Enzymatic destruction, target alteration, reduced entry and efflux
Expansion
Four mechanisms
- Enzymatic inactivation: beta-lactamases, including extended spectrum beta-lactamases (ESBL) and carbapenemases; aminoglycoside-modifying enzymes
- Target alteration: MRSA acquires PBP2a with low beta-lactam affinity; VRE alters D-ala-D-ala to D-ala-D-lac; macrolide resistance by ribosomal methylation
- Reduced permeability: loss of porin channels, important in Gram negatives
- Efflux pumps: tetracycline and quinolone resistance
Genetic basis: chromosomal mutation, or acquisition of genes by plasmids, transposons and integrons, which allows rapid horizontal spread between species.
Drivers: unnecessary prescribing, inadequate dose or duration, agricultural use, and poor infection control.
Stewardship principles: take cultures before starting, use the narrowest effective spectrum, the shortest effective duration, correct dose, review at 48 to 72 hours, and switch from intravenous to oral when appropriate.
Note the important distinction that MRSA resistance is target-based, so beta-lactamase inhibitors such as clavulanate are useless; treatment requires vancomycin, teicoplanin, linezolid or daptomycin.