Trade-Offs between Antibacterial Resistance and Fitness Cost in the Production of Metallo-β-Lactamases by Enteric Bacteria Manifest as Sporadic Emergence of Carbapenem Resistance in a Clinical Setting.

Meropenem is a clinically important antibacterial reserved for treatment of multiresistant infections. In meropenem-resistant bacteria of the family , NDM-1 is considerably more common than IMP-1, despite both metallo-β-lactamases (MBLs) hydrolyzing meropenem with almost identical kinetics. We show that consistently confers meropenem resistance in wild-type , but does not. The reason is higher expression because of its stronger promoter. However, the cost of meropenem resistance is reduced fitness of -positive . In parallel, from a clinical case, we identified multiple Enterobacter spp. isolates carrying a plasmid-encoded having a modified promoter region. This modification lowered MBL production to a level associated with zero fitness cost, but, consequently, the isolates were not meropenem resistant. However, we identified a Klebsiella pneumoniae isolate from this same clinical case carrying the same plasmid. This isolate was meropenem resistant despite low-level NDM-1 production because of a mutation reducing envelope permeability. Overall, therefore, we show how the resistance/fitness trade-off for MBL carriage can be resolved. The result is sporadic emergence of meropenem resistance in a clinical setting.