Antibacterial Agents II

Question 1

Chemistry of Penicillin and Cephalosporin

Answer 1

Penicillins: beta lactam ring + thiazolidine ring
Cephalosporins: beta lactam ring + dihydrothiazine ring

Question 2

Mechanism of Action

Answer 2

Beta-lactams bind to penicillin-binding proteins (PBPs)
Inhibit transpeptidase activity
Prevent cross-linking of peptidoglycan strands (thus inhibiting final step in cell wall synthesis)
Important role of autolytic enzymes (degrade existing cell wall)

Beta-lactams disrupt the balance between peptidoglycan assembly & degradation. The antibacterial effect results from both inhibition of cell wall synthesis & destruction of the existing cell wall by autolysins

Question 3

Bacterial Cell Wall of Gram Negative Bacteria

Answer 3

Hydrophilic beta lactams can enter through porins

Lipophilic beta lactams can enter through the membrane

NAG NAM units make peptidoglycans

Beta Lactamase: located in periplasmic space and beta lactams may enter, but have to get through the beta lactamases to get to PBPs, so protect the cell

Question 4

Group 1 Penicillins

Answer 4

Natural
Types G and V for gram +, gram - cocci, spirochetes, and anaerobes that lack beta lactamases
G = IV > oral
V = oral

Resistance: strep pneumoniae (low affinity PBPs), staph aureus, and Neisseria gonorrhoeae

Question 5

Group 2 Penicillins

Answer 5

Penicillinase resistant
Methicillin, nafcillin, oxacillin, and dicloxacillin
Methicillin - no longer used because of toxicity

Resistant to destruction by narrow spectrum beta lactamases from staph aureus and MSSA

Not effective for MRSA due to mecA

Question 6

Group 3 Penicillins

Answer 6

Extended Spectrum
Ampicillin, Amoxicillin, Ticarcillin, and Pipercillin

Ampicillin and Amoxicillin: similar to Pen G, but better gram - rod coverage

Ticarcillin and Pipercillin: more gram - rods from amoxicillin including pseudomonas

All are subject to degradation by beta lactamases

Question 7

First Generation Cephalosporins

Answer 7

Cefazolin (IV) and Cephalexin (oral)
Resistance to beta lactamases and high potency

Used for gram + cocci, some gram - cocci and rods

Question 8

Second Generation Cephalosporins

Answer 8

Subgroup 1: Cefuroxime and Cefaclor
Subgroup 2: Cefotetan and Cefoxitin

Used for: same as 1st generation, but more gram - rods and cocci
PeCK - proteus, E. coli, and klebsiella

Question 9

Second Generation Subgroup 1

Answer 9

Cefuroxime and Cefaclor

H. influenzae, but not Bacteriodes fragilis or Serratia

Question 10

Second Generation Subgroup 2

Answer 10

Cefotetan and Cefoxitin

B. fraglis, some Serratia, but less active for H. influenzae

Question 11

Third Generation Cephalosporins

Answer 11

Ceftriazone, Cefotaxime, and Ceftazidime

Used for: same pathogens as 1st and 2nd generation + more gram - coverage such as Neisseria species and rods (Serratia, Klebsiella, etc.)

Pseudomonas responds to Ceftazidime

Question 12

Fourth Generation Cephalosporins

Answer 12

Cefepime
More resistant to some beta lactamases than 3rd generation, some extended spectrum beta lactamases (ESBLs) and chromosomally encoded, inducible type 1 beta lactamases (ex. Amp-C)
Multi-drug resistance pneumococci
Excellent activity for gram - rods, P. aeruginosa, and enterobacter

Question 13

Beta Lactamase Inhibitors

Answer 13

Clavulonic Acid, Sulbactam, and Tazobactam

Use with penicillin agents, not alone

Example: Clavulonic Acid + Amoxicillin
Clavulonic acid prevents the breakdown of amoxicillin by inhibiting the beta lactamases and allowing for amoxicillin to work

Question 14

Ceftriazane and Cefotaxime

Answer 14

Third Generation Cephalosporins

Used for initial (empirical) tx of meningitis in adults and children
Exhibit some activity for penicillin resistant pneumococci in combination with 2nd drug, good activity for gram - pathogens involved in meningitis, and community acquired pneumonia (CAP)