Antibacterial Drugs

Question 1

What are the targets for selective toxicity?

Answer 1

• Cell wall synthesis (Inhibitors of cell wall synthesis)
• Membrane integrity
• Protein synthesis (IPS)
• Nucleic acid synthesis
• Nucleic acid integrity

Question 2

Beta-lactam antibiotics and vancomycin block

Answer 2

Enzymatic steps outside of the cell or in the periplasmic space
Other ICWS inhibitors act at IC sites

Question 3

Penicillins

Answer 3

Very selective toxicity (extremely high chemotherapeutic index)
Bactericidal in growing, proliferating cells
Primarily used for gram (+)

Question 4

Penicillin MOA

Answer 4

1. Covalent binding to transpeptidases/penicillin binding proteins
2. Inhibition of transpeptidation reaction (Cross-linking of cell wall)
3. Activation of murein hydrolases (autolysins)

Question 5

Penicillin Pharmacokinetics: Absorption

Answer 5

• Many penicillins are acid-sensitive but can be still given orally
• Parenteral penicillins: IV, IM (depo)
• Benzathine penicillin: IM, insoluble, time release, compliance issues

Question 6

Penicillin Distribution

Answer 6

• Penicillins do not get across the blood-brain barrier, eye, ocular fluid, prostate
• Meningitis may facilitate crossing blood-brain barrier

Question 7

Penicillin Excretion

Answer 7

• Penicillins excreted by tubular secretion (actively secreted by Organic Acid Secretory System, blocking this with Probenecid extends half-life)
• Exceptions: Nafcillin secreted in bile, Oxa- and Cloxa- in urine and bile
• Penicillins are rapidly cleared (1/2 life 30-60 min)

Question 8

Time above minimal bacterial concentration (MBC)

Answer 8

relates to efficacy

Question 9

Cell wall synthesis inhibitors (Penicillin, Cephalosporins, and Vancomycin) exhibit

Answer 9

Time-Dependent Killing (concentration independent). Need extended half life to work effectively.

Question 10

Pen G and Pen V are primarily useful against

Answer 10

Gram (+)

Question 11

Staph became rapidly resistant to anti-staphylococcal penicillins b/c

Answer 11

The target of anti-staphylococcal penicillins is beta lactamase (which rapidly mutated)

Question 12

Anti-staphylococcal penicillins

Answer 12

Nafcillin, Methicillin, Isoxazoyl penicillins (ox-, clox-)

Beta-lactamase resistant

Question 13

Extended Spectrum penicillins

Answer 13

Ampicillin, Amoxicillin, Ticarcillin, Piperacillin, Mezlocillin
Developed to increase gram (-) activity (broader spectrum)
Can get through lipid membrane

Question 14

Anti-pseudomonal penicillins

Answer 14

Exclusively for pseudomonal infections!

Question 15

Adverse effects of penicillins

Answer 15

Ampicillin rash

Hypersensitivity reaction

Question 16

Resistance to Penicillins

Answer 16

1. No cell wall, no activation of murein hydrolases, metabolically inactive
2. Inaccessible PBPs
   - gram (-)
   - Methicillin-resistant Staph. aureus (MRSA)
3. Beta-lactamase production
   - Major mechanism of resistance
   - Plasma mediated
   - Use beta-lactamase resistant penicillin (Nafcillin, Oxacillin, Cloxacillin)
   - Co-administer Beta-lactamase inhibitor (Clauvanic acid, Sulbactam, Tazobactam)

Question 17

Problems associated with Penicillin use/overuse

Answer 17

Sensitization
Selection for resistant strains (90% of staph are resistant)
Superinfections by resistant organisms (esp. proteus, pseudomonas, serratia, fungi)

Question 18

Cephalosporins

Answer 18

Structure and function similar to penicillins
Less sensitive to beta-lactamases
Broader spectrum of activity
Poor oral absorption
Renal toxicity
Cross-reactivity with penicillin
More expensive than penicillin
Secondary to ICWS: If a penicillin would work, use it

Question 19

1st generation cephalosporins

Answer 19

only effective against (+) bacteria

Question 20

Subsequent generation cephalosporins

Answer 20

Greater gram (-) activity
Some with less gram (+) activity (2nd generation)
Less beta-lactamase sensitivity
Cephalosporin resistant (especially 4th generation, Cefepime)
Decreased toxicity
Better distribution to CNS

Question 21

1st Generation Cephalosporins

Answer 21

Narrow spectrum
Cefazolin
Cephalexin (o)

Question 22

2nd Generation Cephalosporins

Answer 22

Intermediate spectrum
Cefuroxime (o)
Cefotetan
Ceflacor (o)

Question 23

3rd Generation Cephalosporins

Answer 23

Broad spectrum

Cefotaxime, Ceftriaxone, Ceftazidime, Cefpoxodime (o)

Question 24

4th Generation Cephalosporins

Answer 24

Broad spectrum

Cefepime

Question 25

Cephalosporine adverse effects

Answer 25

Local irritation from injection Renal toxicity (enhanced by aminoglycosides) Cefotetan and Cefoperazone can cause Disulfram Effect (Bleeding and platelet disorders, administer vitamin K) Hypersensitivity: cross-reactivity with penicillin

Question 26

Monobactum: Aztreonam

Answer 26

Gram (-) activity; inactive against Gram (+) or anaerobes Beta-lactamase resistant Crosses blood-brain barrier No cross-reactivity with penicillin

Question 27

Carbanepems: :Imipenem

Answer 27

Broad spectrum: Gram (+) and Gram (-) anaerobes Beta-Lactamase resistant Pseudomonas develops resistance rapidly, use with aminoglycosides IV only Cross blood-brain barrier Inactivated by renal dipeptidase so co-administer Cilastatin Low cross-reactivity with penicillin

Question 28

Meropenem

Answer 28

Dipeptidase-resistant carbapenem

Question 29

Vancomycin

Answer 29

Inhibits transglycosylation (step before transpeptidation) Bactericidal for gram +IV for systemic use, oral for C difficile Systemic: MRSA (synergistic with aminoglycosides) IV drug cleared through kidney: enhances oto and renal toxicity of aminoglycosides Red man or neck syndrome: histamine release Misuse/overuse is problem Vacomycin-dependent Enterococci

Question 30

Fosfomycin

Answer 30

Newest ICWS; Gram (+) and (-) - Inhibits cytoplasmic step in cell wall precursor synthesis - Active uptake by G6P-transporter - Oral and parenteral - Active drug excreted by kidney - Single dose approved for UTI - Synergistic with Beta-lactams, aminoglycosides, or fluoroquinolones

Question 31

Bacitracin

Answer 31

``` Markedly nephrotoxic Topical antibiotic (OTC only) ```

Question 32

Membrane-active drugs: Polymixins

Answer 32

Polymixin B and Polymixin E (Colistin) Basic peptides (detergents) Active against gram (-) except Proteus and Neisseria Topical use due to systemic toxicity (renal) Salvage therapy for highly resistant strains of Acinetobacter, Pseudomonas, and Enterobacteriae