B-Lactams Part 1

Question 1

Abx Targets

Answer 1

• Processes/proteins necessary for survival in prokaryotes but absent in eukaryotes
• EX: ribosomes 50s/30s, cell wall, requires folate synthesis, differences in DNA gyrase/topoisomerase

Question 2

B-Lactams

Answer 2

• Focus on cell wall synthesis
• Covalently bind to PBP active site to block enzymatic activity and prevent cell wall synthesis
• Leads to increased osmotic pressure and cell lysis/death
• EX: penicillins, cephalosporins, carbapenems, monobactams

Question 3

Bacterial Cell Wall

Answer 3

• Made up of peptidoglycans
• Glycan units joined to each other by peptide cross-links
• Cross linking is catalyzed by transpeptidases (AKA penicillin binding proteins)

Question 4

Natural B Lactam Resistance

Answer 4

• No peptidoglycan wall (atypicals)

- Impermeable to drugs (P. aeruginosa which lacks high-permeability porins)

Question 5

Acquired B Lactam Resistance

Answer 5

• Acquisition of genes that encodes resistance to multiple agents
  1. B-lactamases: hydrolyze a bond in B-lactam ring which is formed or acquired from plasmids. Major cause of resistance to penicillins
  2. Altered PBP: decreased binding to penicillins (mecA gene of MRSA)
  3. Decreased permeability: outer cell membrane (porin) or presence of efflux pump decreasing drug perfusion

Question 6

B-Lactams are generally…

Answer 6

• Bactericidal
• Most active against growing organisms (active cell wall synthesis)
• PKPD Efficacy: T>MIC
• Many have Gram “+” and “-“ activity (not all)

Question 7

B-Lactams differ in…

Answer 7

• Spectrum of action
• PK
• Stability
• Mode of administration
• Resistance profiles

Question 8

B-Lactam Ring Classes

Answer 8

1. Penicllins: thiazolidine ring
2. Cephalosporins: dihydrothiazine ring
3. Monobactam: no ring
4. Carbapenem: unsaturated ring with sulfur external to ring

Causes differences in oral availability, stability, spectrum, half-life, etc.

Question 9

Five Classes of Penicillins

Answer 9

1. Natural penicillins
2. Aminopenicillins
3. Anti-staphylococcal penicillins
4. Carboxypenicillins (not in U.S.)
5. Ureidopenicillins

Differ in stability and spectrum

Question 10

Natural Penicillins

Answer 10

• Penicillin G (parenteral) and V (oral)
• Limited spectrum, mainly Gram “+”
• Used for S. pyogenes, V. streptococci, penecillin-susceptible strains of S. pneumoniae and Enterococci, T. pallidum (syphilis), and N. meningitis

Question 11

Aminopenicillins

Answer 11

• Ampicillin, amoxicillin
• Broad spectrum, some enteric Gram “-“
• ”+” beta-lactamase inhibitors, use in conjunction to extend their coverage to B-lactamase producers like MSSA, B. fragilis, and some Gram “-“ bacterium
• Increased stability and permeability of Gram “-“ membrane

Question 12

Anti-staphylcoccal Penicillins

Answer 12

• Nafcillin, methicillin, oxacillin, dicloxacillin
• Limited spectrum, mainly Gram “+”
• Resistant to staphylococcal B-lactamases
• Used for MSSA (nafcillin, dicloxacillin) and penicillin-susceptible strains of strept

Question 13

Ureidopenicillins

Answer 13

• Piperacillin
• Works against P. aeruginosa
• Used with Zosyn almost always, some Gram “+” and “-“ activity
• Anti-pseudomonal PCNs
• Ampicillin with amino side chain converted to include Urea
• Accumulates in renal failure and may increase bleed times

Question 14

Ampicillin

Answer 14

• IV or PO
• Take on empty stomach to increase absorption
• Temperature dependent stability
• Probenecid used to slow excretion by kidney

Question 15

Amoxicillin

Answer 15

• PO
• Better absorbed
• Extremely common in use

Question 16

B-lactamase Inhibitors

Answer 16

-Extend spectrum of activity for B-lactams

Examples

• Sulbactam
• Clavulanate
• Tazobactam
• Avibactam

Question 17

Dicloxacillin

Answer 17

• PO

- 1 hour before or after meals

Question 18

Methicillin

Answer 18

• May cause interstitial nephritis

- No longer used clinically

Question 19

Oxacillin

Answer 19

• Mainly excreted by kidney

- Possibly hepatotoxic

Question 20

Nafcillin

Answer 20

• Main route is IV
• Highly protein bound so lowers concentration free in serum
• Biliary excretion
• Associated with neutropenia

Question 21

Penicillin + PK Considerations

Answer 21

1. Acid stability? Lactamase resistance?
2. Protein binding contributes to levels of free antibiotic in serum, except amoxicillin, take 1-2 h before meals to avoid binding to food proteins and low pH
3. Short half-life 30-90 minutes
4. CSF concentration during inflammation = 5% of serum levels, but wide therapeutic window!
5. Cross the placental barrier but none are teratogenic.
6. Renal excretion: Care in renally impaired individuals: probenecid or nafcillin use

Question 22

PNC + PK/PD Goal

Answer 22

• Maximize time above MIC
• More frequent dosing
• Extend infusion time
• Continuous infusion

Question 23

PNC SE/Monitoring

Answer 23

• GI upset, diarrhea, rash, allergic reaction, anaphylaxis
• Rare: renal failure, myelosuppression, elevated LFTs, seizures with high accumulation, neutropenia, and vasculitis
• Monitoring: renal fxn, anaphylaxis with first dose, CBCs, LFTs
• PCN can increase concentration of MTX and alter warfarin metabolism
• Nafcillin is a moderate CYP3A4 inducer