1. 8th ISAP Symposium Can PK/PD be used in everyday clinical practice? Francesco Scaglione Department of Pharmacology, Toxicology and Chemotherapy, University of Milan, Milan, Italy

2. PK/PD results and evolution 2000 Persistend effect Time/Conc. dependent activity } Improvement of dose and intervals } Outcome resistance ?

3. Several objectives Phase 2-3 clinical trial resistance Improvement of therapy

4. PK/PD evolution Custom-made therapy 2000

5. Effect over the time; the time; Peculiar Effects Effect over the time; the time; Peculiar Effects ADMEADME In Vitro and in vivo activity In Vitro and in vivo activity Pharmacology : what for physician? 0 2 4 6 8 10 12 14 16 18 20 01 23456789101112 time h concentration (µg/ml)

6. Optimizing antimicrobial therapy Concentration at infection site Pathogen MIC DRUG PK Pharmacodynamics = relationship between concentration and effect Bacterial kill

7. PHARMACODYNAMICS PEAK/ MIC MIC T>MIC t AUC/MIC c

8. Improving the probability of positive outcomes IMPROVING THE ODDS HOST BUG DRUG

9. PK/PD parameters determining efficacy Absorption Absorption Serum levels Serum levels Distribution and penetration to site of infection Distribution and penetration to site of infection Intracellular penetration Intracellular penetration Relationship of PK parameters to MIC Relationship of PK parameters to MIC

10. Peak level of tobramycin 3mg/kg in ten patients in ICU

11. Trauma FACTORS INVOLVED IN INLAMMATION Complement Necrosis Bacteria PMN MN Lymphocytes TNF-  IL - 1 IL - 6 PAF PGE LTC TXA Protease oxygen Radicals endothelial Damage Increase of capillary permeability Oedema

12. VARIATIONS OF INTERSTITIAL FLUID DURING INFECTIONS blood INTERSTITIAL FLUID Cells

13. THEORETICAL CONCENTRATION OF AN ANTIBIOTIC Time Serum Interstitial fluid Concentration Large volume compartment

14. ‘Time above MIC’ Concentration M IC 1 Time M IC 2 Time Over MIC Peak/MIC

15. Ideal approach to adjust the dose  Initial dosing regimen(chosen by patient’s physician)  Blood sampling( two or more post- distributional sample)  Pharmacokinetic analysis (peak,AUC,CL)  Adjust dose or/and intervals (PK/PD)  Redetermine concentrations  Adjust again ?

16. First problem PK approach to adjust the dose is poor applicable for routinely use (at moment)  N°samples  Personnel  Costs

17. second problem PK/PD breakpoints betalactams (ceftriaxone) aminoglicosides quinolones glicopeptides macrolides tetraciclines

18. Program to customize the therapy in our hospital  Isolation of the pathogen and MIC  Design therapy traditionally(by patient’s physician)  Pharmacokinetic  Adjust dose or interval using PK/PD  Redetermine concentrations

19. PK/PD values adopted Aminoglicosides Peak/MIC  8 Quinolones peak/MIC  10 Betalactams peak/MIC  4 and T>MIC  70% same value for monotherapy or combination

20. Sampling time Aminoglicosides Peak : 0.5 h from end 30 min infusion Quinolones peak : 0.5 h from end 60 min infusion Betalactams peak :0.5 h from end 30 min infusion And T>MIC : 5.6 hours from start infusion

21. Concentrations of ceftazidime and cefotaxime in serum 0 5 10 15 20 25 30 35 40 45 50 55 60 65 mg/L C 0.5 h C 5.6 h

22. Peak levels of amikacin 0 10 20 30 40 mg/L

23. PK/PD dose adjustment Levofloxacin 500 mg to 750 OD or BID Ciprofloxacin 500mg to 750 BID Cefotaxime-Ceftazidime 2g q 8 to 2g q6 Amikacin 10 mg/kg OD to 15 mg/kg OD

24. preliminary results October 2000 – April 2001 Patients included 680 Evaluated for PK/PD 223 (32.8%) Dose or interval adjusted 84 (37.7%) Adjustment failed in 6 (5 cipro -1 amikacin)

25. diagnosis Nosocomial pneumonia 105 Sepsis 44 upper UTI 57 Necrotizing Fascitis 8 Others 9

26. Organisms isolated Pseudomonas aeruginosa 87 Staphylococcus aureus 42 Enterobacter species 33 Klebsiella species 15 Escherichia coli 14 Haemophilus influenzae 11 Serratia marcescens 7 Streptococcus pneumoniae4 Stenotrophomonas spp 4 Legionella species2 Citrobacter species2 Acinetobacter1 Proteus species1

27. Aminoglicosides Dose adjusted according to creatinine clearance Creatinine clearance % of initial dose at mL/min 24h dosing interval: 40 92% 30 86 25 81 20 75 17 70 15 67 12 61 10 56

28. Ceftazidime-Cefotaxime-Levofloxacin Dose adjusted according to creatinine clearance >50 mL/min: normal dose 20-50 mL/min: 1/2-3/4 normal dose <20 mL/min: 1/4-1/2 normal dose

29. Ciprofloxacin Dose adjusted according to creatinine clearance > 20 mL/min: normal dose <20 mL/min: 1/2 normal dose

30. outcome Length hospitalization - days* failuremortality PK/PD analysed 11 (7-16) 39/223 (17.5%) 11(4.9%) PK/PD Not analysed 16 (9-23 ) 147/457 (31.9 %) 46(10.1%) *From the diagnosis of infection

31. 0255075100125150175 0 5 10 15 20 hours to adjust doses hospitalization days correlation between time to adjust the dose and hospitalisation days

32. Conclusions I The PK/PD approach may:  improve the outcome  shorten the time to clinical improvement  Reduce the length of hospitalisation

33. Conclusions II The initial higher costs for analysis and personnel are compensate for the reduction of the hospitalisation, with a financial gain

34. Conclusions III Can PK/PD be used in everyday clinical practice? yes

35. Conclusions IV homework When you came back at home, please tray to convince Top Managers as well as Physicians (mainly surgeons), that the PK/PD approach is clinically and economical advantageous