1. Optimisation of combination therapy for treatment of Pseudomonas aeruginosa Alex Cochrane Bristol Centre for Antimicrobial Research and Evaluation University of Bristol

2. Why use combination therapy? Monotherapy or Combination Therapy? The Pseudomonas aeruginosa Conundrum Kristi Traugott, Pharmacotherapy 2011 Medline search 1950 to 2010 Medline search 1950 to 2010 P. aeruginosa bacteraemia and pneumonia P. aeruginosa bacteraemia and pneumonia Conclusions Conclusions Is there clinically significant synergy? Is there clinically significant synergy? Unknown Unknown Is there clinically significant reduction in resistance? Is there clinically significant reduction in resistance? Unknown Unknown

3. Initial Study Antimicrobials Antimicrobials Piperacillin Tazobactam Piperacillin Tazobactam Gentamicin Gentamicin Organism Organism Bloodculture isolate of Pseudomonas aeruginosa Bloodculture isolate of Pseudomonas aeruginosa MIC gentamicin = 2 (sensitive) MIC gentamicin = 2 (sensitive) MIC piperacillin tazobactam = 8 (sensitive) MIC piperacillin tazobactam = 8 (sensitive) Methodology Methodology Kill curve Kill curve Sampled at 0, 1,3,6,12,24,36 and 48 hours. Sampled at 0, 1,3,6,12,24,36 and 48 hours. Antibiotic concentrations chosen to reflect concentrations that would be found in serum during a standard dosing regimen Antibiotic concentrations chosen to reflect concentrations that would be found in serum during a standard dosing regimen

4. Antibiotic concentrations used Gentamicin Concentration 15mg/l4.5mg/l0.5mg/l0.125mg/lnil P/T concentration 196mg/lABCDE 28mg/lFGHIJ 1mg/lKLMNO nilPQRS Growth control

5. Results Monotherapy

8. Results Combination therapy

13. Combinations for reduction of development of resistance: 24 hours Gentamicin Concentration 15mg/l4.5mg/l0.5mg/l 0.125mg /l nil P/T concentration 196mg/l 28mg/l 1mg/l nil Growth control Resistance at 4 X MICResistance at 32 X MIC

14. Resistance - Summary High level resistance to Piperacillin/Tazobactam developed within 48 hours only in the absence of gentamicin. High level resistance to Piperacillin/Tazobactam developed within 48 hours only in the absence of gentamicin. High level resistance to gentamicin developed within 48 hours only in the absence of Piperacillin/Tazobactam High level resistance to gentamicin developed within 48 hours only in the absence of Piperacillin/Tazobactam

15. Next step Compare standard dosing and continuous infusion schedules of P/T alone or in combination with 24hrly and 8hrly dosing of gentamicin in an in vitro dynamic model. Compare standard dosing and continuous infusion schedules of P/T alone or in combination with 24hrly and 8hrly dosing of gentamicin in an in vitro dynamic model.

16. Acknowledgements Alan Noel Karen Bowker Alasdair MacGowan All staff at Bristol Centre for Antimicrobial Research and Evaluation University of Bristol

25. Combinations for reduction of development of resistance: 48 hours Gentamicin Concentration 15mg/l4.5mg/l0.5mg/l 0.125mg /l nil P/T concentration 196mg/l 28mg/l 1mg/l nil Growth control Resistance at 4 X MICResistance at 32 X MIC

26. Combinations for reduction of development of resistance: 24 hours Gentamicin Concentration 15mg/l4.5mg/l0.5mg/l 0.125mg /l nil P/T concentration 196mg/l 28mg/l 1mg/l nil Growth control Resistance at 4 X MICResistance at 32 X MIC