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Flashcards in Penicillins Deck (38):
1

β-Lactam Characteristics

* 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

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Penicillins discovery

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

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penicillin common structure

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

4

how do penicillins work?

• 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)

5

3 mechanisms of penicillin resistance

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

6

Production of β-lactamase enzymes

• 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)

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gram + vs gram - use of β-lactamases

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

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

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.

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Natural Penicillins

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)

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Penicillin VK

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

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penicillin G

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

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Benzathine penicillin G

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

13

natural penicillins are given for

- 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

14

Penicillinase-Resistant Penicillins

• 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

15

Penicillinase-Resistant Penicillins are used for

methicillin-susceptible S. aureus* (MSSA)

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penicillinase is

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

17

3 ways to overcome penicillanase produced by MSSA

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

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Carboxypenicillins


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

example: Ticarcillin

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Nafcillin

penicillinase-resistant penicillin used to treat MSSA

has a higher risk of Interstitial Nephritis than other penicillins

20

Carboxypenicillins
 (ticarcillin) have increased potency against

gram - bacteria :
Enterobacter spp.
Pseudomonas aeruginosa*

21

Ureidopenicillins

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

22

Ureidopenicillins are good to use against

anaerobes (target organism)
Pseudomonas aeruginosa*
Enterobacter sp.

23

β-Lactamase Inhibitors

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)

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β-Lactamase Inhibitor Combinations

Available only in fixed-dose combinations with specific penicillins

25

efficacy of penicillins depends on

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

26

absorption of penicillins

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

27

aminopenicillins

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

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Amoxicillin

aminopenicillin commonly given orally

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aminopenicillins commonly used against

- 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

30

distribution of penicillins

• 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

31

elimination of penicillins

• 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 (

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sodium load of penicillins

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

33

Carboxypenicillins and Ureidopenicillins

- 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) *

34

penicillin hypersensitivity

- 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

35

neurologic adverse affects of penicillin

direct toxic effect
Especially in patients receiving high IV doses in the presence of renal insufficiency

Irritability, jerking, confusion, seizures

36

hemologic adverse effects of penicillins

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

Reversible upon discontinuation

37

GI adverse effects of penicillins

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

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renal adverse effects of penicillins

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