Key Principles and Beta Lactam Drugs

Question 1

How can antibacterial drugs be classified?

Answer 1

Bactericidal vs bacteriostatic.
By spectrum of activity.
Mechanism of action.

Question 2

1. Bacteriostatic vs bactericidal.
2. What happens to the number of bacterial cells once bacteriostatic drug added?
3. What happens to the number of bacterial cells once bactericidal drug added?

Answer 2

1. Bactericidal kill bacteria, bacteriostatic slow growth and stop replication.
2. There is a slow in replication and a halt in growth and the bacterial cells will eventually reduce as bacteria have a life span and the bacterial cells present at that time will die off, leaving no more bacteria as the body’s immune system has been given a chance to fight the bacteria.
3. The number of bacterial cells decreases instantly as they are killed by the drug.

Question 3

1. Give 5 drug classes that are bacteriostatic.
2. Give 5 drug classes that are bactericidal and say briefly what each does.
3. What drug class is either bactericidal or bacteriostatic depending on their concentration?

Answer 3

1. Sulphonamides, trimethoprim, tetracyclines, chloramphenicol, lincomycin.
2. • Penicillin – target cell walls.
     - Cephalosporins – target cell walls.
     - Fluoroquinolones – target DNA.
     - Aminoglycosides – Affect protein synthesis.
     - Metronidazole – Affects protein synthesis.
     - Trimethoprim and sulphonamides together (bacteriostatic individually) – affect folate synthesis.
3. Erythromycin – affects protein synthesis. (bacteriostatic at lower doses and bactericidal at higher doses) (usually bacteriostatic in clinical setting).

Question 4

1. Further classification of bactericidal drugs.

Answer 4

• Time dependent vs concentration dependent
• Spectrum of activity.

Question 5

Time-dependent vs concentration-dependent.

Answer 5

1. time dependent vs conc dependent. (affects administration).
   – Time dependent work slowly so need to be given over a longer time period – days.
   - Plasma levels should be above minimum inhibitory concentration (MIC) for as long as possible in each 24 hour period. (conc of drug in plasma needed for time dependent drug to be effective.
   - examples – penicillins, cephalosporins, sulphonamide + trimethoprim concentration.
   - affects administration intervals. (regular).
   – Concentration dependent
   - peak conc determines how effective the drug will be.
   - examples – aminoglycosides, fluoroquinolones and metronidazoles.
   - affects dosage of administration.

Question 6

Spectrum of activity

Answer 6

Drugs that are effective against gram + or gram - bacteria.
Drugs that are effective against anaerobic bacteria or aerobic bacteria.

E.g. gram positive aerobes, gram negative aerobes, obligate aerobes and penicillinase-producing staphylococcus**
** Show resistance because they break down penicillins .

Question 7

What is the colour coding for effectiveness of drugs?

Answer 7

White – Excellent activity against most bacteria in this quadrant.
Cross-hatched blue – Good activity against bacteria in this quadrant, with some possible individual exceptions.
Purple – Moderate activity against pathogens in this quadrant, unpredictable resistance.
Blue shaded – No useful activity against bacteria in this quadrant, but may be some individual exceptions.

Question 8

1. What is an important component of bacterial cell walls that is targeted by many drugs?
   – How do they target it?
   – What drugs do this?
2. How is the mechanism of these drugs beneficial for the patients they are administered to?

Answer 8

1. Peptidoglycan. – inhibit its synthesis.
   – Beta lactams: penicillins, cephalosporins.
2. The drugs are specific to targeting the cell walls which are not a component of mammalian cells so no further harm will be brought to mammalian cells and therefore the patient by drug administration. Selective effects on bacteria!

Question 9

1. What is peptidoglycan?
2. Difference between gram + and gram - bacteria peptidoglycan.
3. How can the gram - bacteria stop some of the drug acting on it?
4. What is the name of the proteins at the interface between the cell wall and the plasma membrane?

Answer 9

1. Long chains of amino sugars in cell wall.
2. Gram + bacteria have much thicker cell walls than gram - bacteria so the peptidoglycan content is higher in gram + than gram - (50% of gram + is peptidoglycan and 5%).
3. Has an outer cell membrane that can stop some of the drug before it gets to the cell wall.
4. Penicillin-binding proteins.

Question 10

1. Structure of peptidoglycan.
2. Action of penicillins and cephalosporins.

Answer 10

1. Long chain of amino sugars which are then cross-linked by peptide crosslinks to form a lattice which maintains integrity of the bacterial cell wall.
2. Stop the peptide chains being joined together by crosslinking so stop the formation of the lattice.

Question 11

1. Structure of the beta lactam ring?
2. Once bound to the penicillin-binding protein, what enzymes do beta lactam drugs target? – what are these enzymes responsible for?
3. What happens if the PBPs mutate? – Give an example of a bacteria that has achieved this.

Answer 11

1. 3 carbons and a nitrogen with a different branch coming off it dependent on the drug.
2. transpeptidases – responsible for crosslinking the amino sugar chains.
3. Reduce effectiveness of the drug trying to bind to them and act upon them. – source of resistance.
   – MRSA (methicillin resistant staphylococcus aureus).

Question 12

1. Give a key source of resistance of bacteria to beta lactam drugs.
2. How have the medical field been able to combat this type of resistance?

Answer 12

1. Beta lactamase – enzyme produced by bacteria that breaks down beta lactam ring of the drug. e.g. penicillinase. – breaks bond between N and C, so the frug cannot bind to the PBPs.
2. By the use of clavulanic acid in conjunction with beta lactam drugs. Clavulanic acid is a beta lactamase inhibitor. Amoxicillin is the only beta lactam drug licensed for use in conjunction with clavulanic acid in vet practice. e.g. Synulox.

Question 13

Give the acid stability, lactamase stability and spectrum of…
1. benzylpenicillin*
2. cloxacillin
3. ampicillin
4. amoxicillin*

*focus on these

Answer 13

1. poor acid stability, susceptible to beta lactamase, works on gram + cocci.
2. good acid stability, stable against beta lactamase, works on gram + cocci.
3. Medium acid stability, susceptible to beta lactamase, works on G+ cocci and some G- bacteria.
4. v good acid stability, susceptible to beta lactamase, works on G+ cocci and some G- bacteria.

Question 14

1. What needs to be considered in terms of administration for a drug with poor acid stability?
2. How is using a broader spectrum drug advantageous?
3. How is using broader spectrum drugs disadvantageous?

Answer 14

1. Cannot be taken orally as will be destroyed by stomach acid. Must be given by injection.
2. Has more chance of working when the bacteria causing the infection is unknown.
3. Encourages the development of resistance.

Question 15

1. Oral availability of penicillins?
2. Distribution of penicillins within the body?
   – Advantage?
3. Elimination of penicillins?
   – consideration?

Answer 15

1. Dept on acid stability.
2. Widely distributed throughout the body, do not cross BBB.
   – Good for widespread infections in the body.
3. Kidneys. – may have an animal with impaired kidney function, increasing half life of the drug, increasing side effects.

Question 16

1. Administration of cephalosporins?
2. Distribution of cephalosporins throughout the body?
3. Elimination of cephalosporins?

Answer 16

1. Some orally, most parenterally.
2. Widely distributed, some cross BBB.
3. Kidney.

Question 17

1. What does it mean to have a wide therapeutic ratio?
2. Most common reactions with penicillins and cephalosporins?
3. Issue associated with these drugs and the GI tract.

Answer 17

1. The dose that works therapeutically can be increased by quite a long way before you see v serious side effects because they are selectively targeting a bacterial process (walls).
2. Hypersensitivity (allergic) reactions – almost immediate, usually mild but can be fatal (anaphylaxis).
3. GI superinfection (when given orally) – death of susceptible gut flora allows proliferation of non-susceptible bacteria.

Question 18

1. Example of infection caused by mycobacteria?
2. Why important?
3. Combination of drugs to treat mycobacterial infections and each of their actions??
   How long will this treatment take?

Answer 18

1. Bovine TB.
2. These are v difficult to kill.
3. Fluoroquinolone – inhibits DNA gyrase.
   Clarithromycin – inhibits protein synthesis.
   Rifampicin – inhibits RNA synthesis.
4. Around 6 months.