Development of resistance in wild-type and hypermutable Pseudomonas aeruginosa strains exposed to clinical pharmacokinetic profiles of meropenem and ceftazidime simulated in vitro.
In this study we investigated the interplay of antibiotic pharmacokinetic profiles and the development of mutation-mediated resistance in wild-type and hypermutable Pseudomonas aeruginosa strains. We used in vitro models simulating profiles of the commonly used therapeutic drugs meropenem and ceftazidime, two agents with high levels of antipseudomonal activity said to have different potentials for stimulating resistance development. During ceftazidime treatment of the wild-type strain (PAO1), fully resistant mutants overproducing AmpC were selected rapidly and they completely replaced wild-type cells in the population. During treatment with meropenem, mutants of PAO1 were not selected as rapidly and showed only intermediate resistance due to the loss of OprD. These mutants also replaced the parent strain in the population. During the treatment of the mutator P. aeruginosa strain with meropenem, the slowly selected mutants did not accumulate several resistance mechanisms but only lost OprD and did not completely replace the parent strain in the population. Our results indicate that the commonly used dosing regimens for meropenem and ceftazidime cannot avoid the selection of mutants of wild-type and hypermutable P. aeruginosa strains. For the treatment outcome, including the prevention of resistance development, it would be beneficial for the antibiotic concentration to remain above the mutant prevention concentration for a longer period of time than it does in present regimens.
Henrichfreise
Beate
B
Pharmaceutical Microbiology Unit, Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Meckenheimer Allee 168, 53115, Bonn, Germany. bhenrich@uni-bonn.de
Wiegand
Irith
I
Luhmer-Becker
Ingeborg
I
Wiedemann
Bernd
B
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002442:Ceftazidime / Q000493:pharmacokinetics / Q000494:pharmacology*; D015169:Colony Count, Microbial; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D018272:Porins / Q000235:genetics; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D018272:Porins; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; C077157:OprD protein, Pseudomonas aeruginosa; D002442:Ceftazidime; D000077731:Meropenem