New Antibiotics For GNB in the ICU Setting: 2016 and Beyond

Size: px

Start display at page:

Download "New Antibiotics For GNB in the ICU Setting: 2016 and Beyond"

Ashley Shaw
5 years ago
Views:

1 New Antibiotics For GNB in the ICU Setting: 2016 and Beyond 1 Marin H. Kollef, MD Professor of Medicine Virginia E. and Sam J. Golman Chair in Respiratory Intensive Care Medicine Washington University School of Medicine St. Louis, Missouri

2 Merck Actavis Arsanis Cubist Cardeas 2 Conflicts of Interest Medimmune Astrazeneca Accelerate Academy for Infection Management Barnes-Jewish Hospital Foundation

Selected Resistance Mechanisms in Gram-Negative Pathogens Increased Efflux Decreased Permeability Outer Membrane Inner Membrane Membrane Alterations Cytoplasm b-lactamases Changes in Target Proteins

3 Selected Resistance Mechanisms in Gram-Negative Pathogens Increased Efflux Decreased Permeability Outer Membrane Inner Membrane Membrane Alterations Cytoplasm b-lactamases Changes in Target Proteins 3 1. Livermore DM. Clin Infect Dis. 2002;34: Livermore DM, Woodford N. Trends in Microbiology. 2006;14: Spratt BG. Science. 1994;264: Chambers, HF. Penicillins. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6 th ed. Philadelphia, PA: Elsevier; 2005:

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

4 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 4 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)

5 Lack of New Antimicrobials New antibacterial agents approved by the US Food and Drug Administration per 5-year period, through Approvals New antibiotic approvals dropped dramatically, with only 3 new options for GNB in the past 15 years leaving limited options for these dangerous pathogens. 5 Molton JS, et al. Clin Infect Dis. 2013;56: Boucher HW, e t al. Clin Infect Dis. 2013;56:

6 Resistance Influences Outcomes! 6

7 In the Critically ill Patient Hit Hard and Fast 7

8 Current Treatment Options for MDR GNB Infections Pathogen Major resistance mechanisms Antibiotics affected Therapy options* E. coli ESBL All penicillins, narrow spectrum cephalosporins, oxymino-betalactams (cefotaxime, ceftazidime, cefepime), aztreonam Carbapenems K. pneumoniae Carbapenemases (i.e. KPC, NDM) P. aeruginosa Active efflux, porin loss, carbapenemases A. baumanii Active efflux, porin loss, amp-c, cephalosporinases, carbapenemases All penicillins, cephalosporins, carbapenems Quinolones, aminoglycosides, anti-pseudomonal penicillins, cephalosporins, carbapenems Quinolones, penicillins, cephalosporins, carbapenems Polymyxins, tigecycline Polymyxins Polymyxins, tigecycline 8 *Based on limited clinical data Pop-Vicas A, Opal SM. Virulence 2014;5:1 7.

9 The 10 '20 Initiative: Pursuing a Global Commitment to Develop 10 New Antibacterial Drugs by Stakeholders Governments Pharmaceutical and diagnostics industries Healthcare providers Policy and legal communities Medical/research universities Public health philanthropic organizations Patient advocacy groups 9 IDSA, Clin Infect Dis. 2010;50:

10 New Drugs in the Pipeline for Antibiotic-Resistant GNB Product Ceftolozane/tazobactam (CXA-201; CXA- 101/tazobactam) Ceftazidime-avibactam (ceftazidime/nxl104) Ceftaroline-avibactam (CPT-avibactam; ceftaroline/nxl104) 10 Class (Mechanism of action) Cephalosporin/BLI combination (cell wall synthesis inhibitor) Antipseudomonal Cephalosporin/BLI combination (cell wall synthesis inhibitor) Antipseudomonal Anti-MRSA cephalosporin/ BLI combination (cell wall synthesis inhibitor) Status Phase 3 cuti, ciai, VAP Phase 3 ciai, cuti, HAP Phase 2 cuti ESBL = Enterobacteriacae; AB = Acinetobacter Boucher et al. Clin Infect Dis 2013;56: Activity Targets ESBL PA AB Yes Yes No Yes Yes No Yes No No

11 New Drugs in the Pipeline for Antibiotic-resistant GNB Product Class (Mechanism of action) Status Activity Targets ESBL P. aeruginosa AB Imipenem/MK-7655 (Relebactam) Carbapenem/BLI combination (cell wall synthesis inhibitor) Phase 2/3 cuti, ciai Yes Yes No Plazomicin (ACHN- 490) Aminoglycoside (protein synthesis inhibitor) Phase 3 CRE Yes No No Eravacycline (TP- 434) Fluorocycline (protein synthesis inhibitor targeting the ribosome) Phase 3 cuti (?neg) Yes No Yes Brilacidin (PMX ) Peptide defense protein mimetic (cell membrane disruption) Phase 2 ABSSSI Yes? No 11 ESBL = Enterobacteriacae; AB = Acinetobacter Boucher et al. Clin Infect Dis 2013;56:

12 New Drugs in the Pipeline for MDR GNB Product Carbavance (Carbapenem+ novel boronic BLI) BAL30072 (+/- carbapenem) S (Siderophore cephalosporin) Trojan Horse Class (Mechanism of action) Carbapenem/BLI combination (cell wall synthesis inhibitor) Siderophore monosulfactam (synergy with CAR) Binds to iron taken to peirplasmic space to bind PBPs (cell wall synthesis inhibitor) Status Phase 3 ciai, HAP Phase 1 Phase 2 cuti, ciai Activity Targets ESBL PA AB Yes Plus KPC No (Yes with carbapenem) Yes Plus KPC Plus NDM Yes Yes Yes Yes Yes Yes Aztreonam + avibactam Monobactam/novel BLI (cell wall synthesis inhibitor) Phase 2 cuti, ciai Yes Plus KPC Plus NDM No No ESBL = Enterobacteriacae; AB = Acinetobacter 12 Boucher et al. Clin Infect Dis 2013;56:

13 Activity for Carbapenemase-Producing Bacteria and Clinical Indications of New Antibiotics 13 Bassetti M, et al. Curr Opin Crit Care 2015;21:

14 Activity of Ceftolozone/Tazobactam in NP Pathogens From USA and Europe Pseudomonas aeruginosa (1019) MIC50 MIC90 Sensitive Ceftolozane/tazobactam * Ceftazidime 2 > Cefepime 4 > Doripenem Meropenem 0.5 > Piperacillin/tazobactam 8 > Levofloxacin 0.5 > Gentamicin 2 > Amikacin Colistin *Percentage inhibited at C/T MICs of 8 mg/l; for comparison purposes only. 14 Farrell DJ, et al. Int J Antimicrob Agents 2014;43:

15 The CENIT study evaluated the in vitro activity of ceftolozane/tazobactam and comparators against clinical isolates of P. aeruginosa ( n = 500) Spain 15 Tato M, et al. Int J Antimicrob Agents 2015 Nov;46(5):

16 ASPECT-cUTI Phase 3 Study 16 Wagenlehner FM, et al. Lancet 2015;385:

17 17 The primary endpoint was a composite of micro eradication and clinical cure 5-9 days after treatment in the mmitt group, with a non-inferiority margin of 10%.

18 18 Wagenlehner FM, et al. Lancet 2015;385:

19 ASPECT-cIAI Phase 3 Study 19 Solomkin J, et al. Clin Infect Dis 2015;60:

20 20 Solomkin J, et al. Clin Infect Dis 2015;60:

21 21 Solomkin J, et al. Clin Infect Dis 2015;60:

22 1.5 g 3.0 g PTA = Probability of Target Attainment Xiao AJ, et 22 al. J Clin Pharmacol 2016 ;56:56-66.

23 Clinical Pharmacology Mean (SD) Ceftazidime Avibactam C max 88.1 (14) 15.2 (14) AUC (mg-h/l) 289 (15) 42.1 (16) T 1/2 (h) 3.27 (33) 2.22 (31) CL (L/h) 6.93 (15) 11.9 (16) Vss (L) 18.1 (20) 23.2 (23) PK parameters assessed following administration of 2.5 g in healthy adult male subjects with normal renal function 23

24 Organism Ceftazidime avibactam Ceftazidime MIC 50/90 MIC range %S MIC 50/90 MIC range %S C. freundii 0.125/ /> > E. aerogenes 0.25/ /> > K. pneumoniae 0.12/ / E. coli 0.12/ / > ESBLproducing 0.12/ />32 1 > AmpChyperproducing 0.12/ />32 1 > K. oxytoca 0.12/ / > ESBLproducing OXA-48- producing KPCproducing 24 Pathogen Susceptibility 0.5/ /> /0.5 < / N/A 0.25/ >256/> >256 0 Lagacé-Wiens P, et al. Core Evid 2014 Jan 24;9:13-25.

25 Pathogen Susceptibility Organism Ceftazidime avibactam Ceftazidime MIC 50/90 MIC range MIC 50/90 MIC range Bacteroides fragilis 4/ >64 0.5/> >128 Other B. fragilis complex Prevotella/Porphyro monasspp. 32/>128 4 >128 >128/>128 8 >128 2/ /> >128 Fusobacterium spp. N/A N/A Lagacé-Wiens P, et al. Core Evid 2014 Jan 24;9:13-25.

26 In vitro activity of ceftazidime-avibactam against 2014 isolates of P. aeruginosa from US medical centers 26 Huband MD, et al. AAC 2016 Jan 25. pii: AAC [Epub ahead of print]

27 ciai Phase III > 50 ml/min ml/min AvyCaz + metronidazole 85% (322/379) 45% (14/31) Meropenem 86% (321/373) 74% (26/35) Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCL 30 to 50 ml/min. 31 to 50 ml/min 1.25g (ceftaz 1g/Avi.5 g) q 8 hr 16 to 30 ml/min 0.94 g (ceftaz 0.75g/Avi 0.19g) q 12 hr 6 to 15 ml/min 0.94 g (ceftaz 0.75g/Avi 0.19g) q 24 hr < 5* ml/min 0.94 g (ceftaz 0.75g/Avi 0.19g) q 48 hr *Ceftazidime and Avibactam are both dialyzable, give post dialysis. 27

28 Avycaz Label 28

29 Ceftazidime 2,000 mg + avibactam 500 mg + metronidazole 500 mg, each IV q8h for 5 to 14 days ciai Phase II Randomized: n=101 CE: n=87 ME: n=68 mmitt: n=85 Favorable clinical response at test-of-cure visit: CE: 92.0% (80/87) ME: 91.2% (62/68) mmitt: 82.4% (70/85) Meropenem 1,000 mg IV q8h for 5 to 14 days Randomized: n=102 CE: n=90 ME: n=76 mmitt: n=89 Favorable clinical response at test-of-cure visit: CE: 94.4% (85/90) ME: 93.4% (71/76) mmitt: 88.8% (79/89) Most common sites of infection were appendix (47%) and stomach/duodenum (26%), and the majority of patients (83%) had an APACHE II score of Lucasti C, et al. J Antimicrob Chemother 2013;68:

30 Ceftazidime 500 mg + avibactam 125 mg, each IV q8h for a minimum of 4 days (step-down to oral ciprofloxacin was permitted) cuti Phase II Randomized: n=69 CE: n=28 ME: n=27 mmitt: n=46 Favorable microbiological response at test-of-cure visit: ME: 70.4% (19/27) mmitt: 67.4% (31/46) Favorable clinical response at test-of-cure visit: CE: 85.7% (24/28) Imipenem cilastatin 500 mg IV q6h for a minimum of 4 days (step-down to oral ciprofloxacin was permitted) Randomized: n=68 CE: n=36 ME: n=35 mmitt: n=49 Favorable microbiological response at test-of-cure visit: ME: 71.4% (25/35) mmitt: 63.3% (31/49) Favorable clinical response at test-of-cure visit: CE: 80.6% (29/36) Acute pyelonephritis was the primary diagnosis in 62% of trial participants. 30 Vazquez JA, et al. Curr Med Res Opin. 2012;28:

31 RECAPTURE 1 and 2 (n = 1033) trials from 30 countries For the FDA, mmitt and non-inferiority margin 10% (1) Symptomatic resolution of UTI-specific symptoms except flank pain (frequency/urgency/dysuria/suprapubic pain) and resolution of, or improvement in, flank pain based on the patient-reported symptom assessment response at the Day 5 visit. CAZ-AVI doripenem: -2.39% and 10.42% (2) Proportion of patients with both a symptomatic resolution of UTI-specific symptoms at Test of Cure (TOC) visit and a favorable microbiological response at TOC. CAZ-AVI doripenem: 0.30% and 13.12% For the EMA, the primary analysis of favorable microbiological response was conducted at the TOC in the mmitt population and the non-inferiority margin was 12.5%. CAZ-AVI doripenem: 0.3% and 12.4% 31

32 66 yo woman with pancreatic cancer, splenic vein thrombosis, sepsis at UCLA. 32 Humphries RM, et al. AAC 2015;59:

33 Geometric mean (SD) plasma and median ELF following administration of 2g ceftazidime mg of avibactam (a) or 3g ceftazidime mg of avibactam (b). Ceftazidime Avibactam 33 Nicolau DP, et al. JAC 2015;70:

34 Acinetobacter N = 158 Acinetobacter US Isolates MIC (μg/ml) 50% 90% Range % Susceptible Ceftazidime 16 > >16 33 Meropenem >8 > >8 31 Gentamicin 8 > >8 45 Ciprofloxacin >4 > >4 31 Trimetho-sulfa >4 >4 0.5 >4 34 Tetracycline >16 >16 2 >16 10 Tigecycline Eravacycline Abdallah M, et al. Antimicrob Agents Chemother 2015;59:

35 RX-P873 is a novel antibiotic (pyrrolocytosine) w/ high binding affinity for the bacterial ribosome and in vitro activity against MDR-GNB A. baumannii MIC 50 MIC 90 MIC Range S/I/R (n = 202) RX-P Ampicillinsulbactam 16 > > /11.4/40.6 Ceftazidime >16 > > /2.5/59.4 Cefepime 16 > > /13.4/50.0 Ciprofloxacin >8 > >8 36.1/0.0/63.9 Tobramycin 4 > > /3.4/43.1 Amikacin 8 > > /6.0/35.6 Meropenem >8 > >8 46.0/1.5/52.5 Colistin >8 97.0/0.0/3.0 Tigecycline >4 35 Flamm RK, et al. AAC 2015;59:

36 36 Tsuji M, et al. Poster 256, ID Week 2014; October 9, 2014.

37 37 Tsuji M, et al. Poster 256, ID Week 2014; October 9, 2014.

38 Actively Recruiting Clinical Trials of Aerosolized Antibiotics Drug Sponsor Phase Colistin NIAID I Tobramycin/ Vancomycin Wright State Univer IV Amikacin/Fosfomycin Cardeas Pharma II Amikacin Bayer/Nektar III Vancomycin Seoul National Univer II Arbekacin Meiji Seika Pharma I 38 Clinicaltrials.gov accessed Oct 2015

39 Fosfomycin induces uptake of tobramycin in P. aeruginosa in a dose-dependent fashion [ 3 H]tobramycin into bacterial cells after adding unlabeled fosfomycin. Values are means ± SD from four independent experiments (*, P < 0.05; **, P < 0.005). 39 MacLeod DL, et al. AAC 2012;56:

40 The amikacin-fosfomycin combination had a 5:2 ratio of amikacin to fosfomycin. 40 Montgomery AB, et al. AAC 2014;58:

PARI eflow Inline Nebulizer Single patient use, multiple treatment nebulizer Reusable controller Continuous nebulization Inspiratory arm acts as reservoir chamber Vibrating plate technology Small

41 PARI eflow Inline Nebulizer Single patient use, multiple treatment nebulizer Reusable controller Continuous nebulization Inspiratory arm acts as reservoir chamber Vibrating plate technology Small particle size Humidity left on Differences from other nebulizers Multiple use Does not require multiple circuit breaks Small particle size provides less rain out and better peripheral delivery Particle size 3.2 µ with humidity 41

42 Mean peak [amikacin] and [fosfomycin] in tracheal aspirates after aerosolized fosfomycin 20 mg/ml (with amikacin 50 mg/ml) by PARI eflow Inline Nebulizer in 7 VAP patients 25x reference MIC of 256 μg/ml (i.e., 6,400 μg/ml) 42 Montgomery AB, et al. Am J Respir Crit Care Med 2013; 187:A3236.

43 Antibiotic Use Counterintuitive 43 Antibiotic Resistance

44 Conclusions Understand your local epidemiology Appropriate drug selection and Adequate dosing/duration/infusion/timing Use microbiology results to de-escalate Employ new agents/technology as available Insure compliance w/ ASP 44

45 45 Thank you!

Intrinsic, implied and default resistance

Appendix A Intrinsic, implied and default resistance Magiorakos et al. [1] and CLSI [2] are our primary sources of information on intrinsic resistance. Sanford et al. [3] and Gilbert et al. [4] have been