All are sulfate salts which are highly water soluble; solutions are stable for monthsThey ionize in solution are not absorbed orally, distribute only extracellularly, do not penetrate brain or csf. More active in alkaliner ph. There is only partial cross resistance among them.Streptomycin – 1944Actinomycetes – Streptomycesgriseus
Term aminoglycoside stems from there structure characterized by two amino sugars joined to a non sugar aminocyclitol by –o- glycosidic bond. In majority of aminoglycosides this aminocyclitol or non sugar moeity is 2-deoxystrepamine, however in streptomycin, the aminocyclitol is streptidine which is not placed centrally as in other aminoglycosides. Rather it is placed laterally to the amino sugar streptose which is joined by other aminosugar, (N-Methyl L glucosamine, these 2 amino sugars are jointly called Streptobiosamine.
Streptomycin and all other aminoglycosides whose name end with suffix mycin are obtained from genus streptomyces. Gentamicin other micins they are obtained from micromonospora or semisyntheticallye.gnetilimycin
Ribosomes are involved in protein synthesis by bacteria
This complex moves along mrna so that sucessivecodons of mRNA pass along ribosome from a site to p site Codon is triplet of 3 nucleotides which codes for specific amino acid needed for protein synthesis
That is why beta lactum antibiotics which weaken or inhibit bacterial cell wall synthesis facilitate passive diffusion of aminoglycosides if given together- synergistic action. Subsequently further transport of aminoglycosides across the cytoplasmic membrane takes place by energy dependent and oxygen dependent active transport . As such transport cannot take place in anaerobic conditions, aminoglycosides are inactive against anaerobic bacteria.
These drugs then bind to 30 S ribosomal units of bacteria and prevent formation of initiation complex. Which is prerequisite for peptide synthesis. Lack of formation of initiation complex causes 30 S subunit to misread genetic code on mRNA. Incorrect aminoacids are thus incorporated into growing peptide chain which are of no use for bacterial growth. The formation of improper initiation complex also blocks the movement of ribosomes, resulting in mRNA chain attached with single ribosomes (Monosomes). Thus aminoglycosides also interfere with in the assembly of polysomes which result in accumulation of nonfunctional ribosomes.Penetration is favoured by high pH.Aminoglycosides are 20 times more active in alkaline than acidic pH.Cidal action: secondary changes in integrity of bacterial cell membrane, because other antibiotics which inhibit protein synthesis are bacteriostatic. After exposure to aminoglycosides , sensitive bacteria become more permeable ; ions aminoacids and even protein leak out followed by cell death. This probably results from incorporation of faulty proteins into cell membrane.one of the consequences of aminoglycoside induced alteration of cell membrane is augmentation of carrier mediated entry of the antibiotic. This reinforces the lethal action.The cidal action of aminoglycosides is concentration dependentand they also exert prolonged post antibiotic effect.
Antibacterial activity of aminoglycosides, fluoroquinolones and metronidazole is conc dependent. While that of beta lactums and vancomycin is time dependent. Conc dependent killing: more effective if higher blood conc are reached periodically. Time dependent killing: more effective if blood levels are maintained above the MIC for as long duration as possible. Post antibiotic effect: A persistantsupression of bacterial growth. After brief a brief exposure of an antimicrobial agent. Inhibiton of bacterial growth is even seen when Conc of drug falls below MIC. REFLECTS time required by bacteria to return to normal growth. PAE is most significant with drugs that act by inhibiting bacterial protein synthesis or DNA synthesis. (Amino, Fluro, tetracycline, chloramphenicol, rifampicin. Post antibiotioc effect explains why these drugs can be given in a single daily dose even though they have a short half life (1-3) Hrs.
Bacterial transferase enzymes are: phosphotransferases, acetyl tranferases and adenyltransferases. Which inactivate aminoglycosides by acetylatuion, adennylkation and phosphorylation.Decreased transport may result from mutation or deletion of porin channels or protein involved in transportor by makink o2+ energy dependent transport system non functional.
Highly polar basic drugs: do not permit their membrane permeability, as a result they have very poor oral bioavailabilty entire oral dose excreted in faeces. When given parenterally they fail to reach intraoccular fluid or csf as they do not penetrate most cellular compartments. They do not undergo any significant metabolismNearly all of IV dose is excreted unchanged in urine. Cleared by kidneys through glomerular filtration resulting in fairly high urinary conc. Which makes them useful in UTI. Use of urinary alkalinzer makes these drugs more effective. Excretion is directly proportional to renal clearance. nOrmal half life= 1.5 -3 hrs in renal insufficiency it may increase to 24 -48 hrs. these are only removed partly by hemodialysis and peritoneal dialysis. Hence dose adjustment is needed to avoid toxicity.
Howevr more precise method for calculating dose of such patient must use creatinine clearance valuesof an individual because aminoglycoside clearance is directly proportional to his creatinine clearance value
Concentrated in labyrinthine fluid endolymph and perilymph and slowly removed from it. Conc dependent destructive changes are observed. Cocleardamage:Initailly is asymptomatic can only be detected by audiometry. Tinnitus then appears follwed by hearing loss. Tinnitus disappears in 4 -10 days but frequency loss persists. Hearing loss affects high frequency sound first then to low frequency sounds. Hearing loss is permanent because no regeneration of sensory cells occurs. Older pt and those with prexixting hearing defect are mosre susceptible. Vestibular damage: headache is usually first to appear, followed by nausea, vomiting, diziness, nystagmus, vertigo. When drug is stopped in this phase, it passes into chronic phase lasting for 6-10 weeks in which patient is asymptomatic while in bed and only difficulty during walking. Compensation by visual and proprioceptive positioning and recovery occurs in often occurs over 1-2 years. Aminoglycoside induced ototoxicity is worsened by coadministration of vancomycin, furosemide, ethacrynic acid. While lessened by Calcium.EARLY DISCONTINUATION OF DRUGPREVENTS DAMAGE AND PERMITRECOVERY
Larger the number of constituent Amino group on aminoglycoside molecule more are the chances for its inherent nephrotoxic potential. Neomycin, gentamicin, amikacin and tobramycin are more toxic than More in elderly and prexisting kidney disease. Caused by inhibition of an intracellular lysosomalPhospholipase A2 in renal brush border. This leads to lysosomal distension, rupture and release of acid hydrolases and free aminoglycoside into cytosol. Which binds to other cellular organelles like mitochondria, displaces calcium and leads to mitochondrial degeneration and necrosis. Necrotic cellular debris are then sloughed off and passes into urine, leaving denuded basement mebrane. It manifests as tubular dammage resulting in loss of urinary conc power, low GFR, nitrogen retention, albuminuria and casts . Aminoglycosides attain high conc in renal cortex toxicity is related to total amount of drug received by patient . Interfere with pg production related to decreased GFR Renal proximal tubular cellsaccumulate and retain drug• Mild proteinuria, appearance ofcasts, hyaline or granularProximal tubular cells have regenerativecapacity• Neomycin highly toxic- systemicadministration contraindicated• Reduced excretion predisposed toototoxicity• Monitor plasma drug conc. in prolongedand high dose therapy
also interfere with mobilization of centrally located synaptic vesicles to fuse with terminal membrane. (probably by anatagonizing calcium as well as decrease the sensitivity of muscle end plate to Ach. Not manifested ordinarily in clinical settings . However apnoea and fatalities have occurred when these antibiotics were put into pleural or peritoneal cavities after operation especially if curare like drug used for sk muscle relaxation. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
Nephrotoxic drugs: cycloserine, amphotericn B
Oldest aminoglycoside antibiotic obtained from streptomyces griseousIn intestinal and urinary tract resistant organisms may emerge in 2 days of therapy , E coli, h influenzae, staph aureus, strep pneumoniae and streppyogenes have become largely resistant. Streptomycin dependence: certain mutuants become dependent on it. Growth promoted occurs when antibitoc induced misreading becomes a normal feature of organism. Adverse effects: 1/5 pt experience vestibular disturbances, auditory disturbances are less common. Streptomycin has lowest nephrotoxicity among aminoglycosides, probably because it is not concentrated in renal cortex. Hypersensitivity reactions are rare , rashes, eosinophilia, fever, exfoliative dermatitis have been noted.anaphylaxis is rare, topical use contraindicated for fear of contact sensitization. Superinfections are not significant, pain at site of injection is common. Paresthesia and scotoma are occasional. Dose: acute infection 1 gm IM BD for 7-10 days TB -1gm or .75 gm IM od or twice weekly for 30-60 daysIn SABE: 4-6 WEEKS PLAGUE: it effects rapiod cure 7-12 days. May be employed in confirmed cases. Tularemia: drug of choice for this rare disease. Effects cure in 7-10 days. Tetracyclines alternative drugs especially in milder casesIn most other situations like UTI, peritonitis, septcaemia etc gentamicin or newer aminoglycoside is preferred due to low potency and wide spread resistance. Oral use for diarrhoea is banned in india.
In 1964Low cost reliabilty of use and long experience MIC for most organisms is 4-8 times lower. Also ineffective against streptococcus pyogenes and pneumomniae
Due to its narrow therapeutic indexCombined with metronidazole to enlarge spectrumagaistbacteriodesfragilisVancomycin: synergistic action- useful in enterococcalendocarditis in patients with history of penicillin allergy
Dose= 3-5 mg/kg/dy in divided doses 8 hrly interval for 7-10 days. 5-7 mg/kg is equally effective and even less toxic . Topically used as cream, ointment or eye drops fr treatment of infected burns, wound and bacterial conjunctivitis. Howevr it is inactivated by purulent exudate of wounds. Hence it is not useful in presence of pus.
2-4 times more active against pseudomonas and proteus even those which are resistant to gentamicin. Obtained fro m s TENEBRARIUS. Sisomycin: ineither is it resistant to degradation by aminoglycoside inactivating enzymes nor does it offer ant advantageovergentamicin in terms of toxicity.
Kanamycin is not used due to because of higher ototoxicity and nephrotoxicityOutstanding feature of amikacin is resistance to bacterial aminoglycoside inactivating enzymes More hearing loss than vestibular toxicity. Relatively high doses required for pseudomonas, proteus and staph Dose in UTI: 7.5 mg/kg/dayEffective even against tobramycin and gentamicin resistant Gm-ve bacilli like pseudomonas, serratia, proteus.Also effective against atypical mycobacteria
Less ototoxic than gentamicin and tobramycin but reports are inconclusive Could be preferable in critically ill and neutripenic patients and retain activity in hospitals where gentamicin resistance has spread.
Obtained from S fridiaeHighly toxic for internal ear mainly auditory and also kidney Oral and topical administration does not cause systemic toxicity
Bacitracin- gm+ve, polymyxin- pseudomonas. Preparation of bowel before surgery: along with metronidazole 500 mg tds may reduce post operative infectionsRole of neomycin in hepatic coma: 1 gm tds with reduced protein intake it is useful in hepatic coma as it supresses ammonia producing coliform bacterial flora. Blood ammonia levels therefore get decreased and encephalopathy is prevented. Blood urea levels are also decreased because less ammonia is now available for conversion to urea. Clinical improvement is seen in 2-3 days. Lactulose causes reduction of 25-50% 0f ammonia in patients with hepatic encephalopathy. Ammonia produced by bacteria in colon is converted to ionized NH4+ salts and is not absorbed Neomycin and polymyxin B used for bladder irrigation in solution containing 40mg neomycin & 2 lac units of polymyxin-B per ml.1 ml added to 1 liter of 0.9% sodium chloride solution and is used for continuous irrigation of bladder in order to prevent bacteremia and bacteriurea associated with use of indwelling catheters at the rate of 1000 ml/day.ORAL NEOMYCIN HAS DAMAGING EFFECT ON INTESTINAL VILLI PROLONGED TREATMENT CAN INDUCE MALABSORPTION SYNDROME WITH DIARRHOEA AND STEATORRHOEA. SUPER INFECTION WITH CANDIDA CAN OCCUR.
Obtained from s. lavendulaeSoframycin eye drops 0.5 % and cream 1 %
Aminoglycosides• Streptomycin – 1944• Actinomycetes – Streptomyces griseus• Bactericidal antibiotics• Interfere with protein synthesis• Used to treat aerobic Gram –ve bacteria• Resemble each other in MOA, pharmacokinetic therapeutic and toxic properties• Relatively low margin of safety• Exhibit ototoxicity and nephrotoxicity
Mechanism of action• Initially they penetrate bacterial cell wall, to reach periplasmic space through porin channels (passive diffusion)• Further transport across cytoplasmic membrane takes place by active transport by proton pump; an oxygen- dependent process
Mechanism of Action• Bind 30S ribosomal subunits and interfere the initiation complex• Induce misreading of genetic code on mRNA• Breakup of polysomes into monosomes
Post antibiotic effect• Aminoglycosides exhibit concentration dependent killing.• They also possess significant Post-antibiotic effect.• Single daily dosing at least as effective as and no more toxic than multiple dosing.
Mechanism of resistance• Synthesis of plasmid mediated bacterial transferase enzyme: Inactivate aminoglycosides• ↓ transport into bacterial cytosol• Deletion/alteration of receptor protein on 30 S ribosomal unit by mutation: prevents attachment
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
Pharmacokinetics• Highly polar basic drugs: poor oral BA• Administered parenterally or applied locally• Poorly distributed and poorly protein bound• Do not undergo any significant metabolism• Nearly all IV dose is excreted unchanged in urine• Dose adjustment is needed in renal insufficiency
Dose for a case of renal insufficiency= Normal therapeutic dose Sr creatinine value (mg/dl)
Dose for a case of renal insufficiency• Cockroft gault formula: CrCl = (140-age) x weight [kg] (sCr x 72) – For females multiply above value by 0.85 • Corrected dose = Normal dose x pt CrCl Normal CrCl
Clinical uses• Gram –ve bacillary infection – Septicaemia, pelvic & abdominal sepsis• Bacterial endocarditis – – enterococcal, streptococcal or staphylococcal infection of heart valves• Pneumonias, Tuberculosis• Tularemia• Plague, Brucellosis• Topical – Neomycin, Framycetin.• Infections of conjunctiva or external ear• To sterilize the bowel of patients who receive immunosuppressive therapy, before surgery & in hepatic coma
Ototoxicity• 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
Nephrotoxicity• Gentamicin, amikacin and tobramycin are more toxic than streptomycin• Responsible for 10-15% of all renal failure cases• Reversible if drug promptly discontinued• ↓ GFR, ↑ sr creatinine• ↓clearance of antibiotic → ↑ ototoxicity
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 ↑by these drugs
Precautions / 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
Streptomycin• Ribosomal resistance develops fast• Limited usefulness as single agent• Plague, tularemia and brucellosis – In combination with tetracycline• SABE: due to Streptococcus Viridans & faecalis – With penicillin but gentamicin preferred• Reserve first line drug for tuberculosis used only in combination
Gentamicin• Obtained from Micromonospora purpurea• Most commonly used aminoglycoside – More potent than Streptomycin – Broader spectrum: pseudomonas, proteus, E.coli, klebsiella, enterobacter, serratia – Low cost, reliability of use, long experience – Acts synergistically with ampicillin, penicillin G, Ticarcillin, ceftriaxone, Vancomycin• Ineffective against M.tuberculosis• Relatively more nephrotoxic
Gentamicin (Uses)• 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
Guideline for adjustment of dose in renal insufficiency
Tobramycin• Identical to gentamicin• Used in pseudomonas and proteus infections• Ototoxicty and nephrotoxicity probably lower Sisomicin• Identical to gentamicin• More potent on pseudomonas and -hemolytic streptococci• Used interchangeably with gentamicin
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
Netilimicin• Semisynthetic derivative of sisomicin• Relatively resistant to aminoglycoside inactivating enzymes• More active against klebsiella, enterobacter & staphylococci• Less active against pseudomonas aeruginosa• Doses and pharmacokinetics similar to gentamicin
Neomycin• wide spectrum active against Gm-ve bacilli and some gm+ve cocci• Pseudomonas and strep.pyogenes not sensitive• Too toxic for parenteral use , limited to topical use
Neomycin (uses)• Topically used in skin, eye and external ear infections combined with bacitracin or polymyxin-B to widen antibacterial spectrum and to prevent emergence of resistant strains• Orally – Preparation of bowel before surgery 1 gm TDS – Hepatic coma: Supresses ammonia forming coliforms prevents encephalopathy (Lactulose more preferred)• Bladder irrigation along with polymyxin B
Framycetin• Very similar to neomycin• Too toxic for systemic administration• Used topically on skin, eye ear