Cell wall synthesis inhibitors Flashcards
What is the major group of cell wall synthesis inhibitors?
Beta Lactams
What molecular feature distinguishes beta lactams?
Beta lactam ring (site of action and resistance)
What was the first beta lactam discovered?
Penicillin
What is the mechanism of action of beta lactam drugs?
- Inhibits peptidoglycan
synthesis - b-lactam agents bind to the
transpeptidase and inhibit cell
wall synthesis - Disrupts bacterial cell wall
integrity and causes lysis
What is the name of the molecule that Beta Lactams bind to?
Penicillin binding protein (PBP), the transpeptidase
What is a mechanism of resistance to penicillin that bacteria can acquire from other bacteria?
Bacteria acquire new PBP from other bacteria that are
resistant to b-lactams
What are some drug penetration mechanisms of resistance?
Inability to penetrate to site of action
* Gram (–) outer membrane tough to penetrate
* Gram (-) outer membrane modified with impenetrable porins–no longer permeable
* Can’t handle pus, acidic pH
What is the biggest mechanism of resistance to beta-lactam drugs?
b-lactamase enzymes present in bacteria that
target the active site of the drug
What group of penicillin derivatives can traverse the outer membrane of gram negatives? What are 2 drawbacks of use of these drugs?
- Aminopenicillins (ampicillin and amoxicillin) have added amino groups to get through the porins of the outer membrane in gram negative bacteria
- These drugs are vulnerable to beta-lactamases so are combined with beta-lactamase inhibitors like clavulenic acid (+ amoxicillin = clavamox)
- Oral administration will kill hindgut fermenters
What drug group is less vulnerable to beta lactamase?
Methicillin (antistaphylococcal penicilin) is chemically modified to be less vulnerable to beta-lactamases
How does clavulenic acid work?
it is a b-lactamase inhibitor, it binds the
b-lactamase enzyme
What is the spectrum of activity of Penicillin?
- Most Gram (+) aerobes
- Most Gram (+) anaerobes
- Little activity against Staph aureus sp.
- Gram (-) are typically resistant
What are the most important side effects of Penicillin?
Penicillin hypersensitivity: true for all penicillin
classes!!!
* In order of decreasing frequency: urticaria, fever,
bronchospasm, vasculitis, serum sickness, exfoliative
dermatitis, anaphylaxis
* Can occur without any prior exposure
* Reactions after IM injection of Procaine
What are the 4 types of penicillin derivatives and examples?
(5 total)
- Anti-staph penicillins: Methicillin
- Aminopenicillins: Amoxicillin, ampicillin
- Anti-pseudomonas penicillin
- Potentiated penicillin: Clavamox = Amoxicillin + Clavulenic acid
What is therapy goal with use of Antistaphylococcal penicillins and what is an example drug?
Methicillin
Goal is treatment of penicillin-resistant bacteria because they are not as vulnerable to b-lactamases
What is therapeutic goal of treatment with Aminopenicillins and what are 2 example drugs?
Amoxicillin and Ampicillin
Goal is to treat gram negatives because spectrum of Activity:
* Extended spectrum to include some Gram (-)
-E. coli
-Proteus mirabilis
-Salmonella
* Improved ability to penetrate the outer membrane
of Gram (-) bacteria
* Susceptible to b-lactamases
What is the most important adverse effect of Aminopenicillins?
Oral administration will KILL HINDGUT FERMENTERS (horses, guinea pigs, rabbits, hamsters, gerbils)
What is therapeutic goal of treatment with Antipseudomonal penicillins?
Spectrum of Activity extended to include Gram (-)
* Pseudomonas aeruginosa
* Enterobacter
* Proteus
How are antipseudomonal penicillins given?
Not good orally, typically given parenterally
What is therapeutic goal of potentiated penicillins and an example drug?
Potentiated penicillin: Clavamox = Amoxicillin + Clavulenic acid
Penicillins mixed with b-lactamase inhibitors
Spectrum of activity
* Staphylococci sp.
* Bacterioides
* E. coli
What is the mechanism of action of cephalosporins?
Inhibits peptidoglycan
synthesis, same as penicillins
What type of penicillin would you use to treat enterobacter, proteus, and pseudomonas? How would you give them?
Antipseudomonal Penicillins
Not good orally, typically given parenterally
What is the difference between first, second, third, and fourth generation cephalosporins?
First generation: mostly Gram (+), modest Gram (-)
Second generation: added Gram (-)
Third generation: less Gram (+), more Gram (-)
Fourth generation: extended spectrum from 3rd
generation
What type of drug and generation is Ceftiofur?
3rd generation cephalosporin
What are most important side effects of cephalosporins in general? Of Ceftiofur?
In general, very safe drugs, hypersensitivity, most common, similar to penicillins
Antimicrobial induced colitis from Ceftiofur
* Younger horses, high stress (racehorses), given IV fast instead of IM
Which cephalosporin can you use IM?
Ceftiofur
Which generation of cephalosporins is most resistant to beta-lactamases?
Fourth generation
What generation of cepahlosporin would you use to treat an infection with a gram positive organism?
First generation
Do cephalosporins need to be metabolized to be active?
Little metabolism…
EXCEPTION! 3rd generation Ceftiofur requires
metabolization to active metabolite for antimicrobial
activity (desfuroylceftiofur)
What is mechanism of action of carbapenems?
Disrupts bacterial cell wall synthesis by binding penicillin binding proteins; resistant to most b lactamases
What are the three subclasses of beta-lactam drugs?
Penicillins and derivatives
Cephalosporins
Carbapenems
What is the therapeutic use of carbapenems?
Most powerful bactericidal activity of the b-lactams
Big gun, use as last resort
What are the most important side effects of carbapenems?
Extensive metabolism by renal tubules to potentially toxic compound
What are the non-beta lactam cell wall synthesis inhibitor drugs?
Bacitracin
Vancomycin
Teixobactin
When would you use bacitracin? Why?
Only used topically: ophthalmic and dermatologic ointments
VERY NEPHROTOXIC if given parenterally
What is the most important thing to know about vancomycin?
NO VETERINARY FORMULATIONS
APPROVED—BIG GUN!
What is the method of action of Teixobactin? Spectrum of activity?
Works on 3 different sites to disrupt cell wall synthesis
– Binds Lipid II—precursor for peptidoglycan component of cell wall (same site of action for Vancomycin)
– Binds Lipid III—precursor for wall teichoic acid (WTA), building block of cell wall
– Blocks precursor recycling—leads to depletion of cell wall components
Spectrum of activity
– Gram(+)—attacks sugar molecules in cell wall
– Gram(-)—resistant due to outer membrane
Which generation of cephalosporins is most resistant to beta-lactamases?
Fourth generation
