Oral session: PK/PD-based optimized broad-spectrum beta-lactam therapy (Sunday 10 April, 11:30) Achieving pharmacokinetic/pharmacodynamic (PK/PD) targets.

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Presentation transcript:

Oral session: PK/PD-based optimized broad-spectrum beta-lactam therapy (Sunday 10 April, 11:30) Achieving pharmacokinetic/pharmacodynamic (PK/PD) targets of β-lactams in critically ill patients at first dose: Can we do it with standard dosing ? Isabelle K. Delattre1,7, Fabio S. Taccone2, Frédérique Jacobs3, Thierry Dugernier4, Herbert Spapen5, Pierre-François Laterre6, Pierre E. Wallemacq7, Vincent Tam8, Françoise Van Bambeke1, Paul M. Tulkens1 1 Université catholique de Louvain, Louvain Drug Research Institute, Brussels, Belgium 2 Hôpital universitaire Erasme, Service des soins intensifs, Brussels, Belgium 3 Hôpital universitaire Erasme, Service des maladies infectieuses, Brussels, Belgium 4 Clinique St-Pierre, Ottignies, Service des soins intensifs, Brussels, Belgium 5 Universitair Ziekenhuis Brussel, Service des soins intensifs, Brussels, Belgium 6 Cliniques Universitaires St-Luc, Service des soins intensifs, Brussels, Belgium 7 Université catholique de Louvain, Institut de recherche expérimentale et Clinique, Brussels, Belgium 8 University of Houston, College of Pharmacy, Houston, United States 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

General Considerations PK/PD parameter predictive of β-lactam efficacy ? Concentration vs. time profile T>MIC Time during with concentrations above the minimal inhibitory concentration (MIC) Conc. MIC T>MIC Time Maximize the exposure time 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

%fT>MIC required for β-lactams % of Time? Threshold? %fT>MIC required for β-lactams 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

Reported PK/PD targets % of Time? Threshold? Literature review Original papers in PubMed published from 2000 to 2015 Serum or plasma concentrations in critically ill patients Search terms: title: piperacillin, ceftazidime, cefepime or meropenem text: pharmacokinetics or PK, pharmacodynamics or PD and minimal inhibitory concentration or MIC Example for piperacillin: what is the target ? Reported PK/PD targets 100%T>1xMIC 14/27 50%T>1xMIC 9/27 50%T>4xMIC 3/27 100%T>4xMIC 1/27 70 papers reviewed… … 22 usable papers 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

% of Time? Threshold? Literature review Original papers in PubMed published from 2000 to 2015 Serum or plasma concentrations in critically ill patients Search terms: title: piperacillin, ceftazidime, cefepime or meropenem text: pharmacokinetics or PK, pharmacodynamics or PD and minimal inhibitory concentration or MIC Example for piperacillin: which Mics ? Reported MIC data Actual MIC 7/23 EUCAST 8/23 CLSI 1/23 Unknown 70 papers reviewed… … 22 usable papers 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

!Lack of clinical outcome data! % of Time? Threshold? Literature review Original papers in PubMed published from 2000 to 2015 Serum or plasma concentrations in critically ill patients Search terms: title: piperacillin, ceftazidime, cefepime or meropenem text: pharmacokinetics or PK, pharmacodynamics or PD and minimal inhibitory concentration or MIC Ex. Piperacillin !Lack of clinical outcome data! Reported MIC data Actual MIC 30% EUCAST 35% CLSI 4% Unknown 31% Impossible to assess and/or compare the clinical efficacy of the PK/PD targets 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

The ‘Australian’ Hypothesis β-lactam concentrations 4xMIC 1xMIC % time 100 The authors “would advocate a PD target of 100%T>1xMIC for intermittent dosing as this is likely to result in a concentration 4xMIC for 40-70% of the dosing interval as required for the different classes of β-lactams”. 40-70%T > 4xMIC ~ 100%T > 1xMIC 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

Maximal killing: 100%T > 4xMIC The ‘Houston’ Target Maximal killing: 100%T > 4xMIC 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

Maximal killing: 100%T > 4xMIC The ‘Houston’ Target Maximal killing: 100%T > 4xMIC fCmin/MIC = 6 to suppress resistance emergence 100%fT > 4xMIC for microbiological success 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

Objectives of the Study In critically-ill patients receiving a first dose of β-lactam: Do we reach ‘Australian double target’ (100%T>1xMIC ~ 40-70%T>4xMIC) with the standard dosage ? Which dose do we need to reach the ‘Houston’ target (100%T>4xMIC) ? 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

Patients Critically ill septic patients treated with a first dose of: piperacillin [4g] (n=22), ceftazidime [2g] (n=18), cefepime [2g] (n=19) or meropenem [1g] (n=19) infused over 30 minutes * Chang HJ et al. JAMA 2010;304(16) http://jama.jamanetwork.com/article.aspx?articleid=186795 Last access: April 1, 2016 * Taccone FS et al. Crit Care 2010;14:R126 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

Modeling and Simulations (1/2) PK data Population modeling (Delattre et al. Clin Biochem 2012;45:780-6) Two-compartment model Population estimates (basic model): Piperacillin Ceftazidime Cefepime Meropenem V1 (L for 70kg) 24 20 18 CL (L/h for 70kg) 6.8 3.5 4.5 7.5 V1, central volume of distribution; CL, total body clearance Simulations: NONMEM For each β-lactam 1000 patients 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

Modeling and Simulations (2/2) Target MIC EUCAST “S” breakpoints for Pseudomonas spp.* EUCAST breakpoints for Pseudomonas spp. Piperacillin S ≤ 16 mg/L R > 16 mg/L Ceftazidime S ≤ 8 mg/L R > 8 mg/L Cefepime Meropenem S ≤ 2 mg/L S, susceptibility; R, resistance * 2016-01-01, v 6.0; http://www.eucast.org Last access: April 1, 2016 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

The ‘Australian’ Targets (1/3) 100%T>1xMIC ~ 40-70%T>4xMIC “S” breakpoint from EUCAST for Pseudomonas spp.: 16 mg/L for piperacillin, 8 mg/L for ceftazidime 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

The ‘Australian’ Targets (1/3) 100%T>1xMIC ~ 40-70%T>4xMIC 100%T>1xMIC + 50%T>4xMIC 100%T>1xMIC + 70%T>4xMIC 50%T>4xMIC 70%T>4xMIC 257/560 307/871 560 / 1000 871/1000 100%T>1xMIC 100%T>1xMIC “S” breakpoint from EUCAST for Pseudomonas spp.: 16 mg/L for piperacillin, 8 mg/L for ceftazidime 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

The ‘Australian’ Targets (2/3) 100%T>1xMIC ~ 40-70%T>4xMIC 100%T>1xMIC + 70%T>4xMIC 100%T>1xMIC + 40%T>4xMIC 70%T>4xMIC 128/628 555/592 628/1000 592/1000 100%T>1xMIC “S” breakpoint from EUCAST for Pseudomonas spp.: 8 mg/L for cefepime, 2 mg/L for meropenem 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

Are 'Australian' targets reached ? Is a PK/PD target of 100%T>1xMIC likely to result in a concentration 4xMIC for 40-70% of the dosing interval as required for the different classes of β-lactams? For 1,000 critically-ill septic patients treated with a first dose of β-lactam: Dosage (0.5h inf.) no. of atients with 100%T>MIC no. of patients with 100% T>1xMIC and 40-70%T>4xMIC Piperacillin 4g [q6h] 560 (56%) 257 (26%) Ceftazidime 2g [q8h] 871 (87%) 307 (31%) Cefepime 628 (63%) 128 (13%) Meropenem 1g [q8h] 592 (59%) 555 (55%) NO at first dose except for meropenem 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

Required median first doses to reach 100% at 4 x MIC The ‘Houston’ Target … Required median first doses to reach 100% at 4 x MIC Standard dose Required dose (25%-75%) 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

Which dose is needed to reach 100%T>4xMIC? The ‘Houston’ Target … Which dose is needed to reach 100%T>4xMIC? First dose of β-lactam in critically ill patients Standard dose Optimal median dose 0.5h infusion 3h infusion Piperacillin 4g (q6h) 9.5g x 2.4 7.1g x 1.8 Ceftazidime 2g (q8h) 2.9g x 1.5 2.6g x 1.3 Cefepime 4.9g x 2.5 3.9g x 2.0 Meropenem 1g (q8h) 2.0g 1.5g ~ 50% to 150% increase of the standard dose even with a 3-h infusion 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

100%T>4xMIC : a new Graal ? Conclusions The ‘Australian’ targets (100%T>1xMIC ~ 40-70%T>4xMIC) Not reached with standard dosing (except for meropenem but low target MICs !!) The ‘Houston’ target (100%T>4xMIC) Will require a 50-150% increase over standard dose Systematic 3-h infusion? 100%T>4xMIC : a new Graal ? Increasing the first dose is probably essential to be optimal in severely-ill patients. https://walexperience.com/wp-content/uploads/2014/10/IL-SANTO-GRAAL.jpg 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)

The discussion is open… 10/04/2016 26th ECCMID (Session: PK/PD-based optimized broad-spectrum beta-lactam therapy)