Aminoglycosides

a presentation on aminoglycosides

1. Aminoglycosides PRESENTED BY SREYA. S M. Pharmacy DEPT OF PHARMACOLOGY

2. Introduction Aminoglycosides are a group of bactericidal antibiotics, Used to treat aerobic Gram – ve bacteria Aminoglycosides are called bactericidal antibiotics because they kill bacteria directly. They accomplish this by stopping bacteria from producing proteins needed for their survival. Because aminoglycosides are normally used to treat serious infections, they are typically administered into the veins of the body (intravenously, or IV ). However, some aminoglycosides can be taken orally, or as ear or eye drops

3. History and Source Natural products or semisynthetic derivatives of compounds produced by a variety of soil actinomycetes Streptomycin was first discovered in 1944 by waksman Isolated from a strain of Streptomyces griseus Gentamicin and netilmicin are derived from species of the actinomycete Micromonospora

4. Systemic aminoglycosides Topical aminoglycosides Streptomycin Neomycin Gentamicin Framycetin Kanamycin Tobramycin Amikacin Sisomicin Netilmicin Paromomycin CLASSIFICATION

5. Mechanism of Action Aminoglycosides bind to 30s ribosomal units of bacteria.An oxygen-dependent transport system is necessary for aminoglycosides to reach their target site; Pevents the formation of intiation complex,which is the prerequisite for peptide synthesis Lack of the formation of intiation complex causes the 30s sub unit to MISREAD THE GENITIC CODE on mRNA Incorrect aminoacids are thus incorporated into the growing peptide chain,which are of no use for bacterial growth LEADS TO BACTERIAL DEATH

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7. Aminoglycosides also act by Formed improper intiation complex blocks the movement of ribosomes Resulting in a mRNA chain attached with single ribosomes ( monosomes ) Thus amino glycoside also interfer in the assemble of poly somes Results in the accumulation of non functional ribosomes

8. PHARMACOKINETICS ABSORPTION :Aminoglycosides are highly polar , so they have very poor oral bioavailability. Therefore they are given parenterally or applied locally. DISTRIBUTION : These are poorly distributed and poorly protein bound when given parenterally they failed to reach intraoccular fluid or CSF. METABOLISM: As they do not penetrate more celluar compartments they do not under go any significant metabolism

9. EXCRETION : Mainly by kidney through glomerular filtration. Resulting in fairly high urinary concentration. so they can be used in the treatment of URINARY TRACT INFECTIONS . Their excetion is directly proportional to creatinine clearence . Though normal half life varies from 1.5-3 hrs,it may increased to 24-48 hrs in patients with renal insufficiency

10. Dosing regimens Gentamicin / tobramycin sisomycin / netilmycin Streptomycin/ kanamycin amikacin Single total daily dose regimen for patients with normal renal function because of: Aminoglycosides have concentration dependent killing and a long post antibiotic effect b. Plasma concentration remain subthresold for ototoxicity and nephrotoxicity 3-5mg/kg/day 7.5-15mg/kg/day

11. Single daily dose regimen is not used in: Patient with abnormal renal function and children Gentamicin is combined with β- lactam for bacterial endocarditis Aminoglycosides exhibit CONCENTRATION DEPENDENT KILLING i;e their increased concentration kills an increased proportion of bacteria at rapid rate DOSE OF RENAL IN- = SUFF I CIE N CY NO R M A L T H ERA P EUTIC SERUM CREATININE VALUE (mg/dl)

12. Post antibiotic effect Aminoglycosides exhibit concentration dependent killing. They also possess significant Post-antibiotic effect. Postantibiotic effect  (PAE) is the term used to describe suppression of bacterial growth that persists after brief exposure of organisms to antimicrobials. PAE have clinical  impact  on  antimicrobial  dosing regimens. Single daily dosing at least as effective as and no more toxic than multiple dosing

13. Mechanism of resistance Aquisition of cell membrane bound inactivating enzymes that adenylate / acetylate or phosphorylate drug Mainly by conjugation and transfer of plasmids Nosocomial microbes have become rich in such plasmids, some of which encode for multidrug resistance Decreased efficiency of transporting mechanismof the aminoglycosides into bacterial cytosol Less common • Found in pseudomonas: 2nd phase active transport defective Deletion/alteration of receptor protein on 30 S ribosomal unit by mutation: prevents attachment Less common , Specific for particular drug , Seen in E.coli

14. Antibacterial spectrum Primarily against Gm – ve aerobic bacilli – Proteus, pseudomonas – E.Coli,enterobacter – Klebsiella – Shigella Only few Gm + ve cocci : – staph aureus , strepto viridans Not effective against Gm + ve bacilli, Gm- ve cocci and anaerobes

15. Shared toxicities Ototoxicity – Vestibular damage – Cochlear damage Nephrotoxicity Neuromuscular blockade

16. Ototoxicity Ototoxicity results in irreversible, bilateral highfrequency hearing loss and temporary vestibular hypofunction Impairment of VIII cranial nerve function , May be irreversible Cochlear damage Hearing loss and tinnitus – More with neomycin , amikacin and kanamycin Vestibular damage Vertigo, ataxia, loss of balance More with Streptomycin, gentamycin • Tobramycin has both types of toxicity • Netilimycin claimed to have low ototoxicity

17. Nephrotoxicity Tubular damage causes: Low g.f.r , Nitrogen retention Albuminuria , Casts High concentration is found in renal cortex and toxicity related to total amount of drug received Mechanism Inhibit various phospholipases , sphingomyelinases , and ATPases , and they alter the function of mitochondria and ribosomes ↓ PG synthesis and ↓ g.f.r Incidence: 8-26% Factor affecting nephrotoxicity Total amount of drug administered Duration of drug received Advanced age, liver disease, diabetes mellitus, and septic shock↑ toxicity Streptomycin and tobramycin are least nephrotoxic

18. Neuromuscular blockade Cause N-M junction blockade by – Displacing Ca2+ from NM junction – By blocking post synaptic NM receptors – Inhibiting Ach release from motor nerve Neomycin & streptomycin: more propensity Tobramycin least likely to produce it Myasthenic weakness increases by these drugs

19. Contraindications Pregnancy: foetal ototoxicity With other ototoxic drugs: furosemide , minocycline With nephrotoxic drugs: vancomycin , cisplatin Elderly patients Those with kidney disease Cautious use of muscle relaxants Do not mix with any other drug in same syringe

20. Gentamicin Cheapest and first line antibiotic 3rd systemically antibiotic obtained from micromonospora purpurea in 1964 Spectrum Gram- ve bacilli like: E.coli , Klebsillea , Enterobacter , H.Influenzae , proteus , serrratia , and pseudomonas Many strain of brucella , campylobacter citrobacter , Fransisella and yersinia are sensitive Uses

21. USE Use restricted to serious Gm- ve bacillary infections Septicaemia , sepsis, fever in immunocompromised patients – Used with penicillins Pelvic infections : with metronidazole SABE: with Penicillin G or ampicillin or vancomycin Coliform infection: with ampicillin or ceftriaxone Pseudomonal infections: with ticarcillin Meningitis by Gm- ve bacilli : III generation cephalosporin alone or with gentamicin

22. Streptomycin Oldest aminoglycoside obtained from sreptomyces griseus Spectrum H.Ducreyi , Brucella , Yersinia , Nocardia , Campylobacter granulomatis , Francisella tularensis , M. Tuberculosis Uses Tuberculosis : Tuberculocidal Acts only on extracellular bacilli Use: in 2nd category T.B. for first two months Dose:15 mg/kg i.m . thrice a week for 2 month Subacute bacterial endocarditis Plague : rapid cure within 7-12 days but tetracycline is drug of choice Tularemia : Streptomycin is drug

23. Streptomycin dependence : Certain mutant grown in presence of streptomycin dependent on it Seen in tuberculosis Toxicity Lowest nephrotoxicity Hypersensitivity reaction are rare: rashes, eosinophillia , exfoliative dermatitis, and fever are reported Anaphylaxis is very rare

24. Kanamycin Obtained frorn S. kanamyceticus :in 1957 Similar to streptomycin in all aspects Toxicity and narrow spectrum not used now Occasionally used in 2nd line drug in tuberculosis Tobramycin Similar to gentamycin Used pseudomonas and proteus resistant to gentamycin Ototoxicty and nephrotoxicity is less Sisomicin Identical to gentamicin More potent on pseudomonas and -hemolytic streptococci Used interchangeably with gentamicin

25. Amikacin Less toxic semisynthetic derivative of kanamycin Resistant to enzymes that inactivate gentamicin and tobramcyin Widest spectrum of activity Uses: – Same as gentamicin – Reserve drug for hospital acquired Gm- ve bacillary infections – Multidrug resistant TB along with other drugs Dose : 15mg/kg/day in 1-3 doses

26. Netilmicin Semisynthetic derivative of gentamycin Broader spectrum Relatively resistant to aminoglycoside inactivating enzymes More active against klebsilla , Enterobacter and styphylococcus Less active against pseudomonas Less ototoxic

27. Neomycin Wide spectrum Use Topically combine with polymixin and bacitacin ) ,Infected wound ,Ulcers , Burns , External ear infections , Conjuctivitis Orally Preparation for bowel surgery:3 doses of 1g along with metronidazole 0.5 g on day before surgery reduce postoperative infection Hepatic coma: By suppressing intestinal flora it decrease NH3 production Because of toxicity lactulose is used

28. Side effects Malabsorption syndrome with diarrhoea and stetorrhoea Hypersensitivity reactions, primarily skin rashes, occur in 6-8% of patients –with topical therapy Superinfection with candida Nephrotoxicity and ototoxicity Neuromuscular blockade with respiratory paralysis Framycetin Very similar to neomycin Too toxic for systemic administration Used topically on skin, eye ear

29. REFERENCES Tripathi K.D. Essentials Of Medical Pharmacology. 7 th ed. Jaypee Brothers Medical Publishers; 2014:[182-191] Rang H.P ,Dale M.M, Ritter J.M, Flower R.J.Pharmacology . 6 th ed.Elsevire : Churchill livingstone;2008:[226-237 http://www.medindia.net/articles/aminoglucosides.htm http://en.wikipedia.org/wiki/aminoglycosides

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