Pulmonary infections in critically ill patients are common, frequently lethal and treatment may be complicated by bacterial resistance. Piperacillin-tazobactam (PTZ) is a broad-spectrum β-lactam antibiotic, frequently used for pulmonary infections. Lung antibiotic concentration reflects target site concentrations in patients with pneumonia. Critically ill patient’s exhibit marked pharmacokinetic (PK) variability. PTZ exposures resulting in maximal bacterial killing and prevention of emergence of drug resistance are not known. Administration of PTZ by extended infusions (EI) or using Bayesian dosage optimisation, instead of a fixed bolus regimen, may improve clinical outcomes. Experimental work was conducted in an in vitro hollow fibre infection model (HFIM) using two densities of Pseudomonas aeruginosa. Experimental data was described by a mathematical model allowing identification of PTZ exposures associated with bacterial killing and suppression of the emergence of resistance. The population PK of PTZ in the plasma and lung of 17 critically ill patients was estimated. Monte Carlo simulation was used to explore the proportion of patients that achieve the plasma and lung PTZ exposures associated with bacterial killing and resistance suppression and to determine the effect of administration schedule. Finally, the population PK of PTZ in the plasma of 146 critically ill patients was estimated and used to construct computer software that can individualise PTZ dosing. Precision of the dosing software was assessed in 8 additional individuals. At low bacterial density a trough piperacillin:MIC ratio of 3.4 for bolus and 10.4 for EI regimens were able to suppress the emergence of resistance. At higher bacterial density all regimens were associated with growth of a resistant sub-population. Pulmonary piperacillin and tazobactam concentrations were unpredictable and negatively correlated to pulmonary permeability. Simulations revealed that EI, compared with bolus dosing, of PTZ is associated with a higher likelihood of bacteria killing. Similar probability of developing resistance was predicted with PTZ administration by EI and by bolus administration. Performance of the dose optimisation software was satisfactory. Current PTZ regimens are insufficient to treat pneumonia in approximately 14% of critically ill patients. Delivery of PTZ by EI may be a more effective method of administration for some patients with nosocomial infections. Individualised PTZ regimens, delivering a target piperacillin concentration, identified in a HFIM, are achievable and should improved clinical outcomes. Patients with a high bacterial burden may required alternative therapeutic strategies to maximize bacterial killing and prevent antimicrobial resistance.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626967 |
| Date | January 2014 |
| Creators | Felton, Timothy |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/antimicrobial-therapy-in-critically-ill-patients-improving-clinical-outcomes-using-a-translational-pharmacological-approach(afffd886-c447-4974-ab0b-a9e8a8c8f2b2).html |
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