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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 PAO?mutS. fAUC/MIC values of 36, 72 and 168 were assessed at initial inocula of 106 and 104 cfu/mL (all strains) and 101.2 cfu/mL (PAO?mutS 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 106 cfu/mL inoculum. The hypermutable PAO?mutS 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.

SUBMITTER: Rees VE

PROVIDER: S-EPMC5079302 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Rees Vanessa E VE Bulitta Jürgen B JB Oliver Antonio A Tsuji Brian T BT Rayner Craig R CR Nation Roger L RL Landersdorfer Cornelia B CB

The Journal of antimicrobial chemotherapy 20160811 11

<h4>Objectives</h4>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.<h4>Methods</h4>Static concentration time-kill studies over 24 h used Pseudomonas aeruginosa WT strains (ATCC 27853 and PAO1) and hypermutable PAOΔm ...[more]

PMID: 27521357

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Project description:Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔmutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T>MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

Dataset Information

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

Publications

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

Similar Datasets

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