Antibacterial Agents II - Cell Wall Synthesis Inhibitors 2

Question 1

Cephalosporins: Mechanism of action

Answer 1

Competitive inhibitor of the transpeptidase enzyme; inhibits bacterial cell wall synthesis

• –Broader spectrum of action vs gram-negative bacteria
• –Less susceptibility to penicillinase (a β-lactamase) but cephalosporinases are emerging
• –Less cross-reactivity in penicillin sensitive patients (on the order of 1%)

Question 2

Cephalosporins: Pharmacokinetics

Answer 2

• Absorption. Several agents can be given orally (acid-stable) while others must be administered parenterally (IV-IM)
• Distribution. Cephalosporins penetrate well into most tissues and fluids (including placenta) except brain and CSF. Major pharmacokinetics feature of 3rd generation agents -> penetration into CSF
• Metabolism - Excretion. ***Primarily excreted by kidneys, thus require dosage adjustment in renal insufficiency (exception ceftriaxone)

Question 3

Cephalosporins: Spectrum of activity (4 different generations)

Answer 3

1) First Generation. Rarely drugs of choice despite low toxicity and broad spectrum of activity. Gram (+) cocci and gram (-) bacilli
2) Second generation: gram (-) bacilli and anaerobes
3) Third generation: gram (+) cocci, gram (-) cocci, gram (-) bacilli

Question 4

Cephalosporins: major clinical uses

Answer 4

1) First generation: cephalexin and cefazloin
- Excellent g+ coverage
- Excellent for skin infections

2) Second generation:
- more g-
- Cefuroxime: anaerobic coverage

3) Third generation:
- Ceftiaxone has excellent penetration into the CSF (meningitis)

Question 5

Cephalosporins: side effects and DDIs

Answer 5

1. allergy
2. superinfection
3. delayed rash

• Cross-reactivity with penicillins
• NOTE: Should not be given to patients with history of immediate sensitivity to penicillin
• Action to suppress intestinal flora (↓ synthesis of Vit K) can intensify effect of oral anticoagulants (Warfarin)

Question 6

Carbapenems: Mechanism of action

Answer 6

Structurally related to β-lactam antibiotics. Carbapenems are β-lactamase resistant, but imipenem is inactivated by renal dihydropeptidase (thus administered with cilastatin, an inhibitor of the enzyme). The carbapenems readily gain access to organisms where it is an inhibitor of bacterial cell wall synthesis. They interact with the penicillin-binding proteins (considered to be transpeptidases) responsible for cell wall elongation (stage 3 of cell wall synthesis).

Question 7

Carbapenems: Pharmacokinetics

Answer 7

• IV/IM.
• Penetrates all tissues, including CSF.
• Imipenem = metab in the kidney by renal dipeptidase and then eliminated by the kidney (given w/ cilastatin).
• Meropenem and ertapenem (longest T1/2) not given with cilastatin.
• renal failure inc T1/2

Question 8

Carbapenems: spectrum of activity

Answer 8

Broad!
**RESERVED for multiple drug resistant organisms
• Carbapenems are active against both gram-positive and gram-negative aerobic and anaerobic bacteria including enterococci, but lack activity against MRSA and E. faecium

Question 9

Carbapenems: major clinical uses

Answer 9

• p. aeruginosa, E. coli
• bacteriodes
• C. perfringens

Question 10

Carbapenems: side effects and major DDIs

Answer 10

• Most common adverse effects are nausea / vomiting, diarrhea, skin rash; Seizures noted in small number of patients with higher doses
• some cross-sensitivity with penicillins, seizure incidence lower with meropenem

Question 11

Monobactams: spectrum of activity and major clinical uses

Answer 11

• g-b (like aminoglycosides but less toxic)
• g- “magic bullet”
• p. aeruginosa*****

Question 12

Monobactams: side effects and DDIs

Answer 12

general, VERY SAFE drug. Mild gastrointestinal upset, eosinophilia, skin rash, transient elevation of liver enzymes. Can be tolerated by penicillin-allergic patients