Should we be performing TDM in seriously ill patients with Gram negative infections?

Transcription

1 Should we be performing TDM in seriously ill patients with Gram negative infections? Jason A Roberts B Pharm (Hons), PhD, FSHP Royal Brisbane and Women s Hospital, Australia. The University of Queensland, Australia. j.roberts2@uq.edu.au

2 YES

3 Contents 1. Antibiotic PK/PD 2. PK in ICU patients 3. What is TDM? 4. When should TDM be used? 5. For which drugs should we use TDM? 6. Conclusion

4 Why is antibiotic dosing important? Bacteriologic cure Optimal antibiotic dosing Ineffectual Antibiotic Dosing Clinical cure Reduction in antibiotic resistance

5 PD C max :MIC Changing concentrations vs Pseudomonas aeruginosa

6 PD T>MIC K. pneumoniae vs cefotaxime in mice

7 PD characteristics of antibiotics

8 Contents 1. Antibiotic PK/PD 2. PK in ICU patients 3. What is TDM? 4. When should TDM be used? 5. For which drugs should we use TDM? 6. Conclusion

9 Sepsis changes PK and PD Extracorporeal circuits Altered CL and Increased Vd cf AKI? Plasma concentrations If dosing does not account for these changes sub-optimal therapy! Sub-optimal patient outcomes

10 What is different about patients with serious infections? PK that is not known or not quantified Therefore, altered antibiotic exposure to bacteria and altered PD (effect) Drug administration PK Concentration at target site PD Effect (desired/adverse)

11 Why is PK different? Different Cl (renal elimination of drug) Supranormal (sepsis and stress response) Impaired (ARF, CRF) Different Vd Increased (obesity, sepsis, burns, pregnancy) Decreased (unlikely long stay) Different Cl and Vd

12 Concentration variability

13 Concentration variability piperacillin in ICU patients Time (hours)

14 PD: ICU Susceptibility Patterns Decreased susceptibility of organisms in ICU Increased doses needed to achieve PK/PD targets Doripenem -Chosen PD target 40% or 100% ft>mic -Target concentration - 4 mg/l vs 8 mg/l -Difference between 1g and 2g dose! all isolates ICU AAC 2010; 54(6):

15 Contents 1. Antibiotic PK/PD 2. PK in ICU patients 3. What is TDM? 4. When should TDM be used? 5. For which drugs should we use TDM? 6. Conclusion

16 TDM - definition Therapeutic drug monitoring (TDM) is a branch of clinical chemistry and clinical pharmacology that specialises in the measurement of drug concentrations in blood. It is aim at improving patient care by individually adjusting the dose of drugs based on the results of the analyses (source Wikipedia)

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18 Application of TDM in patients with serious Gram negative infections? Van Lent Evers (Ther Drug Monit 1999; 21: 63-73) N=232

19 Other drugs subject to TDM? Glycopeptides Quinolones Beta-lactams Linezolid Colistin

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21 Beta-lactam dose adjustment data

22 Does the assay matter?

23 Contents 1. Antibiotic PK/PD 2. PK in ICU patients 3. What is TDM? 4. When should TDM be used? 5. For which drugs should we use TDM? 6. Conclusion

24 Patients at risk of unintended exposures Data from our beta-lactam TDM program: ARC (CrCL >130ml/min) dose increase in 76% SeCr >180 80% dose decrease CRRT 20% dose increase 50% dose decrease Presence of surgical drains 62% dose increase

25 Contents 1. Antibiotic PK/PD 2. PK in ICU patients 3. What is TDM? 4. When should TDM be used? 5. For which drugs should we use TDM? 6. Conclusion

26 Relevant antibiotics? Tx of Gram negative infections Aminoglycosides Quinolones Beta-lactams Colistin Tx of Gram positive infections glycopeptides linezolid

27 Contents 1. Antibiotic PK/PD 2. PK in ICU patients 3. What is TDM? 4. When should TDM be used? 5. For which drugs should we use TDM? 6. Conclusion

28 Conclusions Most patients can be administered typical doses of antibiotics Some patients are difficult-to-dose with uncertain or unpredictable PK Understanding of PK can assist dose-optimisation Clinical utility of TDM yet to be clarified