Antimicrobial Drugs

Question 1

Antibiotics Definition

Answer 1

Agents produced by one organism that have some toxic or inhibitory effect on another organism or cell
Used to treat bacteria, fungi and cancer cells
NO impact on viruses

Question 2

Selective toxicity

Answer 2

The idea that you can use toxic drugs, which as long as they are more toxic to your target than to normal tissues, can be useful

Question 3

Bacteriocidal Antibiotics

Answer 3

Drugs that cause the death of the bacteria

Required if the patient is immunosuppressed

Question 4

Bacteriostatic Antibiotics

Answer 4

Drugs that inhibit the growth of the bacteria
Growth resumes when the drug is removed
Success depends on there being an effective immune response

Question 5

6 general features of bacterial cells we can attack

Answer 5

1. A completely unique structure (ex: peptidoglycan)
2. Pathways that are absent in mammalian cells (folic acid synthesis)
3. Structures that differ between human and bacterial cells (ribosomal subunits)
4. Enzymes that differ (ex: DNA gyrase)
5. Cellular constituents that are different (certain lipids)
6. Cellular constituents that are enriched (other lipids)

Question 6

Transpeptidation

Answer 6

Forming the cross bridge between the 2 NAMs

Terminal Ala is removed, then first Ala can join to Gly

Question 7

3 groups of beta lactam drugs that inhibit transpeptidation

Answer 7

1. Penicillins
2. Cephalosporins
3. Cabapenems

Question 8

Why is penicillin V better than G?

Answer 8

Penicillin G breaks down in acid

Question 9

Narrow Spectrum vs Extended-Spectrum

Answer 9

Narrow (penicillin V): against Gram + bacteria
Extended (amoxicillin): against Gram + and some Gram - (they are better drugs - wider spectrum, better absorbed, longer half life)

Question 10

What can we do about the beta lactamases?

Answer 10

1. Use a beta-lactamase-resistant antibiotic (Nafcillin)

2. Combine with a beta lactamase inhibitor (Clavulanate)

Question 11

What properties have changed from first to 4th generations cephalosporins?

Answer 11

1. Better activity against gram negative bacteria
2. Better ability to cross into tissue spaces
3. Generally more resistant to beta lactamases

Question 12

Carbapenems

Answer 12

Ex: Imipenem
Penicillin-like antibiotics in which the sulfur atom of the penicillin structure is replaced with a carbon
Altered spectrum
Resistant to beta-lactamases

Question 13

Vancomycin

Answer 13

Cell Wall synthesis inhibitor
Binds to the growing peptide chain
Prevents subsequent ability to cross link

Question 14

Bacitracin

Answer 14

Cell wall synthesis inhibitor
Mixture of cyclic peptides
Works inside the cell to block cell wall synthesis (stops lipid recycling - no dephosphorylation)

Question 15

4 drugs that effect the function of ribosomes and how they work

Answer 15

1. Erythromycin and other macrolides (binds to 50S subunit, prevents translocation-movement of ribosome along mRNA)
2. Tetracyclines (like tetracycline) - interferes with attachment of tRNA to mRNA-ribosome complex
3. Aminoglycosides such as gentamicin or streptomycin (changes shape of 30S subunit, causes code on mRNA to be read incorrectly)
4. Chloramphenicol (Binds to 50S portion and inhibits formation of peptide bonds)

Question 16

Chloramphenicol

Answer 16

Broad spectrum, active against many different bacteria
Bacteriostatic
Binds to 50S portion and inhibits formation of peptide bonds
Problems: bone marrow disturbances, common interactions with other drugs, gray baby syndrome

Question 17

Macrolides

Answer 17

Work best against gram positive microorganisms
Bacteriostatic
Include: erythromycin, clarithromycin, azithromycin

Question 18

Erythromycin

Answer 18

Macrolide
Base is somewhat unstable in acid conditions
Food reduces absorption
Works well against gram positive organisms
Poor against gram negatives
Useful in penicillin-resistant infections

Question 19

Clarithromycin

Answer 19

Macrolide
Chemically modified from erythromycin
Additional methyl group
Improved acid stability
Improved oral absorption
Most active against gram positives

Question 20

Azithromycin

Answer 20

Macrolide
Further modified from clarithromycin
Additional lactone ring
Excellent tissue penetration
Released from tissue slowly
Longer half-life
Best activity against gram negative anaerobes
Acts against spirochetes
Less likely to become involved in drug interactions

Question 21

Aminoglycosides

examples, targets, route of administration, toxic to what

Answer 21

Ex: Streptomycin, gentamicin
Used mostly against gram negative enteric bacteria
Oral doses are very poorly absorbed
Usually given intramuscularly or intravenously
Toxic to ears and kidneys

Question 22

3 functions of aminoglycosides

Answer 22

1. Block formation of the initiation complex
2. Miscoding in the polypeptide chain
3. Block of translocation

Question 23

Tetracyclines

Answer 23

Broad-spectrum
Active against bacteria, mycoplasma, some protozoa
bacteriostatic
Resistance is common
Chelate divalent metal ions
Adverse effects: GI irritation, accumulate in bone and teeth, teratogenic

Question 24

If macrolides, tetracyclines and aminoglycosides all block protein synthesis in bacteria, why are they different in use?

Answer 24

1. They’re different chemically, which affects things like their stability and absorption.
2. They interfere at different sites on the bacterial ribosomes, which means they have different therapeutic actions.

Question 25

Where can we attack bacteria?

Answer 25

1. Interfere with their ability to synthesize materials needed for DNA (folic acid) 2. Cell wall syntheis 3. Protein synthesis 4. DNA gyrase 5. RNA elongation 6. PM structure 7. DNA-directed RNA polymerase

Question 26

Sulfamethoxazole/trimethoprim

Answer 26

Septra - blocks the folic acid pathway (bacteriocidal) More effective than either drug alone Still works if resistance develops to one drug Used at a dose ration of 1:5, which gives a plasma concentration ratio of 1:20 (optimal)

Question 27

DNA gyrase (topoisomerase type 2)

Answer 27

Untangles the DNA in a cell (cuts it) | Fluoroquinolones block it (ex: ciprofloxacin)

Question 28

Fluoroquinolones

Answer 28

Inhibit DNA gyrase Useful against systemic infections Stop the bacterium form using its DNA Overuse has lead to widespread resistance (especially respiratory pathogens)

Question 29

Polymyxins

Answer 29

Cause disruption of the bacterial membrane Molecule has detergent like properties Binds to phosphatidylethanolamine in PM Problems: humans have PE too, so toxic if given systemically Advantages: resistance and allergy is rare

Question 30

3 advantages and 3 risks of using antimicrobial drugs in combination

Answer 30

``` Advantages: 1. Wider spectrum for mixed infections 2. Reduced dose for individual agents 3. Synergism between antibiotics Disadvantages: 1. Increased possibility of adverse reactions 2. Antagonism between antibiotics 3. Greater risk of antibiotic resistance ```

Question 31

Example of an antagonistic combination

Answer 31

Chloramphenicol and aminoglycoside

Question 32

4 examples of synergistic combinations

Answer 32

1. Cell wall synthesis inhibitors and amino glycosides 2. Beta lactam drugs and beta lactamase inhibitors 3. Beta lactams that act on different PBPs 4. Sulfonamides and trimethoprim

Question 33

5 mechanisms of antibiotic resistance

Answer 33

1. Decreased entry 2. Efflux pump 3. Altered target site 4. Bypass pathway 5. Enzymatic degradation

Question 34

Sulfonamide resistance may be due to (3 things)

Answer 34

1. Decreased permeability of the cell membrane 2. The bacteria produce a form of dihydropteroate synthetase that binds teh sulfonamide poorly 3. Increased production of PABA by the bacteria

Question 35

Trimethoprim resistance may be due to (3 things)

Answer 35

1. Decreased permeability of the cell membrane 2. The bacteria produce a form of dihydrofolate reductase that binds trimethoprim poorly 3. The bacteria produce more dihydrofolate reductase

Question 36

3 antifungals to treat candidiasis

Answer 36

1. Ketoconazole (potentially hepatotoxic) 2. Fluconazole (alternative to ketoconazole and less toxic) 3. Amphotericin B (for extreme cases given IV, significantly toxic and may case renal damage)

Question 37

2 general ways antifungals work

Answer 37

1. Bind ergosterol and form pores that leak out cell contents 2. Inhibit enzymes that are important in making ergosterol

Question 38

Amphotericin B

Answer 38

Antifungal Polyene macrolide antibiotic Large molecule that is lipophilic on one side and hydrophilic on the other (so can form pores in the membrane by binding to ergosterol) Some binding to human cell membranes so it has nephrotoxicity

Question 39

Fluconazole

Answer 39

``` Azole antifungal drug Acts by inhibiting fungal cytochrome P450 enzymes Stops synthesis of ergosterol Lower affinity for human P450 enzymes Less toxic than polyene antifungals ```

Question 40

Therapeutic Window

Answer 40

From the minimal beneficial effects to minimal toxic effects

Question 41

Therapeutic index

Answer 41

Toxic dose 50/ Effective dose 50