmark. Antimicrobial Agents and Chemotherapy. 45(7):2054−2059.
  2. Aminov, RI. 2010. A brief history of the antibiotic era: lessons learned and challenges for the future. Frontiers in Microbiology. 1:134.
  3. Becattini, S, Y Taur, and EG Pamer. 2016. Antibiotic-induced changes in the intestinal microbiota and disease. Trends in Molecular Medicine. 22(6):458−478.
  4. Dixon, B. 2006. Sulfa’s true significance. Microbe. 1(11): 500−501.
  5. Gellatly, SL, and RE Hancock. 2013. Pseudomonas aeruginosa: new insights into pathogenesis and host defenses. Pathogens and Disease. 67(3), pp.159−173.
  6. Holman, DB, and MR Chénier. 2015. Antimicrobial use in swine production and its effect on the swine gut microbiota and antimicrobial resistance. Canadian Journal of Microbiology. 61(11):785−798.
  7. Hopwood, DA. 2007. Streptomyces in Nature and Medicine: The Antibiotic Makers. Oxford University Press, Oxford, England.
  8. Inglis, GD, TA McAllister, HW Busz, LJ Yanke, DW Morck, ME Olson, and RR Read. 2005. Effects of subtherapeutic administration of antimicrobial agents to beef cattle on the prevalence of antimicrobial resistance in Campylobacter jejuni and Campylobacter hyointestinalis. Applied and Environmental Microbiology. 71:3872−3881.
  9. Keyes, K, MD Lee, and JJ Maurer. 2003. Antibiotics: mode of action, mechanisms of resistance and transfer. Microbial Food Safety in Animal Agriculture: Current Topics. Edited by ME Torrence and RE Isaacson. Iowa State Press, Ames, Iowa, USA.
  10. Levy, SB. 2002. The Antibiotic Paradox, 2nd ed. Perseus Publishing, Cambridge, Massachusetts, USA.
  11. Luangtongkum, T, TY Morishita, AJ Ison, S Huang, PF McDermott, and Q Zhang. 2006. Effect of conventional and organic production practices on the prevalence and antimicrobial resistance of Campylobacter spp. in poultry. Applied and Environmental Microbiology. 72(5):3600−3607.
  12. Martinez, MN, MG Papich, and GL Drusano. 2012. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrobial Agents and Chemotherapy. 56:2795−2805.
  13. Mellon, M, C Benbrook, and KL Benbrook. 2001. Hogging It! Estimates of Antimicrobial Abuse in Livestock. Union of Concerned Scientists, Cambridge. Accessed online June 2008.
  14. Mulla, S, A Kumar, and S Rajdev. 2016. Comparison of MIC with MBEC assay for in vitro antimicrobial susceptibility testing in biofilm forming clinical bacterial isolates. Advances in Microbiology. 6:73−78.
  15. Olson, ME, H Ceri, DW Morck, AG Buret, and RR Read. 2002. Biofilm bacteria: formation and comparative susceptibility to antibiotics. Canadian Journal of Veterinary Research. 66:86−92. 
  16. Otten, H. 1986. Domagk and the development of the sulphonamides. Journal of Antimicrobial Chemotherapy. 17:689−696.
  17. Schwartz, RS. 2004. Paul Ehrlich’s Magic Bullets. New England Journal of Medicine. 350(11):1079−1080.
  18. Smith, T, KA Wolff, and L Nguyen. 2013. Molecular biology of drug resistance in Mycobacterium tuberculosis. Current Topics in Microbiology and Immunology. 374:53−80.
  19. Sneader, W. 2005. Drug Discovery: A History. John Wiley & Sons, Chichester, England.
  20. Thoburn, AL. 1983. Paul Ehrlich: Pioneer of chemotherapy and cure by arsenic. British Journal of Venereal Diseases. 59:404−405.
  21. Turnidge, J, and DL Paterson. 2007. Setting and revising antibacterial susceptibility breakpoints. Clinical Microbiology Reviews. 20(3):391−408.
  22. United States Food & Drug Administration. 2015. FACT SHEET: Veterinary Feed Directive Final Rule and Next Steps. Accessed online December 2016.
  23. United States General Accounting Office. 2004. Antibiotic Resistance: federal agencies need to better focus efforts to address risk to humans from antibiotic use in animals. Report to Congressional Requesters. Accessed online June, 2008.
  24. Weese, JS. 2006. Prudent Use of Antimicrobials. Antimicrobial therapy in Veterinary Medicine 4th ed. Edited by S Giguère, JF Prescott, JD Baggot, RD Walker and PM Dowlin. Blackwell Publishing, Ames, Iowa, USA.
  25. The White House. 2015. National Action Plan for Combating Antibiotic-Resistant Bacteria. Accessed online December 2016. 
  26. The White House. 2014. Executive Order—Combating Antibiotic-Resistant Bacteria. Accessed online December 2016.
  27. Winau, F, O Westphal, and R Winau. 2004. Paul Ehrlich in search of the Magic Bullet. Microbes and Infection. 6:786−789.
  28. World Health Organization (WHO). 2015. Global Action Plan on Antimicrobial Resistance. Accessed online December 2016.