PM716 C45 Aminoglycosides Slides PDF

PM 716 Pharmacology I Chapter 45 Protein Synthesis Inhibitors RMRocco PhD PM716 C45 PSI 1 PM716 C45 PSI 2  Antibiotics (PSI Part II) lincosamides clindamycin aminoglycosides streptogramins streptogramin A + B oxazolidinones linezolid...

PM 716 Pharmacology I Chapter 45 Protein Synthesis Inhibitors RMRocco PhD PM716 C45 PSI 1 PM716 C45 PSI 2  Antibiotics (PSI Part II) lincosamides clindamycin aminoglycosides streptogramins streptogramin A + B oxazolidinones linezolid PM716 C45 PSI 3  Lincosamides 1. Structure/Source: Clindamycin only one. Streptomyces lincolnensis. 2. Mechanism of Action: Bind to 50S subunit, identical to erythromycin and other macrolides. PM716 C45 PSI 4  Lincosamides 3. Pharmacokinetics: po or iv. Fairly high Vd with penetration into most tissues. No dosage adjustment for renal failure required. 4. Antimicrobial Activity: Gram pos and neg. Streptococci, staphylococci, pneumococci. PM716 C45 PSI 5  Spectrum of Activity Clindamycin (Cleocin®) Most Gram Pos organisms (Staph and Strep) Most anaerobes (Bacteroides but up to ~ 20% are resistant). PM716 C45 PSI 6  Lincosamides 5. Clinical Uses: Severe anaerobic infection caused by bacteroides and other anaerobes. 6. Adverse Effects and ADRs: Skin rashes, impaired liver function, antibiotic- associated colitis due to C. difficile, often fatal. Treat with metronidazole. PM716 C45 PSI 7  Clindamycin Most often reported ADR is diarrhea in up to 20% of patients on this drug. Diarrhea resolves after drug is stopped. DOSE: 600 - 900 mg q8h iv or im or 150 - 300 mg three times a day po. No dosage adjustment required for reduced CC because drug is hepatic cleared. Hepatic failure requires dosage adjustment. PM716 C45 PSI 8  Lincosamides 7. Mechanism of Resistance: confers cross resistance to macrolides. 1. Mutation in ribosomal receptor binding site. 2. Enzymatic inactivation of drug 3. Mutation alteration of receptor by induced methylase. PM716 C45 PSI 9  Clindamycin Clinical uses in lower extremity infections: Staph infection in patients allergic to penicillin drugs Oral therapy for mild diabetic ulcerations. Combined with Gram Neg antibiotic in severe diabetic ulcerations. Osteomyelitis due to staph because of good penetration into bone. PM716 C45 PSI 10  Aminoglycosides Micromonospora Streptomyces gentamicin streptomycin netilmicin neomycin tobramycin amikacin gentamicin PM716 C45 PSI 11  Aminoglycosides streptomycin 1. Structure/Source Various species of Streptomyces Water soluble hexose rings with amino sugars attached through glycosidic linkages. PM716 C45 PSI 12  Aminoglycosides 2. Mechanism of Action Irreversible inhibition of protein synthesis Bactericidal effects. Drugs enter cell through porins in outer bacterial membrane. Drugs concentrate inside through oxygen dependent proton pump and bind to ribosomes (streptomycin binds to 30S-subunit) PM716 C45 PSI 13 2. Mechanism of Action 1. Block peptide formation at initiation step. 2. Cause misreading of mRNA, wrong amino acid inserted, non- functional protein. 3. Cause breakup of polysomes into non- functional monosomes. PM716 C45 PSI 14  3. Pharmacokinetics Most given im or iv only (except neomycin and kanamycin, po and mostly topical) Once daily dosing iv is usual Toxicity correlates with Cp levels, > 2 ug/mL trough level (just before next iv dose) is considered toxic. Dosage adjustments must be made for impaired renal function (CC) to avoid toxicity. PM716 C45 PSI 15  4. Antimicrobial Activity Mostly used against gram neg enteric bacteria Broad spectrum (but many anaerobes are resistant, see Mechanisms of Resistance) PM716 C45 PSI 16  5. Clinical Uses Used for most gram neg enterics Useful in sepsis Used almost always in combination with a beta lactam to obtain coverage of the gram pos. Drugs are synergistic with beta lactams. Penicillins cause cell wall abnormalities which help promote entry of aminoglycosides into the bacterium. PM716 C45 PSI 17  6. Adverse Effects and ADRs Ototoxicity, nephrotoxicity and neuromuscular toxicity. Small margin of safety (tobramycin trough 2-4 ug/mL, toxic > 4 ug/mL) Ototoxicity: auditory damage (tinnitus, high frequency hearing loss) vestibular damage (vertigo, ataxia, loss of balance) Nephrotoxicity: rise in CC, rise serum Creatinine, rise in trough level. Curare-like effect at neuromuscular junction, respiratory paralysis. Reverse with neostigmine. PM716 C45 PSI 18  7. Mechanisms of Resistance 1. Organism produces a transferase enzyme that inactivates the drug through adenylylation, acetylation, or phosphorylation. 2. Mutation deletion of a porin or phenotypic induced by oxygen-dependent transport process becomes non functional. 3. Mutation deletion or alteration of 30S protein receptor on ribosome. PM716 C45 PSI 19  Streptomycin 1. Structure/Source:Streptomyces griseus 2. Mechanism of Action: Bind to 30S protein on ribosomes 3. Pharmacokinetics: im or iv 4. Antimicrobial Activity: Second line of treatment for TB PM716 C45 PSI 20  Streptomycin 5. Clinical Uses: Mostly for TB as an adjunct drug. 6. Adverse Effects and ADRs: Hypersensitivity reactions (rash, fever) patients and those who handle the drug. Vestibular toxicity(vertigo, loss of balance) Toxicity correlates with Cp and CC. PM716 C45 PSI 21  Streptomycin 7. Mechanisms of Resistance: Mostly by mutation in 30S ribosomal protein. Frequency so high that drug useless alone for TB and not used for much else. Some enterococcoal infections resistant to other aminoglycosides (~15 % isolates) streptomycin is useful. PM716 C45 PSI 22  Other Aminoglycosides Gentamicin, amikacin, tobramycin, neomycin Similar in points # 1- 7 as for streptomycin. PM716 C45 PSI 23  Neomycin 1. Structure/Source: from streptomyces. 2. Mechanism of Actions: similar to others 3. Pharmacokinetics: both too toxic for iv use. Used po and topical, but po absorption very poor. 4. Antimicrobial Activity: gram pos and gram neg and some mycobacteria. Pseudomonas and streptococci resistant. PM716 C45 PSI 24  Neomycin 5. Clinical Uses: injected into infected joints, pleural cavity, infected surfaces, abscess cavities. Used po to reduce normal flora prior to bowel surgery. 6. Adverse Effects and ADR: renal and ototoxicity as others. PM716 C45 PSI 25  Neomycin Topical Neosporin® PM716 C45 PSI 26  Streptogramins 1. Structure/Source: Combination of streptogramin A (dalfopristin) and streptogramin B (quinupristin). Produced by various Streptomyces species. FDA approved 1999 (Synercid®) PM716 C45 PSI 27  Streptogramins 2. Mechanism of Action: Inhibit peptide bond formation in 50S ribosome. 3. Pharmacokinetics: iv only, less than 20% excretion through kidney, renal failure adjustment not required. Dose reduction required for liver failure patients. PM716 C45 PSI 28  Streptogramins 4. Antimicrobial Activity: Gram pos cocci including multi-drug resistant strains of streptococci, penicillin resistant strains of staph. 5. Clinical Uses: Approved for use in vancomycin-resistant strains of some gram neg. PM716 C45 PSI 29  Streptogramins 6. Adverse Effects and ADRs: Drug significantly inhibits CY 3A4 which requires dosage reductions of the drugs whose metabolism is effected (from warfarin to cyclosporin). 7. Mechanism of Resistance: mostly modification of binding site on ribosome. PM716 C45 PSI 30  Oxazolidinones 1. Structure/Source: synthetic, linezolid (Zyvox®). A new class of antibiotic which is a protein synthesis inhibitor. PM716 C45 PSI 31  Linezolid 2. Mechanism of Action: Binds to 23S on the 50S ribosomal RNA unit, this blocks binding of the ribosome to the mRNA. 3. Pharmacokinetics: po or iv. Does not induce or inhibit CYP 450. 4. Antimicrobial Activity: many gram pos PM716 C45 PSI 32  Linezolid 5. Clinical Uses: vancomycin-resistant infections, nosocomial pneumonia, community acquitred pneumonia, skin infections. Reserved for treatment of multiple drug-resistant gram-positive bacteria. 6. Adverse Effects and ADRs: Thrombocytopenia in 3% of patients, neutropenia. PM716 C45 PSI 33  Case Study 45-year old male, 3rd degree burns, 40% of her body, febrile (39.5o C), WBC 20 000/uL all 10 days post admission. Blood cultures pending. Treat empirically for Pseudomonas. Tobramycin, CC is 90 mL/min, 70 kg body weight. What dosing regimen, how to monitor for toxicity. PM716 C45 PSI 34  Case Study Normal renal function, use standard once daily dosing (iv). Trough serum level of 1.5 - 6 mcg/mL indicates good clearance. Or use use same doses divided every 8 hours. Target peak 5-10 mcg/mL Target trough < 2 mcg/mL PM716 C45 PSI 35