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1 Novel PK/PD data on the optimisation of colistin and the carbapenems Diamantis Plachouras Athens, Greece Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course, 31 May - 01 June 2013, Athens

2 Overview Principles of PK/PD in ICU Carbapenems: prolonged/continuous or intermittent infusion? Colistin dosing Combination treatment Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

3 Principles of PK/PD in ICU Carbapenems: prolonged/continuous or intermittent infusion? Colistin dosing Combination treatment Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

4 Killing curves concentration dependent time dependent Craig WA. Scand J Infect Dis 1992

5 MIC PK/PD indices T>MIC AUC AUC PK/PD indices T>MIC AUC/MIC Cmax/MIC

6 Meropenem vs. Klebsiella

7 Meropenem vs. Klebsiella

8 β-lactam PK/PD target (T>MIC percentage of dosing interval) Class Organism Stasis Maximum killing Cephalosporins Gram-negative Stapholococcus Penicillins Gram-negative Stapholococcus Carbapenems Gram-negative Stapholococcus Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

9 What is special in the ICU? More severe infections More resistant bugs Altered pharmacokinetics Volume of distribution (V d ) Endothelial dysfunction Edema Hypoalbuminemia increased clearance Inotropes increased clearance Rapid alteration in physiological status Immuno-compromised host Hydrophilic antimicrobials Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens McKenzie C. J Antimicrob Chemoth 2011

10 Antibiotic dosing in critical illness Higher PK/PD targets Higher inocula e.g. VAP Continuous prolonged vs short infusions Resistance prevention Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens McKenzie A. JAC 2011

11 Principles of PK/PD in ICU Carbapenems: prolonged/continuous or intermittent infusion? Colistin dosing Combination treatment Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

12 Meropenem PK/PD Bolus Continuous Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

13 Prolonged vs 30 min infusion of meropenem Kuti JL. J Clin Pharmacol 2003 ; 43( 10) :

14 Target attainment with 30 min vs 4 h infusion Lodise TP. Clin Infect Dis 2007

15 Clinical efficacy with 30 min vs 44 h h infusion Lodise TP. Clin Infect Dis 2007 Lodise TP. Clin Infect Dis 2007

16 Target attainment with various meropenem dosage regimens Roberts JA. J. Antimicrob. Chemother. (2009) 64 (1): Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

17 In vitro pharmacodynamic simulation of 3h meropenem infusion against CPKP Bulik CC. Antimicrob. Agents Chemother 2010; 54 (2):

18 Clinical Outcomes With Extended or Continuous Versus Short-term Intravenous Infusion of Carbapenems and Piperacillin/Tazobactam: A Systematic Review and Meta-analysis Falagas ME. Clin Infect Dis. (2013) 56 (2):

19 Characteristics and outcomes of the carbapenem studies included in the metaanalysis Author, Year Esterly, 2010 Okimoto, 2009 Wang, 2009 Sakka, 2007 Itabashi, 2007 Lorente, 2006 Dow, 2011 Study Design; Years, Country Retrospective; NR, USA Prospective; NR, Japan Retrospective; 2006, China RCT; NR, Germany Prospective; , Japan Retrospective; , Spain Retrospective; , USA No. of Patients ; Infections Bacteria Dosage Regimen (IV) 71; bacteremia A. baumannii, P. aerug, ESBL (+) Enterobacteriaceae IMI/CIL or MER 3-h in vs IMI/CIL or MER 30- min in 50; CAP in Gram ( ): 15 MER 1 g continuously the elderly Gram (+): 14 vs Unknown: 21 MER 500 mg q12h 30min in 30; ICU - A. baumannii MER 500 mg q6h 3-h HAP in vs MER 1g q8h 1h 20; ICUacquired Gram ( ) IMI/CIL 2/2 g continuously pneumonia vs IMI/CIL 1/1 g q8h 40-min in 42 ; severe Gram ( ): 10 MER 500 mg q12h 4- pneumonia Gram (+): 10 h in Others, unkn.: 34 vs MER 500 mg q12h 1- h in 89 ; VAP Gram ( ) MER 1 g continuously vs MER 1 g q6h 30-min in 121 ; ICU Gram ( ) PIP/TAZ 3/0.375 g infections q8h or MER 500 mg q6h 3 or 4-h in vs PIP/TAZ 3/0.375 g q6h or MER 500 mg q6h 30-min inf Clinical Cure Mortality Extended or Short-Term Extended or Short-Term Continuous Infusion, Continuous Infusion, Infusion, n/n n/n (%) Infusion, n/n n/n (%) (%) (%) NR NR 12/42 (28.6) 7/29 (24.1) 20/25 (80) 19/25 (76) 0/25 (0) 0/25 (0) 15/15 (100) 15/15 (100) 0/15 (0) 0/15 (0) NR NR 1/10 (10) 2/10 (20) NR NR 1/18 (5.6) 9/24 (37.5) 38/42 (90.5) 28/47 (59.6) NR NR NR NR 8/67 (11.9) 11/54 (20.4) Falagas ME. Clin Infect Dis. (2013) 56 (2): Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

20 Forest plot of mortality Falagas ME. Clin Infect Dis. (2013) 56 (2): Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

21 What about stability? Meropenem less stable than doripenem More degradation with increased temperature and concentration Meropenem probably should be restricted to 3h infusions Berthoin K. J Antimicrob Chemother Feb 2010 Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

22 Possible advantages and disadvantages of continuous/long infusion vs bolus Administrations method Advantages Disadvantages Continuous / long infusion Predictable PK Requires education Lower daily dose may be effective Less time consuming for pharmacist / nurse Requires infusion pumps Issues of stability Bolus Simple Unpredictable PK Less likely failure / error Neurological side-effects probably more common Modified from Abdul-Aziz MH. Ann Intensive Care. 2012; 2: 37. Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

23 Doripenem / Ertapenem combination control ertapenem doripenem In vitro Doripenem + ertapenem In vivo Bulik CC. Antimicrob. Agents Chemother 2011;55(6):

24 Principles of PK/PD in ICU Carbapenems: prolonged/continuous or intermittent infusion? Colistin dosing Combination treatment Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

25 Target AUC/MIC: Colistin PK/PD Dudhani RV. Antimicrob Agents Chemother. 2010;54:

26 Colistin PK in critically ill patients 18 patients Cmax 0.6 mg/l after first dose Cmax 2.3 mg/l at steady state Plachouras D et al. Antimicrob Agents Chemother Aug;53(8):3430-6

27 CMS Concentration (mg/l) Dosage regimen simulation 3 MU x 3 9 MU MU x 2 12 MU MU x 2 9 MU (2h infusion) MU x 2 12 MU (2h infusion) MU x Time after first dose (hours) Colistin Concentration (mg/l) MU x 3 9 MU MU x 2 12 MU MU x 2 9 MU (2h infusion) MU x 2 12 MU (2h infusion) MU x Time after first dose (hours) Plachouras D et al. Antimicrob Agents Chemother Aug;53(8):3430-6

28 Concentration (µm) Plachouras et al., 2009 New data: PK of CMS and Colistin after 9MU 3MUq8h 0.25h inf Mohamed et al., MU Load, 3M 0.25h inf Karaiskos et al., unpublished data 9MU Load, h inf 9MU Load, 4.5 1h inf Time after dose (h) Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens 1st Dose 4th - 8th D Compound CMS Colistin Courtesy of Lena Friberg (Personal Communication)

29 Colistin pharmacodynamics Modelling of bacterial killing by various dosing regimens Mohamed AF.Antimicrob. Agents Chemother 2012;56(8):

30 Population PK in 105 critically ill patients Garnonzik SM. Antimicrob Agents Chemother 2010;54(3):

31 Colistin dosage individualisation Patient group All patients Not on renal replacement On hemodialysis On continuous hemofiltration *Ideal or actual body weight in kg (whichever is lower) Daily dose over 10mIU with caution Dose (miu CMS) for concentration target 2 mg/l Loading dose BW * /7.5 (max 10) Maintenance dose (Cl Cr /10)+2 in 2-3 doses 1 st dose 24 h after loading dose 2 (in two doses) +30% of the dose on the day of dialysis after the session 12 In two or three doses Garonzik SM et al. AAC 2011 (modified)

32 Colistin pharmacokinetics in patients on continuous venovenous hemodiafiltration (CVVHDF) Serum CMS (A) and colistin (B) concentrations CMS (A) and colistin (B) concentration before and after filter 5 patients 2 miu tid iv Cmax : 0.92 mg/l Extraction: 68% Karvanen M. Antimicrob. Agents Chemother 2013;57(1):

33 Is colistin effective? Prospective cohort study 495 patients Israel OR 1.99 bacteremic patients Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

34 Concentration dependent Bactericidal But Emergence of resistance Heteroresistance Adaptive resistance

35 Closing the Loop A Colistin Clinical Study to Confirm Dosing Recommendations From PK/PD Modeling Prospective study in 16 bed ICU 28 patients with infections by Colistin only susceptible (COS) Gramneg 14 patients on monotherapy Clinical cure: 23/28 patients (82.1%) Renal toxicity: 5/28 (17.8%) No emergence of colistin resistance under treatment Limitations: Uncontrolled study with few patients Dalfino L. Clin Infect Dis Jun;54(12): Roberts JA, Lipman J. Clin Infect Dis Jun;54(12): Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

36 Principles of PK/PD in ICU Carbapenems: prolonged/continuous or intermittent infusion? Colistin dosing Combination treatment Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

37 Colistin Carbapenem combination against carbapenemase producing enterobacteriaceae Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

38 Colistin Doripenem combination is synergistic and bactericidal against carbapenemase-producing colistin-resistant KP Backbone agent Colistin Doripenem Agent tested in combination Synergy, n (%) Indifference, n (%) Doripenem 6 (50) 6 (50) 0 Gentamicin 3 (25) 8 (67) 1 (8) Doxycycline 1 (8) 8 (67) 3 (25) Gentamicin 1 (8) 9 (75) 2 (17) Doxycycline 3 (25) 7 (58) 2 (17) Gentamicin Doxycycline 5 (42) 5 (42) 2 (17) Antagonism, n (%) Jernigan MG. Antimicrob. Agents Chemother 2012 ; 56(6):

39 Mortality according to treatment regimen in 67 patients with bloodstream infections with carbapenenemase producing KP Mortality % two active drugs one active drug inappropriate treatment Daikos Gl. Antimicrob Agents Chemother 2009;53:

40 Multicenter, open-label, randomized clinical trial to compare colistin alone vs. colistin plus carbapenem for severe infections caused by carbapenem-resistant bacteria. Preserving old antibiotics for the future Assessment of clinical efficacy by a pharmacokinetic/ pharmacodynamic approach to optimize effectiveness and reduce resistance for off-patent antibiotics

41 Conclusions Prolonged infusion of carbapenems may be more effective for the treatment of infections by multidrug resistant gram negative bacteria in critically ill patients Loading dose for colistin improves efficacy A combination of colistin and carbapenem may be of benefit in difficult to treat infections in critically ill patients Hot Topics on Infections in the Critically Ill Patient, ESCMID Postgraduate Education Course.31 May - 01 June 2013, Athens

42 Lena Friberg Otto Cars Matti Karvanen Ami Fazlin Mohamed Salim Bouchene David Khan Elisabet Nielsen Britt Jansson Swedish Foundation of Strategic Research Acknowledgements Ilias Karaiskos Helen Giamarellou K Pontikis E Papadomichelakis A Antoniadou A Armaganidis I Tsangaris G Poulakou F Kontopidou