Resistance suppression by high-intensity, short-duration aminoglycoside exposure against hypermutable and non-hypermutable Pseudomonas aeruginosa

<span class="paragraphSection"><div class="boxTitle">Objectives</div>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 <span style="font-style:italic;">f</span>AUC/MIC, and determine the tobramycin exposure durations that prevent resistance.<div class="boxTitle">Methods</div>Static concentration time–kill studies over 24 h used <span style="font-style:italic;">Pseudomonas aeruginosa</span> WT strains (ATCC 27853 and PAO1) and hypermutable PAOΔ<span style="font-style:italic;">mutS. f</span>AUC/MIC values of 36, 72 and 168 were assessed at initial inocula of 10⁶ and 10⁴ cfu/mL (all strains) and 10^1.2 cfu/mL (PAOΔ<span style="font-style:italic;">mutS</span> 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.<div class="boxTitle">Results</div>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 <span style="font-style:italic;">f</span>AUC/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 10⁶ cfu/mL inoculum. The hypermutable PAOΔ<span style="font-style:italic;">mutS</span> showed the highest numbers of resistant bacteria. Total and resistant bacterial counts were described well by novel mechanism-based modelling.<div class="boxTitle">Conclusions</div>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.</span>

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