The projects within this broad topic will characterise pharmacokinetics of antimicrobials in critically ill patients with ventilator associated pneumonia, community acquired pneumonia and in critically ill patients receiving renal replacement therapy.

Pneumonia is the most common infection in critically ill patients and is diagnosed in 10% of all patients with as much as 35% of pneumonia caused by a resistant pathogen. Uncertainty relating to antibiotic penetration into the site of infection is present with many agents. For example, ceftazidime is reported to have only 20.6 + 8.9% penetration into epithelial lining fluid (ELF), the infection site in pneumonia.

Pharmacokinetic studies in critically ill patients receiving renal replacement therapy (RRT) are resource intensive and reliance on this approach to generate clinically relevant antimicrobial doses for the various RRT modalities and settings is problematic. It is also unethical to change RRT settings in ICU patients without clinical justification.

We will use an alternative approach to measure the effect of changes of RRT modality (haemofiltration, haemodiafiltration) and settings (e.g. blood flow rate, effluent flow rate, filter surface area) in a simulated ex vivo RRT circuit.

This approach, supported by mechanism-based pharmacokinetic modelling may serve to validate this technique for estimating RRT clearance in ICU patients as a substitute for expensive clinical PK studies.

Relevant Publications

Yadav R., Rogers K., Bergen P., Bulitta J., Kirkpatrick CM., Wallis, S., Peterson DL., Nation R., Lipman J., Roberts JA. & Landersdorfer, CB. Optimisation and evaluation of piperacillin plus tobramycin combination dosage regimens against Pseudomonas aeruginosa for patients with altered pharmacokinetics via the hollow-fiber infection model an mechanism-based modelling, Antimicrob Agents Chemother 2018; in press (date accepted 13th February 2018; AAC00078-18).

Bergen P., Bulitta JB., Sime FB., Lipman J., McGregor MJ., Millen N., Paterson DL., Kirkpatrick CMJ., Roberts JA. & Landersdorfer CB. Differences in supression of regrowth and resistance despite similar initial bacterial killing for meropenem and piperacillin/tazobactam against Pseudomonas aeruginosa and Escherichia coli. Diagn Microbiol Infect Dis 2018; in press (date accepted 4th January 2018; DMID-16-942).

De Waele JJ., Akova M., Antonelli M., Canton R., Carlet J., De Backer D., Dimopolous G., Garnarcho-Montero J., Kesecioglu J., Lipman J., Mer M., Paiva JA., Poljak M., Roberts JA., Rodriguez-Bano J., Timsit JF., Zahar JR. & Bassetti M. Antimicrobial resistance and antibiotic stewardship programs in the ICU: insistence and persistence in the fight against resistance. A position statement from ESICM/ESCMID/WAAAR ROund Table on Multi-Drug Resistance. Intensive Care Med 2017; in press (date accepted 18th December 2017; ICME-D-17-01392).

Abdul-Aziz, M.H., Lipman, J. and Roberts, J.A. Antibiotic dosing for multidrug-resistant pathogen pneumonia, Curr Opin Infect Dis, 2017, 30:231-239 DOI:10.1097/QCO.0000000000000348

Roberts, J., Lefrant, J., & Lipman, J. (2017). What's new in pharmacokinetics of antimicrobials in AKI and RRT? Intensive Care Medicine, 43(6), 904-906. DOI: 10.1007/s00134-017-4789-x

Rhodes, Nathaniel J., Liu, Jiajun, O'Donnell, J. Nicholas, Dulhunty, Joel M., Abdul-Aziz, Mohd H., Berko, Patsy Y., Nadler, Barbara, Lipman, Jeffery and Roberts, Jason A. (2018) Prolonged Infusion Piperacillin-Tazobactam Decreases Mortality and Improves Outcomes in Severely Ill Patients: Results of a Systematic Review and Meta-Analysis. Critical Care Medicine, 46 2: 236-243. doi:10.1097/CCM.0000000000002836