Virulence of Pseudomonas aeruginosa strains with mechanisms of microbial persistence for beta-lactam and aminoglycoside antibiotics in a mouse infection model.

A series of mutations and transductants producing low-level aminoglycoside and beta-lactam antibiotic resistance of Pseudomonas aeruginosa have been constructed in an isogenic background. The phenotypes of these mutations are identical to or closely resemble those of clinical isolates of P. aeruginosa associated with therapeutic failure or microbial persistence in the presence of members of one or both groups of drugs. Virulence of the mutants was examined in an infection model using iron-dextran treated mice and bacteria grown in low-iron medium. All beta-lactam resistant mutants affecting affinity of penicillin-binding proteins for beta-lactams, constitutive beta-lactamase, or permeability of beta-lactams retained parental levels of virulence. Aminoglycoside-resistant mutants with defective energy generation or transductants with modified lipopolysaccharide showed reduced virulence. Strains with the preceding forms of resistance are likely to account for therapeutic failure or microbial persistence with antibiotic treatment. We propose that mechanisms of low or unstable forms of resistance should be designated mechanisms of persistence to differentiate them from more classical mechanisms of resistance.