A patient with KPC-producing Klebsiella pneumoniae bacteraemia is treated with ceftazidime-avibactam. Four weeks later, cultures reveal avibactam resistance. Which molecular mechanism is most commonly responsible for this emergence?
- A Upregulation of OXA-48 co-production silences KPC expression via plasmid incompatibility
- B Deletion of chromosomal ompK35 and ompK36 porin genes prevents avibactam from entering the periplasm
- C Acquisition of NDM-1 gene replaces KPC, conferring resistance to all beta-lactam/inhibitor combinations
- D Point mutations in the KPC enzyme (D179Y or V240G) reduce avibactam binding affinity without substantially impairing carbapenem hydrolysis ✓
Explanation
The most characterized mechanism of ceftazidime-avibactam resistance development in KPC-producing K. pneumoniae involves point mutations in the KPC beta-lactamase gene, particularly at positions D179Y (Asp179Tyr) and V240G. These mutations alter the omega loop or active site geometry, dramatically reducing avibactam binding (deacylation rate increases) while paradoxically retaining or even enhancing carbapenemase activity, resulting in carbapenem resistance as well. This makes the isolate pan-resistant. Monitoring for this resistance mechanism is critical, and treatment options become extremely limited, sometimes requiring aztreonam-avibactam combinations for NDM co-producers.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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