Penicillins

Question 1

Penicillin Mechanism of Action

Answer 1

binds to transpeptidases aka “Penicillin binding proteins” which cross-link alainine resideues in bacterial cell walls to make it functional.

Mimics alanine (“D-alanyl-D-alanine”) residues • Inactivates enzymes • Wall breakdown > wall creation → Autolysis • Enzymes that hydrolyze cell wall continue to work • Cell death (bactericidal)

Question 2

2 Natural Penicillins

& special feature:

Answer 2

Penicillin G (IM and IV)

Penicillin VK (oral)

Probenecid • Gout drug • Inhibits renal secretion PCN • Boosts PCN levels → co-administered in special circumstances

Question 3

3 mechanisms of Resistance to Natural Penicillins

Answer 3

Modified penicillin binding proteins

May result from genetic mutations • Example: S. pneumonia often produces altered PBPs

Reduced bacterial cell penetration

Gram negative bacteria: poor penetration • Porins: gram negative proteins that transport nutrients/waste • Bacteria may decrease number of porins

Beta lactamase enzyme

Question 4

whats Beta Lactamase? who has it?

Answer 4

Bacterial enzymes that Degrade beta lactam compounds • Penicillin G and VK • Some other penicillins • Some cephalosporins

Many gram negative bacteria & Staphylococcus aureus

Question 5

Beta Lactamase in (-) bacteria found in:

in (+) bacteria:

Answer 5

Gram negative bacteria • Beta lactamase found in periplasm

Gram positive bacteria (S. Aureus) • No periplasm - Beta lactamase secreted • Generally produce more enzyme than GN

Question 6

3 β-Lactamase Inhibitors:

Answer 6

Clavulanic Acid

Sulbactam

Tazobactam

Question 7

β-Lactamase Inhibitors effectivness:

Answer 7

• Little/no effect used alone therefore Added to some penicillins to expand coverage • Aminopenicillins • Antistaphylococcal penicillins

Question 8

Clinical Uses for Penicillin G and VK

Answer 8

Narrow spectrum – few specific modern uses

Gram positives • Strep pyogenes (strep throat) • Actinomyces

Treponema Pallidum (syphilis)

Rare uses: (only in susceptible isolates) • Neisseria meningitides • Strep. pneumonia

Question 9

Penicillin Adverse Effects:

acute:

immediate:

skin:

Answer 9

Acute (“immediate”) • Type I, IgE-mediated • Usually within 1 hour of taking drug

“Non-immediate” reaction • Most common with aminopenicillins • Maculopapules • Itchy or may be non-pruritic • Absence of fever, wheezing, joint pain • Days or weeks after starting drug • Type-IV (T-cell-mediated) mechanism

Stevens-Johnson Syndrome • Fever, necrosis • Sloughing of skin • Dermal-epidermal junction • Vesicles, blisters • Toxic epidermal necrolysis • Severe form SJS (>30% skin) Immune mediated • CD8 T-cells play important roll

Question 10

Penicillin Adverse Effects: Interstitial Nephritis

Answer 10

Drug acts as hapten → immune response in kidneys • Hypersensitivity (allergic) reaction • Complex mechanism • Considered a Type IV hypersensitivity reaction • T cells, Mast cells

Classic presentation • Fever • Oliguria • Increased BUN/Cr** • **Eosinophils** in urine • White cells and **WBC casts (“sterile pyuria”)

Question 11

Penicillin Adverse Effects: Hemolytic Anemia

Answer 11

High doses can lead to extrinsic hemolytic anemia • PCN binds to surface RBCs (hapten**) • Elicits immune response • **Antibodies against PCN bound to RBCs • Direct Coombs test: positive • Type II hypersensitivity

Question 12

Penicillin Adverse Effects: Serum Sickness

Answer 12

• Immune complex disorder (IgG) • Days/weeks after exposure • Complement activation • Type III hypersensitivity reaction • Urticaria, fever, arthritis, lymphadenopathy

Question 13

Penicillin Immunology:

types 1-4:

Answer 13

Question 14

Penicillin Adverse Effects: C. Difficile Infection?

Answer 14

Frequent associations

Clindamycin* classicallly • Fluoroquinolones • Cephalosporins • Penicillins

Question 15

3 Antistaphylococcal Penicillins:

mechanism of action:

Answer 15

Oxacillin, nafcillin, dicloxacillin

Side chain protects β-lactam from staph penicillinase

Covers Staph Aureus (non-MRSA) and most strep

Question 16

Common uses for Antistaphylococcal Penicillins

Answer 16

Community acquired cellulitis • Impetigo

Staph endocarditis based on culture data(never empirically tho)

Question 17

2 Aminopenicillins

what do they do:

coverage:

Answer 17

Amoxicillin (oral) • Ampicillin (IV) • (Poor bioavailability when given orally)

Penetrate porin channel of gram-negative bacteria • Sensitive to beta lactamase enzymes

Covers penicillin bacteria plus some gram negatives

Question 18

6 bugs commonly treated by Aminopenicillins Amoxicillin/Ampicillin

Answer 18

Bacteria:

H. Influenza

E. Coli

Proteus

Salmonella

Shigella

Listeria (gram +)

Question 19

3 main clinical uses for Aminopenicillins Amoxicillin/Ampicillin:

Answer 19

Otitis Media

Bacterial sinusitis

Meningitis • Newborns, elderly • Listeria coverage

Question 20

Aminopenicillins Maculopapular Rash:

classic case:

Answer 20

Most common with aminopenicillins

More common in viral infection • Classic case • EBV infection with sore throat • Amoxicillin given for presumed bacterial pharyngitis • Maculopapular rash

Question 21

β-Lactamase Inhibitors Clavulanic Acid, Sulbactam, Tazobactam • Commonly used with

Answer 21

aminopenicillins

Question 22

2 Common uses of β-Lactamase Inhibitors (Clavulanic Acid, Sulbactam, Tazobactam) • + aminopenicillins:

Answer 22

Otitis media/sinusitis (Broad-spectrum) • Bite wounds (Polymicrobial with anaerobes)

Question 23

2 Antipseudomonal Penicillins:

Answer 23

Ticarcillin, Piperacillin

Question 24

Antipseudomonal Penicillins:

greater:

more - coverage than_

susceptible to:

broad spectrum b/c:

usually given to:

Answer 24

Greater porin channel penetration • Effective against Pseudomonas aeruginosa • More gram (-) coverage vs. aminopenicillins

Susceptible to β-lactamases

Given with β-lactamase inhibitor

Broad-spectrum antibiotics • Most gram-positive (not MRSA) • More gram-negative (pseudomonas) • Most anaerobic bacteria

Hospitalized patients with sepsis/PNA