Open AccessEfficacy and Potential for Resistance Selection of Antipseudomonal Treatments in a Mouse Model of Lung Infection by Hypermutable Pseudomonas aeruginosa
Author(s) -
María D. Maciá,
Núria Borrell,
Miguel F. Segura,
Cristina Gómez,
José Luís Pérez,
Antonio Oliver
Publication year - 2006
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.50.3.975-983.2006
Subject(s) - tobramycin , pseudomonas aeruginosa , in vivo , ciprofloxacin , microbiology and biotechnology , pharmacodynamics , pharmacokinetics , antibiotics , biology , pharmacology , medicine , bacteria , gentamicin , genetics
HypermutablePseudomonas aeruginosa strains are found with high frequency in the lungs of patients with chronic infections and are associated with high antibiotic resistance rates. The in vivo consequences of hypermutation for treatment in a mouse model of lung infection using strain PAO1 and its hypermutable derivative PAOΔmutS are investigated. Groups of 30 mice were treated for 3 days with humanized regimens of ciprofloxacin (CIP), tobramycin (TOB), CIP plus TOB, or placebo, and mortality, total lung bacterial load, and 4×- and 16×-MIC mutants were recorded. The rates of mutation and the initial in vivo frequencies of mutants (at the onset of treatment) were also estimated and the in vitro- and in vivo-selected mutants characterized. Since both strains had identical MICs, the same pharmacokinetic/pharmacodynamic (PK/PD) parameters were obtained: area under the 24-h concentration-time curve (f AUC)/MIC = 385 for CIP and maximum concentration of drug in serum (f C max )/MIC = 19 for TOB. Despite adequate PK/PD parameters, persistence of high bacterial numbers and amplification (50,000-fold) of resistant mutants (MexCD-OprJ hyperexpression) were documented with CIP treatment for PAOΔmutS , in contrast to complete resistance suppression for PAO1 (P < 0.01), showing that conventional PK/PD parameters may not be applicable to infections by hypermutable strains. On the other hand, the efficacy of TOB monotherapy in terms of mortality reduction and bacterial load was very low regardless of the strain but not due to resistance development, since mutants were not selected for PAO1 and were only modestly amplified for PAOΔmutS . Finally, the CIP-plus-TOB combination was synergistic, further reducing mortality and bacterial load and completely preventing resistance even for PAOΔmutS (P < 0.01 compared to monotherapy), showing that it is possible to suppress resistance selection in infections by hypermutableP. aeruginosa using appropriate combined regimens.