1. Antibiotics 101
Puja Van Epps
1/20/14

2. Beta-lactams
Core PCN structure
Core Cephalosporin structure

3. Beta-lactams
Beta-lactamases are enzymes produced by some bacteria that provide resistance against beta lactams through hydrolysis of the β-lactam ring

4. Natural Penicillins Bicillin L-A (Penicillin G benzathine) – IM only
Penicillin G (IV)
Penicillin V = PO

5. Natural Penicillins- Spectra
Groups
Important Organisms
Gram Positive
Group A/B/C/G strep
S. pneumoniae*
viridans streptococci gr.*, Strep milleri*
Enterococcus (feacalis>faecium)
Gram Negative
Neisseria meningitidis*
Pasteuralla multocida
Haemophilus ducreyi
Anaerobes
Actinomyces
Clostridial sp.
Peptostreptococcus
Fusobacterium
Other
Treponema pallidum

6. Natural Penicillins
Bicillin: Primary, secondary, latent and late latent syphillis
PCN G: Neurosyphillis; systemic infection due to susceptible bacteria (Streptococci)
PCN V: Group A strep pharyngitis

7. Anti-staphylococcal Penicillins
Nafcillin, oxacillin, methicillin, dicloxacillin (PO)
Penicillinase is a specific type of β-lactamase, showing specificity for Penicillins
First β-lactamase to be identified; PCN R in S. aureus
Major Uses:
Methicillin-susceptible S. aureus or Coagulase Negative Staph; PCN-susceptible strains of Streptococci
No gram negative activity

8. Aminopenicillins
Ampicillin/amoxicillin; Augmentin (Amox-Clav); Unasyn (Amp-Sulbactam)
Amp/amox – Great for susceptible streps and enterococcus; very limited GN activity; cover anaerobes
Addition of Clavulanate or Sulbactam enhances Gram negative activity
No activity against MSSA without the beta-lactamase inhibitor.

9. Aminopenicillins
Important holes in coverage
Pseudomonas sp.
Atypical gram negatives – mycoplasma pneumoniae, chlamydia pneumoniae, legionella sp.
Enterobacter sp.
If susceptible Ampicillin is the DOC for Enterococcus and Listeria

10. Anti-Pseudomonal Penicillins
Ticarcillin, Ticar-Clav, Piperacillin, Pip-Tazo
Generally good gram positive, gram negative and anaerobic coverage
Ticarcillin and Piperacillin without their beta-lactamase inhibitor DO NOT cover MSSA
Important holes in coverage: MRSA (ESBL+, KPC+, or other resistant GN)
Stenotrophomonas maltophilia – Ticar-Clav is second line, Pip/Tazo does not cover.

11. Cephalosporins
5 generations, increasing gram negative coverage with each generation

12. First Generation Cephalosporins
Cefadroxil, Cephalexin (PO)
Cefazolin (IV)
Gram Positive
Group A, B, C, G Strep
Strep pneumo
Viridans strep
MSSA
Gram Negative
E. coli, Klebsiella sp., Proteus mirabilis
Anaerobes
No activity

13. First Generation Cephalosporins
Important holes in coverage –
MRSA, Enterococcus, Pseudomonas, anerobes

14. Second Generation Cephalosporins
Cefuroxime (IV, PO), Cefotetan (IV), Cefoxitin (IV)
In addition to the coverage of 1st generation
- H. influenzae, M. catarrhalis, Neisseria sp., and anearobic coverage (variable)
Important holes in coverage:
- MRSA, Enterococcus, Pseudomonas

15. Third Generation Cephalosporins
Ceftriaxone, Cefotaxime, Ceftazadime (IV)
Cefixime, Cefdinir (PO)
In general less active against gram-positive aerobes than previous generations, but have greater activity against gram-negatives
Cefotaxime and Ceftriaxone have the best gram + coverage in the group
Only Ceftazadime covers Pseudomonas

16. Third Generation Cephalosporins
Major holes in coverage –
- Enterococcus, MRSA, Pseudomonas (except Ceftazidime), +/- Acinetobacter, Listeria
Ceftazidime crosses BBB, Ceftriaxone in inflamed meninges

17. Fourth Generation Cephalosporins
Cefepime (IV)
gram-positives: similar to first generation
gram-negatives: broad, including Pseudomonas
Major holes: MRSA, poor anaerobic coverage, listeria
Crosses BBB

18. Fifth Generation Cephalosporin
Ceftaroline (IV)
Major advantage:
- MRSA
Major holes in coverage:
- Pseudomonas, enterococcus and anaerobes
CAP, SSTI

19. Cephalosporin Review Antipseudomonal – Ceftazadime and Cefepime
Anti-MRSA –
Ceftaroline
Anti-Enterococcal –
None (Ceftaroline has in-vitro activity against E. faecalis)
Enterobacter sp. can develop resistance to cephalosporins during treatment, therefore not the treatment of choice

20. Carbapenems Ertapenem, Doripenem, Imipenem, Meropenem
Broadest spectrum of activity
Have activity against gram-positive and gram-negative aerobes and anaerobes
Bacteria not covered by carbapenems include MRSA, VRE, MR coagulase-negative staph
Additional ertapenem exceptions:
Pseudomonas, Acinetobacter, Enterococcus

21. Carbapenems Major holes in coverage:
- Atypicals (Legionella, Mycoplasma) , MRSA, VRE, Stenotrophomonas maltophilia, KPC+
Ertapenem does not cover:
- Pseudomonas, Acinetobacter, Enterococcus

22. Monobactam
Aztreonam: binds preferentially to PBP 3 of gram-negative aerobes
No gram positive or anaerobic activity
Major uses – Hospital acquired infections in patients with anaphylaxis to any beta lactams (does not have cross reactivity)
Important gram neg holes: Acinetobacter, ESBL+, KPC+

23. Fluoroquinolones Ciprofloxacin, Levofloxacin, Moxifloxacin
Broad spectrum of activity, excellent bioavailability, tissue penetration
Cipro has poor gram + coverage
Disadvantages: resistance, expense, C diff
Advantages: Atypical coverage, Antipseudomonal (Cipro, Levo)

24. Aminoglycosides Gentamicin, Tobramycin, Amikacin
inhibit protein synthesis by irreversibly binding to 30S ribosome, bactericidal
For gram + use in combination with cell wall agents
Broad spectrum gram neg coverage including Pseudomonas and Acinetobacter
Also have mycobacterial coverage

25. Aminoglycosides – adverse effects
Nephrotoxicity
Nonoligouric renal failure from damage to the proximal tubules
Underlying CKD, Age, other nephrotixins, duration, high troughs
Ototoxicity
8th cranial nerve damage - vestibular and auditory toxicity; irreversible
Related to duration of therapy (>2wks)

26. Macrolides Clarithromycin, Erythromycin, Azithromycin
Inhibit protein synthesis by reversibly binding to the 50s ribosomal unit

27. Macrolides Gram-Positive Aerobes – Clarithro>Erythro>Azithro
Gram-Negative Aerobes – Azithro>Clarithro>Erythro
No activity against any Enterobacteriaceae or Pseudomonas
Anaerobes – activity against upper airway anaerobes
Atypical Bacteria – Excellent
Also cover – Mycobacterium avium complex, Campylobacter, Borrelia, Bordetella, Brucella.

28. Anti-MRSA drugs

29. Vancomycin
Inhibits synthesis and assembly of the second stage of peptidoglycan polymers
Gram-positive bacteria: excellent coverage
Major uses:
MRSA, MSSA (in PCN all), PCN R streptococci
No activity against gram-negatives or anaerobes
If MIC to Vancomycin in MRSA is ≥ 2, Do not use

30. Vancomycin Red-Man Syndrome flushing, pruritus, rash
related to rate of infusion
resolves spontaneously
may lengthen infusion
NOT AN ALLERGY

31. Daptomycin
Lipopeptide; binds to components of the cell membrane and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein
Major uses
- SAB, Right-sided IE caused by S. aureus, VRE
Indicated for SSTI, R sided IE
Do not use for lung infections including MRSA PNA – pulmonary surfactant inhibits Daptomycin

32. Linezolid
Binds to the 50S ribosomal subunit near the surface interface of 30S subunit – causes inhibition of 70S initiation complex which inhibits protein synthesis
Active against wide range of Gram + bacteria, limited to no Gram negative or anearobic activity
Major uses –
MRSA, VRE.
Major problem
thrombocytopenia with prolonged use (>2wks), bacteriostatic (cidal against Enterococcus)

33. Tigecyline
Binds to the 30S ribosomal subunit of susceptible bacteria, inhibiting protein synthesis.
Broad spectrum of activity including –
- MRSA, VRE, gram negatives (including resistant GN)
Major holes-
The 3 P’s – Pseudomonas, Proteus and doesn’t get in the urine
Indicated for complicated SSTI, intra-abdominal infections, CAP
Major problems: GI issues, and shown to have increased mortality in serious infections – monotherapy only as a last resort.

34. Clindamycin Major uses - MRSA (some isolates), anaerobic coverage
Inhibits protein synthesis by binding exclusively to the 50S ribosomal subunit
Major uses
- MRSA (some isolates), anaerobic coverage

35. Clindamycin
A positive D test indicates the presence of macrolide-inducible resistance to clindamycin produced by an inducible methylase that alters the common ribosomal binding site for macrolides, clindamycin

36. Tetracylines Doxycyline, Minocyline
Good gram pos, neg and anaerobic coverage
Major uses
MRSA, anti-malarial prophylaxis, rickettsial infections, Borrelia burgdorferi

37. Trimethoprim, TMX-Sulfa
Inhibit various steps within the folic acid biosynthetic pathway
Good gram pos and gram neg coverage (CA-MRSA)
Important uses: Pneumocystis, Stenotrophomonas maltophilia, Nocardia
Major holes
Pseudomonas, anaerobes