Therapy of MDR/XDR Gram-negative bacteria: dealing with the devil. CRE: high dosing, how much? by author

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1 Therapy of MDR/XDR Gram-negative bacteria: dealing with the devil CRE: high dosing, how much? George L. Daikos, MD National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece

2 Disclosures I have received research funding or honoraria from: Pfizer, Achaogen, Rempex, MSD, Gilead, Astellas.

3 CRE: high dosing, how much? Carbapenems Aminoglycosides Polymixins Tigecycline

4 Log10 cfu per lung at 24h % Time > MIC for Carbapenems with different 10 effects Craig WA. Clin Infect Dis 1998, 26: 1-12 Andes D & Craig WA. IJAA 2002; 19: % Moderately severe infection in a non- immunopressed patient Bactericidal effect ( 2-log10 kill) 20% Bacteriostatic effect (< 2-log kill) 100% Severe infection In immunosupressed patients Maximal effect?

5 Probability of Clinical Response with Meropenem of Febrile Neutropenic Patients with Bacteremia as a Function of %T>MIC Ariano et al. Annals of Pharmacotherapy 2005; 39: 32-8

6 Improving Exposure to Carbapenems Increasing the dose while keeping the dosage interval the same Administering the drug more frequently while keeping the dose fixed Increasing the duration of IV infusion

7 PTA (40% ft>mic) for meropenem in critically ill patien Roberts et al. J Antimicrob Chemother 2009; 64:

8 Can we Attain the Carbapenem PK/PD Targets for CPE Infections?

9 No. of Isolates Distribution of Meropenem MICs for 372 Consecutive K. pneumoniae Blood Isolates MICs (μg/ml) VIM KPC, KPC+VIM NO CARBAPENEMASE

10 Distribution of Meropenem MICs of 661 KPC-Kp (Italian Study Group on Resistant Infections) Percentage MIC (μg/ml) Tumbarello M J Antimicrob Chemother 2015; 70:

11 Activity of imipenem against VIM 1 metallo β lactamase producing Klebsiella pneumoniae in the murine thigh infection model VIM-negative MIC=0.12mg/L VIM-positive MIC=4mg/L Daikos GL et al Clin Microbiol Infect 2007; 13: VIM-positive MIC=2mg/L VIM-positive MIC=32mg/L

12 Comparison of the efficacies of two different doses of doripenem against carbapenemase-producing K. pneumoniae isolates in immunocompromised and immunocompetent animals. Bulik C C, Nicolau D P Antimicrob. Agents Chemother. 2010;54: MIC: 354=4, 356=8, 359=16

13 Carbapenem Monotherapy in 50 Patients with Serious CPE Infections (Results compiled from 15 studies) MIC (μg/ml) No. of patients No. of successes No. of failures % failure > Tzouvelekis et al CMR 2012; 25:

14 205 patients with CP Kp bacteremia Treatment with a combination: Independent predictor of survival!! P=0.003 Mortality % No active drug 33.3 Monotherapy 44.4 Combination 27.2 without a carbapenem 30.6 with a carbapenem and MIC 8 mg/l 19.3 and MIC>8 mg/l 35.5 P 0.018

15 Mortality associated with different antimicrobial drug regimen categories in patients with different presenting features or in patients with different KPC-Kp isolate characteristics Tumbarello M et al JAC 2015; 70: 2133

16 Effect of combination therapy containing a high-dose carbapenem on mortality in patients with CR-Kp BSIs Post hoc analysis of the Italian cohort of 595 pts with CR- Kp BSIs who received combination therapy Meropenem dose: 2g q 8h, 3h infusion Cox regression analysis adjusted for the propensity score to account for population imbalances between patients receiving combination therapy with or without meropenem Outcome: 14 day mortality Gianella M IJAA 2018; 51:

17 Cox Regression Analysis Adjusted for the Propensity Score Variable HR (95% CI) P Charlson CI 1.65 ( ) <0.001 Corticosteroids 1.93 ( ) Surgical ward 0.44 ( ) Septic Shock 4.7 ( ) <0.001 Colistin resistance 1.65 ( ) Carbapenem combination 0.64 ( ) 0.03 Gianella M IJAA 2018; 51:

18 Cox Regression Analysis of Survival Stratified for Carbapenem MIC ahr for carbapenem combination 0.63, 95%CI , P=0.03 Giannella M et al IJAA 2018; 51:

19 Nomograms based on CLCr estimates for the calculation of the meropenem daily dosage administered by continuous infusion which is necessary for the achievement of a target Css of 8 mg/liter (circles), 12 mg/liter (triangles), and 16 mg/liter (squares) in critically ill patients. Pea F et al. 2012;56:

20 Optimal PK/PD exposure with TDM Maximum permissible Css: mg/l Target: Css/MIC: 1-4mg/L Continuous infusion of MEM 1.7g-13.2g/day Clinical Outcome MIC 16mg/L; Cure 14/15 (93%) MIC 32-64mg/L; Cure 8/12 (67%) MIC >64mh/L; Cure 0/3 (0%)

21 Univariate regression analysis of variables associated with clinical cure from KPC-Kp related infections Variable OR (95%CI) P-value Charlson CI ( ) 0.05 Site of Infection, BSI ( ) 0.09 Meropenem MIC ( ) 0.07 Meropenem Css/MIC ( ) 0.01 Meropenem Css/MIC ( ) 0.03 No. of co-administered antimicrobials 1 active drug 2 active drugs Pea F et al IJAA 2017; 49: ( ) ( )

22 Probability of target attainment (PTA) of 100% T>1 MIC with some permissible high-dose continuous-infusion meropenem regimens in relation to different classes of renal function. Piergiorgio Cojutti et al. Antimicrob. Agents Chemother. 2017;61:e

23 Dosing algorithm for choosing the most advisable high-dose continuous-infusion meropenem regimen in relation to different classes of renal function for the empirical treatment of infection suspected to be caused by Klebsiella pneumoniae carbapenemaseproducing Klebsiella pneumoniae (KPC-Kp). Piergiorgio Cojutti et al. Antimicrob. Agents Chemother. 2017;61:e

24 Summary (Carbapenems) High-dose continuous-infusion of meropenem associated with TDM to drive the PK/PD profile to acceptable exposures (100% T>1-4XMIC) can be used For CPE infections with MEM MIC up to 64 mg/l Provided that his class of agents is administered in combination with another active compound

25 PK/PD Targets for Aminoglycosides Cmax/MIC 8 AUC/MIC 70

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27 Expected Gentamicin Peak/MIC and AUC/MIC Values for Organisms with High MICs (Craig W ESCMID Lecture Library) PK/PD Index MIC 5mg/kg 7mg/kg 10mg/kg Peak/MIC AUC/MIC Peak/MIC AUC/MIC Peak/MIC AUC/MIC 1 1 EUCAST 2 2 CLSI

28 Distribution of Peak Concentrations of Amikacin after Loading dose 25mg/kg in 74 ICU patients with Sepsis Taccone et al. Critical Care 2010, 14:R53 MIC=8mg/L Cmax/MIC 8 Target achieved In 70% of pts

29 P= pts with KPC infections; 29 received gentamicin as monotherapy or combination Genta MIC 2mg/L=13 Genta MIC >2-4 mg/l=16 Genta dose 4-5 mg/kg/24h Targets: Cmax=15-20 mg/l, Cmin 1mg/L

30 Factors associated with clinical success following aminoglycoside therapy for CR-Kp bacteremia. Overall clinical success rate was 54% All cause 30-day mortality was 30% Ryan K. Shields AAC 2016; 60: 3187

31 15 adult ICU patients with MDR-GN infections High-dose AMK (median, 29mg/kg, GM (11 mg/kg) Infecting organism MIC S by EUCAST CVVHDF high flow at >45ml/kg/h PK/PD target: Cmax/MIC 8-12, AMK toxicity; Cmin 5 mg/l, GN toxicity 2 mg/l

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33 Multivariate Analysis of Factors Associated with in Hospital Mortality in 258 Patients with MDR-GN Infections Treated with Colistin Variable aor (95%CI) P Higher colistin dose 1.22 ( ) APACHE II 0.89 ( ) <0.001 Hematologic diseases 0.23 ( ) Cure of infection 9 ( ) <0.001 Creatinine rise 0.21 ( ) < Falagas et al IJAA 2010; 35:

34 2016; 63(12): consecutive patients; 144 were treated with HD colistin (9 MIU) and 385 with lower-dose (4MIU) In the propensity-matched cohort no difference in mortality was observed between the groups treated with HD or LD Nephrotoxocity was significantly more common with HD

35 PK/PD Therapeutic Target for Optimization of Colistin Efficacy AUC 0-24h 50 mg.h/l which is equivalent to a target average steady-state plasma concentration Css,avg of 2 mg/l This target should be considered as a maximum tolerable exposure, as concentrations higher than this have been shown to increase the incidence and severity of AKI fauc/mic is the PK/PD index that correlates best with antibacterial activity Nation et al CID 2017; 64: 565

36 Patients with Increased CrCL Creatinine Clearance (ml/min/1.73m 2 ) Garonzik et al, AAC 2011 & ECCMID 2013 Karaiskos et al, AAC 2015; 59: 7240 In patients with high CrCL there is decreased ability to reliably attain plasma colistin Css,avg 2mg/L Only 11/39 patients with CrCl > 80 attained Css,avg 2mg/L (1) Only 4/12 patients with CrCl > 80 attained Css,avg 2mg/L (2) Proportion of pts who attained a plasma colistin - Css,avg 2 mg/l Garonzik et al Karaiskos et al /7 2/ /16 0/ /10 1/2 >140 1/6 1/3

37 Daily Doses of CMS for a Desired Target Colistin Css,avg of 2 mg/l Creatinine clearance, ml/min CBA, mg/d Dose of Colistimethate Million IU/d to < to < to < to < to < to < to < to < to < Nation et al CID 2017; 64: 565

38 Continuous Renal Replacement Therapy-Related Strategies to Avoid Colistin Toxicity: A Clinically Orientated Review Patrick M. Honoré a Rita Jacobs a Olivier Joannes-Boyau d Stijn Lochy a Willem Boer c Elisabeth De Waele a Viola Van Gorp a Jouke De Regt a Vincent Collin b Herbert D. Spapen a a Department of Intensive Care Medicine, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, and b Clinique de L Europe St. Michel, Brussels, and c Department of Anesthesiology and Critical Care Medicine, Ziekenhuis Loading Oost-Limburg, Genk dose, Belgium; of d Haut colistin: Leveque University 9 Hospital MIU of Bordeaux, University of Bordeaux 2, Pessac, France Maintenance dose 4.5 MIU q 8h CVVH at 35 ml/kg/h Key Words Acute kidney injury Colistin Colistin dosing Continuous renal replacement therapy Dialysis Nephrotoxicity Renal replacement therapy Highly adsorptive filters Abstract Polymyxins Blood are Purif old antimicrobials 2014;37: which were abandoned for almost 30 years because of significant renal and neurological toxicity. However, the alarming rise in multiresistant perience, we postulate that patients undergoing CRR receive substantially higher doses of colistin (i.e. a high ing dose, followed by a maintenance dose of up to 4 lion IU t.i.d.). Treatment can be continued for a prol time period without increasing toxicity. CRRT count colistin accumulation because the drug is continuou tered and also significantly adsorbed in the bulk of the sis membrane. Implementing such a CRRT rescue th does require the strict use of highly adsorptive dialysis branes in association with citrate anticoagulation to in

39 MIC distributions of 164 CP-KP strains And KP from EUCAST MIC distribution doi.org/ / PTA (fauc/mic >0.9) 10,000 simulated pts given tigecycline at different dosages

40 Cumulative Fraction Response (CFR) for Achieving PK/PD with Tigecycline against CP-KP and KP from the EUCAST MIC Distribution PK/PD Index fauc/mic>0.9 Antibiotic regimen Tigecycline 50mg q 12h Tigecycline 75mg q 12h Tigecycline 100mg q 12h CP-KP CFR (%) EUCAST doi.org/ /

41 Logistic regression analysis of factors associated with clinical cure in 63 patients with ventilator-associated pneumonia

42 30 patients with IAIs 12 received high-dose tigecycline in combination with colistin 18 received standard-dose of tigecycline in combination with colistin

43 23 received TIG 100 mg q 12h - Mortality: 52% 17 received TIG 50 mg q 12h - Mortality: 76.5%

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45 Conclusions Real-time TDM may improve drug exposure and result in better clinical outcome. High-flow CRRT may prove a valuable tool to achieve acceptable PK/Pd profile for nephrotoxic agents (AG and colistin) in critically ill patients infected with CRE organisms while avoiding drug accumulation and toxicity.