Lessons from recent studies. João Gonçalves Pereira UCIP DALI

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1 Lessons from recent studies João Gonçalves Pereira UCIP DALI 1

2 Patterns of Antimicrobial Activity Concentration C max Aminoglycosides Cmax/MIC>10 Metronidazol Area under the concentration curve Azithromycin Fluoroquinolones AUC/MIC >125 MIC T>MIC Beta-lactams T> MIC 50% Carbapenems T> MIC 40% Time (hours)

3 Antibiotics Pharmacokinetics Healthy Organ Failure Sepsis Vd Vd Vd Cl Cl Cl C max C max AUC C max AUC AUC T>MIC MIC T>MIC MIC T>MIC MIC Time Time Time Gonçalves-Pereira. Crit Care 2011, 15:R206

4 Pharmacokinetics / Pharmacodynamics First dose 80 Infected critically ill patients SOFA 8 (5-10) Ventilation 71% Acute renal failure (not dialysis) 27% Proportion of Patients attaining their PK/PD target* Meropenem n=16 Ceftazidime n=18 Cefepime n=19 Pip Tazobactam n=27 57% 45% 34% 33% 0% 20% 40% 60% 80% 100% * T>4*MIC: 70% for Ceftazidime, Cefepime, 50% for Pip Tazobactam and 40% for Meropenem No relationship with age, organ failure, SOFA or sepsis severity Taccone Crit Care R126

5 Volume of Distribution Vd of β-lactams in critically ill patients and healthy volunteers. Meropenem Imipenem Vd in healthy volunteers Vd in critical patients (weighted mean) Piperacillin Cefpirome Cefepime Ceftazidime Volume of Distribution (L) Gonçalves-Pereira. Crit Care 2011, 15: R206

6 Increased Clearance Frequency of hyperfiltration (Cr Cl>120 ml/min) 54% of 1611 patients (32.6% of patient-days). 29.9% of patients always over 120 ml/min 8% Clearance > 200mL/min Dumoulin, Poster rd ESICM, 2010 Barcelona

7 DALI Study As presented in the 25 th ESICM Congress Multi-national - 68 ICUs in 10 countries throughout Europe. Point-prevalence PK study September 2011 (France April 2012) PK sampling during one week (1 day for each patient) 2 blood samples for beta-lactams (50% and end of dose interval) 3 blood samples for glycopeptides and triazoles End-Point: To determine whether contemporary antibiotic dosing for critically ill patients achieves concentrations associated with maximal activity. Roberts BMC Infectious Diseases 2012, 12:152

8 DALI Study Pharmacokinetics and efficacy Critically ill PK/PD targets 50% f T>MIC 50% f T>4*MIC 100% f T>MIC 100% f T>4*MIC 60 patients with febrile Neutropenia Meropenem Vd 0,22l/kg Clinical success Cefepime or ceftazidime 42 responders T>MIC 83% 18 failures T>MIC 59% Ariano, Ann Pharm 2005; 39: 3 AUIC 250 Cure 79% vs. 33%; P = T>MIC of 100% Cure 82% vs. 33%; P = Mckinnon. Int J Antimicrob Agents 2008; 31: 345

9 DALI Data As presented in the 25 th ESICM Congress Demographic Data Age 61 yrs (47-74) Weight 75 Kg (65-85) APACHE II 18 (13-25) SOFA 5 (2-8) PIRO 1 (1-2) Antibiotics Prophylaxis 23.2% Treatment 76.8% Extended or continuous infusion 28% Renal Replacement Therapy 10% Surgery within last 24h 20% Mortality 30-days 24.2% Related to infection 47.7% N=323

10 PK monitoring DALI Data Volume of Distribution As presented in the 25 th ESICM Congress N Vd (L) Vol (L) Variation Cefepime (58.6) % Meropenem (80.5) % Piperacillin (29.5) % Vancomycin (81) %

11 DALI Data As presented in the 25 th ESICM Congress PK monitoring Clearance N Cl (L/H) Vol (L/H) Variation Cr Cl (ml/min) RRT (N) Cefepime 14 8 (7.3) % 106 (80) 2 Meropenem (11.5) % 48 (75) 17 Piperacillin (9.2) % 58 (63) 11 Vancomycin (3.9) (46) 9

12 DALI Data As presented in the 25 th ESICM Congress Trough Concentrations Piperacillin Meropenem Amoxycillin Cefepime

13 DALI Data As presented in the 25 th ESICM Congress Pitfalls and limitations of the study Pharmacokinetics Prophylaxys 23.2% (non septic patients probably different) RRT 10% (dependent of dialysis Cl) Only two or three samples per patient (limited value and interpretation of PK curves) Sampling any day during therapy (PK may be different according to the time of infection evolution)

14 Ventilator Associated Pneumonia Dose of antibiotics Normalization of the increase in Vd and Cl (with sepsis resolution) Progressive normalization of PK High antibiotic concentration Meropenem PK Triginer Intensive Care Med 1990;16: Early Late SOFA 5.5 [ ] 3.0 [ ] Vdss/Weight (L/Kg) 0.26 [ ] 0.20 [ ] Vdss (p)/vdss (%) 71% [56%-82%] 58% [43%-70%] Cl (L/h) 6.8 [ ] 6.0 [ ] Trough (mg/l) 3.0 [ ] 2.5 [ ] Gonçalves-Pereira 2012, submitted

15 DALI Data As presented in the 25 th ESICM Congress Outcomes Cefepime Meropenem Piperacillin 50% T>MIC 50% T>4*MIC 100% T>MIC 100% T>4*MIC Meropenem Piperacillin Cefepime clinical cure 65% 54% 71%

16 DALI Data As presented in the 25 th ESICM Congress Outcomes N Cure Target attainment Conc/MIC (50%) Cefepime 14 71% 57% 4.9 Meropenem 90 54% 65% 7.5 Piperacillin % 53% 4.6 Vancomycin 43 65% 71% (AUC/MIC>400) 60% Success 1* MIC at 50% dosing interval 80% Success - ±15* MIC at 50% dosing interval

17 MIC: Inoculum effect Staphylococcus aureus Udekwu, J Antimicrob Chemother. 2009; 63: 745

18 MIC: Biofilms

19 DALI Data Outcomes Conc/MIC at 50% dosing interval As presented in the 25 th ESICM Congress Meropenem Cefepime Pip Tazo

20 DALI Data As presented in the 25 th ESICM Congress Pitfalls and limitations of the study Pharmacodynamics Prophylaxys 23.2% RRT 10% (non infected patients probably different) (dependent of dialysis Cl) Only two or three samples per patient (limited value and interpretation of PK curves) Anytime during therapy (PK may be different according to the time of infection evolution) Very few isolates with MIC - Use of the EUCAST MIC 90 (limited value of the PD calculations) Ideal therapeutic targets of β Lactams poorly defined

21 DALI Data As presented in the 25 th ESICM Congress Vancomycin Continuous Infusion (N=25) Intermittent (N=18) Trough 58% (Css>20) 42% (>15) AUC/MIC>400 88% 45% Cure 70% 58%

22 Concentration (μg/ml) Plasma Concentrations vs Time Infusion over 1h or 4h 25 administered over 1h administered over 4h DALI 28% received continuous or extended antibiotic infusions 10 5 Increase of T>MIC 25% to 56% 0 50% to 75% Time (hr) Cirillo J Clin Pharmacol. 2009;49:

23 N=346 Gonçalves-Pereira. Plos One 2012, 7:e49845

24 Implications of the DALI study Assessing antibiotic dose Resistance MIC Biofilms Inoculum Genetic identification Biomarkers Bacteria Source control Host Organ failure Immune system Biomarkers Immune monitorization Antibiotic Pharmacokinetic changes Therapeutic drug monitoring Dose modulation

25 Vasopressors Cardiac output Diuresis Dose modulation: A new concept of antibiotic therapy J Gonçalves Pereira, JA Paiva. J Crit Care, in press Critically ill septic patient Large Volume of Distribution Renal or Hepatic failure Initial High Loading Dose No Increased Clearance (measure Cr Clearance) Yes Large volume resuscitation Invasive Ventilation Surgical procedure Adjust Dose accordingly Maintain High Dose Reassess after 48-72h Any of: Bacteria with a low MIC Normalization of (measured) Cr Clearance Sepsis resolution Adjust Dose

26 The longest journey begins with a small step. Lao Tsu BC To infinity and far beyond!... Buzzlightyear