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Flashcards in Antimicrobial Drugs Deck (41):
1

Antibiotics Definition

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

2

Selective toxicity

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

3

Bacteriocidal Antibiotics

Drugs that cause the death of the bacteria
Required if the patient is immunosuppressed

4

Bacteriostatic Antibiotics

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

5

6 general features of bacterial cells we can attack

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)

6

Transpeptidation

Forming the cross bridge between the 2 NAMs
Terminal Ala is removed, then first Ala can join to Gly

7

3 groups of beta lactam drugs that inhibit transpeptidation

1. Penicillins
2. Cephalosporins
3. Cabapenems

8

Why is penicillin V better than G?

Penicillin G breaks down in acid

9

Narrow Spectrum vs Extended-Spectrum

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

10

What can we do about the beta lactamases?

1. Use a beta-lactamase-resistant antibiotic (Nafcillin)
2. Combine with a beta lactamase inhibitor (Clavulanate)

11

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

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

12

Carbapenems

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

13

Vancomycin

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

14

Bacitracin

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

15

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

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)

16

Chloramphenicol

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

17

Macrolides

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

18

Erythromycin

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

19

Clarithromycin

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

20

Azithromycin

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

21

Aminoglycosides
(examples, targets, route of administration, toxic to what)

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

22

3 functions of aminoglycosides

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

23

Tetracyclines

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

24

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

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.

25

Where can we attack bacteria?

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

26

Sulfamethoxazole/trimethoprim

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)

27

DNA gyrase (topoisomerase type 2)

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

28

Fluoroquinolones

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

29

Polymyxins

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

30

3 advantages and 3 risks of using antimicrobial drugs in combination

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

31

Example of an antagonistic combination

Chloramphenicol and aminoglycoside

32

4 examples of synergistic combinations

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

33

5 mechanisms of antibiotic resistance

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

34

Sulfonamide resistance may be due to (3 things)

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

35

Trimethoprim resistance may be due to (3 things)

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

36

3 antifungals to treat candidiasis

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)

37

2 general ways antifungals work

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

38

Amphotericin B

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

39

Fluconazole

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

40

Therapeutic Window

From the minimal beneficial effects to minimal toxic effects

41

Therapeutic index

Toxic dose 50/ Effective dose 50