Beta Lactams

Question 1

3 classes of Beta Lactam Antibiotics:

Answer 1

Carbapenems, Aztreonam, Cephalosporins

Question 2

Beta Lactam Antibiotics mechanism

Answer 2

• Similar mechanism to penicillin • Bind transpeptidases (penicillin-binding proteins/PBPs) • Prevent peptidoglycan crosslinking • Autolysis • Usually bactericidal • Potentially susceptible to beta lactamase

Question 3

Carbapenems

Answer 3

Imipenem, meropenem, ertapenem, doripenem

• Resistant to cleavage by most β-lactamase

Question 4

ESBL Extended Spectrum Beta Lactamase:

Answer 4

Plasmid-mediated bacterial enzymes

Confer resistance to most beta-lactam antibiotics • Penicillins, cephalosporins, aztreonam

Found only in gram-negative bacteria • Pseudomonas • Klebsiella • E. coli • Enterobacter • Salmonella • Serratia • Shigella

Question 5

Drug of choice for ESBL bacteria:

Answer 5

Carbapenems:

Broad spectrum: • Gram (+) • Gram (-) including pseudomonas, enterobacter • Anaerobes including B. fragilis • Used in hospitalized patients

Question 6

whats unique about Imipenem?

Answer 6

First commercially available carbapenem • Metabolized in kidneys • Loss of antibacterial effect • Nephrotoxic metabolites • Proximal tubule enzyme: dehydropeptidase I • Given with cilastatin (enzyme inhibitor)

Question 7

Carbapenems adverse reactions:

Answer 7

Common side effects • Nausea, vomiting, diarrhea • Skin rash

Neurotoxicity • Seizures • Inhibition of GABA receptors • Especially at high doses or with renal failure • Lower risk with meropenem

Question 8

Aztreonam

unique molecular stuff about it:

effective against:

administration:

synergy:

Answer 8

• Monobactam: β-lactam ring not fused to another ring
• Binds penicillin-binding protein 3 (PBP-3)

Only active against gram (-) bacteria • Does not bind PBP of gram (+) bacteria • No activity against gram (+) or anaerobes • Active against pseudomonas

• Intravenous administration (hospitalized patients) • Synergistic with aminoglycosides

Question 9

key use for Aztreonam:

Answer 9

• Key niche: penicillin allergy b/c no cross reactivity in penicillin allergic patients

Question 10

1st Generation Cephalosporins: covers: does not cover:

main uses:

Answer 10

• Cefazolin, cephalexin
• Developed to treat S. Aureus resistance to penicillin • Covers many gram (+) including S. Aureus (not MRSA) • Stable against S. Aureus beta lactamase • Does not cover enterococcus or listeria • Susceptible to gram negative beta lactamases

Main uses: • Surgical wound (skin) infections • Cefazolin given pre-op for prevention

Question 11

2 nd Generation Cephalosporins:

Answer 11

Cefuroxime, Cefoxitin, Cefotetan

Question 12

2 nd Generation Cephalosporins

Answer 12

• Developed to treat amoxicillin-resistant infections

Increased affinity for gram (-) PBPs

More resistant to beta lactamase

Increased gram (-) • H. influenza, Enterobacter, Proteus • E. coli, Klebsiella, Serratia, N. gonorrheae • Increased anaerobic coverage (B. fragilis)

Question 13

2 nd Generation Cephalosporins uses:

Answer 13

• Cefuroxime (oral): • Otitis media (S. pneumonia, H. flu) • UTI in children (E. coli; no fluoroquinolones)

Cefoxitin/cefotetan (IV): • PID (covers Neisseria; also give doxycycline for Chlamydia) • Pre-op in children with appendicitis • E. coli • Covers gram negatives and some anaerobes • Usually given with metronidazole

Question 14

3 rd Generation Cephalosporins

Answer 14

Ceftriaxone, Cefotaxime, Ceftazidime

Question 15

3 rd Generation Cephalosporins:

coverage:

specific penetration aspect to know:

Answer 15

Broad gram (-) coverage • More resistance to beta lactamase enzymes • More gram (-) PBP affinity

Ceftriaxone, Cefotaxime: Poor coverage pseudomonas

Ceftazidime: Covers pseudomonas • Used in hospitalized patients with gram negative infections • Sepsis/pneumonia

Most achieve good CSF penetration (meningitis)

Question 16

Ceftriaxone commonly used for:

Answer 16

• Commonly used for N. gonorrhea • Commonly used in meningitis • Active against S. pneumonia, N. meningitidis • Good CSF penetration

Question 17

4th Generation Cephalosporins

Answer 17

Cefepime

Question 18

4th Generation Cephalosporins

Answer 18

Broad spectrum (>3rd generation drugs) • MSSA • Many gram (+)’s • Many gram (-)’s including pseudomonas • Resistant to some ESBL • Hospitalized patients with gram (-) infections

Question 19

β-lactamase Sensitivity Based on side chain

Answer 19

Question 20

5th Generation Cephalosporins

Answer 20

Ceftaroline

Question 21

5th Generation Cephalosporins

Answer 21

Ceftaroline

Active against MRSA • FDA approval 2010 • Prodrug converted to active metabolite • Binds PBP2a • MRSA-specific PBP • Low affinity for most other beta-lactams • Covers MRSA and VRSA • Some gram negatives (not pseudomonas)

Question 22

Cephalosporins Resistance Mechanism

Answer 22

• Modified penicillin-binding proteins (PBPs) • Altered cell permeability • Beta lactamase

Question 23

Cephalosporins Adverse Reactions

Answer 23

Hypersensitivity Reactions (similar to PCN) • Anaphylaxis • Maculopapular rash • Serum sickness (fever, rash, arthritis) • Hemolytic anemia (drug as hapten) • Interstitial nephritis • Stevens-Johnson Syndrome/Toxic epidermal necrolysis

Some cross-reactivity with penicillins

Question 24

Cephalosporins Adverse Reactions

Answer 24

Hypoprothrombinemia

• Cefotetan, cefazolin • Inhibits epoxide reductase (similar to warfarin) • ↓ hepatic synthesis of clotting factors

Most reports among malnourished patients

Question 25

Cephalosporins Adverse Reactions Disulfiram reaction:

Answer 25

Alcohol consumption with cephalosporins • Warmth, flushing, sweating • Inhibition of acetaldehyde dehydrogenase • Accumulation of acetaldehyde • Occurs with certain side chain structures • Cefoperazone, cefamandole, and cefotetan