Housekeeping Reminders

Transcription

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2 Housekeeping Reminders Thank you to Achaogen for their unrestricted educa2onal grant in support of this program To receive credit, please complete your CE Program Form or see instruc>ons in the program booklet You can earn addi>onal credit through a Self Directed Performance Improvement ac>vity - addi2onal informa2on is in your workbook Also, please make sure your badge was scanned or you signed in for this session.

3 Disclosures Scien>fic Integrity and Disclosure of Financial Interests: Center for Educa2on Development (CED) requires that all CE/CME informa2on be based on the applica2on of research findings and the implementa2on of evidence- based medicine. CED promotes balance, objec2vity, and absence of bias in its content. All persons in a posi2on to control the content of this ac2vity must disclose any conflicts of interest. CED has mechanisms in place to resolve all conflicts of interest prior to an educa2onal ac2vity being delivered to the learners.

4 Disclosures This informa,on can be found in the Program Book The faculty and planners for this program disclose the following: Andrew F. Shorr, MD, MPH Speaker for, consultant to or goken research support from: Actavis, Astellas, AZ, Bayer, Cubist/Merck, Pfizer, Roche, Theravance, Wockhardt, Medco, and Consultant/ Advisor for Alios, AKP, Cempra, Entasis, Zavante Therapeu2cs Yehuda Carmeli, MD, MPH Consultant to, researcher/inves2gator for, or spoken for: Achaogen, Allecra Therapeu2cs, AstraZeneca, Biomerieux SA, DaVolterra, Durata Therapeu2cs, Valneva SE, Merck, Nabriva Therapeu2cs, Omnix, PPD, Rempex Pharmaceu2cals, Roche, Syntezza Bioscience LTD, Takeda Pharmaceu2cal Company Limited Keith Rodvold, PharmD, FCCP, FIDSA Research Grants and Contracts: Allergan, Theravance Biopharma, ARLG / NIAID / NIH; Consultant / Advisory Board: Achaogen, Allergan, Bayer, Janssen Pharmaceu2cals, Melinta Therapeu2cs, Merck, Mo2f Biosciences, Nabriva Therapeu2cs, Spero Therapeu2cs, Tetraphase Pharmaceu2cals, Theravance Biopharma, Wockhardt, Zavante Therapeu2cs; Speaker s Bureau: Allergan, Medicine Company, Merck CED planners and reviewers have nothing to disclose.

5 Agenda The Clinical Impacts of Resistant Gram- Nega)ve Infec>ons Andrew F. Shorr, MD, MPH Gram- Nega)ve Resistance and Its Impact on Treatment Decisions Yehuda Carmeli, MD The Evolu>on of An>bio>cs to Treat Gram- Nega)ve Pathogens Keith Rodvold, PharmD, FCCP, FIDSA

6 THE CLINICAL IMPACTS OF RESISTANT GRAM- NEGATIVE INFECTIONS Andrew F. Shorr, MD, MPH Washington Hospital Center Georgetown University

7 Disclosures I have served as a consultant to, researcher/inves2gator for, or spoken for: Actavis Astellas AstraZeneca Bayer Cubist/Merck Pfizer MedCo Roche Theravance Wockhardt Alios AKP Cempra Entasis Therapeu2cs Zavante Therapeu2cs

8 Overview Defini2ons Epidemiology Outcomes Drivers of Resistance

9 The Vocabulary MDR = Resistant to more than 1 agent in 3 or more an2microbial categories XDR = Nonsuscep2ble to more than 1 agent in all but 2 categories PDR = Resistant to all categories Table 1 Definitions of multidrug resistance and predominant mechanisms of resistance to traditional gram-negative antibiotics Enterobacteriaceae Pseudomonas aeruginosa Acinetobacter spp Resistance category definitions Common Resistance Phenotypes Third- fourth-generation cephalosporins Carbapenem resistance Fluoroquinolones Aminoglycosides Carbapenem resistance and other b-lactam resistance Fluoroquinolones Aminoglycosides Cephalosporin and carbapenem resistance Aminoglycoside resistance Fluoroquinolone resistance Major Mechanisms of Resistance ESBL, AmpC b-lactamases Carbapenemases DNA gyrase and topoisomerase mutations Aminoglycoside-modifying enzymes Metallo-b-lactamases AmpC and other b-lactamases Multidrug efflux pumps Deletion of membrane porins DNA gyrase and topoisomerase mutations Aminoglycoside-modifying enzymes Cephalosporinases Carbapenemases Multidrug efflux pumps Porin mutations Penicillin-binding protein changes Aminoglycoside-modifying enzymes DNA gyrase and topoisomerase mutations MDR is defined as resistant to more than 1 agent in 3 or more antimicrobial categories XDR is defined as nonsusceptible to more than 1 agent in all but 2 categories PDR is defined as resistant to all categories Intrinsic resistance to specific antimicrobial agent would automatically eliminate that agent from being included in defining resistance Fraimow H, et al. Crit Care Clin 2013; 29:

10 Defining Resistance Table 3 Breakpoints for susceptibility as approved by EUCAST, SCLIS, and FDA (in mg/ml) EUCAST Cefepime/ Imipenem/ Tobramycin CLSI Cefepime/ Imipenem/ Tobramycin FDA Cefepime/ Imipenem/ Tobramycin Enterobacteriaceae Pseudomonas aeruginosa Acinetobacter spp Fraimow H, et al. Crit Care Clin 2013; 29:

11 EPIC II Point prevalence study Interna2onal ICUs (n=1265) Popula2on: pa2ents; 51% infected Cohort Mean SOFA: % medical, 72% surgery/trauma 56% on MV Vincent JA, et al. JAMA 2009; 302:

12 Globally, Majority of ICU infec>ons Are Due to Gram- nega>ve Bacteria Gram- nega>ve isolates (%) 70% of infected pa>ents have posi>ve cultures; 62% are Gram- nega>ve % of Gram- nega>ve cultures are Pseudomonas spp Pseudomonas spp. Escherichia coli Klebsiella spp. Acinetobacter spp. Enterobacter spp. Other Data from the Extended Prevalence of Infec2on in Intensive Care (EPIC II) Study, a global, 1- day point prevalence study of 13,796 pa2ents from 1265 ICUs in 75 countries in Vincent et al. JAMA. 2009;302:

13 CDC Iden>fied Threats: 2013 Number of Pa>ents Cases Fatali2es CRE ESBL AB MDR PA URGENT THREAT Case Fatality Rate Approximately 7% and does NOT vary by pathogen Assembled from: hkp://

14 Klebsiella pneumoniae Percentage of Invasive Isolates with Combined Resistance to Third- Genera>on cephalosporins, Fluoroquinolones and Aminoglycosides EU/EEA, 2010 EU/EEA, 2014 Percentage (%) Resistance European Centre for Disease Preven2on and Control. An2microbial resistance surveillance in Europe 2014.

15 Acinetobacter species: Percentage of Invasive Isolates with Combined Resistance to Fluoroquinolones, Aminoglycosides and Carbapenems EU/EEA, 2014

16 EBSL: Classifica>on Rou2nely encountered in Enterobacteriaceae (eg E. coli & K. Pneumoniae) but not limited to these species Classified as: Bush- Jacoby- Medeiros: 2be Ambler: Class A Major enzyme types: SHV TEM CTX AmpC: Unique beta- lactamase not inhibited by clavulanate Harris PNA, et al. Lancet ID 2015; 15:

17 Predicted Trends in EBSL UTI Hospitaliza>ons B. Year i s. 4 a J CO 52 0 u Ul ^vvvv#vv #v Year <. 2 f= 2 i 03 a. 0 ^\#^\#^VV #*# Year Base Lower bound Upper bound p ###^\o^vv ^V Year _c*> -<<S ^c9>.cs> FIGURE i. Annual urinary tract infection (UTI) hospitalization rates with the resistant pathogen of interest per 1,000 hospitalizations, A, multidrug-resistant Pseudomonas aeruginosa (MDR PA). B, extended-spectrum j3-lactamase-producing Escherichia col ESBL). C, extended-spectrum /3-lactamase-producing Klebsiella pneumoniae (KP ESBL). D, carbapenem-resistant Enterobacteriaceae (CRE

18 AB Resistance Based on Infec>on Site % of Isolates MDR3 CRAB 0 CLABSI CAUTI VAP SSI Sievert DM, et al. ICHE 2013; 34: 1-14.

19 Epidemic Can Become Endemic Retrospec2ve analysis Single center experience Longitudinal evalua2on of AB isola2on n=4484 first isolates Munoz- Price LS, et al. CCM. 2013: 41; Acinetobacter baumannii

20 Outcomes: Predictors in GNR Sep>c Shock Retrospec2ve analysis Subjects: GNR bacteremia resul2ng in sep2c shock N=1064 E. coli: 27% K. pneumoniae: 20% P. auerginosa: 17% Endpoint: Mortality Predictors of Hospital Mortality Table 3 Predictors of hospital mortality Odds ratio 95% confidence interval P value Non-IAAT to <0.001 Chronic liver disease to Septic shock to <0.001 Pneumonia to Mechanical ventilation to APACHE II score (per 1 point) to <0.001 Surgery to Admitted from home to Urosepsis to a Independent variables included but not retained in the model at alpha 0.05: Zilberberg MD, et al. Crit Care Med : 596.

21 Inappropriate Therapy: A Modifiable Risk Factor Predictors of Receiving Ini>ally Inappropriate An>bio>c Therapy Odds ratio 95% confidence interval P value Multidrug resistant <0.001 HIV Transferred from another hospital <0.001 Nursing home resident Prior antibiotics <0.001 Polymicrobial Congestive heart failure APACHE II score (per 1 point) <0.001 a Independent variables included but not retained in the model at alpha 0.05:

22 Appropriate Ini>al Therapy 100 An earlier study of sep>c shock (n = 2,731) explicitly demonstrated the importance of an>microbial >ming Odds Ra2o of Death (95% Confidence Interval) 10 1 Time From Hypotension Onset (hr) Every hour s delay un2l appropriate therapy resulted in a 12% increase in mortality Compared with star2ng appropriate therapy within 1 hour of the onset of hypotension, the OR for mortality increased from 1.67 in Hour 2 to with delays >36 hours Kumar A, et al. Crit Care Med. 2006;34:

23 Impact of Resistance on Outcomes How Many Time Do We Have to Get it Right to Save One Life? Vazquez- Guillamet C, et al. CCM 2014; 42: Retrospec2ve analysis of impact of appropriate therapy on mortality 1250 subjects with sep2c shock Inappropriate an2bio2cs: 3.4 x independent increase in risk for death NNT calculated per pathogen For every 5 pa>ents given appropriate therapy one added survivor!

24 SO HOW DID WE GET HERE?

25 Resistance Driving Resistance: The ESBL / Carbapenem Resistance Loop Increased carbapenem- R strains Increased MDR enterics (ESBLs) Pseudomonas aeruginosa Acinetobacter X transmiss. + spread of R- genes Enterobacteriaceae Increased carbapenem use Select carbapenem- R strains

26 Carbapenem- resistant K. pneumoniae (CRKP) Mul>variate analysis of risk factors for the emergence of CRKP Variables Odds ra>o 95% C.I. P Prior fluoroquinolone use Prior carbapenem use ICU admission >0.001 Exposure to at least 1 ABX drug prior to isola2on of K. pneumoniae Hussein K, et al. Infect Control Hosp Epidemiol. 2009;30:

27 Correla>on Between Carbapenem Consump>on and P. aeruginosa Resistance Carbapenem resistance (%) Carbapenem consump>on (DDDs) Lepper PM, et al. An2microb Agents Chemother. 2002;46:

28 ARE WE EVEN DOSING ANTIBIOTICS IN THE ICU CORRECTLY?

29 Changes in the Cri>cally Ill Pa>ent Affec>ng An>bio>cs Systemic Inflamma2on Altered Major Organ Blood Flow + Endothelial Dysfunc2on and Capillary Leak Large volume IV fluid resuscita2on Obesity Vasopressor medica2ons Extracorporeal circuits Low plasma protein concentra2ons Drug- drug interac2ons Deranged CL (AKI or ARC) + Increased V d (hydrophilic agents) Reduced An2bio2c Exposure + Higher MIC Udy AA, et al. ICM. 2013; 39: Treatment Failure and/or the Selec2on of Resistant Organisms

30 Explana>on of Augmented Renal Clearance Inflamma2on Infec2on Pancrea22s Vasodila2on SIRI CO Burns Surgery ARC arises from interac2on of: Systemic inflamma2on Physiologic reserve ARC noted in: RBF IV fluids Young pa2ents Renal reserve GRF Vasoac2ve medica2ons Trauma pa2ents ARC Udy et al Clin Pharmacokinet 2010; 49:1-16

31 β- lactam Underdosing in Pa>ents with Augmented Renal Clearance (ARC)? Trough concentration: MIC ClCr (ml/min/1.73m 2 ) ARC = supranormal glomerular filtra2on ClCr > 130 ml/min/ 1.73m2 Cockcrop Gault CrCl Most common in cri2cally ill pa2ents with: SIRS/Sepsis Trauma Bap2sta JP et al. Crit Care 2011;15:R139. Udy AA et al. Chest 2012;142:30-39.

32 Dosing Malers: Was This All Due to ARC? Infec>on type Treatment group Predicted mortality* (%) Actual mortality (%) Non- VAP Cepobiprole Non- VAP Linezolid/Cepazidime VAP Cepobiprole Cepobiprole 500 mg q 8 vs. Linezolid 600 mg q 12 hours & Cepazidime 2 g q 8 VAP Linezolid/Cepazidime *Based on Knaus et al. Crit Care Med 1985;13:818 Study primary enrolled - Young pa2ents with normal es2mated renal func2on - Trauma pa2ents Basilea (On File)

33 Clinical Cure & All- Cause 28- Day Mortality Doripenem Imipenem 7- day course 10- day course n N % n N % Diff (%) 95% CI Clinical cure rate MITT ( ; 3.8) ME ( ; 0.8) Crea2nine clearance* (MITT) 150 ml/min (- 55.4; 1.4) ; 20.9 >50 - < ; 33.0 > All cause 28- day mortality MITT (- 5.0; 18.5) MITT = Microbiological ITT, ME = Microbiologically Evaluable * Calculated using Cockcrop - Gault formulas rela2ng serum crea2nine with age & body weight Kollef, MH, et al. Crit Care 2012;16(6):R218.

34 Beta- Lactam (BL) Infusion in Severe Sepsis Trial (BLISS) Prospec2ve, randomized, non- blinded Interven2ons Bolus infusion (BI) of BL vs Con2nuous infusion (CI) Agents: cefipeme, pip/taz, meropenem Subjects: (n=140), Adults, severe sepsis, & organ dysfunc2on Endpoints Clinical cure 14d aper d/c abx PK/PD targets (BL levels measured in central lab) Abdul Aziz MH, et al. ICM; published online Jan. 2016

35 BLISS Abdul Aziz MH, et al. ICM; published online Jan CI = Con2nuous Infusion IB = IntermiKent Bolus

36 BLISS % of Pa2ents BI CI 20 0 * * ** T>MIC (Day 1) T>MIC (Day 3) Clinical Cure *p<0.001, **p<0.01 Abdul Aziz MH, et al. ICM; published online Jan CI = Con2nuous Infusion IB = IntermiKent Bolus

37 Conclusions Resistance among GNR increasing PaKern seen globally and in mul2ple pathogen types Resistance drives inappropriate therapy We know very likle about how to use an2bio2cs in the pa2ents who need them most urgently

38 GRAM- NEGATIVE RESISTANCE & ITS IMPACT ON TREATMENT DECISIONS CARBAPENEM- RESISTANT ENTEROBACTERIACEAE (CRE): A REAL LIFE EXPERIENCE Yehuda Carmeli, MD, MPH The Na2onal Center for Infec2on Control and An2microbial Resistance, Tel Aviv Medical Center, Israel

39 Disclosures I have served as a consultant to, researcher/inves2gator for, or spoken for: Achaogen Allecra Therapeu2cs AstraZeneca Biomerieux SA DaVolterra Durata Therapeu2cs, Inc Valneva SE Merck & Co. Inc Nabriva Therapeu2cs Omnix PPD Rempex Pharmaceu2cals Roche Syntezza Bioscience LTD Takeda Pharmaceu2cal Company Limited

40 Israel Size and popula2on ~ New Jersey Size: 8,500 square miles Popula2on: 8 million 15,000 acute hospital beds 28 hospitals 3,500 PACs (chronic ven2la2on, skilled nursing) beds 14 hospitals 25,000 LTCFs beds 300 facili2es

41 No Carbapenamases in 2004: All carbapenem non- suscep>bile strains due to ESBL+porin loss 6 % non- suscep2bly to carbapenems Ertapenem Imipenem Meropenem 1,030 ESBL producing E. coli & Klebsiella spp. Collected during 2004 from 10 largest hospitals Adapted from Colodner R. DMID 2007; Leavit A, AAC 2009

42 Na>onwide emergence of carbapenem- resistant Kpn - Israel 15 Bacteremia % carbapenem resistance 10 5 All sites EARSS (5 hospitals) 3 hospitals (>500 bed)

43 Natural history of carbapenem- resistant K. pneumoniae spread in countries without regional infec>on control 35 Propor>on Resistant to Carbapenems Greece Israel Cyprus Italy Romania Friedman D. SubmiKed for publica2on 1st 2nd 3rd Year of CRE Outbreak

44 The Israeli CRE na>onal outbreak First-time CRE isolations per clinical culture, Jan 05-April Number of Isolations Jan-05 Feb-05 Mar-05 Apr-05 May-05 Jun-05 Jul-05 Aug-05 Sep-05 Oct-05 Nov-05 Dec-05 Jan-06 Feb-06 Mar-06 Apr-06 Month May-06 Jun-06 Jul-06 Aug-06 Sep-06 Oct-06 Nov-06 Dec-06 Jan-07 Feb-07 Mar-07 Apr-07

45 Carbapenem resistant K. pneumonia status in 2007 % carbapenem resistance Es>mates: Incidence: 1600 inpa>ents infec>ons Reservoir: 17,000 carriers Mortality: 700 fatali>es (100 per million) 700 cases 44% mortality Year EARSS report Schwaber M. AAC 2008

46 Emergence of KPC- 2 and KPC- 3 in Carbapenem- Resistant Klebsiella pneumoniae Strains in an Israeli Hospital Azita LeaviK et al. An2microb. Agents Chemother. 2007;51:

47 One hospital experience Tel Aviv Medical Center Ter2ary care teaching hospital 1500 beds 100,000 pa2ents admissions per year 27% of pa2ents with CRE had bacteremia 21 of 48 pa2ents infected with CRE died (CFR 44%) Colis2n was used empirically in units where CRE was isolated At hospital emergency staff mee2ng Chief of surgery stated: situa2on at surgical ICU become too risky to admit pa2ents for elec2ve colorectal surgery, dras2c measures are required to ensure pa2ent safety 3 of 4 pa2ents carriers of CRE who underwent BMT died aper transplant due to CRE bacteremia Ethical commikee convened to discuss if it is ethical to perform BMT in CRE carriers given the individual risk and risk to others Schwaber M. AAC 2008

48 Cohor>ng with dedicated staff It become evident that CRE outbreak risks the hospital ability to provide safe care to pa2ents Cohor2ng of all CRE carriers in isola2on units effec2ve but difficult: NO. OF CASES Incidence of KPC- producing Klebsiella spp. LAG TIME P=0.01 At the peak 32 carriers in Medical, surgical and ICU cohorts Difficul2es to discharge carriers to LTCFs TIME (weeks) Schechner V, ICAAC 2007

49 Targeted screening for CRE upon admission 40 <1% posi2vity No_Posi>ve_Pat No_Nega>ve_Pat 35 NO OF PATIENTS DATE

50 Poten>al Role of Ac>ve Surveillance in the Control of a Hospital- Wide Outbreak of Carbapenem- Resistant Klebsiella pneumoniae Infec>on Ben- David D. ICHE 2010

51 Gastrointes>nal coloniza>on by KPC- producing Klebsiella pneumoniae following hospital discharge: dura>on of carriage and risk factors for persistent carriage In pa2ents admiked from and discharged to home: 50% clear carriage at 3 months. Pa2ents in LTFCs, may remain carriers for prolonged periods. Feldman N. CMI 2013

52 JCM 2013 Environmental Contamina>on by Carbapenem- Resistant Enterobacteriaceae

53 Risk of transmission is not uniform: Environmental CRE contamina>on Fraction of patients Lerner A. CMI 2014

54 The movement of KPC Kp through 30 pa>ents in 4 different wards Index case January February March April Patient 1 Pa>ent 2 Pa>ent 3 * Pa>ent 4 * Pa>ent 5 * Pa>ent 6 X Pa>ent 7 X Pa>ent 8 * Pa>ent 9 * Pa>ent 10 * Pa>ent 11 * Pa>ent 12 Pa>ent 13 X * Pa>ent 14 * Pa>ent 15 * Pa>ent 16 Pa>ent 17 X * Pa>ent 18 * Pa>ent 19 X * Pa>ent 20 X * Pa>ent 21 X * Pa>ent 22 * Pa>ent 23 * Pa>ent 24 * Pa>ent 25 Pa>ent 26 X * Pa>ent 27 * Pa>ent 28 * Pa>ent 29 * Pa>ent 30 X * Schechner V. ICAAC 2008 Note: Internal medicine X Internal medicine Y Internal medicine Z Internal medicine W Positive KPC Kp clinical culture * Positive KPC Kp surveillance culture X Negative surveillance culture Dedicated KPC Kp ward

55 CRE nosocomial acquisi>ons, clinical culture, general hospitals, /2015 Interven2ons in LTCF

56 An Ongoing Na>onal Interven>on to Contain the Spread of Carbapenem- Resistant Enterobacteriaceae % carbapenem resistance among K. pneumoniae blood isolates Decreased from a peak of 25% (2007) to <4% (2015) Update on: Schwaber MJ. CID 2014

57 The story of one nursing home Jan 2010: all residents were screened 48% were CRE carriers אחרים Detected חולים on other בבתי facility on same facility סיקורים Detected במוסד גילויים

58 Interven>on Infec2on control educa2on Periodic hospital- wide ac2ve screening Implementa2on of screening on admission Separa2on into 4 cohorts (physical and staff) known carriers unknown new admissions prior carriers no carriage Closed for new admissions un2l full compliance was achieved (3 months)

59 Nursing home CRE acquisi>ons on same facility סיקורים Detected במוסד גילויים hospitals בבתי on other חוליםDetected אחרים

60 Comparison Between 4 PPS in PACHs Prevalence of new CRKP Prevalence of CRKP%

61 CRE incidence PACHs,

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63 The changing CRE epidemiology 2016 KPC OXA- 48 NDM Friedman D. SubmiKed 2016

64 Distribu>on of CPE in Israel 2016 (%)

65 2016 Israeli Tes>ng Guidelines for CPE Suspected CPE PCR (KPC, NDM, OXA- 48, VIM) CARBA NP Posi2ve CPE Nega2ve CARBA NP/MHT Posi2ve CPE Posi2ve Send to reference lab Nega2ve If Meropenem MIC>1 Non- CPE CRE PCR (KPC, NDM, OXA- 48, VIM) Nega2ve Send to reference lab

66 Asymptoma>c rectal carriage of bla KPC producing carbapenem- resistant Enterobacteriaceae: who is prone to become clinically infected? During subsequent 2 years (May 2007 and 30 April 2009) 5% (10,040) pa2ents admissions considered high risk popula2on screened for carriage of CRE 502 were newly iden2fied CRE rectal carriers 44 (8.8%) developed subsequent posi2ve clinical cultures with CRE CMI 2012

67 Bloodstream infec>ons among carriers of carbapenem- resistant Klebsiella pneumoniae: e>ology, incidence and predictors 7 days Case Fatality rate: Non CRE GNR 24% CRE 39% No pathogen specific Predictors iden2fied CMI 2015

68 Summary CRE may spread rapidly within and between ins2tu2ons May lead to units closure and to limit the healthcare system to provide advanced safe care Substan2al efforts and resources may be required to limit the spread of CRE CRE carriers are at high risk to develop CRE as well as other mostly GNR infec2ons. These infec2ons are associated with exteremely high case- fatality rate Preven2ve and treatment strategies are required to confront the global epidemic of CRE

69 THE EVOLUTION OF ANTIBIOTICS TO TREAT GRAM- NEGATIVE PATHOGENS Keith A. Rodvold, Pharm.D., FCCP, FIDSA Colleges of Pharmacy and Medicine University of Illinois at Chicago

70 Disclosure Statement (past 12 months) Research Grants and Contracts: Allergan, Theravance Biopharma, ARLG / NIAID / NIH Consultant / Advisory Board: Achaogen, Allergan, Bayer, Janssen Pharmaceu2cals, Melinta Therapeu2cs, Merck, Mo2f Biosciences, Nabriva Therapeu2cs, Spero Therapeu2cs, Tetraphase Pharmaceu2cals, Theravance Biopharma, Wockhardt, Zavante Therapeu2cs Speaker s Bureau: Allergan, Medicine Company, Merck

71 An>bio>c Resistance Threats in the United States, 2013 Gram- Nega>ve Organism Cases (%) Deaths (%) Threat Level ESBL- producing Enterobacteriaceae 26,000 (1.93) 1700 (7.44) Serious Carbapenem- resistant Enterobacteriaceae 9300 (0.69) 610 (2.67) Urgent Mul2drug- resistant Pseudomonas aeruginosa 6700 (0.5) 440 (1.92) Serious Mul2drug- resistant Acinetobacter spp (0.54) 500 (2.18) Serious Es2mated annual incidence of infec2on due to notable an2microbial- resistant organisms Total: 1,349,766 cases and 22,840 deaths ESBL, extended- spectrum beta- lactamase Thabit AK, et al. Expert Opin Pharmacother 2015; 16: hkp:// threats pdf

72 An>bio>c Treatment of Resistant Gram- Nega>ve Organisms Infec2ons caused by resistant Gram- nega2ve organisms are associated with increased morbidity and mortality compared to suscep2ble counterparts Choice of empiric therapy has become more difficult for serious infec2ons because an2microbial resistance to first- line agents Clinicians also have the dilemma between choosing: an agent that is inac2ve versus broad- spectrum agent monotherapy versus combina2on therapy determining the role of adjunc2ve therapy newer versus older agents

73 Colis>n and Polymyxin B Assumed an important role as salvage therapy for otherwise untreatable Gram- nega2ve infec2ons Emerging pharmacokine2c- pharmacodynamic data indicate the monotherapy is unlikely to generate plasma concentra2ons that are reliably efficacious Regrowth and the emergence of resistance with monotherapy are commonly reported even when concentra2ons exceed those achieved clinically Combina2on therapy has been suggested as a possible means of increasing an2microbial ac2vity and reducing the development of resistance Bergen PJ, et al. Pharmacother 2015; 35: Kassamali Z, Danziger L. Pharmacother 2015; 35: 17-21

74 Combina>on An>bio>c Treatment of Resistant Gram- Nega>ve Organisms Choice of agents open involves: Aminoglycosides Polymyxins Beta- lactam- beta- lactamase inhibitors Rifampin Carbapenem Tetracyclines Fosfomycin Tigecycline Clinical evidence regarding effec2veness of different treatment regimens is principally derived from retrospec2ve studies, case reports or small prospec2ve studies; no randomized clinical trials Need for new an2microbial agents to treat resistant gram- nega2ve organisms is inevitably important

75 Evolu>on of Novel An>bacterial Agents Chronological Order of First Public Reports Pucci MJ, Page MGP, Bush K. Microbe 2014; 9:

76 Agents Being Developed to Treat Resistant Gram- Nega>ve Bacteria Agent Related- Class Sponsor Cepolozane - Tazobactam BL- BLI Merck Cepazidime - Avibactam BL- BLI Allergan Meropenem - Vaborbactam BL- BLI Medicine Company Imipenem - Relebactam BL- BLI Merck Aztreonam - Avibactam BL- BLI Astra- Zeneca S Cephalosporin Shionogi BAL30072 Monocyclic BL Basilea Plazomicin Aminoglycoside Achaogen Eravacycline Tetracycline Tetraphase BL, Beta-lactam; BLI, beta-lactamase inhibitor

77 Cevolozane - Tazobactam Cephalosporin plus beta- lactamase inhibitor Spectrum of ac2vity: Gram- nega2ves, including MDR Pseudomonas aeruginosa and ESBL- producing strains FDA approval in December 2014 Complicated Urinary Tract Infec2ons, including Pyelonephri2s Complicated Intraabdominal Infec2ons (plus metronidazole) IV dose: 1.5 g (1 g cepolozane; 0.5 g tazobactam) q8h (1- h infusion) Clinical trial: Ven2lated nosocomial pneumonia at an increased dose: 3.0 g (2 g cepolozane; 1 g tazobactam) q8h Ongoing trial (NCT ; clinicaltrials.gov) Plasma- to- epithelial lining fluid penetra2on: ~30% van Duin D, Bonomo RA. Clin Infect Dis 2016; 63: Chandorkar G, et al. J An,microb Chemother 2012; 67: Nicolau DP, et al. J Clin Pharmacol 2016; 56: 56-66

78 Cevazidime - Avibactam Cephalosporin plus beta- lactamase inhibitor Spectrum of ac2vity: Gram- nega2ves, including MDR Pseudomonas aeruginosa, ESBL- producing strains, KPCs FDA approval in February 2015 (based Phase 2 data) Complicated Urinary Tract Infec2ons, including Pyelonephri2s Complicated Intraabdominal Infec2ons (plus metronidazole) For pa2ents with limited or no alterna2ve treatment op2ons IV dose: 2.5 g (2 g cepazidime; 0.5 g avibactam) q8h (2- h infusion) Unavailable as of August 8, 2016 shortage of ac2ve ingredient Clinical trial: Nosocomial pneumonia - Dose of 2.5 g q8h Trial was completed January 2016 (NCT ; clinicaltrials.gov) Plasma- to- epithelial lining fluid penetra2on ~30% van Duin D, Bonomo RA. Clin Infect Dis 2016; 63: Nicolau D, et al. J An,microb Chemother 2015; 70:

79 Carbapenem plus Beta- Lactamase Inhibitor Vaborbactam (RPX7009) Cyclic boronic acid- based beta- lactamase inhibitor Creates a covalent bond between boron moiety and serine hydroxyl beta- lactamase Good affini2es for many class A and C serine beta- lactamases High inhibitory potency against KPC- producing isolates Currently combined with meropenem (Carbavance ) Relebactam (MK- 7655) Diazebicyclooctanone, non- beta- lactam, beta- lactamase inhibitor Similar chemical structure and spectrum of ac2vity as avibactam Class A and C ac2vity with minor D ac2vity Lacking ac2vity against MBLs and most OXAs Currently combined with imipenem- cilasta2n Falagas ME, et al. Expert Rev An,- Infect Ther 2016; 14: Papp- Wallace KM, Bonomoa RA. Infect Dis Clin North Am 2016; 30:

80 In Vitro Ac>vity: Meropenem Vaborbactam 4,500 isolates collected from 11 hospitals in Brooklyn and Queens, NY from November 2013 to January 2014 Species (n) Meropenem Meropenem- Vaborbactam Meropenem- Vaborbactam MIC 50 MIC 90 MIC 50 MIC 90 MIC 50 MIC 90 Klebsiella pneumonia (KPC+) (121) / 4 2 / / / 8 Pseudomonas aeruginosa (96) / 4 32 / 4 8 / 8 32 / 8 Acinetobacter baumannii (98) / 4 64 / 4 32 / 8 64 / 8 MIC values in µg/ml Addi2on of RPX7009 resulted in a 64- to 512- fold decrease in meropenem MIC in majority of KPC- posi2ve isolates All but 2 of these isolates (98.3%) were inhibited by 1 µg/ml meropenem combined with RPX7009 at 8 µg/ml Lapuebla A, et al. An,microb Agents Chemother 2015; 59:

81 Meropenem Vaborbactam (RPX7009) In vitro hollow- fiber model (simula2ng human exposure of 2 g meropenem plus 2 g vaborbactam q8h 3- hour infusion) was bactericidal against KPC- producing Enterobacteriacea In vivo efficacy in murine thigh infec2on model against KPC- producing isolates of K. pneumoniae, E. coli, and E. cloacae (MICs ranging from 0.06 to 8 µg/ml) Efficacy, Safety, Tolerability of Carbavance Compared to Piperacillin- Tazobactam in Complicated Urinary Tract Infec2ons, including Acute Pyelonephri2s, in Adults (TANGO 1) Completed trial in June 2016 (NCT ; clinicaltrials.gov) Overall success in 98.4% of Carbavance treated pa2ents (sta2s2cal superiority) Efficacy, Safety, Tolerability of Carbavance Compared to Best Available Therapy in Serious Infec2ons Due to Carbapenem- Resistant Enterobacteriaceae in Adults (TANGO 2) Ongoing trial (NCT ; clinicaltrials.gov) ICAAC 2014 (abstr. F- 959 & F- 958) Falagas ME, et al. Expert Rev An,- Infect Ther 2016; 14:

82 In Vitro Ac>vity: Imipenem - Relebactam 4,000 isolates collected from 11 hospitals in Brooklyn and Queens, NY from November 2013 to January 2014 Species (n) Imipenem Imipenem - Relebactam MIC 50 MIC 90 MIC 50 MIC 90 Escherichia coli (2778) / / 4 Klebsiella pneumonia (891) / / 4 bla KPC - possessng K. pneumonia (111) 16 > / 4 1 / 4 Enterobacter spp. (211) / / 4 Pseudomonas aeruginosa (490) / 4 2 / 4 Imipenem- resistant P. aeruginosa (144) 8 >16 1 / 4 2 / 4 Acinetobacter baumannii (158) 4 >16 2 / 4 >16 / 4 bla OXA possessing A. baumannii (58) >16 >16 >16 / 4 >16 / 4 MIC values in µg/ml Lapuebla A, et al. An,microb Agents Chemother 2015; 59:

83 Imipenem+Cilasta>n Relebactam (MK- 7655A) In vivo efficacy in murine, neutropenic, thigh infec2on model against imipenem- resistant Pseudomonas aeruginosa with OprD deficiency and expression of AmpC beta- lactamase and imipenem- resistant KPC- producing Klebsiella pneumoniae strains Phase 2 complicated intraabdominal infec2ons trial (n=351 pa2ents): 1:1:1 ra2o in treatment groups of relebactam 250 mg, 125 mg, placebo Clinical response: 93.7%, 95.3%, 94.9% (microbiologically evaluable; n=230) Efficacy and Safety of Imipenem + Cilasta2n / Relebactam (MK- 7655A) versus Colis2methate Sodium plus Imipenem + Cilasta2n in Imipenem- Resistant Bacterial Infec2ons (RESTORE- IMI 1) Ongoing trial (NCT ; clinicaltrials.gov) Imipenem/Relebactam/Cilasta2n versus Piperacillin/Tazobactam for Treatment of Par2cipants with Bacterial Pneumonia (RESTORE- IMI 2) Ongoing trial (NCT ; clinicaltrials.gov) ICAAC 2015 (abstr. F- 259) Mavridou E, et al. An,microb Agents Chemother 2015; 59: Falagas ME, et al. Expert Rev An,- Infect Ther 2016; 14:

84 S Siderophore cephalosporin with a catechol moiety and binds mainly to PBP- 3 of Gram- nega2ve bacteria Catechol moiety to form a chela2ng complex with ferric iron Superior in vitro ac2vity than beta- lactam comparators against ESBL-, KPC- or metallo- beta- lactamase- posi2ve Enterobacteriaceae isolates, and both MDR Pseudomonas aeruginosa and Acinetobacter baumannii strains Ongoing Trials: Study of Efficacy/Safety of Intravenous S versus Imipenem/ Cilasta2n in Complicated Urinary Tract Infec2ons (NCT ; ClinicalTrials.gov) Study of S or Best Available Therapy for the Treatment of Severe Infec2ons Caused by Carbapenem- Resistant Gram- Nega2ve Pathogens (CREDIBLE CR) (NCT ; ClinicalTrials.gov) Ito- Horiyama T, et al. An,microb Agents Chemother 2016; 60: West KN, et al. An,microb Agents Chemother 2016; 60: Ito A, et al. J An,microb Chemother 2016; 71: Falagas ME, et al. Expert Rev An, Infect Ther 2016; 14:

85 BAL30072 Siderophore monocyclic beta- lactam an2bio2c (monosulfactam) stable to metallo- beta- lactamases and class C beta- lactamases; stable against some types of class A (eg., KPC) and class D (eg., OXA) carbapenemases More potent in vitro than beta- lactam comparators against MDR Acinetobacter baumannii strains as well as Burkholderia spp. (MIC90 = µg/ml) and S. maltophilia (MIC90 = 2 µg/ ml) Synergy was observed between BAL30072 and carbapenems (and colis2n) against both MDR Enterobacteriaceae and Pseudomonas aeruginosa isolates Fu H- G, et al. Eur J Med Chem 2016; 110: Landman D, et al. Int J An,microb Agents 2014; 43: Mima T, et al. Int J An,microb Agents 2011; 38: Page MGP, et al. An,microb Agents Chemother 2010; 54: Falagas ME, et al. Expert Rev An, Infect Ther 2016; 14:

86 Genera>ons of Aminoglycosides Aminoglycoside Year of Availability Streptomycin 1944 Neomycin 1949 Kanamycin 1957 Paromomycin 1959 Spec2nomycin 1961 Gentamicin 1963 Tobramycin 1967 Sisomicin 1970 Amikacin 1976 Ne2lmicin 1983 Zhanel GG, et al. Expert Rev Infect Ther 2012; 10: Dozzo P, Moser HE. Expert Opin Ther Pa,ents 2010; 20:

87 Plazomicin (ACHN- 490) Next- genera2on aminoglycoside ( neoglycoside ) synthe2cally derived from sisomicin In vitro ac2vity against both Gram- posi2ve and Gram- nega2ve organisms, including isolates harboring any of the clinically relevant aminoglycoside- modifying enzymes (e.g., acetyltransferases [AAC], nucleo2dyltransferases [ANT], and phosphotransferases [APH]) Plazomicin does func2on as a substrate for AAC (2 )- I enzymes expressed in Providencia stuar2i and some mycobacterial species Krause KM, et al. Cold Spring Harb Perspect Med 2016; 6(6) Zhanel GG, et al. Expert Rev An, Infect Ther 2012; 10:

88 Plazomicin (ACHN- 490) Inhibits bacterial protein synthesis and exhibits dose- dependent bactericidal ac2vity Retains in vitro ac2vity against aminoglycoside- resistant MDR, PDR, and XDR isolates of Enterobacteriaceae, except the New Delhi metallo- beta- lactamase (NDM) posi2ve In vitro synergy ac2vity when combined with carbapenems against of Acinetobacter baumannii and with cefepime, imipenem, piperacillin- tazobactam or doripenem against isolates of Pseudomonas aeruginosa Bacteria MIC 50 MIC 90 Range Citrobacter spp Enterobacter spp Klebsiella pneumonia Francisella tularensis Yersinia pes2s Escherichia coli Serra2a spp Proteus mirabilis Proteus, indole- posi2ve Acinetobacter baumannii Pseudomonas aeruginosa MIC values in µg/ml Zhanel GG, et al. Expert Rev An, Infect Ther 2012; 10: Falagas ME, et al. Expert Rev An, Infect Ther 2016; 14:

89 Plazomicin In vitro ac2vity of plazomicin against aminoglycoside- suscep2ble and non- suscep2ble Pseudomonas aeruginosa: Walkty A, et al. An,microb Agents Chemother 2014; 58: Landman D, et al. J An,microb Chemother 2011; 66: Cumula>ve (%) inhibited at MIC in µg/ml of: >64 Amikacin- S (n=561) Gentamicin- S (n=529) Tobramycin- S (n=560) Amikacin- non- S (n=32) Gentamicin- non- S (n=64) Tobramycin- non- S (n=33) Landman et al: plazomicin MIC 50 = 8 µg/ml and MIC 90 = 32 µg/ml for 679 isolates of P. aeruginosa (amikacin: MIC 50 = 8 µg/ml and MIC 90 = 16 µg/ml) Mechanisms resul2ng in elevated MICs poorly defined; likely that reduced permeability and/or efflux are contribu2ng factors

90 16S Ribosomal RNA Methyltransferase High- level aminoglycoside resistance caused by produc2on of acquired 16S ribosomal RNA methyltransferase (16S- RMTase) in pathogenic Gram- nega2ve bacteria was first reported in the early 2000s Bacteria that produce 16S- RMTase frequently coproduce ESBL, and more recently, carbapenemases, especially New Delhi metallo- beta- lactamases (NDM) Spread of 16S- RMTase- producing bacteria further compromises the already limited treatment op2ons for infec2ons caused by mul2drug- resistant (MDR) and extensively drug- resistant (XDR) pathogens Plazomicin is not ac2ve against isolates that produce acquired 16S- RMTase Doi Y, et al. Infect Dis Clin North Am 2016; 30:

91 Plazomicin (ACHN- 490) Human studies have not reported nephrotoxicity or ototoxicity, and lack of ototoxicity in the guinea pig model Aper IV 15 mg/kg dose, maximum plasma concentra2on ~113 µg/ml, AUC0-24 of 235 µg h/ml, t1/2 of 4 hours, and apparent Vss of 0.25 L/kg Mean (SD) plasma and ELF concentra2on- 2me profile in healthy subjects following a single 15 mg/kg dose 10- minute IV infusion Zhanel GG, et al. Expert Rev An, Infect Ther 2012; 10: Cass RT, et al. An,microb Agents Chemother 2011; 55: Cass R, et al. ECCMID 2013, poster # P- 1637

92 Plazomicin A Phase 3, Randomized, Mul2center, Double- Blind Study to Evaluate the Efficacy and Safety of Plazomicin Compared with Meropenem Followed by Op2onal Oral Therapy for the Treatment of Complicated Urinary Tract Infec2on, including Pyelonephri2s, in Adults NCT ClinicalTrials.gov A Phase 3, Mul2center, Randomized, Open- Label Study to Evaluate the Efficacy and Safety of Plazomicin Compared with Colis2n in Pa2ents with Infec2on Due to Carbapenem- Resistant Enterobacteriaceae (CRE) [CARE] Plazomicin in combina2on with meropenem or 2gecycline Colis2n in combina2on with meropenem or 2gecycline Treatment of pa2ents with bloodstream infec2on, hospital- acquired or ven2lator- associated bacterial pneumonia NCT ClinicalTrials.gov

93 Aerosolized An>bio>cs Local ins2lla2on or aerosoliza2on is a way to enhance an2bio2c penetra2on to the lower respiratory tract Polymyxin B and aminoglycosides most commonly used and studied Microbiological eradica2on was significantly greater in pa2ents receiving aerosolized an2bio2cs in a single prospec2ve randomized trial of adjunc2ve use of endotracheal tobramycin with IV therapy in the treatment of VAP (AAC 1990; 34: ) Aerosolized an2bio2cs maybe useful to treat microorganisms that, on the basis of high MIC values, are resistant to systemic therapy Anecdotal reports of pa2ents with VAP due to MDR Pseudomonas aeruginosa unresponsive to systemic an2bio2cs, but improved with addi2on of aerosolized aminoglycosides or polymyxin B (AJRCCM 2000; 162: ) ATS & IDSA. Am J Respir Crit Care Med 2005; 171: Wenzler E, et al. Clin Microbiol Rev 2016; 29:

94 Amikacin Inhala>on Solu>on A Prospec2ve, Randomized, Double- Blind, Placebo- Controlled, Mul2center Study to Evaluate the Safety and Efficacy of BAY as Adjunc2ve Therapy in Intubated and Mechanically- Ven2lated Pa2ents with Gram- Nega2ve Pneumonia (INHALE 1 and INHALE 2) Amikacin Inhala2on Solu2on (BAY ) 400 mg of aerosolized amikacin q12h for 10 days administered using the Pulmonary Drug Delivery System (PDDS Clinical) Aerosolized Placebo q12h for 10 days via PDDS Phase II study supported q12h vs q24h vs placebo, with lower mean number of an2bio2cs per pa2ent per day and similar clinical cure rates (93.8% vs 75.0% vs 87.5%) ClinicalTrials.gov: NCT & NCT Niederman MS, et al. Intensive Care Med 2012; 38:

95 PDDS and Amikacin Inhala>on Solu>on PDDS Clinical On- Ven>lator Device PDDS Clinical Handheld Device Luyt C- E, et al. Crit Care 2009; 13: R200 Luyt C- E, et al. J Aerosol Med Pulm Drug Deliv 2011; 24: &

96 How Useful Will These New Agents be in the Future? New agents for treatment of Gram- nega2ve infec2ons are promising and could help preserve and enhance our an2bio2c armamentarium These agents may provide opportuni2es for monotherapy of resistant Gram- nega2ve organisms These advantages will need to be evaluated and compared to older and generic agents in regards to the use of healthcare resources and pa2ent outcomes Results from randomized controlled trials are needed in severely ill pa2ents with resistant Gram- nega2ve infec2ons are both older and newer agents and as monotherapy and combina2on therapy

97 QUESTION & ANSWER SESSION

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