Aminoglycosides and Macrolides
- 1. Aminoglycosides and Macrolides Dr Mohit Kher Assistant Professor Pharmacology, ESIC
- 3. Drugs includes: • Streptomycin • Gentamicin • Kanamycin • Tobramycin • Amikacin • Sisomicin • Netilmicin • Neomycin • Framycetin.
- 4. Common properties • These drugs exhibit CDK and have prolonged PAE, therefore are administered as single daily dose. • Aminoglycosides are bactericidal inhibitors of protein synthesis (faulty protein). • These bind to 30S and 50S ribosomes and freeze initiation, interfere with polysome formation and cause misreading of mRNA code. • Their penetration across the cell wall is dependent on the oxygen dependent transport, therefore these drugs are inactive against anaerobes.
- 5. • Activity only against gram negative organisms. • Ionized or water soluble → Poor oral absorption → IV/IM route • Cell wall synthesis inhibitors (penicillin & vancomycin) → Increase entry of aminoglycosides into bacteria → Frequently prescribed • In a solution penicillin can inactivates aminoglycosides
- 6. Pharmacokinetics • These are not absorbed orally and do not cross blood brain barrier. • These are excreted primarily by glomerular filtration and the dose should be decreased in renal insufficiency. • Resistance to these drugs develops due to the formation of inactivating enzymes which acetylate, phosphorylate or adenylate the aminoglycosides. • All aminoglycosides except amikacin and netilmicin are susceptible to these enzymes. • Amikacin and netilmicin may be effective against organisms resistant to other aminoglycosides.
- 7. Clinical uses: • Gentamicin, tobramycin (inhalational) and amikacin are effective against gram negative organisms including pseudomonas (except salmonella). However these are not reliable for gram positive organisms if used alone. • Aminoglycosides produce synergistic effects against gram positive bacteria when combined with β- lactams or vancomycin. • Streptomycin is the first line drug for the treatment of tuberculosis, plague and tularemia. • Amikacin is a second line drug for the treatment of tuberculosis and is also used for MDR tuberculosis.
- 8. • Netilmicin is used for serious infections only. • Neomycin and framycetin are used only topically because of their high toxic potential. • Neomycin can also be used orally for gut sterilization in hepatic encephalopathy. (Current DOC: Rifaximin) • Spectinomycin is a structurally related drug to aminoglycosides, which act on 30S subunit and inhibits translocation. It is DOC for resistant gonorrhea.
- 9. TOXICITY
- 10. Ototoxicity • Hearing loss: Kanamycin, amikacin (max) and neomycin (KAN) • Vestibular dysfunction: Streptomycin (max) and gentamicin • Tobramycin cause both abnormalities equally. • Ototoxicity is largely irreversible. • Very early changes can be reversed by Ca2+.
- 11. Nephrotoxicity • Reversible • Risk factors: Hypokalemia, pre-existing renal disease and concomitant nephrotoxic medications (like AMB, vancomycin etc.). • Neomycin is most nephrototoxic and is not indicated for systemic use. • Among the systemically used aminoglycosides, gentamicin is most nephrotoxic followed by tobramycin. • Streptomycin is least nephrotoxic.
- 12. Neuromuscular blockade • Inhibition of pre-synaptic release of ACh and partly by decreased sensitivity of post- synaptic receptors → Respiratory depression (rare). • Risk factors: Hypocalcemia, peritoneal administration, use of neuromuscular blockers and pre-existing respiratory depression. • This complication can be avoided by slow i.v. infusion (over 30 min.) or by i.m. route. • If respiratory depression occurs, it is reversed by i.v. administration of calcium. • Neomycin and streptomycin: Max • Tobramycin: least • Therefore C/I in myasthenia gravis
- 13. • Intra-vitreal injection of gentamicin can result in macular infarction. • Plazomicin is recently approved for complicated UTI.
- 14. PRECAUTIONS AND INTERACTIONS • Avoid aminoglycosides during pregnancy: risk of fetal ototoxicity. • Avoid concurrent use of other nephrotoxic drugs, e.g. NSAIDs, amphotericin B, vancomycin, cyclosporine and cisplatin. • Cautious use in patients >60 years age and in those with kidney damage. • Do not mix aminoglycoside with any drug in the same syringe/infusion bottle.
- 15. MACROLIDES • These drugs bind to 50S ribosome and block the translocation of peptide chain from A to P site. • They are primarily bacteriostatic drugs but can be bactericidal at high doses. Active against: • Gram positive organism • Gram negative organism • Atypical organisms
- 16. • Resistance to macrolides can be seen by either mutation of ribosome, drug efflux & enzymatic break down by esterases. • An immunosuppressant drug, tacrolimus is also a macrolide antibiotic. • Ketolides and lincosamides have similar mechanism of action.
- 17. DRUGS • Erythromycin • Clarithromycin • Roxithromycin • Azithromycin • Fidaxomycin
- 18. DOC for: • C: Chancroid • L: Legionella • A: Atypical pneumonia • P: Pertussis • Mild to moderate pseudomembranous colitis • 2nd line drug to penicillin
- 19. Clinical uses Azithromycin: • More active against H. influenza and Neisseria • Long t1/2 → Single dose in urogenital infections and trachoma caused by chlamydia • Clarithromycin: Prophylaxis and treatment of MAC and in the treatment of peptic ulcer caused by H. pylori. • All macrolides: Anti-inflammatory & immunomodulatory action • Spiramycin: DOC for toxoplasmosis in pregnancy. • Fidaxomycin is a non-absorbed macrolide approved for treatment of C. difficile infection.
- 20. Toxicity • Macrolides can stimulates motilin receptors. GI effects are most common side effects of all macrolides. • Erythromycin estolate is implicated in the causation of acute cholestatic hepatitis especially in pregnant females. • Use of erythromycin in infants < 6 weeks of age increases the risk of developing infantile hypertrophic pyloric stenosis.
- 21. • Erythromycin, roxithromycin and clarithromycin (CYP3A4 inhibitor) + terfenadine, astemizole or cisapride (substrates of CYP3A4) → QT prolongation (torsade's de pointes). • IV erythromycin (not oral) can cause dose dependent reversible ototoxicity. • Erythromycin also increases the plasma concentration of theophylline by inhibiting CYP1A2.
- 22. Adverse effects • M: Motilin receptor agonists • A: Allergy • C: Cholestasis • R: Reversible • O: Ototoxicity
- 23. MISCELLANEOUS
- 26. There is growing resistance to cephalosporins and hence current dual therapy is recommended for gonorrhea: • Ceftriaxone 250 mg IM + Azithromycin 1 gm oral – Single dose • Cefixime 400 mg oral + Azithromycin 1 gm oral – Single dose • Alternative: Azithromycin 2 gm oral single dose • Erythromycin: Used in gastroparesis & paralytic ileus • Loop diuretics: Reversible deafness due to change in ions of endolymph. • Penicillinase resistant → Methicillin → MRSA → Vancomycin → VRSA & VRE → Daptomycin
- 27. • Doxycycline → DOC in chlamydial infection → Doxycycline is C/I in pregnancy → Azithromycin is currently DOC in chlamydial infections in pregnancy. Legionella: • Earlier DOC: Erythromycin • Current DOC: Azithromycin Current DOC: • Mycoplasma genitalium: Doxycycline • Mycoplasma pneumoniae: Azithromycin
- 28. • Streptomycin: Require dose adjustment in renal failure • Doxycycline, rifampicin and cefoperazone: Secreted in bile and do not require dose adjustment in renal failure. • Azithromycin is effective against both gonococcal and non-gonococcal (chlamydial) urethritis. Single dose is used for treatment of urethritis.
- 29. Thank You