Antibiotics

Question 1

What are the 3 ways in which you would classify an antibiotic in terms of the site of action?

Answer 1

1) Inhibition of cell wall synthesis
2) Inhibition of protein synthesis
3) Inhibition of nucleic acid synthesis

Question 2

Which antibiotics inhibit cell wall synthesis?

Answer 2

• Beta-lactams which are subdivided into penicillins, cephalosporins & cephamycins
• Lesser categories of beta-lactams which include carbapenams, monobactams and beta-lactamase inhibitors (clavulanic acid)
• vancomycin and teicoplanin

Question 3

Which antibiotics inhibit protein synthesis?

Answer 3

• Aminoglycosides
• Tetracyclines
• Macrolides
• others including linezolid, chloramphenicol, sodium fusidate

Question 4

Which antibiotics inhibit nucleic acid synthesis?

Answer 4

• Sulphanoamides
• Quinolones
• Azoles

Question 5

What mechanisms have bacteria devised to combat beta-lactams?

Answer 5

• Beta-lactamase
• Modification of the penicillin binding proteins, so beta-lactam can’t bind the enzymes
• Reduced permeability of the cell membrane of gram negative bacteria
• Pumps that remove beta-lactam that enters the cell

Question 6

Are penicillin time dependent or concentration dependent? and what does this mean?

Answer 6

Time dependent, so the dose increasing the dose doesn’t affect it’s efficacy, only keeping the concentration at a therapeutic dose for the right prolonged amount of time will have an effect. It is bacterocidal

Question 7

Is it suitable for oral use?

Answer 7

Benzylpenecillin is not as it destroyed by gastric acid. Its only real use orally is for strep throat infections.
Others like phenoxymethyl penecillin resist gastric acid and are absorbed in the upper small bowel.

Question 8

What is the plasma half life of penicillins?

Question 9

Do penicillins enter the CSF?

Answer 9

Yes, they are distribute mainly in the body water.

Question 10

How are penicillins excreted?

Answer 10

Urinary excretion, which is rapid. Dosage should be reduced in patients with severely impaired renal function.

Question 11

What are the main adverse effects of penicillins?

Answer 11

Itching, rashes (eczematous or urticarial), fever and angioedema. Rarely (1 in 10,000) there is anaphylactic shock.

Question 12

What % of patients with a supposed ‘penicillin allergy’ actually react to an intradermal test?

Answer 12

Only around 10%, suggesting huge over diagnosis.

Question 13

What other non-allergic reactions can patients have to penicillins?

Answer 13

Diarrhoea (disturbance of normal gut flora), neutropenia for long doses (10+ days), and they are often combined with sodium or potassium so the clinician should take this extra source into account.

Question 14

What is the half-life of benzylpenicllin and what does this mean for dosage?

Answer 14

t1/2 0.5hrs, so dosage has to be large and is normally well tolerated due to unusually large therapeutic ratio.

Question 15

How is benzylpenicillin excreted?

Answer 15

Kidney, and it’s excretion can be blocked by probenecid if excretion needs to be slowed (e.g. to space out doses)

Question 16

What is benzylpenicillin mainly used for?

Answer 16

• Streptococcus pneumonia
• Streptococcus pyogenes
• Streptococcus viridans (usually sensitive)
• Enterococcus is less sensitive (especially for endocarditis) and must be combined with an aminoglycaside, usually gentamicin
• Nisseria meningitidis (septicaemia, meningococcal meningitis)
• Bacillus anthacis (anthrax)
• Clostridium perfringens (gas gangrene)
• Tetani (tetanus)
• Corynebacterium diphtheriae (diphtheria)
• Treponema pallidum (syphilis)
• Leptospira spp. (leptospirosis)
• Actinomyces israelii (actinomyces)
• Borrelia burgdorferi (lyme disease) in children
• Nisseria gonorrhoeae has variable sensitivity

Question 17

What is a particular complication of benzylpenicillin?

Answer 17

Patients with bacterial endocarditis, where the requirement of a high dose can co-exist with reduced clearance due to immune complex glomerulonephritis, does the risk of dose related toxicity arise (convulsions).

Question 18

How is benzylpenicillin administered

Answer 18

I.V. - bolus 600mg 6 hourly is enough for sensitive infections, though in infective endocarditis, 7.2g are given daily in divided doses.
- Continuous I.V.
I.M. - procaine penicillin, largely fallen out of use due to slow onset of some hours after injection. 360mg 12-24 hourly
Orally - phenoxymethypenicillin 500mg 6 hourly, and generally used one infection has been controlled by initial i.v.

Question 19

What are examples of beta-lactamase resistant agents?

Answer 19

1) Flucloxacillin - t1/2 1h, main adverse effect is thought to be cholestatic jaundice, particularly when used 10+ days or in patients >55yrs
2) Cloxacillin - t1/2 0.5hrs, gastric acid resistant, recently withdrawn form UK market
3) Methicillin + oxacillin - use now confined to lab due to MRSA

Question 20

What do broad penicllins cover?

Answer 20

They extend beyond the gram-positive and negative cocci, covering gram-negatie bacilli.

Question 21

Is there resistance to broad spectrum penicillins?

Answer 21

Yes, they do not resist beta-lactamase enzymes so their effectiveness is decreasing.

Question 22

How does their activity compare to benzylpenicillin and the beta-lactamase resistant penicillins?

Answer 22

They are typically less active against the gram-positive cocci that benzylpenicillin, but more active than the beta-lactamase resistant agents.

Question 23

Which organisms are the broad spectrum penicillins active against?

Answer 23

• Enterococcus faecalis
• Haemophilus influenzae (many strains)
• Enterobactae have varying sensitivity (requires lab testing)
  NB. the differences between this group are largely pharmacological rather than bacteriological

Question 24

Give 3 examples of broad spectrum penicillins.

Answer 24

1) Amoxicillin - t1/2 1h, 250mg 8-hourly P.O. For oral use amoxicillin has a greater bioavailability than ampicillin (it’s precursor)
2) Co-amoxiclav (Augmentin) - t1/2 1h, one tablet 8-hourly. This is a combination tablet containing the ‘suicide’ inhibitor clavulanic acid and Amoxicillin. The claculanic acid is in the form of a potassium salt and 125mg is combined with 250 or 500mg amoxicillin. Clavulanic acid conveys a beta-lactamase resistance to the amoxicillin. This makes it useful for beta-lactamase producing organisms, especially in the respiratory and urogenital tracts. This includes many strains of staphlococcus aureus, many strains of Escheria coli and an increasing number of strains of haemophilius influenzae.
3) Ampicillin - t1/2 1h - It is acid stable, moderately well absorbed, 250mg-1g 6-8hourly. I.M. and I.V. 500mg 4-6 hourly. Drug becomes concentrated in the bile.

Question 25

What are the adverse effects associated with broad spectrum penicillins?

Answer 25

Ampicillin - diarrhoea (less with amoxicillin), though both are associated with c-diff diarrhoea though probably due to their frequency of use more than anything else.

Ampicillin and analogues - Can cause a macular rash resembling measles or rubella accompanied by signs of allergy. This should not be taken as an allergy to all penicillins which cause a true urticarial rash. More common in patients with disease of the lymphoid system (infectious mononucleosis, lymphoma), and those on allopurinol.

Co-amoxicalv - cholestatic jaundice, even up to 6 weeks after uses (possible cause is clavulanic acid)

Question 26

Describe Mecillinam.

Answer 26

Similar to broad specectrum penicillins, but with greater affinity for the Penicillin Binding Protein. Oral agent in the form of Pivmecillinam (t1/2 1h).

Question 27

What agents is Mecillinam used for?

Answer 27

Gram-negative organisms including beta-lactamase-producing Enterobacteriaceae, though inactive against Pseudomonas aeruginosa and relatives. NO ACTIVITY FOR GRAM-POSITIVE ORGANISMS.
It is used to treat urinary tract infections (often gram-negaative in origin)

Question 28

Describe Monobactam.

Answer 28

A class of beta-lactams. e.g. Aztreonam (t1.2 2h)
Active against gram-negative organisms including:
- Pseudomonas aeruginosa
- Haemophilus influlenzae
- Neisseria meningitides + gonorrhoeae
Used to treat complicated UTIs, septicaemia, gram-negative lower UTIs and gonorrhoea.

Question 29

What are the potential adverse effects of monobactams?

Answer 29

Reactions at the site of infusion, rashes, GI upset, thrombocytopenia, hepatitis, neutropenia. Lower chance f beta-lactam allergy.

Question 30

What are the classes of anti-pseudomonal penicillins?

Answer 30

Carboxypenicillins and ureidopenicilins

Question 31

Describe Carboxypenicillins and give and example of one.

Answer 31

Same antibacterial spectrum as ampicillin, are susceptible to beta-lactamases, but active against pseudomonas auroginosa.
Ticarillin (t1/2 1h) - combined with clavulanic acid as Timentin (greater efficacy against beta-lactamases). Given as I.M. slow I.V. injection or rapid I.V infusion. Ticarillin is given as a disodium salt, so care needs to be taken in patients with impaired cardiac or renal function.

Question 32

What happens when carboxypenicillins (and ureidopenicillins) are administered with aminoglycasides in the same preparation?

Answer 32

Carboxypenicillins inactivate aminoglycasides when administered in the same syringe or I.V. infusion.

Question 33

Describe Ureidopenicillins and give examples.

Answer 33

Adapted from ampicillin, side-chain derived from urea. Their advantage over carboxypenicillins is that they are more effective against pseudomonas aeruginosa and are administered as a monosodium salt, so are safer for patients with reduced cardiac and renal function.

Azlocillin - v. effective against pseudomonas aeruginosa, but not as good as other ureidopenicillins against other gram-neagative organism, withdrawn from many countries.
Piperacillin - slightly higher effectiveness against pseudomonas aeruginosa, and works against other gram negative organism. It can be combined with the beta-lactamase inhibitor tazobactam to form Tazocin.

Question 34

How do cephalosporins (and cephamycins) work?

Answer 34

Like the beta-lactams, the attack the cell wall of the bacteria, and are time dependents bacterocidal agents. The addition of side chains conveys different pharmacokinetics and antibacterial activities, and also protects the Beta-lactam ring. This can improve activity agains gram-nageative organism, though often at the expense of gram-positive activity. Resistance is increasing.

Question 35

Do cephalosporins work against MRSA?

Answer 35

No, MRSA should be considered resistant to all cephalosporins.

Question 36

How are cephalosporins excreted?

Answer 36

From the kidney, mostly intact. Many are actively secreted by the renal tubule, which can be blocked by the capitative inhibitor probenecid.

Question 37

What are the adverse effects of cephalosporins?

Answer 37

Mostly well tolerated. Most unwanted effects are allergic reactions of the penicillin type.
If continued for more than 2 weeks - thrombocytopenia, neutropenia, haemolytic anaemia, interstitial nephritis and abnormal liver function tests. These REVERSE on stopping the drug.