Carbapenem resistance in Pseudomonas aeruginosa from cystic fibrosis patients

Abstract

The evolution of imipenem resistance was evaluated in Pseudomonas aeruginosa sequentially isolated from 42 patients with cystic fibrosis. Susceptibility was determined using a commercial microdilution system and imipenem resistance was confirmed by the agar dilution technique. Resistance to imipenem increased during the years from 1988 to 1992. A total of 12 patients (28.5%) carried resistant strains (11.6% of the total P. aeruginosa isolates) but only two of them were treated with the carbapenem. The other patient under imipenem treatment did not harbour resistant isolates. Sixty-four per cent of the imipenem resistant isolates were also meropenem resistant and showed low susceptibility to the other beta-lactams and tobramycin and amikacin. Twenty-one strains were selected for biochemical study. Imipenem susceptible strains showed normal OprD in two strains and diminished OprD in two more. Five strains with MIC of imipenem of 4-8 mg/L lacked OprD while another two had a band with decreased density. All strains with MIC higher than 8 completely lacked this band in western-blot analysis. Imipenem MICs of 0.5-2 mg/L only slightly increased to 1-4 mg/L when a pattern of beta-lactamase derepression was observed. While those with imipenem MICs between 8-16 mg/L increased the imipenem MIC to 16-64 mg/L in the population with a beta-lactamase derepression phenotype.

Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis

“…These results are in line with previous studies that have reported that P. aeruginosa host adaptation is mediated by loss of motility, acquisition of antibiotic resistance, remodeling of regulatory networks, loss of extracellular virulence factors and modification of the cell envelope 1,[22][23][24][25][26][27][28][29] . Furthermore, we anticipate that mutations, in general, are associated with loss of gene function, as 45 of the 52 genes were targeted by frameshift mutations (with the exceptions of gyrA, gyrB, PA1471, pcoA, mexS, vgrG and yecS).…”

Mutators in cystic fibrosis chronic lung infection: Prevalence, mechanisms, and consequences for antimicrobial therapy

“…One of the most striking characteristics of P. aeruginosa is its extraordinary ability for antibiotic resistance acquisition through the selection of mutations in chromosomal genes (Livermore, 2002). Among the mutation-mediated resistance mechanisms are particularly noteworthy those leading to the repression or inactivation of the porin OprD, conferring resistance to carbapenems (Ballesteros et al, 1996) or those leading to the hyperproduction of the chromosomal cephalosporinase AmpC, such as AmpD or PBP4 inactivation (Bagge et al, 2002;Moya et al, 2009), determining resistance to penicillins and cephalosporins. Also remarkable, mutations leading to the upregulation of one of the several efflux pumps encoded in the P. aeruginosa genome, may confer resistance or reduced susceptibility to multiple agents including almost all ␤-lactams, fluoroquinolones, and aminoglycosides (Jalal et al, 2000;Vogne et al, 2004).…”

mexEF-oprN Multidrug Efflux Operon of Pseudomonas aeruginosa : Regulation by the MexT Activator in Response to Nitrosative Stress and Chloramphenicol

“…Enhanced resistance to imipenem, which is also seen for nfxC (28) and mexS (48) strains, results not from MexEF-OprN expression but from the concomitant decrease in levels of the outer membrane protein OprD in these mutants (12,31,48). OprD is an imipenem channel and a primary route of entry of this antibiotic in P. aeruginosa (52), whose absence is often seen in imipenem-resistant strains of P. aeruginosa (3,27). Like other tripartite RND family pumps, the MexEF-OprN efflux system consists of an inner membrane (IM) drug-proton antiporter (the RND component) (MexF), an outer membrane (OM) channel-forming component (OprN), and a periplasmic membrane fusion protein (MFP) (MexE) (38,54).…”