aminoglycosides 9-18-24.pdf

Aminoglycosides, Vancomycin Linezolid, Dalfopristin/Quinipristin, Mupirocin, Fosfomycin, Colistin, Tigecycline, Daptomycin, and Telavancin Jamie Allman, Pharm.D., BCPS [email protected] Aminoglycosides Structure and Chemistry Aminoglycosidic aminocyclitols 6-membered a...

Aminoglycosides, Vancomycin Linezolid, Dalfopristin/Quinipristin, Mupirocin, Fosfomycin, Colistin, Tigecycline, Daptomycin, and Telavancin Jamie Allman, Pharm.D., BCPS [email protected] Aminoglycosides Structure and Chemistry Aminoglycosidic aminocyclitols 6-membered aminocyclitol ring Amino-containing and nonamino-containing sugars attached to ring by glycosidic linkages. Aminoglycoside Mechanism of Action Aminoglycoside binds to outer membrane of cell Results in re-arrangement of Lipopolysaccharide (LPS) Uptake is energy dependent Source of energy is an electrochemical gradient Gradient is decreased in an anaerobic environment Once across the membrane the drug is irreversibly trapped into bacteria cytoplasm AG binds to the 30S and 50 S ribosomal subunit leading to Decreased protein synthesis and misreading of mRNA Very high intracellular concentrations Aminoglycoside Mechanism of Action Bactericidal Although mechanism appears static, its action is cidal - Not fully understood Concentration dependent killing with PAE After exposure to inhibitory concentrations of AMGs, continued killing occurs. Aminoglycoside Pharmacokinetics Absorption Poorly absorbed from GI tract. Distribution Distributed freely into vascular space. Concentrations in the lungs are 25-50% of those achieved in the serum. Distribution to CSF only 20% with inflammation Better in neonates (? immature BBB) Excretion 99 % unchanged via glomerular filtration. Aminoglycosides Pharmacokinetic Alterations Aminoglycosides Pharmacokinetic Characteristics Aminoglycosides Adverse Effects Local Reactions Thrombophlebitis Nephrotoxicity 0-50 % Ototoxicity-Impairment of 8th cranial nerve Neuromuscular Blockade (rare) Aminoglycosides Spectrum of Activity Gram Negative **Kanamycin has little or no Morganella spp. activity. For these organsims Haemophilus influenzae Providencia spp.** Gram Positive Proteus mirabilis Staph spp. Sensitive E.coli ?Clinical effectiveness Klebsiella pneumonia Enterococcus Synergy Serratia spp. Common Combination Pseudomonas aeruginosa** = Ampicillin + Gent Acinetobacter spp.** Citrobacter spp.** Enterobacter spp.** Aminoglycosides Indications Serious gram negative infections Specific uses of Streptomycin/Gentamicin TB (Streptomycin-RIPS vs RIPE) Brucellosis (Gentamicin + TCN or Chloramphenicol) Oral Aminoglycosides Suppression of intestinal bacterial flora for elective colorectal surgical prophylaxis (Neomycin) Hepatic Coma; decreases the number of ammonia-forming bacteria. (Neomycin) Hyperlipidemia; reduces cholesterol absorption. (Neomycin) Intestinal amebiasis; tapeworm (Paromomycin) Topical Aminoglycosides Eye, ear, and skin infections Aminoglycosides Dosing Aminoglycosides Individualization of Dose Pharmacokinetic principles Most accurate method Lowest toxicity and lowest failure rates. Trial and Error Least accurate method Highest toxicity and highest failure rates. Nomograms Substantial variations exist in concentrations achieved compared to predicted values. Acceptable for initial dosing, adjustments made on peaks and troughs obtained Aminoglycosides Once-Daily Dosing Hartford Nomogram 7mg/kg first dose (Less if CrCl is < 50ml/min 5mg/kg) Assess level 6-14 hours after dose to eval Q24, 36, 48 hrs Large daily doses may be equally effective as smaller multiple daily dosing with lower toxicity. Relying on Post-antibiotic effect Low serum concentrations allow the kidney cells to process drug and thereby reduce effects of accumulation. Aminoglycosides Monitoring Narrow therapeutic index. Peak and trough with the 3rd-4th dose (steady state). Dosage adjustments Changes in renal function. Peak concentrations correlate with efficacy: Pneumonia 8-10 mcg/ml Bacteremia/Soft tissue 6-8 mcg/ml Cystitis 4-6 mcg/ml Synergy 3-5 mcg/ml Toxicity: Excessive trough concentrations (> 2 mcg/ml) Prolonged exposure Vancomycin Introduction Glycopeptide antibiotic derived from streptomyces orientalis. Introduced in the late 1950’s Replaced by less toxic anti-Staph pencillins Resurgence of use due to increase in Methicillin Resistant Staph aureus (MRSA). Vancomycin Mechanism of Action Inhibits the biosynthesis of peptidoglycan during cell wall formation Complexes with D-alanyl-D-alanine precursor Bactericidal, for multiplying organisms Exhibits PAE Vancomycin Pharmacokinetics Absorption Poorly absorbed from GI tract. IV only for systemic infections. Oral route for clostridium difficile (Pill vs Drink IV) Distribution Distributed freely into most body fluids and tissues Distribution to CSF only with inflammation Excretion Excreted almost entirely unchanged via glomerular filtration Vancomycin Pharmacokinetic Characteristics Desired Peak: 20-40 mcg/ml Desired Trough: 10-20 mcg/ml Controversial discussions for higher trough range for certain indications (*15-20mcg/ml ) Endocarditis, Osteomyelitis, *Meningitis Half Life 6-12 hrs Dosing interval q8hrs, 12hrs, 24hrs, 48hrs *Be nice and skip q18hrs and 36hrs) Pulse Dosing based on Random Levels (ESRD, CKD, severe AKI) Vancomycin Adverse Effects Local Reactions Hypersensitivity Thrombophlebitis Maculopapular rash Red-Man Syndrome Nephrotoxicity Histamine-like More common with reaction concomitant AMG or Hematologic Reaction other nephrotoxic Neutropenia agents. Eosinophilia Ototoxicity Thrombocytopenia Correlates with peak Vancomycin Spectrum of Activity Gram Positive Organisms Staphylococcus aureus Clostridium spp. Including MRSA Bacillus anthracis Staphylococcus Corynebacteria epidermidis Including MRSE Streptococcus spp. Enterococcus spp. Vancomycin Indications Serious infections caused by beta-lactam resistant gram positive organisms Vancomycin may be less bacteriacidal than beta- lactam agents for beta-lactam susceptible Staph spp. Gram-positive organisms (Serious B-lactam allergy) Clostridium difficile colitis Non-responsive to Metronidazole -OR- Recurrent C. diff (hyper-virulent strain) Severe and potentially life-threatening. Vancomycin Indications Prophylaxis for major surgical procedures involving implantation of prosthetic materials e.g. cardiac and valvular procedures and total hip replacement At institutions that have a high rate of infections caused by MRSA or MRSE 1 dose prior; re-dose if procedure > 6 hours Surgical prophylaxis ( life-threatening allergy to beta-lactam antibiotics) Prophylaxis for endocarditis in patients at high risk for endocarditis. (AHA guidelines)  Vancomycin Uses that Should be Avoided Routine surgical prophylaxis Empiric therapy in febrile neutropenic patients, UNLESS: evidence of possible gram positive infection (inflamed catheter site), hypotension, FQN prophylaxis, Severe mucositis, MRSA/PCN Resistant Strep Pneumo infections are prevalent in the hospital or patient has recent history of these infections Coagulase negative Staph. in one blood culture (contamination) Continued empiric use in patients whose cultures are negative. Eradication of MRSA colonization. Primary treatment of Clostridium difficile colitis Treatment of infections caused by beta-lactam-sensitive gram positive organisms in patients with renal failure (dosing convenience). Vancomycin Dosing Manufacturer Suggested Dosing Varies greatly on ptn Common: 1-15 gm q 12h adjust dose based on levels Must be adjusted in renal insufficiency and geriatrics. Oral for C. difficile = 125-500mg q6hrs Individualization of Dosing Pharmacokinetic principles - most accurate method, associated with lowest toxicity and lowest failure rates. Nomograms - Acceptable for initial dosing, but further adjustments should depend on measured pk and tr values. Vancomycin Monitoring A peak and trough should be ordered with the third dose (steady state) after initiation of therapy. Further peaks and troughs should be ordered after dosage adjustments or with changes in renal function. Quinupristin/Dalfopristin (Synercid) Mechanism: Irreversibly bind to the 50s bacterial ribosomal subunit Quinupristin inhibits chain formation resulting in early termination Dalfopristin inhibits peptide elongation by interfering with peptidyl transferase Individually (Static) but Combination (Cidal) MRSA, PCN-resistant Strep Pneumo, VRE (covers E. faecium, not good against E. faecalis) Anaerobes and some gram negative pathogens (H.flu) IV only (PICC or Central line to preferred) Linezolid (Zyvox) Oxazolidinone class – unique class Mechanism: bind to 23S ribosomal RNA of 50S subunit IV = PO (100% bioavailable) MRSA, VISA, VRE, PCN-resistant Strep pneumo ADR: Myelosupression: Thrombocytopenia (>2 weeks more likely) Superinfection (Yeast) Mitochondrial Toxicity (long courses) --?peripheral or optic neuropathy Drug-Drug Interaction: MonoAmine Oxidase Inhibitor watch co-administration with SSRI for serotonin storm (Limit tyramine foods to 2 Vanc) and VRE Complicated skin and soft tissue infections 4mg/kg daily (requires renal adjustment) Staph aureus and MRSA bacteremia/Right sided Endocarditis 6mg/kg daily (requires renal adjustment) DOES NOT cover Pneumonia Inactivated by pulmonary surfactant ADR: Rhabdomyolysis Monitor CPK baseline and weekly (DC if above 5x ULN) 34 Eosinophilic pneumonia (RARE) Mupirocin (Bactroban) Topical treatment (Cream/Ointment 2%) MRSA colonization eradication from Nares Controversial regarding long term efficacy of eradication Dose: 0.5 grams in each nostril BID x 5 days Other uses: Impetigo or infected wounds Topic Review To Retain Review Antimicrobial Coverage Review Mechanisms of Action of Class of ABX Review Hallmark Side effects of ABX Gram Positive Bugs Gram Negative Bugs Anaerobes Bugs Atypicals Bugs *** Questions/Points to clarify? ***