CH. 20 - Antimicrobial Medications

Bactericidal Vs. Bacteriostatic

Bactericidal - a chemical that kills a bacteria

Bacteriostatic - a chemical that inhibits growth of a bacteria

Chemotherapeutic Agent

any type of drug used to treat any type of disease

Antimicrobial Agent

a chemical/drug that inhibits or kills microbes

Antibiotic

a type of antimicrobial agent that is naturally produced and inhibits or kills microbes

• most antibiotics used clinically come from soil bacteria such as…

  • bacillus

  • streptomyces

  • penicillium

  • cephalosporium

Broad-Spectrum Antibiotic

An antibiotic that is effective against a wide range of bacteria

• including both gram positive and gram negative bacteria

Narrow-Spectrum Antibiotic

An antibiotic that is effective against a limited range of bacteria

9 Features of Antimicrobial Drugs

• Selective Toxicity

  • want antimicrobial agent to selectively kill the microorganism while doing no harm to the host

• Static vs. Cidal Activity

  • cidal means that the antimicrobial agent kills the microbe

  • static means the microbe will only be inhibited from growing as long as drug is present

• Spectrum of Activity

  • how broad or narrow of a group of microbes do you want to inhibit or kill?

  • a few is typically better bc some of our microbes are needed in our body, like our microbiome

• Distribution

  • make sure antibicrobial agent reaches the infection

• Metabolism and Excretion

  • how the body will metabolize and excrete the drug

• Combinations of Antimicrobial Agents

  • know how the drug interacts with other drugs the patient may be taking

• Adverse Effects (side effects)

• Cost of Drug

• Resistance

  • how likely is it that the drug can be inactivated or a microbe can become resistant to the drug?

Therapeutic Index

the ratio of the toxic dose of the drug versus the effective dose 

• want effective dose to be much less than toxic dose

Innate Resistance

Virus is naturally resistant to the drug

• is not preventable

Acquired Resistance

When a microbe that is normally sensitive to an antimicrobial agent becomes resistant

What should you know about each antimicrobial agent?

• Microbe it inhibits/kills

• Target on the microbe

• Mechanism of action

5 Targets for Antibacterial Agents

• Cell Wall Synthesis

• Protein Synthesis

• Nucleic Acid Synthesis

• Metabolic Pathways

• Cell Membrane Integrity

Antibacterial Agents that Target Cell Wall Synthesis

• B-lactam drugs

• Vancomycin

• Bacitracin

B-Lactam Drugs

Inhibit peptidoglycan synthesis by inhibiting penicillin binding proteins to prevent crosslinking of peptidoglycan polymers

• They all work by inhibiting the formation of cross links

  • Cross links are formed by penicillin binding proteins

  • No cross links means weak cell wall, and the bacterial cell will lyse

• Once the cross link is formed, they cant do anything, they only stop the synthesis of crosslinks

• all types of B-lactam drugs share a similar structure

  • Square connected to a pentagon

  • Look like a house with a garage

  • square is the B-lactam ring

• Includes

  • penicillins

    • or any drug that ends in -illin

  • cephalosporins

  • carbapenems

  • monobactams

Vancomycin

Inhibits peptidoglycan synthesis but in a different way

• Binds to the end of the peptide chains coming off of NAM, preventing formation of crosslinks

  • Creates a weak cell wall and the cell to lyse

• Found in a lot of triple antibiotic ointments

• Drug of last resort to treat MRSA infections

Bacitracin

Inhibits peptidoglycan synthesis by preventing the transport of NAG and NAM to where peptidoglycan is being synthesized

How do different strains of penicillin differ from each other?

They all have the same basic structure of the B-lactam ring, but they differ in their side chains

6 Antibacterial Agents that Inhibit Bacterial Protein Synthesis

• Aminoglycosides

• Tetracyclines

• Macrolides

• Chloramphenicol

• Lincosamides

• Oxazolidinones

all inhibit some step in translation

Aminoglycosides

Binds to the 30S subunit on ribosome and blocks initiation of translation

• if initiation still occurs, it causes misreading of mRNA, making a faulty protein

• Ex)

  • Streptomycin

  • tobramycin

  • gentamycin

  • amikacin

Tetracyclines

Binds to 30s unit on ribosome

• Blocks tRNA molecules from entering into the A or P site

• This causes elongation to stop

Macrolides

Binds to 50S subunit to prevent translocation

• ex)

  • Erythromycin

  • azithromycin

  • clarithromycin

Chloramphenicol

Binds to 50S subunit to prevent peptide bond formation

• often used for bacterial meningitis

• makes it so the ribosome cant connect amino acids

Lincosamides

Binds to 50S subunit to prevent elongation

• Ex) Clindamycin

Oxazolidinones

Binds to 50S subunit to prevent initiation

• ex) Linezolid

Streptogramins

Bind to 50s subunit and interferes with different steps of protein synthesis

Pleuromutilins

Binds to 50s subunit and prevent peptide bonds from being formed

Antibacterial Agents that Inhibit Nucleic Acid Synthesis

• Fluoroquinolones

• Rifamycins

Fluoroquinolones

Inhibits topoisomerases (DNA Gyrase)

• DNA gyrase relieves the supercoiling as we unwind bacterial DNA during replication

• Bacteria cant replicate DNA then bc there is so much supercoiling they cant separate their strand of DNA

Rifamycins

blocks bacterial RNA polymerase from initiating transcription

• often used to treat tuberculosis

Antibacterial Agents that Inhibit Metabolic Pathways

• Sulfa Drugs

• Trimethoprim

*These drugs interfere with the pathway for the synthesis of folic acid

*They target a metabolic pathway unique to the bacteria

Sulfa Drugs

Some bacteria make their own folic acid using a specific metabolic pathway

• One of the intermediates in this pathway is PABA, which is the first enzyme in the pathway

• sulfa drugs like sulfanilamide inhibit the PABA enzyme by entering the active sight and blocking it so PABA can’t enter the pathway

• Used to treat UTIS

Trimethoprim

Trimethoprim does the same thing as sulfa drugs in the folic acid metabolic pathway for bacteria, but it inhibits enzyme 3 instead of the first enzyme

Antibacterial Agents that Interfere with Cell Membrane Integrity

The bacterial cell membrane is similar in structure to human cell membranes, only difference is the charge of the lipids in the outer leaflet (bacteria outer lipids are negative, human outer lipids are neutral). This helps drugs know what to target

• Types of Drugs

  • Polymyxin B

  • Daptomycin

Polymyxin B

Binds to cell membrane of Gram negative bacteria

• Alters cell membrane permeability by causing it to be leaky and the cytoplasm to leak out, leading to cell death

Daptomycin

Inserts into cell membrane of Gram positive bacteria

• also causes leakage of cellular contents, and then cell death

• Cannot penetrate the outer membrane of Gram negative bacteria

Antibiogram

an antibiotic susceptibility profile

(tells us what antibiotics work best against a specific bacteria)

How to Determine Drug Susceptibility

Must do testing to find the antibiogram (antibiotic susceptibility profile)

• Once they isolate the bacteria causing the infection, they will take that bacteria and test it against a panel of different antibiotics to see which antibiotic will be most effective

• Methods to do this include:

  • MIC Value

  • Disc Diffusion / E-Tests

MIC Value

In the lab, they will determine the minimal inhibitory concentration for a group of antibiotics

• They use a series of test tubes and each tube contains a dilution of a particular antibiotic

• then they inject each tube with same amount of bacteria and determine what the value of the lowest amount of drug would be to eliminate the bacteria (the lowest concentration that prevents the growth of microbe)

Disc Diffusion Tests

• You have some bacterial growth media in a dish and add bacteria to the surface,

• Then you add filter paper discs, and each disc has a known concentration of a different antibiotic

• Then you incubate it, and the antibiotic will diffuse out of the disk into the media

• Whereever the antibiotic inhibits or kills the bacteria, you will see a zone of inhibition

• You can then measure the diameter of that zone and it will tell you if that bacteria is resistant or susceptible to the antibiotic

E Tests

Same idea as the Disc Diffusion, but instead of filter paper discs, there is a strip of paper has a gradient of the antibiotic

• the antibiotic will diffuse out into the growth media and create a zone of inhibition

• The place where the zone of inhibition meets the strip at the bottom tells us the MIC number

How does mycoplasma pneumoniae exhibit characteristics of innate resistance?

mycoplasma pneumoniae (causes walking pneumonia) does not have a cell wall, so it is inherently resistance to B lactam drugs bc these drugs target peptidoglycan in cell walls

Mechanisms of Acquired Resistance

• Drug-inactivating enzymes

  • b-lactamases

    • A lot of bacteria that is resistant to B lactam drugs produce B-lactamase which is an enxyme that breaks the B lactam ring

  • chloramphenicol acetyltransferase

• Alteration of target

  • there is a mutation that alters the target of the drug so now the drug doesn’t bind to the target anymore

• Decreased uptake of drug

  • due to changes in porin proteins, which affects what can get through the outer membrane

• Increased elimination of drug

  • Efflux pumps in cell membrane that pump out drug as soon as they get inside the bacterial cell

Why is overuse of antibiotics concerning?

The more you take that antibiotic, the more you kill the susceptible bacteria and cause natural selection for resistance bacteria

Bacteria with emerging resistance:

• enterococci

• staphylococci

• streptococci

• mycobacteria

How do bacteria acquire resistance?

• Spontaneous mutations

  • Ex) Mutation in a gene that encodes for a part of the ribosome, changing the target area for drugs so the drug cant bind

  • Cant do anything about it

  • Another ex) Aminoglycosides cause misreading of mRNA, causing mutations

  • Decreased uptake is a type of spontaneous mutation as well

• Horizontal gene transfer

  • Transfer of R plasmids through conjugation or transformation

  • these plasmids carry genes that encode proteins that modify or destroy the antimicrobial agent

• Transposons

  • known to carry drug inactivating enzymes

  • Ex) Efflux pumps

How to Slow the Spread of Antibiotic Resistance

• Limit non-medical use of antibiotics

• Selective and appropriate use of antibiotics

  • Antibiotics only effective for bacterial infections

  • Drug selection (choosing the correct specific drug)

• Ensure dose and duration are adequate

• Combination therapy

  • Using 2 different bacterial agents that target different things

What percentage of prescriptions given to people are given to people with viral infections instead of bacterial infections?

50%

Antiviral Agents

• Very few antiviral agents

• The ones that exist are for a select few viruses

• For the ones out there, each antiviral agent is going to target some step in the viral replication cycle

5 Things Antiviral Agents Target in the Viral Replication Cycle

• Some block entry of the virus

• Some inhibit the uncoating of the virus once inside the cell

  • Only works against flu a, not b

• Some target nucleic acid synthesis of virus

  • Stops it from making copies of itself

• Some target genome integration

  • Retroviruses – have RNA that they convert into DNA, which is inserted into host genome using an enzyme called integrase

  • Integrase inhibitors are effective against this

• Some target assembly and release of virus

  • Ex) Paxlovid interferes with assembly and release of virus for COVID

6 Antifungal Drugs

• Polyenes

• Azoles

• Allylamines

• Griseofulvin

• Flucytosine

• Tavaborole

Polyenes

Binds to ergosterol and disrupts integrity of cell membrane

• When binding to ergosterol, it creates a pore in the membrane and causes leakage of cell contents

• can sometimes bind to cholesterol which can be toxic

• ex) Amphotericin B

Azoles

inhibit synthesis of ergosterol

• Target synthesis of ergosterol by inhibiting enzymes in the pathway

• If it cant make ergosterol, cell membrane doesn’t function properly, causing death of fungus

• Ex) Fluconazole, itraconazole, ketoconazole

Allylamines (terbinafine)

inhibits ergosterol synthesis

Griseofulvin

inhibits tubulin polymerization

• Spindle fibers used to move chromosomes during mitosis are made of tubulin, so if inhibited, you prevent mitosis or meiosis, affecting replication

Flucytosine

Gets converted to 5-fluorouracil, which inhibits the enzyme needed for nucleic acid synthesis

Tavaborole

inhibits protein synthesis by preventing the charging of tRNA’s with amino acids (cant load tRNA with amino acids)

• used only for onychomycosis (fungal nail infections