Aminiglycosides NRSG 131.pptx

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1. AMINOGLYCOSIDES KEMU NRSG 131, PHARMACOLOGY Dr. Faith Mbuba 12 th oct , 2017.

2. Aminoglycosides are used for the treatment of serious infections due to aerobic gram-negative bacilli. However, their clinical utility is limited by serious toxicities. Aminoglycosides are derived from Streptomyces

3. Classification Systemic aminoglycosides Streptomycin Amikacin Gentamicin Sisomicin Kanamycin Netilmicin Tobramycin Paromomycin Topical aminoglycosides Neomycin Framycetin

4. MECHANISM OF ACTION B actericidal antibiotics. All have the same general pattern of action described in two main steps : Transport of the aminoglycoside through the bacterial cell wall and cytoplasmic membrane . ( b) Binding to 30S ribosomes resulting in inhibition of protein synthesis, where they interfere with assembly of the functional ribosomal apparatus and/or cause the 30S subunit of the completed ribosome to misread the genetic code.

5. Antibacterial spectrum E ffective for the majority of aerobic gram negative bacilli , including those that may be multidrug resistant, such as Pseudomonas aeruginosa , Klebsiella pneumoniae , and Enterobacter sp. Aminoglycosides are often combined with a β-lactam antibiotic to employ a synergistic effect, particularly in the treatment of Enterococcus faecalis and Enterococcus faecium infective endocarditis.

6. Resistance Resistance to aminoglycosides occurs via: 1 ) efflux pumps , 2 ) decreased uptake , and/or 3 ) modification and inactivation by plasmid-associated synthesis of enzymes. Each of these enzymes has its own aminoglycoside specificity ; therefore, cross-resistance cannot be presumed. [ Note: Amikacin is less vulnerable to these enzymes than other antibiotics in this group]

7. Pharmacokinetics Absorption: The highly polar, polycationic structure of the aminoglycosides prevents adequate absorption after oral administration . Therefore, all aminoglycosides (except neomycin ) must be given parenterally to achieve adequate serum levels Neomycin is not given parenterally due to severe nephrotoxicity. It is administered topically for skin infections or orally for bowel preparation prior to colorectal surgery .

8. Elimination: More than 90% of the parenteral aminoglycosides are excreted unchanged in the urine Accumulation occurs in patients with renal dysfunction, and dose adjustments are require

9. Uses - i Gentamicin is the cheapest (other than streptomycin ) and the first line aminoglycoside antibiotic. Preventing and treating respiratory infections in critically ill patients; those with impaired host defence (receiving anticancer drugs or high-dose corticosteroids ; AIDS), patients in resuscitation wards, with tracheostomy or on respirators ; postoperative pneumonias; patients with implants and in intensive care units. O ften combined with a penicillin/cephalosporin or another antibiotic in these situations . It is often added when a combination antibiotic regimen is used empirically to treat serious infections by extending the spectrum of coverage . Because of low therapeutic index, its use should be restricted to serious gram-negative bacillary infections.

10. Uses - ii Meningitis caused by gram negative bacilli: Because this is a serious condition, drug combinations including an aminoglycoside are often used. Subacute bacterial endocarditis (SABE ): Gentamicin (1 mg/kg 8 hourly i.m .) is generally combined with penicillin/ampicillin/ vancomycin . Pseudomonas, Proteus or Klebsiella infections: burns , urinary tract infection, pneumonia, lung abscesses, osteomyelitis, middle ear infection , septicaemia, etc., caused mostly by the above bacteria are an important area of use of gentamicin. It may be combined with piperacillin or a third generation cephalosporin for serious infections.

11. Uses - iii Streptomycin Tuberculosis In most other situations, e.g. urinary tract infection , peritonitis, septicaemias, etc

12. Adverse effects - i Ototoxicity : Ototoxicity (vestibular and auditory) is due to high peak plasma levels and the duration of treatment. The antibiotic accumulates in endolymph and perilymph of the inner ear . Deafness may be irreversible and can affect developing fetuses . Patients simultaneously receiving concomitant ototoxic drugs, such as cisplatin or loop diuretics, are particularly at risk. Vertigo (especially in patients receiving streptomycin ) may also occur . 2 . Nephrotoxicity : Retention of the aminoglycosides by the proximal tubular cells disrupts calcium-mediated transport processes. This results in kidney damage ranging from mild, reversible renal impairment to severe, potentially irreversible, acute tubular necrosis .

13. Adverse effects - ii 3. Neuromuscular paralysis: A ssociated with rapid increase in concentrations (for example, high doses infused over a short period) or concurrent administration with neuromuscular blockers. Patients with myasthenia gravis are particularly at risk. Prompt administration of calcium gluconate or neostigmin e can reverse the block that causes neuromuscular paralysis. 4. Allergic reactions: Contact dermatitis is a common reaction to topically applied neomycin.

14. PRECAUTIONS AND INTERACTIONS Avoid aminoglycosides during pregnancy: risk of foetal ototoxicity. Avoid concurrent use of other nephrotoxic drugs , e.g. NSAIDs, amphotericin B, vancomycin , cyclosporine and cisplatin . Cautious use of other potentially ototoxic drugs like vancomycin , minocycline 4 . Cautious use in patients >60 years age and in those with kidney damage. 5 . Cautious use of muscle relaxants in patients receiving an aminoglycoside. 6 . Do not mix aminoglycoside with any drug in the same syringe/infusion bottle.

15. Macrolide’s

16. Classification Erythromycin ( is the first member) Newer maclorides Roxithromycin Clarithromycin Azithromycin Telithromycin

17. Mechanism of action The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting translocation steps of protein Synthesis. They may also interfere with other steps, such as transpeptidation . Considered to be bacteriostatic, but may be bactericidal at higher doses.

18. Antibacterial spectrum - i Erythromycin : Effective against same organisms as penicillin G. Therefore , it may be used in patients with penicillin allergy . Streptococcal pharyngitis, tonsillitis, mastoiditis and community acquired respiratory infections caused by pneumococci and H.influenzae respond equally well to erythromycin. It is an alternative drug for prophylaxis of rheumatic fever and SABE.

19. Antibacterial spectrum - ii Diphtheria: Acute stage as well as for carriers—7 day treatment is recommended. Tetanus : as an adjuvant to antitoxin, toxoid therapy. Syphilis and gonorrhoea: only if other alternative drugs, including tetracyclines als cannot be used. Leptospirosis: I n patients allergic to penicillins .

20. Antibacterial spectrum - iii 2. Clarithromycin : Clarithromycin has activity similar to erythromycin, but also effective against H. influenzae . Its activity against intracellular pathogens, such as Chlamydia , Legionella , Moraxella, Ureaplasma species and Helicobacter pylori, is higher than that of erythromycin.

21. Antibacterial spectrum - iii 3. Azithromycin : Less active against streptococci and staphylococci than erythromycin, but more active against respiratory infections due to H. influenzae and Moraxella catarrhalis . Azithromycin is the preferred therapy for urethritis caused by Chlamydia trachomatis . Mycobacterium avium is preferentially treated with a macrolide-containing regimen, including clarithromycin or azithromycin. The other indications are pharyngitis , tonsillitis, sinusitis, otitis media, pneumonias , acute exacerbations of chronic bronchitis , streptococcal and some staphylococcal skin and soft tissue infections. M ultidrug resistant typhoid fever in patients allergic to cephalosporins ; and in toxoplasmosis .

22. Pharmacokinetics - i Erythromycin is destroyed by gastric acid . Thus, either enteric-coated tablets or esterified forms of the antibiotic are administered. All are adequately absorbed upon oral administration Clarithromycin , azithromycin, and telithromycin are stable in stomach acid and are readily absorbed. Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin . Erythromycin and azithromycin are available in IV formulations

23. Pharmacokinetics - ii Excretion: Erythromycin and azithromycin are primarily concentrated and excreted in the bile as active drugs. Partial reabsorption occurs through the enterohepatic circulation . C larithromycin and its metabolites are eliminated by the kidney as well as the liver. The dosage of this drug should be adjusted in patients with renal impairment .

24. Adverse effects 1. Gastric distress and motility: M ost common adverse effect of the macrolides and may lead to poor patient compliances especially erythromycin. Azithromycin and clarithromycin seem to be better tolerated. Higher doses of erythromycin lead to smooth muscle contractions that result in the movement of gastric contents to the duodenum, an adverse effect sometimes used therapeutically for the treatment of gastroparesis or postoperative ileus . 2. Cholestatic jaundice 3 . Ototoxicity: Transient deafness has been associated with erythromycin, especially at high dosages. Azithromycin has also been associated with irreversible sensorineural hearing loss. 4. Hypersensitivity: Rashes and fever are infrequent.

25. Contraindications: Patients with hepatic dysfunction should be treated cautiously with erythromycin, telithromycin , or azithromycin, because these drugs accumulate in the liver. Severe hepatotoxicity with telithromycin has limited its use, given the availability of alternative therapies. Macrolides may prolong the QTc interval and should be used with caution in those patients with proarrhythmic conditions or concomitant use of proarrhythmic agents .

26. Drug interactions: Erythromycin , telithromycin , and clarithromycin inhibit the hepatic metabolism of a number of drugs, which can lead to toxic accumulation of these compounds. An interaction with digoxin may occur. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin , thus leading to greater reabsorption of the drug from the enterohepatic circulation .

27. LINCOSAMIDE ANTIBIOTICS

28. Clindamycin

29. Clindamycin: MOA This potent lincosamide antibiotic is similar in mechanism of action (inhibits protein synthesis by binding to 50S ribosome) and spectrum of activity to erythromycin. Spectrum of activity Clindamycin inhibits most gram positive cocci (including most species of streptococci, penicillinase producing Staph . pharmacokinetics Oral absorption of clindamycin is good. It penetrates into most skeletal and soft tissues, but not in brain and CSF; accumulates in neutrophils and macrophages. It is largely metabolized and metabolites are excreted in urine and bile. The t ½ is 3 hr . Side effects R ashes , urticaria , abdominal pain , but the major problem is diarrhoea and pseudomembranous enterocolitis due to Clostridium difficile superinfection which is potentially fatal . The drug should be promptly stopped and oral metronidazole (alternatively vancomycin ) given to treat it. Thrombophlebitis of the injected vein can occur on i.v. administration.

30. use of clindamycin: Restricted to anaerobic and mixed infections, especially those involving Bact. fragilis causing abdominal, pelvic and lung abscesses. It is a first line drug for these conditions, and is generally combined with an aminoglycoside or a cephalosporin. Metronidazole and chloramphenicol are the alternatives to clindamycin for covering the anaerobes. Skin and soft tissue infections in patients allergic to penicillins can be treated with clindamycin. Anaerobic streptococcal and Cl. Perfringens infections, especially those involving bone and joints respond well.

31. Uses of clindamycin - ii prophylaxis of endocarditis in penicillin allergic patients with valvular defects who undergo dental surgery, as well as to prevent surgical site infection in colorectal/pelvic surgery. In AIDS patients, it has been combined with pyrimethamine for toxoplasmosis and with primaquine or Pneumocystis jiroveci pneumonia. It is an alternative to doxycycline for supplementing quinine/ artesunate in treating multidrug resistant falciparum malaria. Topically it is used for infected acne vulgaris.

32. GLYCOPEPTIDEANTIBIOTICS Vancomycin

33. Vancomycin : MOA Acts by inhibiting bacterial cell wall synthesis Toxicity : Systemic toxicity of vancomycin is high. It can cause plasma concentration-dependent nerve deafness which may be permanent. Kidney damage is also dose-related. Other oto and nephrotoxic drugs like aminoglycosides must be very carefully administered when vancomycin is being used. Skin allergy and fall in BP during i.v . injection can occur. Vancomycin has the potential to release histamine by direct action on mast cells. Rapid i.v. injection has caused chills , fever, urticaria and intense flushing— called ‘Red man syndrome’.

34. Uses: Given orally (125–500 mg 6 hourly), it is the second choice drug to metronidazole for antibiotic associated pseudomembranous enterocolitis caused by C. difficile . Staphylococcal enterocolitis is another indication of oral vancomycin . It is an alternative drug for serious skin, soft tissue and skeletal infections in which gram-positive bacteria are mostly causative .

35. Uses: For empirical therapy of bacterial meningitis, i.v. vancomycin is usually combined with i.v. ceftriaxone/ cefotaxime . It is also used in dialysis patients and those undergoing cancer chemotherapy. Vancomycin is the preferred surgical prophylactic in MRSA prevalent areas and in penicillin allergic patients. Penicillin-resistant pneumococcal infections and infection caused by diphtheroids respond very well to vancomycin .