Aminoglycoside Ahmad Noor Pharm D Aminoglycosides are a

Aminoglycoside Ahmad Noor, Pharm. D

Aminoglycosides are a group of antibiotics that are effective against: Aminoglycoside (AGL) Aerobic gram( - )bacteria e. g. : pseudomonas, Acinetobacter, enterobacter Some mycobacteria e. g. : bacteria that cause tuberculosis Some gram ( + ) bacteria

Mechanism of action & pharmacokinetic: ¢ MOA : They bind to ribosomal units ( 30 S-50 S ) in bacteria & inhibits protein synthesis ¢ Pharmacokinetic : • PO poor absorption; IM or IV best • Distribution: hydrophillic, poor CSF, cross placenta • Metabolism : Excreted unchanged, special dosing for renal failure

Aminoglycoside (AGL) Stretomyces Suffix -mycin Micromonospora Suffix -micin Streptomycin Paromomycin Gentamicin Neomycin Tobramycin Netilmicin Amikacin

Drug Use Streptomycin ¢ (Streptomycin Sulfate ® ) Second-choice medications: for tuberculosis (TB) ¢ streptococcal endocarditis (with B- lactam) ¢ enterococcal endocarditis ( with penicillins ) Paromomycin ¢ ( Humatin ®) Neomycin ( mycifrdish ®) Tobramycin ( Nebcin ®) , (Tobi®) Gentamicin ( garamycin ®) Amikacin ( Amikin ® ) Netilmicin ( NETROMYCIN ®) Intestinal infections ¢Ttt of hepatic encephalopathy ¢ Ttt of amebiasis prophylaxis GI surgery ¢ prevention of hepatic encephalopathy & hypercholesterolemia ¢ Ttt of systemic infection ¢ respiratory tract infection ¢ ¢Ttt of systemic infection ¢ life threatening infection ¢ eye infection Respiratory tract infection ¢ Skin infection ¢ Urinary tract infection ¢ Blood, abdomen or bones infection ¢ septicemia ¢ Lower respiratory tract infection ¢ Urinary tract infection ¢ peritonitis and endometritis ¢

Drug Streptomycin (Streptomycin Sulfate ® ) Paromomycin Dose regimen Available dosage form (if creatinine clerance > 90 ml/min) ( all aminglycosides have very poor absorption from G. I. T ) I. V 25 -30 mg/weak ( tuberculosis ) Oral 500 mg po tid x 7 d I. V , I. M Oral ( Humatin ®) ( mycifrdish ®) Oral For hepatic encephalopathy : 4 -12 gm/d As prophylactic in GI surgery : 1. 0 gm po x 3 with erythromycin Tobramycin I. V 5. 1 ( 7 if critically ill ) mg/kg q 24 h Neomycin Oral , topical It is not given intravenously, as it is extremely nephrotoxic I. V , I. M , inhalation (Tobi®) ( Nebcin ®) Gentamicin I. V 5. 1 ( 7 if critically ill ) mg/kg q 24 h I. V , I. M , Topical ( garamycin ®) Amikacin I. V 15 mg/kg q 24 h I. V , I. M I. V 6. 5 mg/kg q 24 h I. V , I. M ( Amikin ® ) Netilmicin ( NETROMYCIN ®) The lowest ototoxic AGL

Special concern in treatment: ¢ ¢ ¢ Tobramycin is superior to gentamicin for ttt of P. aeruginosa. Gentamicin is the preferred AGL used in combination ttt of enterococcal endocarditis ( with ampicillin or vancomycin). Streptomycin has the greatest activity of all the AGL against M. tuberculosis. Capreomycin is an AGL use as alternative drug to ttt mycobacterial infection Streptomycin & gentamicin are drugs of choice to ttt tularemia Streptomycin is drug of choice to ttt plague & brucellosis

Single Daily Dose (SDD) of AGL: ¢ • 1. 2. For Adult: There are two main principles for the use of the SDD of AGL: Since the AGL bactericidal effect is related to peak concentrations, higher doses will achieve a higher peak concentration and ensure efficacy of therapy. With this dosing, it is possible to achieve the desired peak: MIC ratio. SDD may reduce the frequency of nephrotoxicity since low or undetectable trough concentrations will be attained. 3. Dose ranges from 3 to 7 mg/kg/day for gentamicin & tobramycin. o For children: • The use of SDD of AGL in children has some limitation because of: 1. Rapid AGL clearance. Unknown duration of post-antibiotic effect. Safety concerns. Limited clinical and efficacy data. 2. 3. 4.

Single Daily Dose of AGL: • SDD relatively contraindications : 1. 2. S. aureus or Enterococcal infection. Bacterial pneumonia with pathogen having high MIC. • Toxicity with SDD: 1. 3. Endotoxin like reactions with SDD AGL’s therapy: - many patients develop rigors, fever, tachycardia. Ototoxicity: develop vestibular dysfunction with high dose. Nephrotoxicity decreased with the use of SDD AGL’s. * N. B: 2. * * * cont. SDD of AGL not for every infection, pathogen, or patient. Must have therapeutic goal based on pathogen susceptibility & location of infection. PK’s remain useful tool to screen patients & to establish desired Cpx: MIC ratio.

Aminglycosides dosage : ¢ AGL dose depend on IBW & cretinine clerance. IMP. Formulae: 1. Creatinine clerance : = (140 -age)(IBW in kg) / (72)(Scr)=ml/min x 0. 85 for Cr. Cl of women. 2. Ideal Body Weight (IBW) : males: 50 kg + 2. 3 kg per inch over 5’= weight in kg females: 45 kg +2. 3 kg per inch over 5’= weight in kg 3. Obesity adjustment : use if Actual Body Weight (ABW) is >30% above IBW. To calculate adjusted dosing weight in kg : IBW+ 0. 4 (ABW-IBW) = adjusted weight.

Aminglycosides dosage : ¢ ¢ cont. SARUBBI-HULL NOMOGRAM FOR AMINOGLYCOSIDES: Drug Therapeutic concentration Max. peak conc. Max. trough conc. Amikacin 15 -25 µg/mg 35 µg/mg Gentamicin 4 -10 µg/mg 2 µg/mg Tobramycin 4 -10 µg/mg 2 µg/mg General dosing information: The following dosing chart by Sarubbi-Hull (Ann Intern Med 1978; 89: 612 -8) may be used to provide the clinician with an initial loading dose and maintenance dose regimen in adult patients. Further dosage adjustments should be individualized and based on peak/trough serum concentrations, which should be drawn after the 3 rd maintenance dose.

Aminglycosides dosage : cont. 1 - Select loading dose ( based on IBW ) to provide peak serum concentration in the range listed below for the desired AGL: AGL Usual loading dose Expected peak serum conc. Gentamicin, Tobramycin 1. 5 -2 mg/kg 4 -10 µg/ml Amikacin 5 -7. 5 mg/kg 15 -30 µg/ml

Aminglycosides dosage : cont. 2 - Select maintenance dose ( as % of loading dose ) to maintain peak serum conc. Indicated above according to desired dosing interval & the patient corrected Cr. Cl: Cr. Cl ( ml/min ) Half-life ( hours ) % of loading dose required for dosage interval selected * 8 hours 12 hours 24 hours 90 3. 1 84 % - - 80 3. 4 80 91 % - 70 3. 9 76 88 - 60 4. 5 71 84 - 50 5. 3 65 79 - 40 6. 5 57 72 92 % 30 8. 4 48 57 81 20 11. 9 37 50 75 17 13. 6 33 46 70 15 15. 1 31 42 67 12 17. 9 27 37 61 10 20. 4 24 34 56 7 25. 9 19 28 47 5 31. 5 16 23 41 2 46. 8 11 16 30 0 69. 3 8 11 21 * This chart is not applicable to children & neonate.

Side effects: • Nephrotoxicity • Risk of Nephrotoxicity with Cyclosporine , Vancomycin , Ampho B , Radiocontrast & NSAIDs. • Risk of nephrotoxicity by once-daily dosing method. • Ototoxicity , deafness • Risk of ototoxicity with loop diuretic. • Risk of nephro/ototoxicity with Cis platinum. • Pseudomembrane colitis • Neuromuscular toxicity • Other drug-drug interactions: • Neuromuscular blocking agents • Non-polarizing muscle relaxant • Oral anticoagulants apnea or respiratory paralysis apnea prothrombin time Note: there is no known method to eliminate risk of AGL nephro/ototoxicity. proper Rx attempts to the % risk.

Follow up & monitoring : ¢ Monitor patient for ototoxicity : tinnitus, vertigo, hearing loss • the drug should be stopped if tinnitus occurs. ¢ ¢ ¢ Monitor patient for nephrotoxicity periodically. if serum creatinine increases by more than 50% over baseline value it may be advisable to discontinue drug ttt & use less nephrotoxic agent. Monitor neuromuscular function when administering the drug IV. Too rapid administration may cause paralysis & apnea. Have Ca gluconate or pyridostigmine available to reverse such effect Monitor patient's neurologic status if the drug is given for hepatic encephalopathy.

Contraindications: ¢ Hypersensitivity to AGL ¢ Pregnancy (AGL is class D during pregnancy ) ¢ ¢ Myasthenia gravis Parkinsonism (AGL may cause neuromuscular blockade, resulting in further skeletal muscle weakness ) ¢ Fetal eight nerve damage ( AGL may cause auditory and vestibular toxicity )

Patient counseling : ¢ Do not take AGL if you are pregnant or could become pregnant during treatment. ¢ Do not take AGL if you are breast-feeding a baby. ¢ Take each dose with a full glass of water. ¢ Take AGL with food. ¢ Store AGL at room temperature away from moisture, heat, and direct light.

References : 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Joel Hardman, Lee Limbird, Alferd Goodman Gilman, eds. The Pharmacological Basis Of Theraputics. 10 th ed. Mcgraw-hill; 2001; p 1219 -1238. Seymour Ehrenpreis, Eli Ehrenpreis, eds. Clinician’s Handbook Of Prescription Drugs. 1 st ed. Mc. Graw-hill; 2001; p 959 -960. David Gilbert, Robert Moellering, George Eliopulos, Merle Sande, eds. The Sanford Guide To Antimicrobial therapy. 35 th ed. Antimicrobial Therapy, Inc; 2005; p 47 -53. Simeon Marglis, Rodney Friedman, Thomas Dickey, Jermy Birch, eds. The Johns Hopikins Consumer Guide to Drugs. 1 st ed. Medletter associates, Inc; 2005; p 766. Frederic Vagnini, Barry Fox, eds. The Side Effects Bible. 1 st ed. Random House, Inc; 2005; p 499 -500. http: //health. yahoo. com/drug/d 00014 a 1. http: //www. rxlist. com/cgi/generic 2/streptomycin. htm. http: //www. medscape. com/viewarticle/448281_print. http: //bmj. bmjjournals. com/cgi/content/full/312/7027/338. http: //depts. washington. edu/druginfo/Formulary/Amin oglycosides. pdf#search='aminoglycosidenomogram.

Thank You Ahmad Noor , Pharm. D