title: Resistance suppression by high-intensity, short-duration aminoglycoside exposure against hypermutable and non-hypermutable Pseudomonas aeruginosa.
abstract: Hypermutable bacteria are causing a drastic problem via their enhanced ability to become resistant. Our objectives were to compare bacterial killing and resistance emergence between differently shaped tobramycin concentration-time profiles at a given fAUC/MIC, and determine the tobramycin exposure durations that prevent resistance.
  
  
  
  Static concentration time-kill studies over 24 h used Pseudomonas aeruginosa WT strains (ATCC 27853 and PAO1) and hypermutable PAOΔmutS. fAUC/MIC values of 36, 72 and 168 were assessed at initial inocula of 106and 104cfu/mL (all strains) and 101.2cfu/mL (PAOΔmutS only) in duplicate. Tobramycin was added at 0 h and removed at 1, 4, 10 or 24 h. Proportions of resistant bacteria and MICs were determined at 24 h. Mechanism-based modelling was conducted.
  
  
  
  For all strains, high tobramycin concentrations over 1 and 4 h resulted in more rapid and extensive initial killing compared with 10 and 24 h exposures at a given fAUC/MIC. No resistance emerged for 1 and 4 h durations of exposure, although extensive regrowth of susceptible bacteria occurred. The 24 h duration of exposure revealed less regrowth, but tobramycin-resistant populations had completely replaced susceptible bacteria by 24 h for the 106cfu/mL inoculum. The hypermutable PAOΔmutS showed the highest numbers of resistant bacteria. Total and resistant bacterial counts were described well by novel mechanism-based modelling.
  
  
  
  Extensive resistance emerged for 10 and 24 h durations of exposure, but not for shorter durations. The tobramycin concentration-time profile shape is vital for resistance prevention and should aid the introduction of optimized combination regimens.
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria 3052, Australia.
authors: Vanessa E
authors: VE
authors: Rees
authors: Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
authors: Jürgen B
authors: JB
authors: Bulitta
authors: Servicio de Microbiología, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain.
authors: Antonio
authors: A
authors: Oliver
authors: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors: Brian T
authors: BT
authors: Tsuji
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria 3052, Australia.|d3 medicine LLC, Parsippany, NJ, USA.
authors: Craig R
authors: CR
authors: Rayner
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria 3052, Australia.
authors: Roger L
authors: RL
authors: Nation
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria 3052, Australia cornelia.landersdorfer@monash.edu.|School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors: Cornelia B
authors: CB
authors: Landersdorfer
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013997:Time Factors; D014031:Tobramycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D014031:Tobramycin