Aminoglycosides and Macrolides

The aminoglycoside class of antibiotics consists of many different agents. In the United States, gentamicin, tobramycin, amikacin, plazomicin, streptomycin, neomycin, and paromomycin are approved by the US Food and Drug Administration (FDA) and are available for clinical use.
Macrolides are a class of drugs used to manage and treat various bacterial infections. Azithromycin, clarithromycin, and erythromycin are commonly used to treat infections like pneumonia, sinusitis, pharyngitis, and tonsillitis. They are also used in uncomplicated skin infections and otitis media in pediatric patients.

1. Aminoglycosides and Macrolides Dr Mohit Kher Assistant Professor Pharmacology, ESIC

2. Aminoglycosides

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 2 nd 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

24. Diphtheria (Carriers) Erythromycin

25. 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

26. 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

27. 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.

28. Thank You