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8th ISAP Symposium

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. PK/PD results and evolution. }. }. Improvement of dose and intervals. Outcome resistance.

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8th ISAP Symposium

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

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

  3. Several objectives resistance Improvement of therapy Phase 2-3clinicaltrial

  4. PK/PD evolution 2000 Custom-made therapy

  5. Pharmacology : what for physician? 20 18 16 14 12 concentration (µg/ml) 10 A D M E 8 6 4 2 0 In Vitro and in vivo activity 2 3 4 5 6 7 8 9 10 11 12 0 1 time h Effect over the time; Peculiar Effects

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

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

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

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

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

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

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

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

  14. Time Over MIC Peak/MIC Concentration M IC2 M IC1 Time ‘Time above 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 problemPK approach to adjust the dose is poor applicable for routinely use(at moment) • N°samples • Personnel • Costs

  17. second problemPK/PD breakpoints betalactams (ceftriaxone) aminoglycosides quinolones glycopeptides macrolides tetracyclines

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

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

  20. Sampling time • Aminoglycosides 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 65 60 55 50 45 mg/L 40 35 30 25 20 15 10 5 0 C 0.5 h C 5.6 h

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

  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 Sepsis44 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 pneumoniae 4 Stenotrophomonas spp 4 Legionella species 2 Citrobacter species 2 Acinetobacter 1 Proteus species 1

  27. AminoglicosidesDose 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-LevofloxacinDose 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. CiprofloxacinDose adjusted according to creatinine clearance > 20 mL/min: normal dose <20 mL/min: 1/2 normal dose

  30. outcome *From the diagnosis of infection

  31. correlation between time to adjust the dose and hospitalisation days 20 15 hospitalization days 10 5 0 0 25 50 75 100 125 150 175 hours to adjust doses

  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 compensated 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 IVhomework When you came back at home, please try to convince Top Managers as well as Physicians (mainly surgeons), that the PK/PD approach is clinically and economically advantageous

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