Penicillins

Question 1

β-Lactam Characteristics

Answer 1

• Same MOA: Inhibit cell wall synthesis
• Same MOR: β-lactamase degradation, PBP alteration, decreased penetration
• Bactericidal in a time-dependent manner, except against Enterococcus spp.
• Short elimination half-life of

Question 2

Penicillins discovery

Answer 2

Penicillin was accidentally discovered by Dr. Alexander Fleming in 1928
First used in 1941 for the treatment of staphylococcal and streptococcal infections (gram +)

Question 3

penicillin common structure

Answer 3

All penicillins share a β-lactam ring attached to a 5-membered thiazolidine ring

Question 4

how do penicillins work?

Answer 4

• Interfere with cell wall synthesis by binding to and inhibiting penicillin-binding proteins (PBPs) located in bacterial cell membranes
• Number, type and location of PBPs vary between bacteria; PBPs are only expressed during cell division
• Inhibition of PBPs leads to inhibition of final transpeptidation step of peptidoglycan synthesis (no cross-linking)
• all are bactericidal (except against Enterococcus)

Question 5

3 mechanisms of penicillin resistance

Answer 5

1. Production of β-lactamase enzymes
2. Alteration in structure of PBPs leading to decreased binding affinity
3. Alteration of outer membrane porin proteins leading to decreased penetration

Question 6

Production of β-lactamase enzymes

Answer 6

• Most important and most common mechanism
• the enzyme hydrolyzes the β-lactam ring inactivating the antibiotic;
• over 100 β-lactamase enzymes have been identified
• can be overcome by addition of β-lactamase inhibitors

ex. Penicillin-resistant Staphylococcus aureus (and many others)

Question 7

gram + vs gram - use of β-lactamases

Answer 7

gram + bacteria release β-lactamase into the extracellular area to inhibit β-lactam

while gram - bacteria release β-lactamase into the periplasma space where β-lactam is distroyed

Question 8

examples of Alteration in structure of PBPs leading to decreased binding affinity as a method of resistance

Answer 8

methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP)

β-lactamase inhibitors will not longer increase the effects of the drugs, bc the binding sites on PBP have changed so the drug cannot bind.

Question 9

Natural Penicillins

Answer 9

First group of penicillins to be discovered and used clinically

Parenteral agents: Aqueous penicillin G (IV), Benzathine penicillin G (IM, long-acting), Procaine penicillin G (IM)
Oral agent: Penicillin VK (only one with high enough bioavailability to be given orally)

Question 10

Penicillin VK

Answer 10

natural penicillin that can be given orally bc it is better absorbed therefore giving it a higher bioavailability

Question 11

penicillin G

Answer 11

natural penicillin (the first one given to humans) must be given via IV

Question 12

Benzathine penicillin G

Answer 12

natural penicillin given via IM, the only long lasting penicillin can be dosed once a week

Question 13

natural penicillins are given for

Answer 13

• Drugs of choice for:

 penicillin-susceptible S. pneumoniae, 
infections due to other streptococci, 
Neisseria meningitidis, 
syphilis**, 
Clostridium perfringens or tetani,
Actinomyces, 
Bacillus anthracis (anthrax)

• Endocarditis prophylaxis; prevention of rheumatic fever

Question 14

Penicillinase-Resistant Penicillins

Answer 14

• Developed in response to the emergence of penicillinase-producing Staphylococcus
• Semisynthetic derivatives of natural penicillin - contain an acyl side chain (prevent hydrolization by penicillinase)

Examples include:
Parenteral agents: Nafcillin *, Oxacillin, and Methicillin (not available)
Oral agent: Dicloxacillin

Question 15

Penicillinase-Resistant Penicillins are used for

Answer 15

methicillin-susceptible S. aureus* (MSSA)

Question 16

penicillinase is

Answer 16

a specific B-lactamase, that hydrolyzes the B-lactam ring

Question 17

3 ways to overcome penicillanase produced by MSSA

Answer 17

1. penicillinase-resistant penicillins,
2. beta-lactamases inhibitors, or
3. changing to cephalosporin core [cefazolin]

Question 18

Carboxypenicillins


Answer 18

Developed to further increase activity against gram-negative aerobes. Lost some gram+ activity in the process

example: Ticarcillin

Question 19

Nafcillin

Answer 19

penicillinase-resistant penicillin used to treat MSSA

has a higher risk of Interstitial Nephritis than other penicillins

Question 20

Carboxypenicillins
 (ticarcillin) have increased potency against

Answer 20

gram - bacteria :
Enterobacter spp.
Pseudomonas aeruginosa*

Question 21

Ureidopenicillins

Answer 21

Developed in response to the need for agents with even more enhanced activity against gram-negative bacteria
• Semisynthetic derivatives of the amino-penicillins with acyl side chain adaptations

Examples include:
Parenteral agent: Piperacillin (not available)
Oral agents: None

Question 22

Ureidopenicillins are good to use against

Answer 22

anaerobes (target organism)
Pseudomonas aeruginosa*
Enterobacter sp.

Question 23

β-Lactamase Inhibitors

Answer 23

Potent inhibitors of many bacterial β-lactamases
Protect penicillins from being hydrolyzed by some β-lactamases by irreversibly binding to catalytic site of β-lactamase enzyme
Very weak to no antibacterial activity
Examples include: Clavulanate, sulbactam, tazobactam, avibactam (used in combo with cephalosporins)

Question 24

β-Lactamase Inhibitor Combinations

Answer 24

Available only in fixed-dose combinations with specific penicillins

Question 25

efficacy of penicillins depends on

Answer 25

time above MIC (time dependent killing) | no post antibiotic effect (PAE) for gram - bacteria

Question 26

absorption of penicillins

Answer 26

Many penicillins are degraded by gastric acid • Oral penicillins are variably absorbed; concs achieved PO are lower than IV • Pen VK absorbed better than oral Pen G • Amoxicillin absorbed better than ampicillin • Dicloxacillin is absorbed the best of the PRPs

Question 27

aminopenicillins

Answer 27

Developed in response to the need for agents with gram-negative activity • Semisynthetic derivative of natural penicillin – addition of amino group • now commonly given with a B-lactamase inhibitor Examples include: Parenteral agent: Ampicillin Oral agents: Amoxicillin

Question 28

Amoxicillin

Answer 28

aminopenicillin commonly given orally

Question 29

aminopenicillins commonly used against

Answer 29

- Respiratory tract infections: pharyngitis, sinusitis, otitis media, bronchitis, urinary tract infections - Enterococcal* infections (often with an aminoglycoside) and infections due to Listeria monocytogenes* - Endocarditis prophylaxis in selected patients with valvular disease

Question 30

distribution of penicillins

Answer 30

* Widely distributed into tissues and fluids * Adequate CSF concentrations achieved ONLY in the presence of inflamed meninges with high-dose parenteral administration * Variable protein binding

Question 31

elimination of penicillins

Answer 31

* Most are eliminated unchanged by the kidney so that dosage adjustment is required in the presence of renal insufficiency; probenecid blocks tubular secretion * Nafcillin and oxacillin are eliminated primarily by the liver – do not require adjustment in renal insufficiency * ALL penicillins have short elimination half-lives (

Question 32

sodium load of penicillins

Answer 32

Sodium is contained in some preparations of parenterally-administered penicillins • Must be used with caution in patients with CHF or renal insufficiency Sodium content: Sodium Penicillin G 2.0 mEq per 1 million units Ticarcillin 5.2 mEq per gram Piperacillin 1.85 mEq per gram

Question 33

Carboxypenicillins and Ureidopenicillins

Answer 33

- Serious infections due to gram-negative aerobic bacteria such as pneumonia, bacteremia, complicated urinary tract infections, skin and soft tissue infections, peritonitis, etc - Empiric therapy for hospital-acquired infections - Infections due to Pseudomonas aeruginosa (esp piperacillin) *

Question 34

penicillin hypersensitivity

Answer 34

- Higher incidence with parenteral administration - Mild to severe allergic reactions ranging from rash to anaphylaxis and death - Antibodies produced against metabolic by-products (penicillin degradation products) or penicillin itself - Cross-reactivity exists among all penicillins and even some other β-lactams - Desensitization is possible

Question 35

neurologic adverse affects of penicillin

Answer 35

direct toxic effect Especially in patients receiving high IV doses in the presence of renal insufficiency Irritability, jerking, confusion, seizures

Question 36

hemologic adverse effects of penicillins

Answer 36

Leukopenia, neutropenia, thrombocytopenia – usually during prolonged therapy (> 2 weeks) Reversible upon discontinuation

Question 37

GI adverse effects of penicillins

Answer 37

Increased LFTs, nausea, vomiting, diarrhea, pseudomembranous colitis (Clostridium difficile diarrhea)

Question 38

renal adverse effects of penicillins

Answer 38

Interstitial Nephritis -- Immune-mediated damage to renal tubules - characterized by an abrupt increase in serum creatinine, eosinophilia, eosinophiluria Can lead to renal failure Especially with nafcillin