1. The ABC’s of Antibiotics
Lourdes Irizarry, MD
Associate Professor of Medicine
Albuquerque VAMC & UNM SOM

2. Principles of Antimicrobial Therapy
Site of action
Individual patient
Ecology of the institution
Efficacy
Toxicity
Cost

3. Classes of Antibiotics
Beta lactams
Monobactams
Carbapenems
Macrolides/Azalides/Lincosamides
Aminoglycosides
Fluoroquinolones
Oxazolidinones

4. 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

5. Inhibition of Cell Cell Wall Synthesis
Vancomycin, teicoplanin
Beta-lactams
Monobactams
Carbapenems

6. Inhibition of Protein Synthesis
50 S inhibitors
macrolides
chloramphenicol
clindamycin
30 S inhibitors
tetracycline
aminoglycosides
oxazolidinones

7. Interference with basic cell functions
quinolones
DNA gyrase
Folic acid metabolism
trimethoprim
sulfonamides

8. 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

9. Antibiotic Essentials’

10. Antibiotic Essentials’ (2)

11. Antibiotic Essentials’ (3)

12. Antibiotic Essentials’ (4)

13. Antibiotic Essentials’ (5)

14. Antibiotic Essentials’ (6)

15. Antibiotic Essentials: (7)

16. Antibiotic Essentials’: (9)

17. 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)

18. Classification of Fuoroquinolones
First generation
nalidixic acid
Second generation
norfloxacin
ciprofloxacin*
ofloxacin
levofloxacin
Third generation**
gatifloxacin
(sparfloxacin, grepafloxacin)
Fourth generation***
moxifloxacin
trovafloxacin, (clinafloxacin)

19. Activity of Fluoroquinolones Against Gram Positive Bacteria

20. Activity of Fluoroquinolones for Gram Negative Bacteria

21. Activity of Fluoroquinolones Against Anaerobes

22. 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:

23. Activity of New Fluoroquinolones Against MRSA, VRE and PRSP
MRSA VRE PRSP QTc change
Levofloxacin /- +/ msc
Gatifloxacin /- +/ msc
Moxifloxacin /- +/ msc
Gemifloxacin / / msc
Ciprofloxacin / /--- +/ ?

24. Quinupristin/Dalfopristin
S. pneumoniae
S.aureus (MRSA)
E. faecium (VRE)
No activity against E. faecalis

26. 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

27. 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

28. Drugs Under Development PRSP, MRSA,VISA,VRE
Lipopetides (Daptomycin: narrow therapeutic index)
Glycyclines
Glycopeptides (Vancomycin analogues)
Fluoroquinolones
Macrolides/Ketolides
Evernimicin (trials on hold)

29. Antibiotics With Immunomodulating Effects
Macrolides
Fluoroquinolones
Quinupristin/dalfopristin

30. 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

31. “A collection of anecdotes is not data.”
Anonymous

32. “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.”

33. “Prediction is very difficult, particularly about the future.”
Neils Bohr

34. ABT-492 4th generation fluororoquinolone Trovafloxacin like activity
Levofloxacin safety profile
Little CNS or CV activity
Iv & po
Phase I trials 2,000

35. 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

36. Macrolides
Inhibits RNA dependent protein synthesis, causing dissociation of peptidyl transfer (tRNA) from the ribosome during elongation phase

37. 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.

38. 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

39. 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.

40. 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