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Pk/Pd features for optimisation of antibiotic therapy

Pk/Pd features for optimisation of antibiotic therapy. PK/PD Clinical Applications. Johan W Mouton. Canisius-Wilhelmina Hospital Nijmegen, The Netherlands. Clinical Applications of Pk/Pd. Dose effect relationships of antimicrobials :the MIC, the dose and the effect

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Pk/Pd features for optimisation of antibiotic therapy

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  1. Pk/Pd features for optimisation ofantibiotic therapy PK/PD Clinical Applications Johan W Mouton Canisius-Wilhelmina Hospital Nijmegen, The Netherlands

  2. Clinical Applications of Pk/Pd • Dose effect relationships • of antimicrobials :the MIC, the dose • and the effect • Define resistance as not likely to • react to therapy GIVEN THE DOSE • Optimize and/or • individualize therapy

  3. Is MIC related to (clinical) outcome? Is dosing related to (clinical) outcome? (are concentrations related to outcome)

  4. Effect of azithromycin susceptibility of S. pneumoniae on bacteriological failure in AOM Based on data from Dagan et al, PIDJ 2000; AAC 2000, IJID 2003

  5. Relationship between AUC/MIC and Effect in CF patients Tobramycin Mouton et al 2005 Diagn Microbiol Infect Dis 52:123-127

  6. Relationship between fAUC/MIC and Effect121 patients with S. pneumoniae respiratory infection Ambrose PG, Bhavnani SM, Owens RC. Infect Dis Clin N Amer. 2003;17:529-543.

  7. MIC Lowest concentration with no visible growth after 18 hour incubation PK X-acin 500 mg .25 .5 1 2 4 8 MIC = 2 mg/L

  8. Pharmacokinetic Parameter (and Dose) MIC • Thus, we have to: • Establish a relationship between the MIC in vitro and concentrations in vivo (thus, dosing regimens) • Determine which dosing regimens are optimal for Treatment in relation to the MIC

  9. AUC and Peak are usually linearly related to Dose PEAK AUC MIC TIME > MIC

  10. 'Normalizing pk/pd relationships' Pharmacokinetic parameter MIC Pharmacodynamic index (AUC/MIC, Peak/MIC, T>MIC)

  11. Relationship between fAUC/MIC and Effect121 patients with S. pneumoniae respiratory infection fAUC/MIC cut-off ~34 Ambrose PG, Bhavnani SM, Owens RC. Infect Dis Clin N Amer. 2003;17:529-543.

  12. Thus, what are we aiming for ? • We wish to have all patients to have an fAUC/MIC ratio of > 34 • This can be achieved by : • AUC  • MIC  but …….

  13. Clinical practice : When starting treatment, we do not know : 1. the AUC in the individual patient 2. The MIC of the bug

  14. GOOD Clinical Practice: Be sure that the fAUC/MIC ratio is at least appr. 34 in every patient This includes patients with a high clearance Bugs with MICs that can be expected

  15. Levofloxacin 500 mg

  16. Pharmacokinetics • Some patients are more equal than others Oktoberfes

  17. Levofloxacin, 500 mg 50% Fig 4

  18. Levofloxacin, 500 mg 50% auc Fig 4

  19. Probability of Target Attainment • The % of patients reaching a specific target, e.g. AUC/MIC. This is plotted as a function of MIC.

  20. S = 1 mg/L EUCAST., 2004

  21. Susceptible (S)A micro-organism is defined as susceptible by a level of antmicrobial activity associated with a high likelihood of therapeutic success. A micro-organism is categorized as susceptible by applying the appropriatebreakpoint in a defined phenotypic test system.Note: This breakpoint may be altered with legitimate changes in circumstancesIntermediate (I)A micro-organism is defined as intermediate by a level of antimicrobial activity associated with indetermiatetherapeutic effect. A micro-organism is categorized as intermediate by applying the appropriate breakpointsin a defined phenotypic test system.Note: This breakpoints may be altered with legitimate changes in circumstances.Resistant (R)bacteria are defined as resistant by a level of antimicrobial activity associated with a high likelihood oftherapeutic failure. A micro-organism is categorized as resistant by applying the appropriate breakpoint in adefined phenotypic test system.Note: This breakpoint may be altered with legitimate changes in circumstances WWW.EUCAST.ORG

  22. High dose levofloxacin 2x 500 mg AUC 70-80 target 35 = 70 /2

  23. Thus: By using pk/pd relationships, therapy for each patient is optimized by applying the Right dose.

  24. Relationship Between T>MIC and Bacterial Eradication with Beta-Lactams in Otitis Media (Circles) and Maxillary Sinusitis (Squares) • Bacteriologic cure for different ß-lactams with S. pneumoniae and H. influenzae from double tap studies in acute otitis media and acute maxillary sinusitis • Time above MIC calculated from serum levels and MICs for different organisms Craig & Andes, Pediatr Infect Dis J 15:255, 1996; Dagan et al JAC 47:129, 2001;Dagan et al Pediatr Infect Dis J 20:829, 2001

  25. Patterns of activity: Kill curves of P. aeruginosa ceftazidime tobramycin Mouton JW Thesis 1993

  26. The difference in concentration between Max effect en no effect is small Aim for concentrations at max effect Mouton & Vinks Clin Pharmacokin 2005

  27. Using continuous infusion and maintaining a concentration above MIC should result in optimal treatment effect. Shown in: • In vitro pharmacokinetic models • Animal models

  28. MIC= 16 mg/l Resistant ..And give no treatment??

  29. How do we use TCD on the ICU? • Estimate pharmacokinetic parameters of individual patient • Determine MICs of micro-organisms • Determine the dose necessary to obtain the predicted effect desired

  30. Conclusions • Pk/pd relationships can be used to : • Describe dose effect relationships • Efficacy • Resistance • Set clinical breakpoints • Optimize therapy

  31. www.isap.org slide shows Workshops preceding : ECCMID, Nice 2006 ICAAC , Washington 2005

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