Aminiglycosides for medical students and bds

Aminiglycosides for medical students and bds

1. AMINOGLYCOSIDES Dr.Ramnarayanreddy

2. Bactericidal Streptomycin, neomycin, amikacin , kanamycin , gentamicin , sisomicin , tobramycin , netilmicin etc, used widely against gram- ve enteric bacteria , especially in bacteremia and sepsis, in combination with vancomycin or penicillin for endocarditis , and for treatment of tuberculosis.

3. A. PHYSICAL AND CHEMICAL PROPERTIES : have a hexose ring, to which various amino sugars are attached by glycosidic linkages . More active at alkaline than at acid pH. B. M O A : initially passive diffusion across the outer membrane, then active transport across the cell membrane into the cytoplasm by an oxygen-dependent process . Transport may be enhanced by cell wall-active drugs such as penicillin or vancomycin . Inside the cell, aminoglycosides bind to specific 30S- ribosomal subunit

4. C. MECHANISMS OF RESISTANCE : principal type is production of a transferase enzyme inactivates the aminoglycoside by adenylylation , acetylation , or phosphorylation . impaired entry of aminoglycoside into the cell. The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a mutation. D. PHARMACOKINETICS & OD DOSING absorbed very poorly from the intact GIT , well absorbed after IM, giving peak conc within 30-90 min. Usually admin IV as a 30- to 60-min infusion.

5. Aminoglycosides have concentration-dependent killing; also have a significant postantibiotic effect , such that the antibacterial activity persists beyond the time during which measurable drug is present. Because of these, aminoglycoside may have better efficacy when administered as a single large dose than when administered as multiple smaller doses.

6. Aminoglycoside toxicity is both time- and concentration-dependent . Above 2 mcg/ mL is predictive of toxicity. At clinically relevant doses, the time above this threshold will be greater with multiple smaller doses of drug than with a single large dose. The efficacy of OD aminoglycoside dosing in combination therapy of enterococcal , streptococcal and staphylococcal endocarditis remains to be defined, and the standard low-dose, thrice-daily administration is still recommended. OD dosing in pregnancy and in neonates also is not well-defined.

7. OD dosing also requires careful monitoring and dosage adjustment to minimize toxicity. Aminoglycosides are cleared by the kidney, and excretion is directly proportional to creatinine clearance . Aminoglycosides are highly polar compounds that do not enter cells readily , except the renal cortex . They are largely excluded from the CNS and the eye. Intrathecal or intraventricular injection is required for high levels in CSF. Normal t1/2 is 2-3 hours, increasing to 24-48 hours in renal impairment.

8. E. ADVERSE EFFECTS : Neomycin, kanamycin , and amikacin - most ototoxic agents. Streptomycin and gentamicin - most vestibulotoxic . Neomycin, tobramycin , and gentamicin - most nephrotoxic . More seen if continued for more than 5 days, at higher doses, in the elderly, and in renal insufficiency. Concurrent use with furosemide , ethacrynic acid or vancomycin & amphotericin can potentiate nephrotoxicity . Curare-like effect with NM blockade (very high doses) results in respiratory paralysis, reversible by calcium gluconate or neostigmine . F. CLINICAL USES : mainly against gram- ve enteric bacteria , especially when the isolate may be drug-resistant and when there is suspicion of sepsis, in combination with a b- lactam antibiotic (to include potential gram+ve pathogens + synergism). Also used in enterococcal endocarditis , viridans streptococcal and staphylococcal endocarditis .

9. STREPTOMYCIN: from Streptomyces griseus . Ribosomal resistance has emerged in most species, limiting its use as a single agent, with the exceptions listed below. Clinical Uses: 1. as a 2 nd line agent for treatment of TB , 0.5-1 g/d IM/IV. In combination with other to prevent emergence of resistance. 2. In plague, tularemia, and brucellosis , 1 g/d, IM in combination with an oral tetracycline . Penicillin + streptomycin are effective for enterococcal endocarditis and viridans endocarditis . Gentamicin has largely replaced streptomycin for these indications. Streptomycin remains a useful agent for treating enterococcal infections , 15% of enterococcal isolates that are resistant to gentamicin .

10. ADR: Fever, skin rashes, and other allergic manifestations may result from hypersensitivity to streptomycin, either on prolonged course of treatment ( eg , for TB) or in medical personnel who handle the drug. Pain at the injection site. Use during pregnancy can cause deafness in the newborn .

11. GENTAMICIN: isolated from Micromonospora purpurea , effective against both gram-positive and gram-negative organisms. Antimicrobial Activity: active alone against staphylococci and coliforms and other gram-negative bacteria, and also as a s ynergistic companion with b- lactam antibiotics , against pseudomonas, proteus , enterobacter , klebsiella , serratia , and other gram-negative rod s. No activity against anaerobes.

12. Resistance: Streptococci and enterococci are relatively resistant due to failure of the drug to penetrate into the cell. Resistance emerges rapidly in staphylococci due to selection of permeability mutants . Among gram- ve bacteria, resistance is most commonly due to plasmid-encoded aminoglycoside -modifying enzymes. The enterococcal bifunctional enzyme also inactivates amikacin , netilmicin , and tobramycin , but not streptomycin. However, gentamicin in combination with vancomycin or a penicillin produces a potent bactericidal effect

13. Clinical Uses: PARENTERAL : sepsis and pneumonia caused by gram- ve bacteria, especially pseudomonas, enterobacter , serratia , proteus , acinetobacter , and klebsiella . Aminoglycosides should not be used for single-agent therapy of pneumonia because penetration of infected lung tissue is poor and local conditions of low pH and low oxygen tension contribute to poor activity. B. TOPICAL : Creams, ointments, and solutions containing 0.1-0.3% gentamicin sulfate have been used for treatment of infected burns, wounds, or skin lesions and the prevention of intravenous catheter infections . Subconjunctivally for treatment of ocular infections.

14. C. INTRATHECAL ADMINISTRATION : Meningitis caused by gram- ve bacteria 1-10 mg/d, but not beneficial in neonates with meningitis , and intraventricular gentamicin is toxic. 3 rd gen cephalosporins now preferred. Adverse Reactions: Nephrotoxicity , usually reversible and mild. Requires dose adjustment, less toxic alternative agent. Vestibular dysfunction , irreversible.

15. TOBRAMYCIN: spectrum, pharmacokinetic properties similar to that of gentamicin . Gentamicin is much less expensive. There is some cross-resistance between gentamicin and tobramycin . Slightly more active against pseudomonas ; Enterococcus faecalis is susceptible to both gentamicin and tobramycin . Ototoxic and nephrotoxic . Inhalation for treatment of Pseudomonas aeruginosa lower RTI complicating cystic fibrosis.

16. AMIKACIN: semisynthetic derivative of kanamycin ; less toxic, resistant to many enzymes that inactivate gentamicin and tobramycin . For many gram-negative enteric bacteria, including proteus , enterobacter , pseudomonas, and serratia . 500 mg BD intramuscularly. M. tuberculosis streptomycin-resistant strains, are susceptible. Kanamycin -resistant strains may be cross-resistant to amikacin . nephrotoxic and ototoxic (auditory portion of the 8 th nerve). NETILMICIN shares many characteristics with gentamicin and tobramycin . However, the addition of an ethyl group protects the netilmicin molecule from enzymatic degradation , active against some gentamicin -resistant and tobramycin -resistant bacteria.

17. NEOMYCIN & KANAMYCIN: Antimicrobial Activity & Resistance active against gram-positive and gram-negative bacteria and some mycobacteria . Pseudomonas & streptococci are generally resistant . Cross-resistance between kanamycin and neomycin is complete. Pharmacokinetics: poorly absorbed from the GIT. Intestinal flora is suppressed and excreted in the feces. Any absorbed drug excreted through glomerular filtration.

18. Clinical Uses: Neomycin and kanamycin are now limited to topical and oral use. Too toxic for parenteral use . A. TOPICAL ADMINISTRATION : infected surfaces or injected into joints, the pleural cavity, tissue spaces, or abscess cavities where infection is present. The total amount should not exceed 15 mg/kg/d. B. ORAL ADMINISTRATION : In preparation for elective bowel surgery , combined erythromycin base reduces the aerobic bowel flora with little effect on anaerobes. In hepatic coma , coliform flora can be suppressed together with reduced protein intake, thus reducing ammonia intoxication(supplanted by lactulose ). Paromomycin effective in intestinal amebiasis . ADR: nephrotoxicity and auditory function is affected more than vestibular. kanamycin from the peritoneal cavity (3-5 g) leads to curare-like action , respiratory arrest. Ca gluconate and neostigmine can act as antidotes. Prolonged application of neomycin-containing ointments to skin and eyes has resulted in severe allergic reactions .

19. SPECTINOMYCIN : aminocyclitol antibiotic lacks amino sugars and glycosidic bonds. Used almost solely as an alternative treatment for drug-resistant gonorrhea or gonorrhea in penicillin-allergic patients. Rapidly absorbed after IM injection. A single dose of 40 mg/kg up to a maximum of 2 g is given. Pain at the injection site and occasionally fever and nausea. Nephrotoxicity and anemia, observed rarely.

20. Macrolides Dr.Ramnarayanreddy

21. Macrolides These group of anti- microbials contains a lactone ring. These are used in patients allergic to beta- lactam antibiotics. These are bacteriostatic mainly.

22. Mechanism of action Binds to 50S ribosomal subunit and inhibits the translocation of the newly synthesized peptide from the acceptor site (A) to the donor site (P)

23. Macrolides 1.Chloramphenicol 2.Macrolides 3.Tetracycline

24. Anti-bacterial spectrum Gram-positive - Streptococcus, C. diptheriae Gram-negative – N. gonorrhea, Legionella Mycoplama , Spirochetes, Chlamydia M. Avium-intracellulare , H.Pylori

25. Erythromycin Erythromycin is inactivated by gastric acid. Erythromycin esters are less susceptible to acid inactivation and are better absorbed It inhibits cytochrome P 450 It is mainly excreted in the bile

26. Macrolides Erythromycin & Azithromycin are excreted in bile. Clarithromycin appear in urine and bile. Azithromycin has large Vd – high tissue distribution – concentrated in neutrophils , macrophages.

27. MACROLIDES Oral absorption Cytochrome P450 Spectrum Half life (hours) Erythromycin yes Inhibits Penicillin 2 Clarithromycin Stable to acid Inhibits MAC My, HP, C,Leg 4 Azithromycin Stable to acid No H.Inf, Chl MAC >40 Roxithromycin Stable to acid Inhibits Same as Azithro 10

28. Adverse effects Epigastric distress - erythromycin Cholestatic jaundice (mainly with erythromycin estolate ) Ototoxicity – erythromycin at high dose.

29. Drug - drug interactions Erythromycin, Clarithromycin and roxithromycin inhibit the cytochrome P450 system. so potentiate the activity of theophylline and terfenadine

30. THERAPEUTIC USES Mycoplasma infections Legionnaires ’ disease Pertussis Chlamydia infections Corynebacterium diphtheriae infections Atypical mycobacterium infections

31. Clindamycin Active against gram + ve and anaerobes Good activity against bacteroides ( including B. fragilis ) & Penicillin resistant streptococcus. No activity against most gram - ve bacteria

32. Clindamycin Well absorbed orally Distribution in most tissues including bone. Excretion is mainly biliary and also in urine.

33. Adverse effects Gastrointestinal super-infections – potentially fatal pseudo-membranous colitis by C. difficile. Oral Metronidazole and Vancomycin are used for Ṛ of the fatal pseudo-membranous colitis.

34. GLYCOPEPTIDE ANTIBIOTICS Vancomycin Bactericidal to gram-positive cocci, Neisseria, Clostridia and diphtheroids . Extensively used for surgical prophylaxis, etc., VRSA and VRE have emerged. MoA : acts by inhibiting bacterial cell wall synthesis. It binds to the terminal dipeptide units prevents cross linking to form the cell wall cannot take place. Not absorbed orally. After i.v ., widely distributed, penetrates serous cavities, inflamed meninges and is excreted mainly unchanged by glomerular filtration.

35. Toxicity: Concentration-dependent permanent nerve deafness. Kidney damage is also dose-related. Aminoglycosides must be very carefully used. Skin allergy and fall in BP during i.v . injection, due to histamine release. Rapid i.v . injection - chills, fever, urticaria and intense flushing-called ' Red man syndrome '.

36. 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 . Systemic use (500 mg 6hourly i.v .) is restricted to serious MRSA infections - most effective drug, and as a penicillin substitute (in allergic patients) for enterococcal endocarditis along with gentamicin . For empirical therapy of bacterial meningitis , i.v . vancomycin is usually combined with i.v . ceftriaxone / cefotaxime . Penicillin-resistant pneumococcal infections and diphtheroids respond very well to vancomycin . Preferred surgical prophylactic in MRSA prevalent areas and in penicillin allergic patients.

37. Quinupristin/Dalfopristin It is a ratio of two streptogramins in the ratio of 30:70 Reserved for the treatment of Vancomycin resistant Enterococcus

38. Quinupristin/Dalfopristin Mechanism of action Each component of this binds to separate site on 50 S ribosome and thus interrupt protein synthesis Bactericidal and has long post-antibiotic effect.

39. Quinupristin/Dalfopristin Anti-bacterial spectrum : Gram + ve bacteria resistant to other antibiotics like enterococcus faecium infections including Vancomycin resistant Enterococcus .

40. Quinupristin/Dalfopristin Kinetics : It is available for parenteral route only. It penetrates macrophages and neutrophils It inhibits cytochrome P 450 Most of the drugs are excreted by bile

41. Quinupristin/Dalfopristin Adverse effects : Venous irritation Hyperbilirubinemia Arthralgia

42. Linezolid F irst oxazolidone antibiotic Blocks 70S ribosome assembly by binding 50 S subunit

43. Linezolid Anti-bacterial spectrum : Gram positive bacteria only Penicillin resistant streptococci Methicillin and Vancomycin staphylococcus Vancomycin resistant enterococcus Lister monocytogenes, Corynebacterium spp Also active against mycobacteria tuberculosis and Clostridium

44. Linezolid Linezolid Orally absorbed Well distributed Excreted by renal and non-renal routes

45. Linezolid Adverse effects : Nausea and diarrhea Thrombocytopenia Inhibits MAO, avoid tyramine containing foods

46. urinary antiseptics: attain antibacterial concentration only in urine, with little or no systemic antibacterial effect. Nitrofurantoin and methenamine, Nalidixic acid also. Nitrofurantoin: bacteriostatic, its activity is enhanced at lower pH. It inhibits many gram-negative bacteria, but due to development of resistance, activity is now restricted largely to E. coli. Pharmacokinetics: well absorbed orally; half is excreted unchanged in urine; Renal excretion is reduced in azotaemic patients; contraindicated in renal failure. Adverse effects: Commonest is gi intolerance - nausea, epigastric pain and diarrhoea . Urine turns dark brown on exposure to air. Use: uncomplicated lower UTI, also for prophylaxis when catheterization or instrumentation of the lower urinary tract is performed. 50, 100 mg tab, 25 mg/5 rnl susp .

47. Methenamine: decomposes in acidic urine to release formaldehyde which inhibits all bacteria. Methenamine is administered in enteric coated tablets to protect it from decomposing in gastric juice. use is restricted to chronic, resistant type of uti , not involving kidney substance. Resistance to formaldehyde does not occur. Adverse effects: Gastritis can occur due to release of formaldehyde in stomach-patient compliance is often poor due to this. Chemical cystitis and haematuria may develop with high doses given for long periods. contraindicated in renal failure and in liver disease. Phenazopyridine It is an orange dye, exerts analgesic action in the urinary tract and affords symptomatic relief of burning sensation, dysuria and urgency due to cystitis. Side effects are nausea and epigastric pain. Dose: 200-400 mg TDS