Impact of Bolus Dosing versus Continuous Infusion of Piperacillin and Tazobactam on the Development of Antimicrobial Resistance in Pseudomonas aeruginosa.
Antimicrob Agents Chemother. 2013 Sep 3;
Authors: Felton TW, Goodwin J, O'Connor L, Sharp A, Gregson L, Livermore J, Howard SJ, Neely MN, Hope WW
Abstract
Management of nosocomial pneumonia is frequently complicated by bacterial resistance. Extended infusions of beta-lactams are increasingly used to improve clinical outcomes. However, the impact of this strategy on the emergence of antimicrobial resistance is not known. A hollow fiber infection model with Pseudomonas aeruginosa (PA01) was used. Human-like pharmacokinetic (PK) profiles of piperacillin/tazobactam were simulated over five days. Three dosages of piperacillin/tazobactam were administered over 0.5 hrs or 4 hrs with re-dosing every 8hrs. Two initial bacteria densities were investigated (≈10(4) CFU/ml and ≈10(7) CFU/ml). The time courses of total bacterial population and the resistant sub-population were determined. All data were described using a mathematical model, which was then used to define the relationship between drug concentrations, bacterial kill and emergence of piperacillin resistance. There was logarithmic growth in controls in the initial 24 hrs reaching a plateau of ≈9 log10CFU/mL. Bacterial killing following administration of piperacillin via bolus dosing or extended infusions was similar. For lower initial bacterial density trough total plasma piperacillin concentration:MIC ratios of 3.4 and 10.4, for bolus and extended infusion regimens, respectively, were able to suppress the emergence of piperacillin resistance. For the higher initial bacterial density, all regimens were associated with progressive growth of a resistant sub-population. A stratified approach, according to bacterial density, is required to treat patients with nosocomial pneumonia. Antimicrobial monotherapy may be sufficient for some patients. However for patients with a high bacterial burden alternative therapeutic strategies, are required to maximize bacterial killing and prevent antimicrobial resistance.
PMID: 24002098 [PubMed - as supplied by publisher]