Sepsis Treatment: Early Identification Remains the Key Issue

Transcription

1 Sepsis Treatment: Early Identification Remains the Key Issue Marin H. Kollef, MD Professor of Medicine Washington University School of Medicine Director, Medical Critical Care Director, Respiratory Care Services Barnes-Jewish Hospital St. Louis, MO 1

2 Conflicts of Interest 1.Merck 2.Actavis 3.Arsanis 4.Cardeas 5.Cubist 6.Medimmune 7.Astrazeneca 8.Accelerate 9.Academy for Infection Management 10.Barnes-Jewish Hospital Foundation 2

3 Infection with MDR/XDR Problematic 3

4 Drug Resistance in Gram-negative Pathogens Has Continually Evolved! Resistant E. coli, P. aeruginosa, Klebsiella spp., Enterobacter spp. CTX-M-15, VIM, IMP, NDM- 1,Porin defects, Metallo -lactamases (Class B) Resistant E. coli, Pseudomonas aeruginosa and Klebsiella spp. AcrAB, bla SHV, bla TEM, AmpC-type -lactamases (Classes C and D) Resistant Escherichia coli TEM and SHV serine -lactamases (Class A) Susceptible Gram-negative pathogens 1960s Ampicillin 1. Hawkey. Antimicrob Chemother. 2008;62:i Hawkey and Jones. J Antimicrob Chemother. 2009;64:i Bush. Antimicrob. Agents Chemother. 2010;54: Livermore. Clin Infect Dis. 2002;34: Olivares et al. Front Microbiol. 2013;4: s Cephalosporins (eg, ceftazidime cefotaxime) 1990s-2000s Carbapenems (eg, imipenem, meropenem) s Fluoroquinolones (eg, norfloxacin, ciprofloxacin, levofloxacin)

5 Number of unique β- lactamases Class A β-lactamases Including ESBLs Have Increased Significantly 750 CTX-M-14 & CTX-M-15 are the primary drivers of the increase in prevalence of ESBLs 1 Class A (ESBLs incl. CTX/TEM/SHV/KPC) Compilation of unique β-lactamase sequences from natural isolates Figure : Based on Bush and Fisher. Annu Rev Microbiol. 2011;65:455. Bush. Ann N Y Acad Sci. 2013;1277: Bonnet ANTIMICRO 5 AGENTS CHEMOTHERAPY, Jan. 2004, p CTX-M-1, in reference to its hydrolytic activity against cefotaxime. Class D (OXA) Class C (AmpC) Class B (IMP/VIM/NDM-1)

6 Globalisation of KPC Finland & Sweden 2009 sporadic or imported Poland regional outbreaks Canada 2008 KPC-3 imported UK 2003 Localised to North West England Ireland 2009 KPC-2 sporadic France 2005 KPC-2 sporadic Hungary 2008 sporadic Greece 2007 KPC-2 endemic USA 1996 KPC-2 & KPC-3 endemic in some states Colombia 2005 KPC-2 & KPC-3 endemic Portugal No clinical cases Spain 2009 KPC-2 sporadic Brazil 2006 KPC-2 endemic Argentina 2006 KPC-2 endemic Italy2008 KPC-2 & KPC-3 endemic Israel 2005 endemic India 2002 sporadic cases reported KPC endemic and predominant KPC scattered and predominant KPC recorded but not widespread KPC recorded but only from environmental sources Other carbapenemase types scattered and predominant over KPC Other carbapenemase types endemic and predominant over KPC China 2004 KPC-2 & KPC-3 endemic Australia & New Zealand imported 6 Munoz-Price LS et al. Lancet Infect Dis 2013;13:785-96

7 Colistin resistance in Klebsiella pneumoniae 7 Ah et al. Int J Antimicrob Agents 2014; 44:8-15 Rates ranging from 1 to 80% To include carbapenem-resistant strains!

8 Prevalence Pseudomonas aeruginosa VAP 8 Kollef MH, et al. Crit Care Med 2014;42:

9 Commissioned Report By UK Government and the Wellcome Trust > Ten Million Deaths Yearly By The Review on Antimicrobial Resistance Chaired by Jim O Neill December 2014

10 Goals of Antimicrobial Stewardship in Sepsis Combat the Emergence of Resistance Antimicrobial Stewardship Control Costs Improve Clinical Outcomes 10 Do Antibiotics Matter in Sepsis? Lawrence KL, Kollef MH. Am J Respir Crit Care Med 2009;179:

11 In the Critically ill Patient Hit Hard and Fast 11

12 Mortality (%) Frequency (%) Number of resistances Non-adequate Adequate Frequency of the appropriateness of empiric antimicrobial therapy (a) and proportion of deaths (b) in relation to the number of antibiotics to which the E. coli isolated from blood cultures was non-susceptible Dead Surviving Adequacy of empiric antibiotic treatment is an independent risk factor for mortality in E. coli bacteraemia Number of resistances Peralta et al. J Antimicrob Chemother 2007;60:

13 Hospital Mortality (%) Increased Mortality With Inadequate Antibiotic Therapy in Infections Requiring ICU Admission N = % 655 (32.8%) infected 169 (25.8%) inappropriate treatment Prospective, single-center, cohort study P<.001 Inadequate antimicrobial treatment Adequate antimicrobial treatment 42% P< % 18% ICU=intensive care unit. 0 All Cause Site of infection includes bloodstream, lung, wound, gastrointestinal tract, urinary tract, and miscellaneous (includes peritoneal infection, meningitis, endocarditis, and infections of the skin and fascia). 13 Kollef MH. Chest. 1999;115: Mortality Type Infection Related

14 N = 1064 Gram-negative bacteremia/sepsis (P < all comparisons) Initial Appropriate Antibiotic Therapy (IAAT) is an important determinant of outcome in sepsis! Non-IAAT to <0.001 Chronic liver disease to Septic shock to <0.001 Pneumonia to Mechanical ventilation to APACHE II score to <0.001 Surgery to Admitted from home to Urosepsis to Zilberberg M, et al. Crit Care 2014;18:596

15 Probability of Adequate Empiric Therapy in Patients with K. pneumoniae Bacteremia 15 Girometti, et al. Medicine 2014;93:

16 Independent Predictors of Mortality for 16 Acinetobacter bacteremia (n = 131; non-iaat = 71%; mortality = 49.6%) Corrected risk ratio 95% CI P value Non-IAAT APACHE II <0.001 Infection source: Urine AUROC = 0.801, Hosmer-Lemeshow p=0.406 Non-IAAT = Non-appropriate Initial Antibiotic Therapy Zilberberg M, et al. BMC ID 2014;14:572

17 MDR ALL MRSA MSSA Candida spp. E. coli Klebsiella spp. MDR GNB VSE P. aeruginosa VRE Anaerobes Enterobacter spp. cinetobacter spp. Pathogen Incidence (%) Number Needed To Treat With Appropriate Antibiotic Therapy To Save One Life NNT were calculated from adjusted mortality stratified by APACHE score, presence of septic shock, mechanical ventilation, and antibiotic resistance patterns. For each combination of confounders, a stratum-specific mortality was computed to obtain a final weighted average of adjusted mortality in appropriate and inappropriate antibiotic groups. N = 2594 Number Needed To Treat 17 Vazquez-Guillamet C, et al. Crit Care Med 2014;42:

18 *24 hr delay = 1.75 day excess LOS Time to appropriate antibiotic therapy (1-hour increments) days per hr delay* 18 Zhang D, et al. Crit Care Med 2015;43:

19 Antibiotic Use Counterintuitive Antibiotic Resistance (MDR/XDR) 19 Inappropriate Therapy

20 Risk Factors for VAP Variable AOR 95% CI P Value OSFI > < Age > Supine* Prior Antibiotics Kollef MH. JAMA 1993;270: *First 24 hours of mechanical ventilation.

21 21 Should We Surrender?

22 Traditional Methods for Detection of BSI Gram Stain Organism identification and susceptibility testing h Hours to Days 22 Subculture

23 Traditional Methods for Detection of BSI 23 Accurate but slow!

24 Ideal Diagnostic Tool for BSI 24

25 New Paradigm - Pathogen directed therapies have arrived! 25

26 Nanosphere Verigene BC Assay Hybridization using microarray technology Hybridization if target DNA present Gold Nanos w/ complementary sequences hybridize Elemental silver amplifies signal Verigene 26

27 Verigene GN Blood Culture (GN-BC) Assay Species Genus Resistance Markers Escherichia coli* Klebsiella pneumoniae Klebsiella oxytoca Pseudomonas aeruginosa Serratia marcescens Acinetobacter spp. Proteus spp. Citrobacter spp. Enterobacter spp. KPC NDM-1 CTX-M VIM IMP OXA 27 *Cannot differentiate from Shigella spp.

28 Load cassette Load reagent cartridge Add sample to vial, load and start 28

29 E. coli vs. 4 μg/ml Piperacillin-Tazobactam MIC=8(S) 29 MIC=128(R)

30 AUTOMATED MICROSCOPY CLINICAL MICROBIOLOGY PRESENCE/ABSENCE > CFU/mL Positive Negative Positive 7 2 Negative Douglas IS, et al. AJRCCM 2015;191: SENS = 100% SPEC = 97%

31 Hours Rapid Testing w/ Verigene Blood Culture Nucleic Acid Test in Combination w/ ASP for GN Bacteremia P < 0.01 Correctly Identified: 95.6% (131/137) Sensitivity: 97.1% (95% CI, 90.7 to 98.4%) Specificity: 99.5% (95% CI, 98.8 to 99.8%) P < Time to Antibiotic Therapy Bork JT, et al. Antimicrob Agents Chemother 2015;59:

32 Before-After Design Scripps Health 32 Box MJ, et al. Pharmacotherapy 2015;35:

33 Mean time to targeted antibiotic therapy and unnecessary duration of antibiotic therapy for contaminants 33 Box MJ, et al. Pharmacotherapy 2015;35:

34 Comparison of time detection for BACTEC 9050 automated blood culture system and the T2Candida Panel (T2) Species Test method Samples (n) % positive p-value Median time (h) p-value C. albicans BC <0.001 T C. glabrata BC NA NA NA 34 T C. parapsilosis BC <0.001 T C. tropicalis BC <0.001 T C. krusei BC <0.001 T NA, not applicable: No growth was detected after 7 days using the BACTEC BC system. Pfaller MA, et al. Future Microbiol 2016; 11:

35 616 bloodstream infection, 185 pneumonia, and 110 sterile fluid and tissue specimens from 529 patients PCR/ESI-MS 35 Vincent JL, et al. Crit Care Med 2015;43:

36 38 yo man ESRD on HD Respiratory distress Diffuse infiltrates 36 BAL 32% lymphocytes BAL 48% neutrophils H1N1 identified Broad-spectrum antibiotics discontinued!

37 37 Crotty MP, et al. Crit Care Nov 18;19:404.

38 38 Crotty MP, et al. Crit Care Nov 18;19:404.

39 39 Crotty MP, et al. Crit Care Nov 18;19:404.

40 Conclusions Understand your local epidemiology Try to treat appropriately and adequately Appropriate drug selection (combination) Adequate dosing/duration/infusion timing Use microbiology results to de-escalate Use new technology to enhance treatment 40

41 41 Thank you!