50S Ribosome Subunit Inhibitors Flashcards
Name the classes and drugs in the classes of 50S ribosome unit inhibitors
Macrolides (Erythromycin, Clarithromycin, Azithromycin)
Lincosamide (Clindamycin)
Oxazolidinone (Linezolid)
Macrolide Mechanism of Action and Bacterial Effect
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
Which macrolide is an alternative to penicillin?
Erythromycin
How are clarithromycin and azithromycin structurally different from erythromycin
Clarithromycin: Methylated
Azithromycin: 15 C lactone ring + Methylated nitrogen group = Reduced inhibitory effect on CYP450
Macrolides are administered _______________
Orally and Parenterally
Macrolide Distribution
Most body tissues but poor CNS penetration
Spectrum Activity of Macrolides
Atypicals effectively
Macrolide Clinical Indications
CAP RTI, Chlamydia infection, Diphtheria, H Pylori, Mycobacterial infection
Macrolide Elimination
Hepatic metabolism and biliary excretion (Azithromycin eliminated unchanged)
4 Adverse Drug Effects of Macrolides
- Gastric Distress and Motility (Erythromycin)
- Hepatotoxicity: Cholestatic jaundice (Biliary excretion)
- Ototoxicity at high IV doses (Irreversible in Azithromycin; Transient in Erythromycin)
- QTc prolongation in arrhythmic patients (Caution in Torsades)
Contraindications of Macrolides
Hepatic dysfunction
Which macrolide is quite safe in pregnancy and which is category C?
Safe: Erythromycin, Azithromycin
Cat C: Clarithromycin
Macrolides can potentiate the effects of drugs like __________, _______ and ________ by interfering with __________.
Corticosteroids, digoxin, warfarin
CYP3A4 mediated metabolism
How does Macrolide resistance arise?
Erythromycin methylase gene acquisition (erm gene)
Efflux pump expression
Spectrum activity of Clindamycin
Anaerobes
Clindamycin MOA
Inhibit peptide synthesis by exclusive binding to 50S subunit of bacterial ribosome
Why can we not use clindamycin and erythromycin together?
- They act at sites of proximity and antagonise each other
- Cross resistance due to erm methylases can occur
Clinical indication of clindamycin
- MRSA, Streptococcus and Penicillin resistant anaerobes (Gram +)
- Penicillin alternatives (Allergy to penicillin)
- Toxic shock syndrome
- Anaerobic infections (Severe or skin/soft tissue - Bacteroides, Clostridioides perfringen)
- Good activity against oral pathogens
Which bacteria are resistant to clindamycin?
Almost all Gram negative bacteria
Clindamycin is administered ______
Orally, IV and topically
Distribution of Clindamycin
Well distributed into body fluids including bone but poor CSF penetration
Good bone and salivary gland penetration
Clindamycin Elimination
Hepatic oxidative metabolism to inactive products
4 Adverse Effects of Clindamycin
- Esophageal irritation
- GI Diarrhea/Vomiting
- Skin rash
- CDAD
Clindamycin resistance via what mechanisms?
50S ribosomal subunit alteration
23S rRNA subunit methylation
Nucleotidylation of Clindamycin hydroxyl group
NOT A SUBSTRATE FOR MACROLIDE EFFLUX PUMPS
Linezolid MOA
Specific binding to 23S rRNA of 50S ribosomal subunit, preventing the formation of functional 70S initiation complex
Spectrum Activity of Linezolid
Gram Positive bacteria including resistant strains (MRSA, VRE, VRSA)
Linezolid is administered ________
Orally and IV due to good oral bioavailability
Distribution of Linezolid
Wide distribution, good CSF penetration
Linezolid Elimination
Non-enzymatic oxidation to 2 inactive metabolites excreted in the urine
How do bacteria develop resistance to Linezolid?
Mutations in 23S rRNA especially in VRE and MRSA
Mutations can also be conferred by cfr rRNA methyltransferase
Why is linezolid reserved as an alternative agent?
Good to target multiple-drug resistant strains
Overuse will add selection pressure and reduce drug efficacy
Linezolid adverse drug events
- GI N/V/D/headache/rash
- Bone Marrow Suppression (Thrombocytopenia when taken > 10 days)
- Non-selective MAO inhibition = Serotonin Syndrome (Reversible)
- Peripheral neuropathy and optic neuritis (Irreversible blindness)
Food containing what nutrients should be avoided when taking linezolid?
Tyramine and histamine rich food (Cheese, smoked meat, soy products)
Linezolid - Safe in pregnancy?
Cat C - No recommended
Linezolid is contraindicated in
- Catheter-related or Catheter-site infections
- Concomitant MAO inhibitors
- Concomitant serotonergic drugs - Hypertensive crisis can result
