Beta Lactams Flashcards
Antimicrobials target cell wall synthesis by targeting:
Beta Lactams
Penecillins
Cephalosporins
Carbapenems
Monobactams
Vancomycin
Bacitracin
Cell Membrane
Daptomycin
Polymyxins
3 Facts about Beta Lactams
- Require actively proliferating microorganisms.
- Are INACTIVE against organisms devoid of peptidoglycans
• i.e., viruses, mycobacteria, and fungi 3. Are Type II Time-Dependent: most effective if dosed to achieve
serum concentrations (T) >MIC for at least 50% of the dosing interval (PD)
• achieve peak therapeutic efficacy & prevent resistance when
dosed in time-dependent manner.
To be effective, b-lactam drugs must first:
- Evade bacterial defenses (i.e., lactamases, amidases,
lipopolysaccharides etc.) - Penetrate the outer cell layers to reach inner cytoplasmic membrane PBP
- Protect their b-lactam ring structure
- Bind to transpeptidase enzymes (a.k.a., penicillin-binding protein,
PBP) located on the bacteria’s inner cytoplasmic membrane
How are new bacterial cell walls synthesized?
Transpeptidase enzymes ( PBP) • clips off the terminal D- alanine residue and crosslinks adjacent glycan chains • Newly formed covalently bonded chains form rigid cell walls that prevent osmotic forces from rupturing bacterial cell walls.
How do b-lactam antimicrobials work?
ThE b-lactam region of b-lactam antimicrobial drugs resembles
the D-Ala-D-Ala end of the normal protein substrate that binds to bacterial
transpeptidase enzymes (a.k.a., PBP) to enable cell wall synthesis.
When a b-lactam antimicrobial binds to the PBP, it prevent
transpeptidation, the last step in new peptidoglycan (cell wall) synthesis.
• Without rigid cell wall, bacterial undergoes autolysis (BACTEROCIDAL)
Facts about Transpeptidase Enzymes
Also known as Penicillin-binding proteins (PBP) • β-lactam AMDs work by binding to and inactivating PBPs to prevent cell wall synthesis • Remember IF either: o the PBP binding site is altered and/or o the b-lactam AMD is inactivated via bacterial beta- lactamase enzymes • THEN the β-lactam AMD will no longer inhibit cell wall synthesis o PBP will still be able to carry out its cross-linking function
Classification of b-lactam Antimicrobials:
6 groups
- Natural Penicillins
- Aminopenicillins:
- Penicillinase-resistant penicillins:
- Anti-Pseudonomal penicillins
- Cephalosporins
- Carbapenems:
Natural Penicillins:
o Penicillin G, penicillin V (a.k.a., penicillin VK)
o highest activity against Gram (+) organisms (ineffective against Staph. aureas)
o Very susceptible to bacterial b-lactamases
Aminopenicillins:
“extended spectrum penicillins”
o ampicillin, amoxicillin
o Extended spectrum to also include some Gram (-)’s, such as H. influenzae, E.coli, and Pr. mirabalis.
o Still susceptible to b-lactamases (OFTEN PAIRED WITH b-LACTAMASE INHIBITORS).
Penicillinase-resistant penicillins:
“anti-staphylococcal penicillins”
o methicillin, nafcillin, oxacillin, and dicloxacicillin
o Relatively resistant to b-lactamases
o Less active against Gram (+) organisms (BUT active against Staph. aureus.); inactive
against Gram (-) organisms
• Nafcillin:
o indicated for treatment of staphylococcal infections, except MRSA.
o first-line treatment of choice for staphylococcal endocarditis in patients without
artificial heart valves (AHA Guide).
Anti-Pseudonomal penicillins:
o Monobactams (i.e., aztreonam) - strong activity against susceptible Gram (-) bacteria,
including P. aeruginosa
o Ureidopenicillins (i.e., piperacillin) – also active against Pseudonomas plus Gram (-) rods
o Carboxypenicillins (i.e., ticarcillin, indanyl carbenicillum) - spectrum expanded further to
include Enterobacter, and Proteus sp.
• NOTE: NOT active against Gram (+) bacteria or anaerobes.
• Resistant to some b-lactamases
o Of all the antipseudomonal penicillins, ticarcillin, and then piperacillin, have the
broadest spectrums of activity.
Cephalosporins:
o b-lactam structure on a 7-aminocephalosporanic acid, instead of penicillin’s traditional 6-
aminopenicillinic acid
o Mechanism analogous to penicillin (BACTERICIDAL, so long as T>MIC is maintained
appropriately)
o Tend to be resistant to common b-lactamases that inactivate other b-lactams, except
penicillinase-resistant penicillins.
o 5 generations, classified based on their activity profile
o Individual drugs discussed later by representative generation.
Carbapenems:
Imipenem (broadest antibacterial available), meropenem, & ertapenem
How are new bacterial cell walls synthesized?
Transpeptidase enzymes (PBP) clips off the terminal D-alanine residue and crosslinks adjacent glycan chains
Newly formed covalently bonded chains form rigid cell walls that prevent osmotic forces from rupturing bacterial cell walls.
How do β-lactam antimicrobials work?
The β-lactam region (dark red) of β-lactam antimicrobial drugs resembles the D-Ala-D-Ala end of the normal protein substrate that binds to bacterial transpeptidase enzymes (a.k.a., PBP) to enable cell wall synthesis.
When a β-lactam antimicrobial binds to the PBP, it prevents transpeptidation, the last step in new peptidoglycan (cell wall) synthesis.
Without rigid cell wall, bacterial undergoes autolysis (BACTEROCIDAL)
Transpeptidase Enzymes
Also known as Penicillin-binding proteins (PBP)
β-lactam AMDs work by biningd to and inactivating PBPs to prevent cell wall synthesis
Remember IF either:
the PBP binding site is altered and/or
the β-lactam AMD is inactivated via bacterial beta-lactamase enzymes
THEN the β-lactam AMD will no longer inhibit cell wall synthesis
PBP will still be able to carry out its cross-linking function
Classification of β−lactam Antimicrobials: (6 groups):
- Natural Penicillans
- Aminopenicillins
- Penicillinase-resistant penicillins
- Anti-Pseudonomal penicillins
- Cephalosporins
- Carbapenems
Natural Penicillins Facts:
Penicillin G, penicillin V (a.k.a., penicillin VK)
highest activity against Gram (+) organisms (ineffective against Staph. aureas)
Very susceptible to bacterial β-lactamases
