Pharmacology of Abx Part 3

Question 1

List antibacterial drugs that inhibit nucleic acid synthesis.

Answer 1

Sulphonamides, trimethoprim, quinolones, nitroimidazoles and rifamycins.

Question 2

Describe sulphur drugs and give examples.

Answer 2

Dapsone: used for Mycobaterium leprae.
Trimethoprim and sulphonamides: inhibit growth by preventing tetrahydrofolate (THF) synthesis.
Bacteriostatic.
Their use has diminished because of the spread of resistance.

Question 3

What is THF and why is it important?

Answer 3

Tetrahydrofolate is the active form of folic acid. It is an essential cofactor for the generation of deoxynucleotides in bacteria. Sulphur drugs inhibit its synthesis, and therefore the synthesis of nucleic acids.

Question 4

Why do sulphonamides have a limited place in general practice?

Answer 4

Sulphamethoxazole combined with trimethoprim has been associated with significant adverse effects due to the sulphonamide, especially in the elderly.
Trimethoprim alone is effective against UTIs, so combination therapy should be restricted unless it is the only treatment option.

Question 5

Describe the use of trimethoprim combined with sulfamethoxazole.

Answer 5

Treatment and prophylaxis of pneumocystitis (fungal infection in AIDS).
Community acquired MRSA
Melioidosis: combination therapy
Listeria monocytogenes: listeric meningitis. Used for patients with penicillin allergy.
Norcardia infections: pneumonia, encephalitis, endocarditis, cellulitis

Question 6

Can trimethoprim be used in children?

Answer 6

Yes. no paediatric formulation available, so may need suspension made from tablets.

Question 7

Can hypersensitivity occur to trimethoprim and sulfamethoxazole>

Answer 7

Yes, they are common. If its use is clinically necessary, desensitisation may be attempted.

Question 8

What are the counselling points for trimethoprim combined with sulfamethoxazole?

Answer 8

Take with food and drink at least 2-3L water daily during prolonged or high dose treatment (prevent crystalluria).
Increases sensitivity to sun.
Tell doctor immediately about sore throat, fever, joint pain, rash, cough or dark urine and pale stools.

Question 9

What are the contraindications for sulphonamides?

Answer 9

Do not use in last trimester of pregnancy or in neonates. Drug competes for billirubin-binding sites on albumin –> increased concentration of unbound billirubin and increased risk of kernicterus (damage to the brain of infants).

Question 10

What are some practice points for trimethoprim alone, and associated side effects?

Answer 10

monitor complete blood picture and folate status during prolonged or high dose treatment. Bone marrow depression is an adverse effect.
Monitor serum potassium if patient has renal impairment, or taking high doses.
Give at night to maximise urinary concentration for UTI.
Single dose treatment for uncomplicated lower UTI in women can be considered, but treatment for 3 days is more effective in preventing relapse.

Question 11

Describe the mechanism of action of the quinolones and give examples.

Answer 11

Bactericidal. Inhibit bacterial DNA synthesis by blocking type II bacterial topoisomerases (DNA gyrase and topoisomerase IV).
Eg ciprofloxacin, moxifloxacin and norfloxacin.

Question 12

What is norfloxacin used for?

Answer 12

Treatment of urinary and gastrointestinal infections.
Uncomplicated UTIs.
No useful activity against anaerobes, and poor activity against strep.

Question 13

Describe the spectrum of ciprofloxacin.

Answer 13

Wide range of activity against G- bacteria including H influenza, enteric G- rods, P aeruginosa, G- cocci, some G+ cocci and intracellular organisms e.g. legionella and mycobacteria.
No useful activity against anaerobes and poor activity against strep.
Used for complicated UTIs.

Question 14

Describe the parental use of quinolones.

Answer 14

Used for serious systemic infections.
Moxifloxacin: increased activity against G+ (inc staph and strep) and wide activity against G- aerobes, but inferior to ciprofloxacin against pseudomonas. Good activity against aerobes, and most pathogens causing atypical pneumonia. can be administered once daily.

Question 15

Quinolones should be reserved for the treatment of:

Answer 15

Infections resistant to cheaper drugs.

Where an oral drug with this particular antibacterial spectrum is essential.

Question 16

Give examples of infections that have become resistant to the use of quinolones.

Answer 16

Staph aereus, P aeruginosa, enteric G-ve rods, Campylobacter and N gonorrhoeae.

Question 17

Adverse effects of quinolones.

Answer 17

Photosensitivity, CNS effects in older patients, damaged joints of immature mammals: used with caution in children under 14 years and pregnant/breastfeeding women.
Ciprofloxacin and norfloxacin should be used in lower doses in patients with impaired renal function.
may cause C. difficile-assosciated diarrhoea.
Achilies tendon rupture in the elderly, or when combined with corticosteroids.
Prolonged QT interval.

Question 18

COunselling points for quinolones.

Answer 18

May cause dizziness or faintness.
alcohol may worsen effects.
Stop taking the medicine, do not exercise and see doctor ASAP if you have any tendon soreness or inflammation.

Question 19

Practice points for quinolones:

Answer 19

Treatment of UTIs where other agents contraindicated.
Moxifloxacin may treat severe Legionella pneumonia and severe community-acqured pneumonia (especially in penicillin-sensitive).
Gonorrhoea has resistance.
Stop treatment at first sign of tendon soreness
Superinfection with enterococci or candida may occur.

Question 20

What is the mechanism of action of nitromidazoles? Give examples.

Answer 20

Forms active metabolites only in some anaerobes and some protozoa. These metabolites inhibit DNA synthesis.
Bactericidal.
Eg metronidazole and tinidazole.

Question 21

Describe the spectrum of nitromidazoles.

Answer 21

Active against most G- anaerobes, most G+ anaerobes and anaerobic protozoa (T vaginalis, Giardia).
Metronidazole is one of the few Abx that has activity against C. difficile, and is the treatment of choice for this.

Question 22

Describe the use of metronidazole, including dosage forms.

Answer 22

Helps control symptoms of Crohn’s disease.
Administered topically in rosacea.
Oral and IV administration. Has excellent absorption so can use tablets or suppositories.
Therapeutic CNS concentrations are achieved with oral dosing.
More suitable for children than tinidazole.

Question 23

Describe the use of tinidazole.

Answer 23

Oral only. Has longer half life than metronidazole so is administered less frequently or as a single dose.

Question 24

what are the common adverse effects of nitromidazoles?

Answer 24

Nausea, diarrhoea and metallic taste.
Disulfuram-like reaction with alcohol.
Parasthesia and peripheral neuropathy, especially when used for long periods or in high doses.
Metronidazole enhances the activity of warfarin.

Question 25

Describe counselling points for metronidazole.

Answer 25

Take tablets with food to avoid stomach upset.
Take liquid 1 hour before food.
May make you feel dizzy or confused, so avoid driving if affected.

Question 26

Describe the mechanism of action and ue of rifamycins, and their spectrum. Give examples.

Answer 26

Inhibit bacterial RNA polymerase, so transcription in the bacteria is inhibited. Bactericidal.
G+ and mycobacteria. Rapid emergence of drug resistance due to modification of bacterial RNA polymerase means they must always be used in combination with unrelated antimicrobials.
Should be reserved for MRSA, TB and prophylaxis of meningitis and epiglottitis.
Eg rifampicin and rifabutin.

Question 27

describe drug interactions of rifamycins.

Answer 27

Inducers of cytochrome P450 activity, affecting plasma concentrations of other drugs (e.g. oral contraceptives, anticoagulants).

Question 28

What are the counselling points of rifampicin?

Answer 28

Take at least 30 mins before food. Take regularly to avoid flu-like symptoms. Can make the pill less effective.

Question 29

Describe the use of rifabutin.

Answer 29

Use rifabutin rather than rifampicin in patients with HIV on combination antiretroviral therapy (treatment is complicated by drug interactions, and rifabutin is not as strong a CYP inducer as rifampicin).
Use rifabutin if rifampicin is unsuitable for TB treatment due to drug interactions.
treatment and prophylaxis of Mycobacterium avium complex (common in AIDS).

Question 30

Describe the use of rifampicin.

Answer 30

Mainly used in TB as part of combination therapy to prevent the development of drug resistance.
Leprosy and MRSA(with other agents).
Prophylaxis against N meningitidis and H influenzae.

Question 31

What are some adverse effects of rifamycins?

Answer 31

Adverse effects are uncommon.
Nausea and anorexia.
Thrombocytopenia, acute renal failure and an influenza-like syndrome can occur due to sensitisation.
Hepatitis: liver function should be checked before commencing treatment with rifampicin.

Question 32

What are some counselling points of rifamycins?

Answer 32

May cause orange discolouration of urine, sweat and tears, and possible staining of soft contact lenses.
Tell doctor about any loss of appetite, nausea, vomiting, unusual tiredness, jaundice and dark urine or pale faeces.
Many drug interactions.