Antimicrobials and Drug Resistance

Antibiotics vs anti-microbials

• Antimicrobials:

  • kill or stops growth of microorganisms

  • chemical or natural compounds

• Antibiotics:

  • specifically target bacteria

  • produced naturally from molds or bacteria

Antibiotic use in animals reasons

• Therapy

• prophylaxis

• metaphylaxis

• growth efficiency

Antibiotic therapy

• purpose: treat infection

• administration of antibiotics to animals with clinical evidence of infectious disease only

Prophylaxis

• purpose: prevent disease (preventative)

• administration of antibiotics to animals at high risk or infectious disease but without current disease

• commonly used when there is an increased risk of infection

  • transport of animals

  • confinement to small, crowded spaces

  • dairy cattle at end of lactation to prevent mastitis

Metaphylaxis

• purpose: mass medicaiton in advance of expected outbreak

• treatment of a group of animals without evidence of disease which are in close proximity to other animals that do have evidence of infectious disease

Antibiotics for growth efficiency

• Purpose: increase feed efficiency

• adminstration of sub-therapeutic doses of antibiotics to stimulate growth in animals or to increase feed efficiency

4 considerations when selecting an antimicrobial agent

1. Selective toxicity: more harm to the pathogen than the host

2. Spectrum of activity: range of microorganisms affected

3. Antimicrobial action: killing vs inhibition of growth

4. Mechanism of action: how they kill or inhibit microogranism

Components of selective toxicity

• more harm to pathogen than host

  • ex; penicillin inhibit bacterial growth but not the host cells

• therpeutic index: the larger the therapeutic index (TI), the safer the drug

Therapeutic index

• a ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is therapeutic

  • if the TI is small, the drug must be dosed carefully and the patient monitored for any sings of toxicity

Spectrum of activity

• broad spectrum: wide target range

• Narrow spectrum: limited target range

Broad sprectrum antibiotics

• target many different types of bacteria

• used when no time to wait for identification (empiral treatment)

• using broad spectrum antibiotics when they’re not needed can create antibiotic resistant bacteria that are hard to treat

Narrow spectrum antibiotics

• narrow spectrum antibiotics target a few types of bacteria

• usually requires bacterial identificaiton

• less disruptive to normal flora

Never prescribe what antibiotics together

bactericidal and bacteriostatic; bactericidal drugs only work if microbes are actively dividing, which bacteriostatic drugs inhibit

Types of antimicrobial action

• Bacteriostatic

• Bactericidal

Bacteriostatic antibiotics

• “-static” = staying stable

• bacteria don’t die - can’t grow or replicate either

• antibiotics - stops bacteria from growing and dividing - host immune system better able to get rid of bacteria

Bactericidal antibiotics

• “-cidal” = kill

• kill actively dividing bacteria

Some antibiotics can be both

bacteriostatic and bactericidal depending on the dose, duration of exposure, and the state of the invading bacteria

5 types of mechanisms of action

1. inhibition of cell wall synthesis

2. disruption of cell membrane (plasma membrane)

3. inhibition of protein synthesis

4. inhibition of nucleic acid synthesis

5. inhibition of metabolis pathways

Inhibition of cell wall synthesis

• inhibit synthesis of cell wall in susceptible microbes by inhibiting peptidoglycan synthesis

• to be maximally effective, requires actively growing cells

  • BACTERICIDAL

• penicillin is in this group

Disruption of cell membrane (plasma membrane)

• binding to the phospholipids of the membrane

• cytoplasm and cell contents are lost

• BACTERICIDAL

Inhibition of protein synthesis

• bacteria synthesize proteins for their structural and functional needs

  • protein synthesis is a multistep process where DNA is first transcribed into a molecule of single stranded messenger RNA (mRNA) (transcritption)

  • ribosomes translate mRNA with with tRNA into amino acids which become proteins (translation)

• prevent proteins forming by inhibiting translation or transcription

• impar growth of bacteria

• BACTERIOSTATIC

Inhibition of nucleic acid synthesis

• interferes with DNA replication or RNA transcription

• DNA replication:

  • inhibit DNA gyrase

• RNA transcription:

  • block RNA synthesis initiation by specifically inhibiting bacterial RNA polymerase

    • BACTERICIDAL

Inhibition of metabolic pathways

• inhibits folic acid synthesis pathway

  • all bacterial cells require folic acid for growth

• Sulfamethoxazole, Trimethoprim

  • each inhibits a different enzyme in synthesis of folic acid

  • BACTERIOSTATIC (INDIVIDUAL), BACTERICIDAL (COMBINATION)

Components of combination therapy

• synergism

• antagonism

CT: Synergism

• 2 antibiotics can be administered simultaenously so that they can exert an additive effect

  • ex; streptomycin and penicillin

    • damage to the cell wall by the penicillin helps better penetration of streptomycin

CT: Antagonism

• drugs are less effective when used in combination than when used alone

  • drug antagonism may reduce antibiotic effectiveness

  • ex; combination of bacteriostatic and bactericidal antibiotics

Antimicrobial resistance: drug resistant bacteria are developing faster than

scientists can develop antibiotics

How does resistance develop?

• some bacteria in the human body are drug resistant

• antibiotics kill bacteria, but not those resistant to the drug

• resistant bacteria then have space to multiply

• bacteria can even transfer their drug resistance to other bacteria (selection pressure)

Antimicrobial resistance is accelerated

• when the presence of antibitoics pressures the bacteria to adapt

  • kill some bacteria that cause infection, but they also kill helpful bacteria that protect our body from infection

  • antibiotic resistant bacteria survive and multiply

How does resistance spread?

between veterinary and human medicine

What two sectors are antibiotics used in?

• human medicine

• veterinary medicine

Antibiotic use in human medicine/ resistance development

• patient has a cold - prescribed with antibiotics - resistant bacteria develops in gut

• patients can spread bacteria in the community

• hospitalized patients can directly or indirectly spread resistant bugs

• patients become source of infection when discharged

Antibiotic use and resistance in veterinary medicine

• farm animals receive antibiotics, creating antibiotic resistant bacteria that develop in the gut

• fertilizer or water contaminated with animal feces and resistant bacteria whe used on crops can transfer resistant bacteria to humans

• meat products that are not cooked/handled properly can do the same thing

Consequences of misuse of antibiotics

• emergence of AMR pathogens

• common infections are no longer treatable

• longer hospital stay; higher medical costs, more deaths

What are the types of bacterial resistance?

• intrinsic resistance

• acquired resistance

What are the three possible outcomes for a bacteria when exposed to an antibiotic?

• they will die

• they will stagnate

• they will multiply

What are the three main factors that predict which antibiotic exposure outcome happens?

• antibiotic concentration

• bacterial mutation

• bacterial genetic exchange

Intrinsic resistance

• when a bacterial species is naturally resistance to a certain antibiotic or family of antibiotics without the need for mutation or gain of further genes

  • these antibiotics can never be used to treat infections caused by that species of bacteria

Examples of intrinsic resistance

• gram - bacteria are resistant to vacomycin because the extra outer membrane prevents the large moleculed vancomycin from entering the cell

• some bacteria don’t produce cell walls, so using an antibiotic such as penicillin that targets cell wall formation would be useless in a microbe that has no cell wall

Acquired resistance

• happens when a type of bacteria changes in a way that protects it from the antibiotic

• can acquire resistance in two ways

What are the 2 ways that bacteria can develop acquired resistance?

• mutation: through a new genetic change

• gene transfer: getting DNA from a bacterium that is already resistant

  • vertical gene transfer: resistance passed onto daughter cells

  • horizontal gene transfer: transferred by DNA packets between bacteria of same or different species in environment

Vertical gene transfer

• resistance passed onto daughter cells

Horizontal gene transfer

• transferred by DNA packets between bacteria of same or different species in environment

What are the mechanisms of resistance?

1. Altered target

2. Enzyme degradation

3. Efflux pumps

4. DNA mutation

5. Gene transfer

MoR: Altered targets

• ex; MRSA (mecA - PBP2a)

• common mechanism used by bacteria to become resistant to antibiotics by modifying the target of the antibiotic

  • modify antibiotic binding receptors = antibiotics no longer attach

MoR: Enzyme degradation

• eg; penicillinerases

• destroy or inactivate antibiotic before it enters the bacterial cell

MoR: Efflux pumps

• function is to primarily rid the bacterial cell of toxic substances, and many of these pumps will transport a large variety of compounds

• pump antibiotics out of the cell thereby preventing them reaching lethal concentrations

• often work along with reduced permeability of the cell membrane to mediate resistance

• reduced permeability, lower the intracellular antibiotic concentration in the bacterial cell by not allowing its importation

MoR: DNA mutation + key idea

• during multiplication, mutations do happen

  • some mutations can make the bacteria resistant to drug treatment

• in the presence of antibiotics, only the resistant bacteria survive and then multiply and thrive

  • REMEMBER: ANTIBIOTIC PRESENCE DOES NOT INCREASE MUTATION FREQUENCY, BUT IT DOES APPLY SELECTION PRESSURE FAVORING RESISTANT BACTERIA

MoR: Gene transfer

• facilitates spread of drug resistance

  • bacteria w/ drug resistant DNA may transfer a copy of these genes to other bacteria (pilus, etc.)

• non-resistant bacteria can receive the new DNA and become resistant to drugs

• in the presence of drugs, only non-resistant bacteria survive, multiply, and thrive

• occurs through 3 main routes

MoR: 3 main routes of gene transfer

• transduction

• transformation

• conjuagation

MoR: Gene Transfer: Transduction

• bacteriophages (viruses infecting bacteria) mediate transfer of DNA between bacteria via transduction

• DNA from a donor bacterium is packaged into a virus particle and transferred into a recipient bacterium during infection

MoR: Gene transfer: Transformation

• some bacteria are able to take up free DNA from the environment and incorporate it into their chromosome

MoR: Gene transfer: conjugation

a sex pilus forms between 2 bacterial cells through which a plasmid is transferred from one to the other

How does patient compliance affect the emergence of antimicrobial resistance?

• low doses of bacterial antibiotics can function as active mutagens

• forgetting to give medicine

• skipping doses

• not giving the right dose

• stopping antibiotics before the presecription is finished

What does antimicrobial stewadship refer to?

the actions veterinary professionals take to rpeserve the effectiveness and availability of antimicrobial drugs through judicious use

How is antimicrobial stewardship maintained?

• determine whether an antimicrobial is needed

• select appropriate antimicrobial

• use antimicrobial drugs in an effective way

• complete the entire dosage regimen

Veterinary nurses as antibiotic guardians

• reduce the incidence of antibiotic resistance in animals

• educate clients

• implement clinical protocols to avoid unnecessary antibiotic use

• excellent hygienic conditions