Empirical Antibiotic Therapy Combo vs Mono : Best

Transcription

1 Empirical Antibiotic Therapy Combo vs Mono : Best Anand Kumar MD, FRCPC, FCCP, FCCM Professor of Medicine University of Manitoba Health Sciences Centre St. Boniface Hospital Winnipeg, Manitoba For available slides: /kumar.html akumar61@yahoo.com ` 1

2 Surviving Sepsis 2016: We suggest empiric combination therapy (using at least two antibiotics of different antimicrobial classes) aimed at the most likely bacterial pathogen(s) for the initial management of septic shock (weak recommendation, low quality of evidence). (Remarks Readers should review Table 6 for definitions of empiric, targeted/definitive, broad-spectrum, combination, and multidrug therapy before reading this section.) CCM/ICM 2017 Infectious Diseases Society of America (IDSA) POSITION STATEMENT: Why IDSA Did Not Endorse the Surviving Sepsis Campaign Guidelines IDSA Sepsis Task Force, CID 2017 Monotherapy Is Adequate for Septic Shock Due to Gram-Negative Organisms Michael Klompas MD, MPH CCM

3 Pathophysiologic Aspects of Septic Shock 1) Immunologic 2) Microbiologic 3) Physiologic 3

4 Sepsis and Septic Shock: An Intensivist s Immunologic View Antimicrobials Infection CARS SIRS Organ Injury Antiinflammatory (endogenous) Time RECOVERY van der Poll T, van Deventer SJH. Infect Dis Clin N Am akumar61@yahoo.com 4

5 Sepsis and Septic Shock: An ID/Microbiologic View A Kumar, Virulence 2014;5:80 97 Cellular dysfunction/tissue injury Inflammatory response Toxic burden Microbial load TIME 5

6 An Integrated Injury Paradigm of Septic Shock: The Golden Hours DEATH A Kumar, Virulence 2014;5:80 97 Cellular dysfunction/tissue injury Inflammatory response Toxic burden Shock Threshold Microbial load TIME 6

7 Speed is Life The speed of clearance of the microbial pathogen is the critical determinant of outcome in septic shock 7

8 An Injury Paradigm of Sepsis and Antimicrobial therapy Septic Shock Cellular dysfunction/tissue injury Inflammatory response Shock Threshold Toxic burden Microbial load A Kumar, Virulence 2014;5:80 97 TIME 8

9 An Injury Paradigm of Sepsis and Septic Shock earlier antimicrobial therapy Cellular dysfunction/tissue injury Shock Threshold Microbial load Inflammatory response Toxic burden A Kumar, Virulence 2014;5:80 97 TIME 9

10 Cumulative Initiation of Effective Antimicrobial Therapy and Survival in Septic Shock fraction of total patients 1.0 survival fraction cumulative antibiotic initiation Kumar et al. CCM. 2006:34: time from hypotension onset (hrs) 10

11 No Faster pathogen clearance matters? ie delay-dependent risk of irreversible and irreplaceable organ failure? Hit faster (increase speed of attainment of therapeutic levels) Yes Hit harder (augment cidality of therapeutic regimen) 1) Appropriateness 2) Speed of initiation 3) Loading dose 1) Synergistic combination ie mono vs combo therapy 2) Pharmacodynamic selection ie static vs cidal therapy 3) Pharmacokinetic optimization ie T>MIC, Cmax/MIC, AUC/MIC Accelerated pathogen clearance

12 more intense antimicrobial therapy An Injury Paradigm of Sepsis and Septic Shock Cellular dysfunction/tissue injury Inflammatory response Shock Threshold Toxic burden Microbial load A Kumar, Virulence 2014;5:80 97 TIME 12

13 Monotherapy vs Combination Therapy: Gram Negative Bacteremia Safdar N (keep this name in mind), Handelsman J, Maki DG, Lancet ID 2004 akumar61@yahoo.com 13

14 RCT Monotherapy vs Combination Therapy: Sepsis Paul et al, BMJ

15 Cefotaxime and Gentamicin in Rat E. coli Bacteremia Change in Log10 CFU/mL blood no antibiotic Cf Ge Cf Ge Ge Cf Cf + Ge Time from Antibiotic Administration (hr) Kumar et al, ICAAC

16 Combination Antimicrobial Therapy in ICU- Requiring CAP: Effect of Combination Therapy in Shock vs Non-shock Non-shock Shock Rodriguez A et al. CCM 2007;35: akumar61@yahoo.com

17 Monotherapy Mortality (%) scoulier et al 1982 kamad et al 1985 vasquez et al 2005 dwyer et al 2006 baddour et al 2004 rodriquez et al 2007 chow et al 1991 kim et al 2003 chokshi et al 2007 martinez et al 2003 damas et al 2006 korvick et al 1992 cometta et al 1994 kreger et al 1980 mccue et al 1985 bouza et al 1987 carbon et al 1987 harbath et al 2005 mccue et al 1987 siegman-igra et al 1998 gullberg et al 1989 leibovici et al 1997 heyland et al (mod) 2008 waterer et al 2001 dupont et al patterson et al 2003 kim et al 2002 fernandez-guerrero et al 1991 kuikka et al 1998 piccart et al 1984 bodey et al 1985 gamacho-montero et al 2007 mendelson et al 1994 vasquez et al 2005 chamot et al 2003 kljucar et al 1990 hilf et al 1989 harbarth et al 2005 aspa et al 2006 katersky et al 1973 montgomerie et al 1980 graninger et al 1992 fainstein et al 1983 maki et al 1988 dwyer et al 2005 gamacho-montero et al 2007 heyland et al (mod) 2008 chow et al 1991 korvick et al 1992 bodey et al 1989 baddour et al (rev) 2004 rodriquez et al 2007 feldman et al 1990 bodey et al 1985 chamot et al 2003 hilf et al 1989 tapper et al 1974 hammond et al 1990 combined (random) odds ratio (95% confidence interval) Meta-analysis of studies of combination vs monotherapy of life-threatening infections associated with sepsis and septic shock Kumar et al, Crit Care Med 2010;38: Kumar et al = Kumar, Safdar!!, 17 Kethireddy & Chateau

18 Monotherapy mortality >25% Monotherapy mortality 15-25% Monotherapy mortality <15% Vazquez b Chamot a,c Kljucar D'Antonio Hilf a Watanakunkorn Klatersky Montgomerie Graninger Baddour b,c Ko Aspa Fainstein Maki Dwyer b Mendelson Garnacho-Montero b Chow b Heyland b,c Korvick b Bodey2 Rodriguez b Feldman Bodey1 b Chamot b,c Hilf b Tapper Hammond combined Odds ratio meta-analysis plot [random effects] Carbon McCue Kuikka Harbarth b,c Gullberg Siegman-Igra Leibovici Heyland a,c Waterer Dupont Patterson Kim Harbarth a,c Fernandez-Guerrero Kuikka Piccart Bodey1 a Garnacho-Montero a combined odds ratio (95% confidence interval) Sculier Karnad Vazquez a Dwyer a Baddour a,c Rodriguez a Chowa Chokshi Martinez Damas Korvick a Cometta Kreger McCue Favors combination Favors monotherapy Kumar et al, Crit Care Med 2010;38: Kim Bouza combined

19 Metaregression: All studies Odds Ratio of Death (Combination Therapy) OR ( ) per 10% mortality increment, p< Monotherapy Mortality Risk (%) Kumar et al, Crit Care Med 2010;38:

20 Metaregression: RCTs OR ( ) per 10% mortality increment, p=.0159 Odds Ratio of Death (Combination Therapy) Monotherapy Mortality Risk (%) Kumar et al, Crit Care Med 2010;38:

21 21

22 Meta-analysis (shock/critically ill stratified): Combination vs Monotherapy Group Odds Ratio I 2 (%) P-value non-shock 1.11 ( ) shock 0.54 ( ) non-critically ill 1.10 ( ) critically ill 0.33 ( ) non-shock/non-critically ill 1.10 ( ) shock/critically ill 0.49 ( ) 0 <.0001 overall 0.76 ( ) Combo Therapy Favored Monotherapy Favored Odds Ratio of Death Kumar et al, Crit Care Med ;38:

23 % Surviving MT vs CT: 28 day survival Kumar et al, Crit Care Med 2010;38: Combination Therapy (CT) Monotherapy (MT) Log-rank p-value: day CT MT Number at risk 23

24 Pressor dependence (%) Liberation from Pressors: Combination vs Mono-Therapy Monotherapy Combined Therapy log rank p-value = # at risk Monotherapy Combined Therapy Time (days)

25 Combination vs Monotherapy: b-lactams Primary Antibiotic penicillins penicillin/ampicillin anti-staph penicillin b-lactam/inhibitor cephalosporins 1st gen ceph 2nd gen ceph non-ps 3rd gen ceph anti-ps 3rd/4th gen ceph carbapenem vancomycin fluoroquinolone macrolide/clindamycin n p value Kumar et al, Crit Care Med 2010;38: Hazard Ratio 25

26 Combination vs Monotherapy: b-lactams Primary Antibiotic penicillins penicillin/ampicillin anti-staph penicillin b-lactam/inhibitor cephalosporins 1st gen ceph 2nd gen ceph non-ps 3rd gen ceph anti-ps 3rd/4th gen ceph carbapenem vancomycin fluoroquinolone macrolide/clindamycin n p value Kumar et al, Crit Care Med 2010;38: Hazard Ratio 26

27 Combination vs Monotherapy: Secondary Antibiotic b-lactams (n=930) AG FQ ML/CL other Vancomycin (n=82) AG FQ ML/CL other Fluoroquinolones (n=50) AG ML/CL All primary drugs (n=1223) AG FQ ML/CL n p value Kumar et al, Crit Care Med 2010;38: Hazard Ratio 27

28 Meropenem ± Moxifloxacin for Sepsis and Septic Shock ITT PP Brunkhorst et al, JAMA

29 Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem on Sepsis-Related Organ Dysfunction in Severe Sepsis: An RCT 31 Brunkhorst et al, JAMA 2012 appendix

30 Reasons for limited applicability of Brunkhorst study non-pragmatic control group very potent (high time > MIC) agent in low resistance outcome predicted by my propensity matching study not reflective of current high resistance environments not reflective of the future resistance environment 32

31 Speed is Life The speed of clearance of the microbial pathogen is the critical determinant of outcome in septic shock 33

32 Eventually, Billy came to dread his father s lectures over all other forms of punishment. 34

33 Subgroup Analysis of Shock Patients Combination Therapy (n=68) Monotherapy (n=96) Combo/Mono RR (95% CI) Adequacy of empiric therapy* 34 (97.1%) 40 (76.9%) Clinical resolution at 28 days 31 (45.6%) 40 (41.7%) Microbiological resolution at 28 days 24 (35.3%) 32 (33.3%) Duration of mechanical ventilation 16.7 [7.8,.] 14.7 [7.0,.] Duration of ICU Stay 21.2 [10.2,.] 21.0 [11.3,.] Duration of Hospital Stay 63.8 [31.0,.] 80.2 [21.9,.] 28 Day Mortality 18 (26.5%) 30 (31.3%) 14 Day Mortality 13 (19.1%) 26 (27.1%) ICU Mortality 16 (23.5%) 31 (32.2%) Hospital Mortality 21 (30.9%) 38 (39.6%) % bacteremic after 48 hours of enrollment 1 (1.5%) 3 (3.1%) Heyland et al, Crit Care Med 2008;36:

34 Subgroup Analysis of Non-Shock Patients Combination Therapy (n=301) Monotherapy (n=274) Combo/Mono RR (95% CI) Adequacy of empiric therapy* 156 (92.3%) 126 (88.1%) Clinical resolution at 28 days 189 (62.8%) 163 (59.5%) Microbiological resolution at 28 days** 124 (41.2%) 102 (37.2%) Duration of mechanical ventilation 7.0 [3.7, 19.6] 7.0 [3.3, 15.0] Duration of ICU Stay 10.9 [6.0, 27.5] 10.3 [6.0, 21.2] Duration of Hospital Stay 42.8 [22.8, 142.9] 36.7 [19.3, 97.1] 28 Day Mortality 53 (17.6%) 37 (13.5%) 14 Day Mortality 32 (10.6%) 21 (7.7%) ICU Mortality 44 (14.6%) 32 (11.7%) Hospital Mortality 68 (22.6%) 55 (20.1%) % bacteremic after 48 hours of enrollment 2 (6.7%) 2 (7.3%) Heyland et al, Crit Care Med 2008;36:

35 Mortality of Severe Infections: Pip-tazo intermittent vs extended infusion Rhodes et al, CCM