50S Ribosome Subunit Inhibitors

Question 1

Name the classes and drugs in the classes of 50S ribosome unit inhibitors

Answer 1

Macrolides (Erythromycin, Clarithromycin, Azithromycin)

Lincosamide (Clindamycin)

Oxazolidinone (Linezolid)

Question 2

Macrolide Mechanism of Action and Bacterial Effect

Answer 2

Bacteriostatic effect and reversibly binds to 50S ribosomal subunits, inhibiting the translocation step

Nascent peptide chain resides at the A site of the transferase reaction so it fails to move to the peptidyl donor (P) site

Question 3

Which macrolide is an alternative to penicillin?

Answer 3

Erythromycin

Question 4

How are clarithromycin and azithromycin structurally different from erythromycin

Answer 4

Clarithromycin: Methylated

Azithromycin: 15 C lactone ring + Methylated nitrogen group = Reduced inhibitory effect on CYP450

Question 5

Macrolides are administered _______________

Answer 5

Orally and Parenterally

Question 6

Macrolide Distribution

Answer 6

Most body tissues but poor CNS penetration

Question 7

Spectrum Activity of Macrolides

Answer 7

Atypicals effectively

Question 8

Macrolide Clinical Indications

Answer 8

CAP RTI, Chlamydia infection, Diphtheria, H Pylori, Mycobacterial infection

Question 9

Macrolide Elimination

Answer 9

Hepatic metabolism and biliary excretion (Azithromycin eliminated unchanged)

Question 10

4 Adverse Drug Effects of Macrolides

Answer 10

1. Gastric Distress and Motility (Erythromycin)
2. Hepatotoxicity: Cholestatic jaundice (Biliary excretion)
3. Ototoxicity at high IV doses (Irreversible in Azithromycin; Transient in Erythromycin)
4. QTc prolongation in arrhythmic patients (Caution in Torsades)

Question 11

Contraindications of Macrolides

Answer 11

Hepatic dysfunction

Question 12

Which macrolide is quite safe in pregnancy and which is category C?

Answer 12

Safe: Erythromycin, Azithromycin

Cat C: Clarithromycin

Question 13

Macrolides can potentiate the effects of drugs like __________, _______ and ________ by interfering with __________.

Answer 13

Corticosteroids, digoxin, warfarin

CYP3A4 mediated metabolism

Question 14

How does Macrolide resistance arise?

Answer 14

Erythromycin methylase gene acquisition (erm gene)

Efflux pump expression

Question 15

Spectrum activity of Clindamycin

Answer 15

Anaerobes

Question 16

Clindamycin MOA

Answer 16

Inhibit peptide synthesis by exclusive binding to 50S subunit of bacterial ribosome

Question 17

Why can we not use clindamycin and erythromycin together?

Answer 17

1. They act at sites of proximity and antagonise each other
2. Cross resistance due to erm methylases can occur

Question 18

Clinical indication of clindamycin

Answer 18

1. MRSA, Streptococcus and Penicillin resistant anaerobes (Gram +)
2. Penicillin alternatives (Allergy to penicillin)
3. Toxic shock syndrome
4. Anaerobic infections (Severe or skin/soft tissue - Bacteroides, Clostridioides perfringen)
5. Good activity against oral pathogens

Question 19

Which bacteria are resistant to clindamycin?

Answer 19

Almost all Gram negative bacteria

Question 20

Clindamycin is administered ______

Answer 20

Orally, IV and topically

Question 21

Distribution of Clindamycin

Answer 21

Well distributed into body fluids including bone but poor CSF penetration

Good bone and salivary gland penetration

Question 22

Clindamycin Elimination

Answer 22

Hepatic oxidative metabolism to inactive products

Question 23

4 Adverse Effects of Clindamycin

Answer 23

1. Esophageal irritation
2. GI Diarrhea/Vomiting
3. Skin rash
4. CDAD

Question 24

Clindamycin resistance via what mechanisms?

Answer 24

50S ribosomal subunit alteration

23S rRNA subunit methylation

Nucleotidylation of Clindamycin hydroxyl group

NOT A SUBSTRATE FOR MACROLIDE EFFLUX PUMPS

Question 25

Linezolid MOA

Answer 25

Specific binding to 23S rRNA of 50S ribosomal subunit, preventing the formation of functional 70S initiation complex

Question 26

Spectrum Activity of Linezolid

Answer 26

Gram Positive bacteria including resistant strains (MRSA, VRE, VRSA)

Question 27

Linezolid is administered ________

Answer 27

Orally and IV due to good oral bioavailability

Question 28

Distribution of Linezolid

Answer 28

Wide distribution, good CSF penetration

Question 29

Linezolid Elimination

Answer 29

Non-enzymatic oxidation to 2 inactive metabolites excreted in the urine

Question 30

How do bacteria develop resistance to Linezolid?

Answer 30

Mutations in 23S rRNA especially in VRE and MRSA Mutations can also be conferred by cfr rRNA methyltransferase

Question 31

Why is linezolid reserved as an alternative agent?

Answer 31

Good to target multiple-drug resistant strains Overuse will add selection pressure and reduce drug efficacy

Question 32

Linezolid adverse drug events

Answer 32

1. GI N/V/D/headache/rash 2. Bone Marrow Suppression (Thrombocytopenia when taken > 10 days) 3. Non-selective MAO inhibition = Serotonin Syndrome (Reversible) 4. Peripheral neuropathy and optic neuritis (Irreversible blindness)

Question 33

Food containing what nutrients should be avoided when taking linezolid?

Answer 33

Tyramine and histamine rich food (Cheese, smoked meat, soy products)

Question 34

Linezolid - Safe in pregnancy?

Answer 34

Cat C - No recommended

Question 35

Linezolid is contraindicated in

Answer 35

1. Catheter-related or Catheter-site infections 2. Concomitant MAO inhibitors 3. Concomitant serotonergic drugs - Hypertensive crisis can result