Speed is Life but a Sledgehammer Helps Too: Combination Antibiotic Therapy For Septic Shock

Transcription

1 Speed is Life but a Sledgehammer Helps Too: Combination Antibiotic Therapy For Septic Shock Anand Kumar MD, FRCPC, FCCP, FCCM Associate Professor of Medicine University of Manitoba Health Sciences Centre St. Boniface Hospital Winnipeg, Manitoba For available slides: /kumar.html akumar61@yahoo.com ` 1

2 Relationship of SIRS, Sepsis and Infection Sepsis Burns Severe sepsis Pancreatitis Infection Septic shock SIRS Trauma Post-pump syndrome 2

3 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 3

4 Sepsis and Septic Shock: An ID-Microbiologic View Cellular dysfunction/tissue injury Inflammatory response Toxic burden Microbial load TIME 4

5 Carl J Wiggers ( ) Shock is a syndrome resulting from depression of many functions, but in which reduction of the effective circulating volume and blood pressure are of basic importance, and in which impairment of circulation steadily progresses until it eventuates in a state of irreversible circulatory failure. akumar61@yahoo.com

6 An Injury Paradigm of Septic Shock: The Golden Hours DEATH 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 TIME 8

9 Frapper fort et frapper vite Hit hard and fast -Paul Erlich, address to the 17 th International Congress of Medicine,

10 An Injury Paradigm of Sepsis and Septic Shock earlier antimicrobial therapy Cellular dysfunction/tissue injury Shock Threshold Microbial load Inflammatory response Toxic burden TIME 10

11 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) 11

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 TIME 12

13 Synergy ie 2 drugs Static vs cidal PK/PD: -time above MIC -AUIC akumar61@yahoo.com 13

14 Monotherapy vs Combination Therapy: Gram Negative Bacteremia Safdar N, Handelsman J, Maki DG, Lancet ID

15 Potential Reasons for Combination Therapy Superiority Increased breadth of activity Decreased risk of superinfection Favorable immunomodulatory effects of seconary antimicrobials Antimicrobial synergism 16

16 Cefotaxime and Gentamicin in Rat E. coli Bacteremia 1 0 antibiotic no Cf -1 Ge Ge Cf Cf Ge + Ge Cf Kumar et al, ICAAC Time from Antibiotic Administration (hr)

17 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

18 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:

19 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 Monotherapy mortality >25% Monotherapy mortality 15-25% 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 Sculier Karnad Vazquez a Dwyer a Baddour a,c Rodriguez a Chowa Kim Chokshi Martinez Damas Korvick a Cometta Kreger McCue Bouza combined Monotherapy mortality <15% odds ratio (95% confidence interval) Favors combination Favors monotherapy Kumar et al, Crit Care Med 2010;38:

20 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:

21 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:

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 Combination Therapy (CT) Monotherapy (MT) Kumar et al, Crit Care Med 2010;38: Log-rank p-value: day CT MT Number at risk 24

24 Liberation from Pressors: Combination vs Mono-Therapy 100 Pressor dependence (%) log rank p-value = 0.03 Monotherapy Combined Therapy 0 # at risk Monotherapy Combined Therapy Time (days)

25 Combination vs Monotherapy: β -lactams Primary Antibiotic penicillins penicillin/ampicillin anti-staph penicillin β -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

26 Combination vs Monotherapy: Secondary Antibiotic β -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

27 Combination vs Monotherapy: all gram + GAS non-gas strep viridans strep S. pneumoniae S. aureus Enterococcus sp Organisms n p value E. coli Klebsiella sp Enterobacter sp other enterobacteriaciae all enterobacteriaciae Ps. aeruginosa Hemophilus sp other non-enterobacteriaciae all non-enterobacteriaciae all gram Kumar et al, Crit Care Med Hazard Ratio 2010;38:

28 Eventually, Billy came to dread his father s lectures over all other forms of punishment. 30