Tetracyclines, macrolides, carbapenems and monobactams.

Question 1

Explain the function of tetracyclines?

Answer 1

Accumulate intracellularly via “energy-dependent protein transport system”. Prevent binding of T-RNA onto ribosomal 30s sub unit, by “reversibly” binding to the ribosome. This prevents the interaction of MRNA and T-RNA, halting translation/protein synthesis as a result.

Question 2

Resistance of tetracyclines?

Answer 2

3 main mechanisms:

1. Efflux pumps
2. Presence of enzymes, which inactivate the drug
3. Intracellular protein which prevent the binding of the tetracycline to 30s subunit.

Question 3

Explain pharmacokinetics of tetracyclines?

Answer 3

Administration: Oral absorption, which can be reduced with co administration of dairy products which contain (magnesium, calcium and aluminium antacids). “DOXACYCLINE” and “MINOCYCLINE” have IV administration.

Distribution: Accumulates in the liver, bile, kidney, gingival fluid, tissues undergoing calcification (teeth/bones) and in tumours with high calcium content.
The tetracyclines are able to penetrate CSF/BPB and can accumulate in foetal dentin and bones.

Elimination: Tetracyclines are excreted in the urine unchanged, Minocycline undergoes hepatic metabolism, whereas doxycycline undergoes biliary excretion into the feces.

Adverse effects - 6 examples:

1. Gastric discomfort: Due to direct irritation to the gastric mucosa, can lead to problems in patient compliance. Oesophagitis may also occur, which can be reduced with co administration of food along with the tetracyclines.
2. Effect of calcified tissues: These tissues (bones and teeth) are in a developing state within children. Accumulation of tetracycline in teeth may lead to hypoplasia and discolouration of teeth –> stunted growth.
3. Hepatotoxicity: Complication of high dose tetracyclines.
4. Photo toxicity: Patients advised to wear protective clothing against UV rays.
5. Vestibular dysfunction: Presented as Vertigo, tinnitus and dizziness and often he result of minocyclines.
6. Pseudomotor cerebri: “Benign intracranial hypertension” presented as blurred vision/headache.

Contra-indication: In pregnancy due to the risk of BPB penetration and accumulation of the drug in the bones and dentin of the foetus.

Question 4

Explain the function of Macrolides? (Macrolide lactone ring structure compounds)

Answer 4

These are a group of anti-biotics, cause irreversible binding to the 50s sub unit ribosome, which prevents “translocation process” of protein synthesis. There are 3 types of macrolide and one ketolide with distinct functions:

1. Eythromycin - used when patients have a penicillin allergy, Has similar actions to penicillin G.
2. Clindamycin - Used for intra cellular pathogens e.g chlamydia. Methylated form of erythromycin.
3. Azithromycin - Used for respiratory pathogens e.g: H.influenzae. Larger lactone ring.
4. Telithromycin (Ketolide). - Avoids the affects of macrloide resistance, similar effects to the azithromycin.

Question 5

Mechanisms of resistance towards the macrolides?

Answer 5

4 mechanisms:

1. Efflux pumps
2. Reduced cell permeability to the anti biotics
3. Reduced affinity of the 50s sub unit to the anti biotics
4. Presence of “Plasma associated eryhthromycin esterases”

Question 6

Pharmacokinetics of the macrolides?

Answer 6

Administration - Macrolides are destroyed by gastric acid, administered oral via enteric coated tablets. Erythrromycin/azithromycin can also be administered via IV infusion.

Distribution - Azithromycin has the largest “cellular distribution” as it is uptakes by macrophages, fibroblasts and neutrophils. All four drugs accumulate in the liver (hepatic metabolism). The drugs distribute generally well to all body fluids except the CSF.

Metabolism - Erythromycin and telithromycin undergo hepatic metabolism.

Excretion - Erythromycin/azithromycin are excreted in the bile/feces. Clarithromycin is excreted in the urine.

Adverse effects - 4 key types

1. Gastric distress: mainly by erythromycin. However high dose erythromycin can cause smooth muscle contraction of stomach, which can be utilised for the treatment of “gatroparesis” and “post-operative ileus”.
2. Cholestatic jaundice
3. Prolonged QTc interval: Should not be used in patients with pro-arrhythmic conditions or co administered with pro arrhythmic agents.
4. Ototoxicity: Transient hearing loss with use of erythromycin. Azithromycin may cause “Sensorineural hearing loss”.

Contraindications - ‘Hepatic insufficiency” as all 4 drugs accumulate in the liver.

Question 7

Explain the function of the “Carbapenems”?

Answer 7

These are “Synthetic beta lactam antibiotics”, differ from structure from the penicillins by having a carbon atom in place of sulfur within the “thiazolidine ring”. “IMIPENEM” plays a role in empiric therapy towards the beta-lactamase producing gram positive and negative pathogens. These drugs function to kill bacteria by binding to “penicillin-binding proteins”, thus inhibiting bacterial cell wall synthesis.

Question 8

Pharmacokinetics of the carbapenems?

Answer 8

IV administration, penetrate the CSF in circumstances of meningeal inflammation and excreted in the urine via glomerular filtration.

Imipenem is inactivated/cleaved by “dehydropeptidase” in the brush border of the PCT. To prolong its action it is “Compounded” with “CILASTATIN” to prevents cleavage in PCT and allow for reabsorption and prolonged action.

Adverse effects - The Imipenem:cilastatin compound causes nausea, vomiting and diarrhoea. Since carbapenems and penicillin share a similar bi-cyclic core, care should be taken when using carbapenems on patients that have a penicillin allergy.

The types of the carbapenems are: IMIPRENEM, MEROPENEM, ETRAPENEM and DORIPENEM.

Question 9

Explain the function of the “Monobactams”?

Answer 9

They function to inhibit the bacterial cell wall synthesis. They have main activity against gram negative bacteria, but none against gram positive. Main monobactam being used is “AZTREONAM”.

Question 10

Pharmacokinetics of the monobactam antibiotics?

Answer 10

• IV or IM administration
• Phlebitis, skin rash and abnormal liver function tests = ADR’s
• Urinary excretion

contraindications: Renal failure causes accumulation of the drug.

One benefit of using aztreonam as an antibiotic is that it has little cross reactivity with penicillins and does not share a similar structure, hence is safe to use in patients with a penicillin allergy.