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 chloramphenicol clindamycin 30 S inhibitors tetracycline aminoglycosides oxazolidinones

Interference with basic cell functions quinolones DNA gyrase Folic acid metabolism 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 Essentials’ (2)

Antibiotic Essentials’ (3)

Antibiotic Essentials’ (4)

Antibiotic Essentials’ (5)

Antibiotic Essentials’ (6)

Antibiotic Essentials: (7)

Antibiotic Essentials’: (9)

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 Second generation norfloxacin ciprofloxacin* ofloxacin levofloxacin Third generation** gatifloxacin (sparfloxacin, grepafloxacin) Fourth generation*** moxifloxacin trovafloxacin, (clinafloxacin)

Activity of Fluoroquinolones Against Gram Positive Bacteria

Activity of Fluoroquinolones for Gram Negative Bacteria

Activity of Fluoroquinolones Against Anaerobes

Susceptibility of S.pneumoniae to Fluoroquinolones Ages 15-64 Age 65 and older Pneumococci With Reduced Susceptibility to Fluoroquinolones (%) No. of Prescriptions per 100 Persons Year Chen DK, et al. N Engl J Med. 1999;341:233-239.

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 (MRSA) E. faecium (VRE) No activity against E. faecalis

Others’... Vancomycin: Inferior to B-lactams against SAU 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 “You have to run towards where the ball is going to be.”

“Prediction is 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 Phase II trials Phase III Fall 2,000 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 triphosphate-hydrolizing 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