Drugs interfering with metabolism and DNA

Question 1

1. What drugs affect folate synthesis in bacteria?
2. How are these drugs selective of bacterial cells over mammalian cells.

Answer 1

1. Sulphonamides and trimethoprim.
2. Mammals obtain their folate from the environment instead of producing it so there is no mammalian process affected by the drugs.

Question 2

1. How do sulphonamides inhibit folate synthesis?
2. How does trimethoprim inhibit folate synthesis?

Answer 2

1. They competitively inhibit dihydropteroate synthetase (DHPS) – an enzyme involved in P-Aminobenzoic acid (PABA) becoming dihydropteroic acid.
2. Inhibits dihydrofolate reductase (DHFR) – an enzyme involved in dihydrofolic acid becoming tetrahydrofolic acid.

Question 3

1.Spectrum of activity of sulphonamides?
2. Sulphonamide absorption?
3. Sulphonamide distribution?
4. Sulphonamide excretion?

Answer 3

1. Wide spectrum of activity against gram +ve and gram -ve bacteria.
2. Well absorbed by the gut.
3. Wide distribution around the body.
4. Renal excretion.

Question 4

1. Sulphonamides bacteriostatic or bactericidal?
2. Sulphonamides adverse reactions?

Answer 4

1. Bacteriostatic.
2. Hypersensitivity reactions, immune-mediated reactions e.g. keratoconjunctivitis sicca, polyarthritis (esp Dobermans).

Question 5

1. What is trimethoprim commonly co-administered with?
2. What is the outcome of this combo?
3. Combo’s spectrum of activity?

Answer 5

1. Sulphonamide.
2. Bactericidal and effective against protozoal infections.
3. Good against gram +ve but some are resistant.
   Moderate activity against all others with unpredictable resistance.

Question 6

1. How do fluoroquinolones affect bacteria?
2. Spectrum of activity of fluoroquinolones
3. Fluoroquinolone absorption?
4. Fluoroquinolone distribution?
5. Fluoroquinolone excretion?

Answer 6

1. Inhibit supercoiling by interfering with the actions of DNA gyrase (topoisomerase II).
2. Wide spectrum – Wide range gram -ve and a number of gram +ve aerobes.
3. Well absorbed by gut.
4. Good distribution to all tissues.
5. Renal and hepatic excretion.

Question 7

1. Adverse reaction of fluoroquinolones.
2. Bactericidal or bacteriostatic.
3. Why are fluoroquinolones popular?

Answer 7

1. Rare – inhibition of cartilage growth in young animals (more in dogs than cats), retinal degeneration in cats (may recover).
2. Bactericidal.
3. Efficacy and lack of toxicity – BUT shouldn’t generally be used as a first line treatment.

Question 8

1. Fluoroquinolone spectrum of activity?

Answer 8

Excellent activity against gram -ve aerobes and penicillinase-producing staphylococcus and, good activity against gram +ve aerobes.

Question 9

1. Metronidazole spectrum of activity?
2. Mechanism of activity of metronidazole?
3. Absorption?
4. Distribution?
5. Excretion?

Answer 9

1. Only works in obligate anaerobic bacteria by oxidation of ferredoxins, producing reactive metabolites.
2. Causes DNA fragmentation.
3. Well absorbed by the gut.
4. Good distribution to all tissues.
5. Renal and hepatic excretion.

Question 10

1. Metronidazole also effective against?
2. Adverse reactions?

Answer 10

1. Protozoal infections.
2. Rare and usually mild. Vomiting, nausea, dry mouth. Very rare neuro signs – ataxia, head tilt, convulsions. Cats may salivate profusely. May be teratogenic – cause birth defects.

Question 11

Biochemical mechanisms of antibiotic resistance?

Answer 11

• Inactivation of antibacterial drug (inhibitors or adding structures to change drug shape.
• Alteration of target site (e.g. MRSA).
• Decrease drug accumulation in the bacterium (e.g. efflux pumps)
• Upregulate synthesis of target.
• Alter metabolic pathway (e.g. folate synthesis).

Question 12

1. What were the first synthetic antibacterial drug class and when?
2. When was Penicillin G developed?

Answer 12

1. Sulphonamides – 1930s.
2. 1942.

Question 13

1. What does minor S. Aureus infection cause?
2. What does more serious S. Aureus infection cause?
3. When was the first report of S. Aureus resistance to penicillin?
4. What is MRSA also resistant to?
5. What can MRSA be treated with?

Answer 13

1. Pimples.
2. pneumonia.
3. 1947.
4. Ampicillin, other penicillins, erythromycin, tetracyclines.
5. Vancomycin only (drug of last resort), but VRSA now also exists.

Question 14

Why has resistance occurred in animals?

Answer 14

Half of all antibiotics produced used in agriculture.
Sprayed on crops to control or prevent bacterial diseases.
Given to animals to treat illness and prevent illness in healthy animals.

Question 15

Why has resistance occurred in humans?

Answer 15

Over-use and misuse in treating non-bacterial illnesses.
50% of antibacterial prescriptions are inappropriate. – not a bacterial infection, wrong choice of antibacterial or inappropriate duration or dose, unsuitable use of broad spectrum drugs.
Owners can be non-compliant to drug regimens.

Question 16

How does antibiotic resistance spread when given to animals?

Answer 16

Animals take antibiotics and develop resistant bacteria in guts. Drug-resistant bacteria can remain on meat and spread to humans when not handled properly or not cooked properly. Or fertiliser or water containing animal faeces and drug-resistant bacteria used on food crops. Bacteria can remain in human gut.

Question 17

How is antibiotic resistance spread when given to humans?

Answer 17

Human takes antibiotics and develops resistant bacteria in gut. May get care at hospital, nursing home or other care facility and spread bacteria to other patients directly, via surfaces in facility or unclean hands of health care providers. May also just spread this bacteria in the general community.

Question 18

7 point plan for responsible use of antimicrobials in vet practice.

Answer 18

1. Work with clients to avoid need for antimicrobials.
   - Pet health checks regularly.
   - Symptomatic relief or topical preparations where appropriate.
   - Integrated disease ctrl programmes.
   - Animal health and welfare planning.
   - Isolate infected animals wherever possible.

Question 19

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Answer 19

2. Avoid inappropriate use
   - For uncomplicated viral infections.
   - Restrict use to ill or at-risk patients.
   - Advise on correct administration and storage of products and completion of course.
   - Avoid underdosing.

Question 20

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Answer 20

3. Choose the right drug for the right bug
   - ID likely target organisms and predict susceptibility.
   - Create practice-based protocols for common infections based on clinical judgement and up-to-date knowledge.
   - Know how antimicrobials work and their pharmacodynamic properties.
   - Use narrow-spectrum drugs where poss.

Question 21

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Answer 21

4. Monitor antimicrobial sensitivity
   - bacterial culture and sensitivity must be determined as well as diagnosis whenever poss so tx change can be implemented if necessary.
   - Monitor bacterial culture and sensitivity trends.

Question 22

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Answer 22

5. Minimise use
   - Use only when necessary and evidence that usage reduces morbidity and/or mortality.
   - Regularly assess antimicrobial use and develop written protocols for appropriate use.
   - Use alongside strict aseptic techniques and written practice guidelines.

Question 23

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Answer 23

6. Record and justify deviations from protocols.
   - Be able to justify choice of antimicrobial and dose.
   - Keep accurate records of treatment and outcome to help evaluate therapeutic regimens.
7. Report suspected treatment failure to VMD.
   - May be first indication of resistance.
   - Report through Suspected Adverse Reaction Surveillance Scheme (SARSS)