New Antimicrobials: Now and In the Future

Transcription

1 New Antimicrobials: Now and In the Future David C. Hooper, M.D. Division of Infectious Diseases Infection Control Unit Massachusetts General Hospital Harvard Medical School

2 Conflicts of Interest Melinta Advisory Board The Medicines Company Advisory Board Shionogi Pharmaceuticals Consultant Paratek Pharmaceuticals Advisory Board

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4 Minimum Estimates of Morbidity and Mortality for Antimicrobial-Resistant Infections Estimated Annual Resistant Pathogen Cases Deaths Carbapenem-Resistant Enterics 9, Drug-Resistant Gonococci 246,000 <5 Multidrug-Resistant Acinetobacter 7, ESBL Enterics 26,000 1,700 Vancomycin-Resistant Enterococci 20,000 1,300 Multidrug-Resistant Pseudomonas 6, Methicillin-Resistant S. aureus 80,000 11,000

5 Clinical Impact of Antimicrobial Resistance

6 Shlaes D, Cooper M. Nature 2011; 472:32

7 Agents with Activity Against MRSA in Addition to Vancomycin β-lactams Ceftaroline Lipoglycopeptides Telavancin Dalbavancin Oritavancin Cyclic lipopeptide Daptomycin Oxazolidinones Linezolid Tedizolid Fluoroquinolones Delafloxacin

8 Tedizolid Phosphate Structure (Oxazolidinone)

9 Tedizolid 4- to 8-fold more potent than linezolid in vitro Remains active vs some linezolid-resistant strains Dose: 200 mg PO or IV once daily 100% oral bioavailability; t ½ = h; fecal excretion; no renal adjustment Weak, reversible MAO inhibition in vitro Possibly lower drug-drug interactions because of lower doses and free drug exposure Little hematologic toxicity up to 3 weeks Platelets <150,000 - tedizolid 4.9% vs linezolid 10.8% in trials Most common AEs: nausea/vomiting (8/3%, < linezolid), HA (6%) Prokocimer P et al. JAMA 2013; 309:559 Prokocimer P et al. AAC 2012; 56:4608 Urbina O et al. Drug Design Devel Ther. 2013;7:243 Burdette SD, Trotman R Clin Infect Dis. 2015; 61:1315

10 Tedizolid Acute Bacterial Skin Infections Phase III double-blind, randomized trial (n = 667) Tedizolid 200 mg PO QD x 6 days vs linezolid 600 mg PO BID x 10 days; PO Clinical response: h (>20% lesion ) 80% vs 79%; EOT 69% vs 72% - Clincal response at post-treatment evaluation by pathogen: MSSA 73/83 (88%) vs 82/87 (94%) MRSA 75/88 (85%) vs 77/90 (86%) Streptococci (S. anginosus, S. pyogenes, S. agalactiae,) 31/40 (78%) vs 25/32 (78%) Phase III double-blind randomized trial (n = 666) Tedizolid 200 mg QD x 6 days vs linezolid 600 mg BID x 10 days; IV to PO Clinical response: h (>20% lesion ) 85% vs 83%; EOT 87% vs 88% Bacteremia cases 7/7 (100%) vs 9/12 (75%) Microbiologic response at 7-14 days after treatment MSSA 100/105 (95%) vs 104/111 (94%) MRSA 43/53 (83%) vs 43/56 (79%) Prokocimer P et al. JAMA 2013; 309:559 Prokocimer P et al. AAC 2012; 56:4608 Moran GJ et al. Lancet Infect Dis 2014; 14:696 Shorr AF et al. AAC 2015; 59:864

11 Dalbavancin (Lipoglycopeptide)

12 Dalbavancin Gram-positive spectrum: Potency relative to vancomycin: S. aureus (MIC µg/ml) -16x, includes VISA strains S. pyogenes (MIC µg/ml) -16x, group B strep 4x Enterococci (MIC µg/ml) -16x not active vs VRE (MIC µg/ml) Dosing: 1 gm IV day 1, 500 mg IV day gm IV once t ½ = h severe renal impairment reduce dose to [750 mg then 375 mg]; no adjustment in hepatic failure Concentrations over 1 week in bone (6.3 => 3.8 µg/ml) and synovial fluid (23 => 12 µg/ml) relative to plasma (85 => ~30 µg/ml) Most common AEs: nausea %; treatment-limiting AEs 2.1%; similar to comparator Zhanel GG et al. Drugs 2010; 70:859 Boucher HW et al. NEJM 2014; 370:2169 Dunne MW et al. Antimicrob Agents Chemother 2015; 59:1849 Dunne MW et al. Drug Safety 2016; 39:147

13 Acute bacterial skin infections Dalbavancin Phase III randomized, double-blind trial, n = 1312 Non-inferior to vancomycin (1 gm or 15 mg/kg Q12h) then PO linezolid (600 mg Q12h) Similar in at h and end of therapy (10-14 d) in subgroups with cellulitis, abscess, MSSA, MRSA (97%), S. pyogenes 100% Catheter-related staphylococcal bacteremia Phase II randomized,open-label trial, n =75 Catheters removed at baseline: 15/23 (65%) vs 18/28 (64%) S. aureus 16/26 (62%) vs 21/28 (75%); coag-neg staph 13 each Significantly better overall success relative to vancomycin 87% vs 50% Microbiologic success at 21 days after treatment period 96% vs 79% Zhanel GG et al. Drugs 2010; 70:859 Boucher HW et al. NEJM 2014; 370:2169 Raad I et al. Clin Infect Dis. 2005; 40:374

14 Single-Dose vs Two-Dose Dalbavancin Clinical Status at 14 d in Clinically Evaluable Patients with Baseline Monomicrobial Infection Dunne MW et al. Clin Infect Dis. 2016; 62:545

15 Oritavancin (Lipoglycopeptide) Dimer Formation Able to bind D-Ala-D-Lac

16 Oritavancin Gram-positive spectrum: Potency relative to vancomycin: S. aureus (MIC µg/ml) 8-16x, includes VISA strains S. pyogenes (MIC µg/ml) - 4x, group B streptococci - 4x Enterococci (MIC µg/ml) x VSE, x VRE (MIC µg/ml) Dosing: 1200 mg IV single dose requires 3 h infusion t ½ = 390 h; no adjustment in renal failure, hemodialysis, or mild to moderate hepatic failure Most common AEs: nausea (11 vs 9% for vancomycin), headache (7.2 vs 7.9%); treatmentlimiting AEs (3.8 vs 5.8%); LFTs in some studies but not in large trials Interferes with PT and PTT tests Zhanel GG et al. Drugs 2010; 70:859; Corey GR et al. NEJM 2014; 370:23 Corey GR et al. Clin Infect Dis. 2015; 60:254 Saravolatz LD, Stein GE Clin Infect Dis 2015; 61:627 Rubino CM et al. Antimicrob Agents Chemother 2015; 59:3365

17 Two randomized, double-blind trials in acute bacterial skin infections (n = 968 and 1019) Non-inferior to vancomycin (1 gm or 15 mg/kg Q12h x 7-10d) Similar at h and post-therapy (7-14 d) evaluations overall and in subgroups with MSSA (83%), MRSA (81%); streptococci (78% vs 89%) Case report Oritavancin Recurrent VRE bacteremia after course of daptomycin + tigecycline for aortic valvevre endocarditis; no residual vegetation or positive culture from spine hardware exploration done positive for PET scan Treated initially with linezolid and tigecycline but poorly tolerated Switched to oritavancin 1200 mg QOD x 3 doses, then weekly x 6 wk Recurrent bacteremia after course completed Cardiac surgery culture-positive valve excised; linezolid and tigecylcine not tolerated post-op Oritavancin twice weekly for additional 10 weeks Apparent cure at 7 months Johnson JA et al. OFID 2015; 1 Corey GR et al. NEJM 2014; 370:23. Corey GR et al. Clin Infect Dis. 2015; 60:254

18 Delafloxacin (Baxdela)

19 Delafloxacin Active against S. aureus (including MRSA), streptococci, E. faecalis in vitro Active against enteric GNR and P. aeruginosa in vitro Potency increases at low ph Dose: 300 mg IV or 450 mg PO q 12 h 60% oral bioavailability; avoid concomitant divalent cation agents Elimination: t ½ = 8-17 h; mostly renal reduce dose at GFR <30 ml/min; 20% hepatic glucuronidation Adverse Effects (n=1492) overall similar to vanco/aztreonam comparator in Phase 3 trials most common diarrhea (7.8% vs 3.2%), nausea (7.6% vs 6.3%) abnormal LFTs (3.1% vs 4.0%), related AE with d/c (0.8% vs 2.4%) no phototoxicity, no glucose effects, no QT prolongation; single C. difficile case Hoover R et al. Clin Ther. 2016; 38:53 Van Bambeke F. Future Microbiol. 2015; 10:1111 Corey GR et al. ID Week 2017; abstract 64438

20 Delafloxacin vs Vancomycin-Aztreonam Phase 3 Double-Blind, Randomized Trial for Acute Bacterial Skin and Skin Structure Infections Responses at hr Delafloxacin IV/PO vs Vanco (15mg/kg) + Aztreonam x 5-14 d ID Week 2016 Poster 1347

21 Delafloxacin vs Vancomycin-Aztreonam Two Phase 3 Double-Blind, Randomized Trial for Acute Bacterial Skin and Skin Structure Infections Key Endpoints DLX VAN/AZ Phase 3 Patients with GP pathogens n/total (%) n/total (%) Objective response 48-72h (micro evaluable [ME]) 405/461 (87.9) 388/446 (87.0) Investigator-Assessed Success (FU ME) 381/389 (97.9) 361/368 (98.1) Investigator-Assessed Success (LFU ME) 377/388 (97.2) 358/367 (97.5) Micro Success (FU ME) for key GP organisms: S. aureus 244/248 (98.4) 233/239 (97.5) MSSA 140/142 (98.6) 136/140 (97.1) MRSA 106/108 (98.1) 97/99 (98.0) S. pyogenes 18/19 (94.7) 15/15 (100) ID Week 2017 Abstract 65442

22 Delafloxacin vs Vancomycin-Aztreonam Two Phase 3 Double-Blind, Randomized Trial for Acute Bacterial Skin and Skin Structure Infections Key Endpoints DLX VAN/AZ Phase 3 Pts with GN pathogens n/total (%) n/total (%) Objective response 48-72h (ME) 77/90 (85.6) 83/94 (88.3) Investigator-Assessed Success (FU ME) 74/75 (98.7) 80/82 (97.6) Investigator-Assessed Success (LFU ME) 73/75 (97.3) 76/78 (97.4) Micro Success (FU ME) for key GN organisms: K. pneumoniae 17/17 (100) 17/17 (100) E. cloacae 11/12 (91.7) 9/10 (90) E. coli 11/11 (100) 16/17 (94.1) P. aeruginosa 11/11 (100) 10/10 (100) ID Week 2017 Abstract 65167

23 Agents for Treatment of Resistant Gram-Negative Bacterial Infections Colistin Tigecycline Ceftolozane-Tazobactam Ceftazidime-Avibactam Meropenem-Vabobactam

24 Ceftolozane-Tazobactam Structure Ceftolozane Tazobactam

25 FDA-approved for: Ceftolozane-Tazobactam Complicated urinary tract infections Complicated intraabdominal infections Spectrum of activity Ceftolozane - increased potency against P. aeruginosa, including AmpC-overexpressing, and efflux pump-resistant mutants; active against other enteric Gram-negative bacteria Tazobactam inhibits many β-lactamases, adding activity against some ESBL-producing enteric bacteria and Bacteroides fragilis; not active against carbapenemases Not active against some ceftazidime-resistant enteric bacteria, Acinetobacter, Stenotrophomonas, staphylococci, or enterococci Walkty A et al. Antimicrob Agents Chemother 2013; 57:5707 Zhanel GG et al. Drugs 2014; 74:31 Scott LJ. Drugs 2016; 76:231 Buehrle DJ et al. Antimicrob Agents Chemother. 2016; 60:3227

26 Pharmacokinetics t 1/2 = 2.6 h ceftolozane, 1 h tazobactam Urinary excretion of unchanged drug: Dosing >95% ceftolozane, 80% tazobactam 1.5 gm (1 gm-0.5 gm) every 8h IV Dose reductions in renal failure: CrCl ml/min 750 mg every 8h CrCl ml/min 375 mg every 8h Hemodialysis 750 mg loading dose, 150 mg every 8 h Adverse effects Ceftolozane-Tazobactam Nausea 7.9%, diarrhea 6.2%, headache 5.8% similar to those with comparators (meropenem, levofloxacin) Miller B et al. Antimicrob Agents Chemother 2012; 56:3086

27 Ceftolozane-Tazobactam vs Levofloxacin for Complicated Urinary Tract Infections (95% CI) Randomized, double-blind Phase 3 trial Wagenlehner FM et al. 2015; Lancet 385:1949

28 Ceftolozane-Tazobactam Plus Metronidazole vs Meropenem for Complicated Intraabdominal Infections Clinical cure by pathogen: E. coli: 216/255 (85%) vs 238/270 (88%) K. pneumoniae: 31/41 (76%) vs 27/35 (77%) P. aeruginosa: 30/38 (79%) vs 70/34 (88%) Randomized, double-blind Phase 3 trial Appendiceal perforation/abscess 45%, ruptured or progressive cholecystitis 17%, Peritonitis from perforated viscus 9% Zhanel GG et al. Drugs 2014; 74:31 Solomkin J et al. Clin Infect Dis. 2015; 1462 Miller B et al. Antimicrob Agents Chemother. 2016; 60:4387

29 Ceftazidime-Avibactam Structure Ceftazidime Avibactam

30 FDA approved for: Complicated urinary tract infections (cuti), including pyelonephritis Complicated intraabdominal infections (ciai) Spectrum of activity Ceftazidime Ceftazidime-Avibactam Third-generation cephalosporin with activity against P. aeruginosa Poor activity against Acinetobacter and Burkholderia Poor activity against anaerobes, Gram-positive bacteria Avibactam synthetic β-lactamase inhibitor inhibiting: ESBLs, AmpC, and KPC and OXA48 carbapenemases Inhibitor resistance from mutations in AmpC and KPC-3 uncommon Does not inhibit metallo- β-lactamases (NDM-1,VIM) Zhanel GG et al. Drugs 2013; 73:159 Livermore DM et al. Antimicrob Agents Chemother. 2015; 59:5324 Lahiri SD et al. J Antimicrob Chemother. 2015; 70:1650

31 Ceftazidime-Avibactam Pharmacokinetics t 1/2 = ceftazidime 2.7 h, avibactam 2.7 h Unchanged drug in urine % ceftazidime, 95% avibactam; both are dialyzable Dosing - every 8 h IV (based on Phase II studies) 2.5 gm (2 gm ceftazidime-0.5 gm avibactam) Dose adjustments in renal failure: CrCl ml/min CrCl ml/min CrCl 6-15 ml/min CrCl <5 ml/min 1.25 gm every 8 h 0.94 gm every 12 h 0.94 gm every 24 h a 0.94 gm every 48 h a a Give after hemodialysis on dialysis days Vazquez JA et al. Curr Med Res Opinion 2012; 28:1921 Lucasti C et al. J Antimicrob Chemother 2013; 68:1183

32 Ceftazidime-Avibactam Plus Metronidazole vs Meropenem for Complicated Intra-abdominal Infections Perforated appendix/abscess - 42%, 41%; APACHE II <10-84%, 83% Ceftaz-avi 2g/500mg Q8h + MNZ 500mg Q8h vs meropenem 1gm Q8h x 5-14d Mazuski JE et al. Clin Infect Dis. 2016; 62:1380

33 Ceftazidime-Avibactam Plus Metronidazole vs Meropenem for Complicated Intra-abdominal Infections Clinical Response at Test of Cure Pathogens n CAZ-AVI n Meropenem Enterics Ceftaz R (82%) (86%) Ceftaz S (82%) (88%) P. aeruginosa Ceftaz R 2 2 (100%) 4 4 (100%) Ceftaz S (90%) (94%) Mazuski JE et al. Clin Infect Dis. 2016; 62:1380

34 Ceftazidime-Avibactam vs Doripenem for Complicated Urinary Tract Infections Ceftaz-Avi Doripenem (n = 393) (n = 417) Pyelonephritis 287 (73%) 296 (71%) Bacteremia 38 (9.7%) 33 (7.9%) Clinical Response Rate at Test of Cure: 332 (84.5%) 360 (86.3%) Microbiological Response Rate at Test of Cure: Enterobacteriaceae Ceftaz R/I 43/68 (63%) 46/79 (58%) Ceftaz S 247/301 (82%) 217/297 (73%) P. aeruginosa Ceftaz R/I 5/7 (71%) 5/6 (83%) Ceftaz S 7/10 (70%) 10/14 (71%) Wagenlehner FM et al. Clin Infect Dis. 2016; 63:754

35 Ceftazidime-Avibactam for CRE Infections Patients (n = 37) Transplant recipients 30%; mean SOFA 5, median Charlson 4, SAPS II 34 VAP/HAP 32%; 1 bacteremia 27%; IAI, SKST, pyelonephritis 11% each Pathogens and resistance genes K. pneumoniae 84%, E. coli 8%, Enterobacter spp. 8% KPC 78%, OXA1-like 11%; ESBL 1, AmpC 1; no NDM, VIM, IMP Treatment Monotherapy 70%, combination 30% (mostly gentamicin) similar effects Median duration 14 d Outcomes Clinical success 59% but late recurrence (34-84 d) 13% Microbiologic failures 27% with resistance in 3 of 10 at median 15 d Rx. Shields RK et al. Clin Infect Dis. 2016; 63:1615 Spellberg B, Bonomo RA. Clin Infect Dis. 2016; 63:1619

36 Meropenem-Vaborbactam Meropenem (Vabomere) Vaborbactam

37 Meropenem-Vaborbactam Cyclic boronic acid β-lactamase inhibitor Inhibits classes A and C, particularly KPC and including KPC3 and KPC2 avibactam-resistant enzymes Does not inhibit metallo (NDM, VIM) or OXA (OXA48) enzymes Expanded spectrum from meropenem Highly similar pharmacokinetics of both components Dose: meropenem 2 g/vaborbactam 2 g IV; reduce dose at creat clearance <50 ml/min

38 Meropenem-Vaborbactam Phase 3 Trials Tango I DB-RCT cuti/ap vs piperacillin-tazobactam IV 5 d IV, then allowed switch to PO levofloxacin; total 14 d Clin cure/microbiol erad: EOT 183/186 (98%) vs 165/176 (94%); TOC (~7d post Rx) 124/162 (73%) vs 112/153 (73%) Adverse effects: HA (9% vs 4%), diarrhea (4% vs 5%) Tango II RCT CRE infections (cuti, ciai, HAP, BSI) vs standard of care (stopped by DSMB) Clin cure: EOT 18/28 (64%) vs 5/15 (33%); TOC 16/28 (57%) vs 4/15 (27%) Microbiol cure: EOT 18/28 (64%) vs 6/15 (40%); TOC 14/28 (50%) vs 5/15 (33%) 28 day mortality: 5/28 (18%) vs 5/15 (33%)

39 Anti-Bacterial Development Compounds in Clinical Development - 38 Stage of clinical trial: Phase 1 10 Phase 2 17 Phase 3 11 Development company size: Big Pharma 11 Small Pharma 27 Activity against: Resistant Gram-negative ESKAPE pathogens 12 CDC Urgent Threat pathogens 18 PEW Charitable Trusts 2016

40 Anti-Bacterial Development Compounds in Clinical Development 38 Cell wall targeting agents 10 Quinolones 6 Oxazolidinones 3 Non-quinolone topoisomerase inhibitors 2 Tetracyclines 2 Fatty acid synthesis inhibitors 2 Ketolides 2 Other agents 1 ea Pleuromutilin, aminoglycoside, fusidic acid, and agents targeting trna synthetase, DHFR, DNA minor groove, LptD PEW Charitable Trusts 2016

41 Plazomicin

42 Aminoglycoside Plazomicin Broad activity, including CRE and S. aureus Unaffected by aminoglycoside-modifying enzymes Not active against strains with plasmid-encoded ribosomal methylase resistance mechanism Dose 15 mg/kg IV daily Phase III studies cuti including pyelonephritis vs meropenem Non-inferior in composite cure (microbiologic erad & clinical cure) d 5 Superior at test of cure visit Serious infections due to CRE Plazomicin vs colistin (in combination with meropenem & tigecycline) Mortality (1/14 vs 6/15) and clearance (12/14 vs 7/15) benefit in BSI subgroup Increases in creatinine less in plazomicin arm (33% vs 52%)

43 Cefiderocol

44 Cefiderocol Cephalosporin stable to all β-lactamases Catechol side-chain that binds Fe and is taken up through siderophore pathway Active against enterics and non-enterics Phase 3 RCT hospitalized patients with cuti vs imipenem Most E. coli & K. pneumoniae - ~1/2 resistant to cefepime Superior in composite endpoint (clin cure and microbial erad) at TOC (73% vs 55%)

45 Imipenem-Relebactam Imipenem Relebactam

46 Imipenem-Relebactam Piperadine β-lactamase inhibitor Inhibits class A and C enzymes, including KPCs No inhibition of metallo- or OXA enzymes Enhanced activity vs CR P. aeruginosa Phase 2 studies ciai similar outcomes with imipenem (95%) vs imipenem-relebactam (125 mg 99%, 250 mg 96%) Phase 3 studies vs piperacillin-tazobactam Nosocomial pneumonia ongoing Adverse effects similar to imipenem alone

47 Omadacycline

48 Omadacycline Aminomethylcycline In vitro activity against S. aureus including MRSA, streptococci Enterobacteriaceae except Proteus, Providencia, Morganella Not active vs P. aeruginosa Anaerobes, Legionella, Chlamydia Unaffected by tetracycline resistance mechanisms Adverse effects Similar to linezolid comparator Nausea 17% vs 15%; D/C for AE 3% vs 0%

49 Omadacycline Phase II study in complicated skin infections 100 mg IV 200 mg PO vs linezolid IV-PO (aztreonam option) x 14 d Clinical success at TOC (prior FDA endpoint) 97/111 (88%) vs 82/108 (76%), incl MRSA Phase III study in complicated skin infections 100 mg IV 300 mg PO vs linezolid IV-PO (moxifloxacin option) x 14 d Clinical success at TOC 58/68 (85%) vs 64/72 (89%), included MRSA Truncated due to change in FDA endpoints

50 Eravacycline

51 Fluorocycline Eravacycline In vitro activity against: 2- to 4-fold more potent than tigecycline S. aureus (incl MRSA), streptococci, enterococci (incl VRE) Enterobacteriaceae; Acinetobacter; less active against Proteus, Morganella Anaerobes except Bacteroides spp. Not active against P. aeruginosa

52 Eravacycline Phase II DB-RCT vs ertapenem for communityacquired ciai (APACHE II <25) x 4-15 d, with outcomes at TOC: 1.5 mg/kg IV daily clin and microbiol cure 39/42 (93%) 1.0 mg/kg IV daily clin and microbiol cure 41/41 (100%) Ertapenem 1 gm daily clin and microbiol cure 24/26 (92%) Phase III DB-RCT vs ertapenem for communityacquired ciai Eravacycline 1 mg/kg q 12h vs ertapenem 1 gm daily x 4-14 d Clin cure in ME population 222/230 (93%) vs 225/238 (94%)

53 Eravacycline Phase III IV-PO cuti vs levofloxacin 1.5 mg/kg IV daily, then 200 mg PO q 12h vs levofloxacin 750 mg IV daily, then PO daily 3 d IV, then PO for total 7 d Primary outcome clinical cure /microbiol response at TOC (6-10 d after EOT) with 10% noninferiority margin 980 patients enrolled by failed to meet noninferiority endpoint. Adverse effects: nausea ± vomiting most common (2-10%)

54 Other Agents in the Pipeline Phase III Phase II Phase I Iclaprim Lafamulin Fusidic acid Solithromycin Cadazolid Zabofloxacin Dihydrofolate reductase inhibitor Pleuromutilin protein synthesis inhibitor Elongation factor G inhibitor Macrolide Oxazolidinone-quinolone hybrid FQ Bacterial topoisomerase inhibitor AMP mimics, topoisomerase inhibitors, macrolides, β-lactam-inhibitors fatty acid synthesis inhibitor, lipid I/II 15 similar diversity of compounds and targets

55 Alternative Regulatory Pathways for Approval of Anti-Bacterials Targeting Resistant Pathogens Rex JH et al. Lancet Infect Dis. 2013; 13:269

56 Current Economic Model of Antimicrobial Development