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Overview of new antibiotics in developmentProfessor David Livermore, Professor of Medical Microbiology, University of East Anglia
DAVID M LIVERMORE
New antibacterials in development
University of East Anglia
DisclosuresConsult / advisory – Accelerate, Achaogen, Adenium, Allecra,
Antabio, BioVersys, Centauri, Janssen/J&J, McKinsey, Medicines Co., Meiji, Melinta, Merck, Nordic, Pfizer, Roche, Shionogi, TAZ, Tetraphase, VenatoRx, Wockhardt, Zambon
Lectures – Astellas, bioMerieux, Beckman-Coulter, Correvio, Cepheid, Nordic, Merck/MSD, Pfizer, Wockhardt
Sponsored research – Meiji, Melinta, Merck, Paratek, Roche, Shionogi, Tetraphase, Wockhardt
Shareholdings – Dechra, GSK, Merck, Perkin Elmer, Pfizer amounting to <10% of portfolio value
Licensed since 2015
Drug Class Unique selling point
Ceftazidime/avibactam Ceph-BLI, iv Covers bacteria with KPC, OXA-48
Ceftolozane/tazobactam Ceph-BLI, iv Antipseudomonal activity
Meropenem/vaborbactam Carb-BLI, iv Covers bacteria with KPC
Plazomicin Aminoglycoside iv Evades modifying enzymes
Eravacycline Tetracycline iv Avoids efflux/ribosomal protection; eravacycline MICs lower than tigecyclineOmadacycline Tetracycline iv/po
DalbavancinLipoglycopeptides iv v. long T1/2; 1-2 dose Rx for ABSSSI
Oritavancin
Delafloxacin Quinolone iv/po Active vs. cipro-R S. aureus
Areas of development
• Agents vs. carbapenemase-producers
• Alternatives to i.v. carbapenems against ESBL producers
• Anti-gram-positive agents
• Anti-gonococcals
• Anti-Pseudomonas only
Diazabicyclooctanes… avibactam & beyond
Nacubactam
Relebactam
Zidebactam
WCK4234
DBOs … avibactam & beyondEnterobacteria with P. aeruginosa A. baumannii
KPC OXA-48 MBLs MBL OXA-23Ceftazidime-avibactam
Aztreonam/avibactam
Imipenem-relebactam
Meropenem-nacubactam
Cefepime-zidebactam
Meropenem-WCK4234
Active Variable Resistant Direct activity or ‘enhancer’ effect
Wright et al., CMI 2017;23:704; Papp-Wallace et al. J Med Chem 2018; 61: 4067
0
5
10
15
20
25
≤0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 ≥128MIC (mg/L)
AZT+AVI Aztreonam
Livermore et al. AAC 2011;55:390
Aztreonam-avibactamAztreonam is stable to MBLs….
17 NDM, 13 IMP, 5 VIM
MICs of nacubactam alone for Enterobacteria with MBLs
0
20
40
60
80
100
120
<=1.0 2 4 8 16 32 >32
Cou
nt
MIC (mg/L)
Providencia Morganella
Klebsiella Escherichia
Enterobacter Citrobacter
Mushtaq et al. JAC 2018 epub
Meropenem-nacubactam vs. NDM (158) & VIM (58) Enterobacteriaceae
0
10
20
30
40
50
60
70
80
90
100
NoDBO
Nac 1 Nac 2 Nac 4 Avi 4 NoDBO
Nac 1 Nac 2 Nac 4 Avi 4
% S
usce
ptib
le
DBO and concentration, mg/L
Additionallysusceptible
Susceptible toDBO alone
S to meropenem 4 mg/L S to meropenem 8mg/L
Mushtaq et al. JAC 2018 epub
OXA-type & meropenem-WCK 4234 vs. A. baumannii
0.25
0.5 1 2 4 8 16 32 64 128 >128
OXA-23 6 3 1
+WCK 1 2 6 1
OXA-24/40 2 3 3 2
+WCK 3 1 2 2 2
OXA-51+++ 4 1 4 1
+WCK 1 1 4 3 1
OXA-58 2 3 5+WCK 1 1 1 6 1
Mushtaq et al. JAC 2017; 72: 1688
Imipenem + relebactam vs. P. aeruginosa BSAC 2014-6
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
0.06 0.125 0.25 0.5 1 2 4 8 16 32 128 >256
Isol
ates
(%)
MIC (mg/L)
IMI IMI-REL
Boronate b-lactamase inhibitorsVaborbactam
Combined with meropenem: 2+2g infusion, over 3h
Overcomes KPC only
VNRX-5133
In phase I with cefepime
Broad spectrum, except IMP & Acinetobacter OXA
Cefepime & cefepime/VNRX-5133 vs. KPC +ve Enterobacteriaceae
0
2
4
6
8
10
12
14
16
<=0.
015
0.03
0.06
0.12
50.
25 0.5 1 2 4 8 16 32 64 12
8>1
28
Cou
nt
Cefepime MIC (mg/L)
Cefepime alone
+ VNRX, 4 mg/L
Mushtaq et al. ECCMID 2018, Poster 1537
Cefepime & cefepime/VNRX-5133 vs. OXA-48 Enterobacteriaceae
0
2
4
6
8
10
12
14
16
<=0.
015
0.03
0.06
0.12
50.
25 0.5 1 2 4 8 16 32 64 12
8>1
28
Cou
nt
Cefepime MIC (mg/L)
Cefepime alone
+ VNRX, 4 mg/L
Mushtaq et al. ECCMID 2018, Poster 1537
Cefepime & cefepime/VNRX-5133 vs. OXA-48 Enterobacteriaceae
0
5
10
15
20
25
30
<=0.0
150.
030.
060.
125
0.25 0.
5 1 2 4 8 16 32 64 128
>128
Cou
nt
Cefepime MIC (mg/L)
NDM (40)VIM (40)IMP (13)
Light colours, with VNRX-5133, 4 mg/L
Mushtaq et al. ECCMID 2018, Poster 1537
Shionogi cefiderocol, catechol cephalosporin
Kohira et al., AAC 2016; 60: 729Ito et al., AAC 2015; 60: 7396
Cefiderocol MICs for CPE… on some very iffy plates
0
10
20
30
40
50
60
≤0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 ≥128
Coun
t
MIC (mg/L)
GES, IMI, SME
OXA-48 like
KPC
IMP
VIM
NDM
Mushtaq et al. ECCMID 2017, Poster 1315
Cefiderocol Phase II, cUTI
Cefiderocol(303)
Imipenem/cilastatin
(149)
Dose for 7-14 days 2g q8h 1g q8h
Composite cure 7 days after end of therapy 73% 55%
Portsmouth et al. LID 2018; 18; 1319p 0.0004
BOS-228 (LYS228)…. a more stable monobactam
Blais et al. 2018 AAC; 62: e01200
New and coming vs. ESBL producers
i.v. oral
Cefepime / tazobactam (Wockhardt)
Sulopenem(Itreum)
Cefepime / AAI101(Allecra)
Tebipenem(Spero)
Ceftibuten/clavulanate(Achaogen)
Licensed Phase III Phase II Phase I
Cefepime-tazobactam 4 mg/L vs. Enterobacteriaceae
0
20
40
60
80
100
120
<0.03 0.0
60.1
20.2
5 0.5 1 2 4 8 16 32 64 128>1
28MIC mg/L
VIMNDMOXA-48KPCK. oxytoca K1ESBLAmpCPenicillinaseControls
Livermore et al JAC 2018; 73: 126
Cefepime is easy to protect…
Cefepime-tazobactam 4 mg/L vs. Enterobacteriaceae
0
20
40
60
80
100
120
<0.03 0.0
60.1
20.2
5 0.5 1 2 4 8 16 32 64 128>1
28MIC mg/L
VIMNDMOXA-48KPCK. oxytoca K1ESBLAmpCPenicillinaseControls
Livermore et al JAC 2018; 73: 126
Cefepime is easy to protect…
Cefepime/tazobactam in Phase III @ 2+2 q8h, 90 min infusion
Cefepime/AAI101 in Phase III @ 2+0.5 q8h, 2h infusion
Activity of tebipenem against ESBL/pAmpC producers, n = 38
0
5
10
15
20
25
30
35
40
<=0.0
15 0.03
0.06
0.12
0.25 0.5 1 2 4 8 16 32 >3
2
No
isol
ates
MIC (mg/L)
ErtapenemImipenemTebipenem
Mendes ASM Microbe 2018 Sunday 560
Iclaprim (MotifBio)
2006-8 Arpida trial @ 0.8 mg/kg iv q12h in ABSSSI vs.linezolid…rejected by FDA & EMA in 2008/9
Now completed Phase III with MotifBio at 80 mg q12h in ABSSSI
Ø Early response 80.9% vs. vancomycin 81.0%
Ø Clinical cure 84.2% vs. vancomycin 87.0%
MIC90 for MRSA >8 mg/L; some cross-resistance to trimethoprim
http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/07/WC500095022.pdf; http://ir.motifbio.com; https://idsa.confex.com/idsa/2016/webprogram/Paper56742.html
Trimethoprim
Iclaprim
Lefamulin (Nabriva)
• iv / oral Pleuromutilin
• Earlier pleuromutilins coccidiostats, or topical (retapamulin, GSK)
• Under FDA review for CAP
Ø Non-inferior to moxifloxacin in Phase III trial
• Covers…S. pneumoniae, H. influenzae, M. catarrhalis, atypicals
• Also active in vitro vs. S. aureus, streptococci & gonococci
Veve, Wagner. Pharmacotherapy 2018; 38: 935
Gepotidacin GSK 2140944
Ross et al. JCM 2014;52:2629Taylor et al. CID 2018; 67: 504.http:://www.clinicaltrials.gov;
Novel inhibitor of topoisomerase II & IV
Inhibits G +ves, fastidious G-ves….. maybe E. coli
Phase II trials for gonorrhoea, SSTI, & pK for uUTI
69 gonorrhoea patients, 66 cures, 2 selections of resistance
Zoliflodacin, oral DNA gyrase inhibitor vs. N. gonorrhoeae
Ø Discovered by AstraZeneca, spun
out to Entasis (AZD/ETX-0914)
Ø Targets DNA topoisomerase II & IV
Ø No X –resistance to quinolones
Ø Active vs. M. genitalium including
macrolide/quinolone-R strains
Ø 99% cure in genital gonorrhoea;
76% in pharyngeal….Jacobsson et al. AAC 2014; 58: 5585
Gouveia et al. JAC 2018; 73: 1291
Sena et al., Microbe 2016; Poster
1308
Murepadavin (POL7080)
• Peptide mimetic : active only vs. P. aeruginosa
• Inhibits LptD - LPS transport to outer membrane
• MIC50/90 0.5/1 mg/L
• MICmax 4 mg/L
• In Phase III for HAP/VAP
Sader et al. AAC 2018, in pressAndolina et al ACS Chem Biol 2018; 13: 666
• Rumours of the death of antibiotic development much exaggerated…
Ø But hard to see how many agents will make a return
• Microbiologists will have fun explaining which cefepime combination to use
Ø … with AAI101, tazobactam, VNRX-5133, zidebactam?
Summary