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The ABC’s of Antibiotics Lourdes Irizarry, MD Associate Professor of Medicine Albuquerque VAMC & UNM SOM Principles of Antimicrobial Therapy Site of action Individual patient Ecology of the institution Efficacy Toxicity Cost Classes of Antibiotics Beta lactams Monobactams Carbapenems Macrolides/Azalides/Lincosamides Aminoglycosides Fluoroquinolones Oxazolidinones Antibiotic brands 50 penicillins 71 cephalosporins 12 tetracyclines 8 aminoglycosides 1 monobactam 3 carbapenems 9 macrolides 2 streptogramins 3 dihydrofolate reductase inhibitors 1 oxazolidinone 5.5 quinolones Inhibition of Cell Cell Wall Synthesis Vancomycin, teicoplanin Beta-lactams Monobactams Carbapenems Inhibition of Protein Synthesis 50 S inhibitors – macrolides 30 S inhibitors – tetracycline – chloramphenicol – aminoglycosides – clindamycin – oxazolidinones Interference with basic cell functions – quinolones Folic acid metabolism DNA gyrase – trimethoprim – sulfonamides Antibiotic Inactivation Destruction or modification – Ex: Beta-lactamase production Alteration of the antibiotic target site(s) – Ex: Abnormal PBPs Prevention of access to target – Ex: Efflux pump & Deletions of porins Antibiotic Essentials’ Antibiotic Gram (+) Gram. (-) Anaerobes CNS PCN + - +/- + Neurosyphilis Nafcillin Ampicillin Strep. A, N.meingitidis Listeria, Eikenella Enterococcus Pasteurella (Not Staph. Not PRSTP) N. meningitidis MSSA - - + + Enterococcus +/- +/- + (Not S. pyogenes, Not Sthaph.) E.coli, Proteus B-lactamase neg. H.flu, Moraxella Listeria Antibiotic Essentials’ (2) Antibiotic Gram. (+) Gram. (-) Anaerobes CNS Ticarcillin + i.e. PCN +++ + +/- Not Enterococcus Piperacillin P.aeruginosa (Not Acitenobacter) + i.e. PCN +++ + +/- + i.e. PCN Enterococcus +++ + +/- E. faecalis Mezlocillin Antibiotic Essentials’ (3) Antibiotic Gram. (+) Gram. (-) Anaerobes CNS Ampicillin/ Sulbactam +++ MSSA, MSSE + +++ - +++ - +++ - Not PRSTP i.e. Ampicillin H. flu, Moraxella Few Klebsiella Ticarcillin/ +++ Clavulanic MSSA, MSSE Not Enterococcus acid Piperacillin/ +++ Tazobactam MSSA, MSSE, Enterococcus +++ No increased activity for Pseudomonas +++ No increased activity for Pseudomonas Antibiotic Essentials’ (4) Antibiotic Gram. (+) Gram. (-) Anaerobes CNS 1st gen. Cephalosporins + MSSA, MSSE +/- - - Not STP Not Enterococcus Not Blactamase producers Antibiotic Essentials’ (5) 3rd Gen Cephalosporin Gram. (+) Gram. (-) Anaerobes CNS Ceftazidime - +++ - +++ - +++ ++ ++ +++ ++ ++ +++ Antipseudomonal Ceftriaxone Cefotaxime Ceftizoxime +++ ++ Not antiMSSA, MSSE, pseudomonal PRSTP Not Enterococcus +++ Not ideal for Staph. Not Enterococcus Not antipseudomonal Not ideal for Staph. Not Enterococcus Not antipseudomonal ++ Antibiotic Essentials’ (6) 4th Generation Cephalosporin Gram. (+) Gram. (-) Anaerobes CNS Cefepeme +++ MSSA, MSSE Not Enterococcus +++ Antipseudomonal - +++ Antibiotic Essentials: (7) Antibiotic Gram. (+) Gram. (-) Anaerobes CNS Meropenem Imipenem +++ +++ +++ + Not MRSA, Not Enterococcus Not. Sternothrophomon as - +++ - +/- Aztreonam Antibiotic Essentials’: (9) Antibiotic Gram. (+) Gram. (-) Anaerobes CNS Azithromycin Clarithromy + H. Flu Moraxella - - +/- H. flu & Moraxella - - Erythromycin Not Enterococcus +/- SAU + Not Enterococcus +/-SAU Macrolides Erythromycin and Clarithromycin have hepatic metabolism via cytochrome p-450 (Increase levels of theophylline, warfarin, triazolam, bromocriptine, carbamazepine and cyclosporin) Erythromycin iv from causes phlebitis, not Azithromycin, no IV Clarithromycin (too venous toxic) Classification of Fuoroquinolones First generation – nalidixic acid Third generation** – gatifloxacin (sparfloxacin, grepafloxacin) Second generation – norfloxacin – ciprofloxacin* – ofloxacin – levofloxacin Fourth generation*** – moxifloxacin – trovafloxacin, (clinafloxacin) Activity of Fluoroquinolones Against Gram Positive Bacteria Species Cipro. Gati. Levo. Moxi. Trova Oflox 0.125-1 MSSA 0.5-.078 0.1-0.13 0.25 0.06 0.06 MRSA 3.13-32 0.2-16 4 4 S. epi 0.39-1 0.2-0.25 0.5-1 0.13 0.015-4 0.125-1 0.78-2 1-3.13 1 0.12-2 1-8 1.56-4 3.13-8 1-4 0.25-8 1-4 0.5 1-3.13 0.120.25 0.120.5 1-2 E. 1.56-4 faecalis E. 3.13-16 faecium S. 1.56-4 pneumo 16 Activity of Fluoroquinolones for Gram Negative Bacteria Species Cipro E.cloac E.coli Amp.-R Kleb. Cefz.-R Pseudo. Gati Levo Moxi Trova Oflox 0.03-0.1 0.06-0.2 0.06 0.06 0.06 0.030.12 0.0160.5 16 0.0160.1 8 0.03 0.008 0.03-0.5 16 8 32 0.060.39 8 0.1-0.39 0.13 0.13 0.13-0.5 4 16 8 16 0.78-8 3.13-32 32 32 2-32 0.25-32 Activity of Fluoroquinolones Against Anaerobes Species Cipro Gati Levo Moxi Trova B. frag 2-128 0.25-1 2 0.12 0.25-2 C.difficile 16-32 1-2 8 - 1-2-16 Peptostre 0.5-8 1 3.13>4 2 0.25-0.5 6 Pneumococci With Reduced Susceptibility to Fluoroquinolones (%) 5 Ages 15-64 4 5 Age 65 and older 4 3 3 2 2 1 1 0 0 88 89 90 91 92 93 Year Chen DK, et al. N Engl J Med. 1999;341:233-239. 94 95 96 97 98 No. of Prescriptions per 100 Persons Susceptibility of S.pneumoniae to Fluoroquinolones Activity of New Fluoroquinolones Against MRSA, VRE and PRSP MRSA VRE PRSP QTc change Levofloxacin +/- +/- ++ 4.6 msc Gatifloxacin +/- +/- ++++ 2.9 msc Moxifloxacin +/- +/- ++++ 6 msc Gemifloxacin +/- +/- ++++ 5 msc Ciprofloxacin +/--- +/--- +/--- ? Quinupristin/Dalfopristin S. pneumoniae S.aureus E. (MRSA) faecium (VRE) – No activity against E. faecalis Others’... Metronidazole anaerobic drug with excellent CNS penetration Clindamycin: good for Gram.(+) and anaerobes. Always include in the treatment of Strep. skin & soft tissue infections. Great for lung abscesses. (No CNS penetration) Vancomycin: Inferior to B-lactams against SAU Other highlights... Cross allergic reaction between Penicillins, Cephalosporins and Carbapenems. Not Aztreonam. Aztreonam cross allergy with Ceftazidime Cephalosporins and Metronidazole: Disulfiram reaction Ticarcillin: bleeding in uremic patients Drugs Under Development PRSP, MRSA,VISA,VRE Lipopetides (Daptomycin: narrow therapeutic index) Glycyclines Glycopeptides (Vancomycin analogues) Fluoroquinolones Macrolides/Ketolides Evernimicin (trials on hold) Antibiotics With Immunomodulating Effects Macrolides Fluoroquinolones Quinupristin/dalfopristin Future Directions on the Treatment of Infections Usage of immunomudalating agents Usage of non-antibiotics as adjuvant therapy New approaches to rational drug design – mapping – binding – genomics “A collection of anecdotes is not data.” Anonymous “You have to run towards where the ball is going to be.” Yogi Berra very difficult, particularly about the future.” Neils Bohr ABT-492 4th generation fluororoquinolone Trovafloxacin like activity Levofloxacin safety profile Little CNS or CV activity Iv & po Phase I trials 2,000 ABT-723 Ketolide – ketone added to erythromycin – quinoline ring increases activity Phase II trials Phase III Fall 2,000 S. pneumoniae activity 2-3x higher than clarithromycin Macrolides Inhibits RNA dependent protein synthesis, causing dissociation of peptidyl transfer (tRNA) from the ribosome during elongation phase Fluoroquinolones Mechanism of Action Inhibit the activities of DNA gyrase (an essential adenosine triphosphatehydrolizing topoisomerase) which in turn inhibits bacterial DNA peplication and transcription. Leading to bacterial death. Mechanism of Action of Quinolones (2) To accommodate within bacterial cell, organism’s DNA helix is coiled and twisted in a direction opposite to the double helix (negative supercoil). DNA gyrase catalyzes the entry of these negative supercoils into circular chromosomal DNA and plasmid DNA Mechanism of Action Quinolone (3) DNA gyrase consists of 2A and 2B subunits. A interrupts supercoiling. After fixing the negative supercoils in place, A reseals the break. Quinolones trap the complex after strand breakage preventing A from resealing the breaks. DNA sythesis is halted. Mechanisms of Resistance Spontaneous mutations in bacterial chromosomes – Mutations in A subunit of bacterial DNA gyrase that lowers affinity of drug at gyrase complex – Mutations of chromosomally mediated drug influx and efflux systems – Selection for resistance dependent on quinolone and organism