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three major mechanisms of antibiotic resistance
1. Modify the drug
2. Modify the target
3. Pump the drug out with efflux pumps
Understand the importance of binding PBP2a.
For example, PBP2a is found in MRSA, which leads to resistance to most beta lactams due to low affinity for PBP2a, but ceftaroline binds and inhibits transpeptidation by PBP2a.
For the types of beta-lactamases understand which classes are serine-based and which class is a metallo-enzyme
Serine Beta Lactamases (Classes A,C,D)
Zinc Beta Lactamases (Class B)
the strategies used to overcome resistance via beta-lactamase inhibitors
Slow substrates
Suicide substrates
Suicide substrates
Clavulanate, Sulbactam, Tazobactam
Used on combo w beta lactams to inactivate beta lactamses
How making beta-lactams that are slow substrates.
Structural modifications in the acyl side chains of B lactam antibiotics to build in slow processing by B lactamases
Why are lactamases such as NDM-1 effective at hydrolyzing beta-lactams that were modified to be slow substrates for ser based lactamases?
Divalent ions in the active site
mechanism doesn’t rely on a serine residue or a covalent intermediate (like in serine-based beta-lactamases), MBLs can easily hydrolyze beta-lactams that were chemically modified to resist serine enzymes
Why do Beta-lactamase inhibitors such as Clavulonic acid (Clavulonate), sulbactam, tazobactam, and vabomere need to be co-administered with a beta lactam antibiotic
inhibit serine-based beta-lactamases but need to be co-administered with a beta lactam antibiotic because they don’t have sufficient antibacterial activity on their own.
vancomycin activates
both VanB and VanA where other glycopeptides such as teicoplanin and Dalbavancin do not activate VanB
(vancomycin is not effective against bacteria with VanA or VanB genes.)
Van C phenotype uses ___ instead of D-Lac
D-Ser
What distinguishes Ortivancin
Does not activate VanA, VanB, and VanC
Be familiar with the VanA, VanB, and resistance types.
VanA is the most clinically significant because of its high-level resistance and plasmid-mediated spread.
VanB resistance is limited to vancomycin, making teicoplanin a possible alternative.
VanC is intrinsic and poses less of a threat, but still requires careful consideration in treatment.