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New Drugs for Bad Bugs: Updates on the Antimicrobial Armamentarium

Matthew Miller, PharmD, BCPS (AQ-ID)

Infectious Diseases Clinical Pharmacist

University of Colorado Hospital

Conflicts

• I have the following conflicts to disclose– Allergan Speaker Bureau

Acknowledgments

• Gerry Barber, RPh, MPH, FASHP

• Kelsey Melander, PharmD

Objectives

1. List relevant pipeline and recently approved antimicrobials.

2. Identify unique spectrum and pharmacokinetic attributes for each agent.

3. Summarize available clinical trial results for each antimicrobial discussed.

4. Develop a process to consider appropriate situations in which the antimicrobials presented may be applied to patient care appropriately.

“…. the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out… In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.”

- Sir Alexander Fleming, June 1945

5

Outline• Recent Approvals

– Meropenem-Vaborbactam (Vabomere®) – Melinta

– Delafloxacin (Baxdela®) – Melinta

– Letermovir (Prevymis®) – Merck

• On the Horizon (Phase 3)– Plazomicin (ACHN-490) – Achaogen -- Eravacycline (TP-434) – Tetraphase– Lefamulin (BC-3781) – Nabriva -- Iclaprim - Motif Bio– Cefiderocol (S-649266) – Shinogi -- Fosfomycin IV (ZTI-01) – Zavante– Fusidic acid (CEM-102) – Cempra -- Fusidic Acid– Aztreonam-avibactam – Allergan/Astellis -- Omadacycline (PTK 0796) - Paratek– VT- 1598 -- SCY-078– CD-101

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Bad Bugs – No Drugs

Clatworth AE. Nature Chemical Biology. 2007; 3: 541-8.

2010 2015 2020

Ceftaz-avibactamCeftolozane-tazoDalbavancinOritavancin

TelavancinCarbapenems

Carbapenems

Mero-vaborDelafloxacin

Fluoroquinolones

Fluoroquinolones

Ceftaz-avibactamCeftolozane-tazo

Resurgence in Antibiotic R&D

• Generating Antibiotic Incentives Now (GAIN) Act - 2012

– Qualified Infectious Diseases Product (QIDP) Status

• Fast track and priority review status designation with FDA

• Expedited approval process

• Increased generic-free market exclusivity from 5-7 years to 10-12 years

• Biomedical Advanced Research and Development Authority (BARDA) – Focus on emergency preparedness

– Broad Spectrum Antimicrobials (BSA) and CARB-X Programs

RECENT APPROVALS

Meropenem-Vaborbactam (Vabomere®)

• FDA Approval – 08/2017 for cUTI

– Dose = 2g/2g (total 4g) q8h over 3 hours

– Requires renal dose adjustment

• Vaborbactam = non-β-lactam, cyclic, boronic acid inhibitor

– Significant inhibition of class A (incl. KPCs) and C β-lactamases

– No effect on Class B/D enzymes or Omp/Efflux-related resistance

– PK = linear, 2-compartment, Vd = 18L (20.2L) and T1/2 = 1.7hr (1.2hr)

Zhanel G. Drugs. 2018; 78: 65-98.

Meropenem-Vaborbactam (Vabomere®)

Data from Melinta

Meropenem-Vaborbactam (Vabomere®)

• MicrobiologyOrganism Meropenem, MIC90 (range) Mero-vaborbactam, MIC90 (range)

A. baumannii 64 (4 - >64) 64 (1 - >64)

P. aeruginosa 8 (≤ 0.015 - >64) 8 (≤ 0.015 - 64)

E. coli- KPC +

0.03 (≤ 0.015 - >32)8 (0.5 – 32)

0.03 (≤ 0.015 - >32)≤ 0.03 (≤ 0.03 – 0.12)

K. pneumoniae- KPC +

0.03 (≤ 0.015 - >32)64 (0.25 - >64)

0.03 (≤ 0.015 - >32)1 (≤ 0.004 - >64)

Enterobacteriaceae- OXA-48 Like- Non-KPC CRE

0.06 (≤ 0.015 - >32)> 32 (0.5 - >32)> 32 (0.25 - >32)

0.06 (≤ 0.015 - >32)> 32 (0.5 - >32)

> 32 (≤ 0.015 - >32)

Zhanel G. Drugs. 2018; 78: 65-98.

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Phase 3 Study Designs

• TANGO I – cUTI (incl. acute pyelonephritis)

– Vs. piperacillin-tazobactam 4.5g IV q8h over 0.5hr

– Primary outcome: overall success at EOIVT in the m-MITT

– Optional switch to PO levofloxacin on day 5, total 10-14d

• TANGO II – Serious infections with CRE Vs. BAT

– Primary outcome: clinical cure at EOT/TOC and 28-day mortality

– Infections included bacteremia, cUTI, HAP, VAP, cIAI

– Excluded – MBL/OXA production, APACHE II > 30, CRRT

Kaye KS. JAMA. 2018; 319(8): 788-99. TANGO II Data from Melinta

Phase 3 Study ResultsTANGO-I TANGO-II

M-V (n=272) TZP (n=273) M-V (n=28) BAT (n=15)

Baseline Characteristics- Age > 65 years- Female- Charlson score ≥ 3- ≥ 2 SIRS Criteria- Pyelonephritis- Bacteremia- E. coli / K. pneumoniae- Meropenem Resistant

32%66.5%52.6%28.3%59.2%4.4%

46%/11%0.34%

37.7%65.9%53.8%33%59%5.5%

42.9%/10.3%1%

50%-

75%42.9%

--

7.1%/79.3%-

40%-

80%40%

--

6.7%/80%-

Efficacy Endpoints- Primary- Micro eradication-TOC- Overall success –TOC- 28d all cause mortality

98.4%*

68.8%74.5%

-

94%*

62.1%70.3%

-

64.3%50%

-17.9%

33.3%33.3%

-33.3%

Safety Endpoints 15.1% 12.8% 24.4% 44%

Kaye KS. JAMA. 2018; 319(8): 788-99. TANGO II Data from Melinta

Comparison of BLI Activity

Zhanel G. Drugs. 2018; 78: 65-98.

Delafloxacin (Baxdela®)• Novel Fluoroquinolone – weakly acidic

– Enhanced intracellular penetration & activity in low pH

– Balanced activity against Topo II and IV

• Indication: ABSSSI - 300mg IV (450mg PO) q12h

• PK Parameter Delaflox IV Delaflox PO Levoflox PO Cipro PO Moxi PO

Bioavailability N/A 58.8% 99% 70% 92%

Vd (L) 35-48 35-48 100 84-189 119-189

Protein Binding 84% 84% 24-38% 20-40% 30-50%

ʄAUC24 (mg h/L) 9.86 7.48 56.2-68.9 16.4-22 24-33.6

Elimination (U/F) 64.5%/28.4% 50.2%/47.7% 87%/4% 57%/20-35% 20%/25%

T1/2 (Hr) 3.7 4.2-8.5 8.8 4-6 10-14

Jorgensen SC. Infect Dis Ther. 2018; epub ahead of print.

Delafloxacin - Microbiology

Jorgensen SC. Infect Dis Ther. 2018; epub ahead of print.

Organism Delafloxacin, MIC 90 (range)

Levofloxacin,MIC 90 (range)

Ciprofloxacin,MIC 90 (range)

Moxifloxacin,MIC 90 (range)

S. aureusMSSAMRSA

0.25 (≤ 0.004-4)0.015 (≤ 0.004-4)0.5 (≤ 0.004-4)

> 4 (≤ 0.12 - >4)2 (≤ 0.12 - >4)

> 4 (≤ 0.12 - >4)

- -

E. FaecalisVRE

1 (≤ 0.004-2)1 (≤ 0.008-2)

>4 (0.25 - >4)>4 (>4)

- -

E. faeciumVRE

> 4 (0.008 - >4)> 4 (>4)

> 4 (0.5 - >4)> 4 (>4)

- -

S. pneumoniaePRSPLvx Resistant

0.03 (≤ 0.004-0.25)0.03 (0.008-0.03)

0.5 (0.015-1)

1 (0.5 - >4)1 (0.5-1)32 (2-32)

- 0.25 (≤ 0.12-4)0.25 (≤ 0.12-0.25)

4 (0.25 - >4)

Viridans Group Strep 0.06 (≤ 0.004-2) 2 (≤ 0.12 - >4) - 0.25 (≤ 0.12-4)

ESBLE. coli > 4 (0.008 - >4) > 4 (≤ 0.12 - >4) > 4 (≤ 0.03 - >4) -

P. aeruginosa > 4 (0.015 - >4) > 4 (≤ 0.12 - >4) > 4 ≤ 0.03 - >4) -

Delafloxacin Resistance Selection

Remy JM. J Antimicrob Chemother. 2012; 67(12): 2814-20.

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Delafloxacin Phase 3 ABSSSI Results• Design

– Multicenter, randomized, double-blind, controlled trial

– Comparator, vancomycin + aztreonam x 5-14 days

• Outcomes

– Primary = early response at 2-3d

– Secondary = clinical response at follow-up & microbiological response

• Baseline characteristics

– Males (62-65%) ≤ 65 years (81-82%)

– N. Am. (46-48%) and Europe (39-41%)

– ~50% obese (BMI ≥ 30 kg/m2)

– ~30% had substance abuse history

– S. aureus > 50% identified pathogen

O’Riordan W. Clin Infect Dis. 2018; epub ahead of print.

Letermovir (Prevymis®)

• Inhibits terminase complex (pUL56)

– CMV specific activity only

• PK

– A: 94% health subjects

• 35% in HSCT w/o CSA & 480mg dose

• 85% in HSCT w/ CSA & 240mg dose

– D: Vd=45.5L

– M: Minor UGT 1A1/1A3

– E: Hepatic uptake (OATP1B1/3)�fecal

Prevymis (Letermovir) Package Insert NEJM. 2014; 370: 1844-6.

Phase 3 Study Methods

• Randomized, double-blind, placebo controlled study

• Inclusion– CMV seropositive Allogeneic HSCT recipient

– No CMV DNAemia at screening

– No acute liver injury and GFR ≥ 10 mL/min

• Objective– Primary: CMV infection prevention through week 24 post-HSCT

– Secondary• Safety

• Efficacy by week 14

• Time to clinically significant CMV infection

Marty FM, et al. N Eng J Med. 2017; epub.

Phase 3 Study Results

• Baseline CharacteristicsCharacteristic Letermovir, n=373 Placebo, n=192

MedianAge, yr 53 54

Male, % 56.6 60.4

CMV+ Donor 61.7 59.4

Malignancy, %AML / MDSNHL / ALL

38.1 / 16.912.6 / 9.4

37.5 / 11.514.6 / 8.9

Transplant type, %MRDMUDMismatchHaploRD

3732.430.616.1

40.632.826.610.9

Cord Blood, % 3.2 5.7

Myeloablative, % 49.9 50.5

Acute GVHD, % 0.5 0.5

High Risk, % 32.4 28.1

• Results:

• No significant difference in safety/ADRs

Endpoint Letermovir, n=325

Placebo, n=170

P-value

Primary End Point at +24 weeksClinically significant CMV infx

- Initiation of preemptive trx- CMV disease

37.5%17.5%16%1.5%

60.6%41.8%40%1.8%

<0.001

Secondary End Point at +14 weeksClinically significant CMV infx

- Initiation of preemptive trx- CMV disease

19.1%7.7%7.4%0.3%

50%39.4%38.2%1.2%

< 0.001

All-cause Mortality at week +24 19.4% 26.5% 0.0317

Marty FM, et al. N Eng J Med. 2017; epub.

Phase 3 Study Results

Marty FM, et al. N Eng J Med. 2017; epub.

Phase 3 Study Results

Marty FM, et al. N Eng J Med. 2017; epub.

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Myelosuppression

• Engraftment similar between groups

• Median time to engraftment was 19 days (letermovir) vs. 18 days (placebo)

Marty FM, et al. N Eng J Med. 2017; epub.

PIPELINE – GRAM-NEGATIVES

Plazomicin - Background

• Next-Gen Aminoglycoside – derived from sisomicin

• Similar PK

– 15mg/kg dosing: Vd = 0.21-0.29 L/kg, T1/2 = 3.5-5hr

– > 80% excreted renally unchanged in 24hr

• Low rate of renal and vestibular/cochlear ADEs

• Stable against most aminoglycoside modifying enzymes

• NDA submitted 10/2017, PDUFA date 06/25/18Thaden JT. Virulence. 2017; 8(4): 403-16. Cass RT. AntimicrobAgents Chemother. 2011; 55(12): 5874-80.

Plazomicin - Microbiology

Lopez-Diaz MC. AntimicrobAgents Chemother. 2017; 61(2): 2454-16.Zhang Y. AntimicrobAgents Chemother. 2017; 72: 2792-95.

• Plazomicin substrate for AMEs AAC(2’)-la and APH(2”)-la • Inactive with 16S rRNA ribosomal methyltransferases

Plazomicin – Clinical Efficacy

• EPIC Study – Phase 3 cUTI vs. Meropenem

– N=226 with cUTI and N=162 with pyelonephritis

– Composite cure at TOC for plazomicin and meropenem:

• cUTI-78.5% vs. 68.9% and pyelonephritis-85.7% vs. 71.8%

• CARE Study – Phase 3 CRE Bacteremia vs. Colistin

– Combinations allowed (mostly meropenem and tigecycline)

– 28-day all cause mortality lower with plazo (14% vs. 53%)

– Bacteremia clearance by day 5 higher with plazomicin (86% vs 47%)

Cloutier D. Poster Presented at ID Week; 2017 Oct. 4-8; San Diego, CA.McKinnell JA. Poster Presented at ID Week; 2017 Oct. 4-8; San Diego, CA.

Eravacycline• Synthetic fluorocycline ~ tigecycline

– 2-4 fold more potent vs. tige for GPs

– 2-8 fold more potent vs. tige for GNs

• PK: Parameter Erava IV –1.5mg/kg

Erava PO –200mg

Tige IV –50mg

Mino IV/PO –200mg PO (IV)

Bioavailability N/A 58.8% N/A 95-100%

Vd (L) 262-320 262-320 350-500 80-115

Protein Binding 79-90% 79-90% 73-79% 76%

Cmax(mg/L) 1.3 (1mg/kg) 0.23 0.38-0.62 3.1-3.6 (3-4.1)

AUC24 (mg h/L) 8.98 3.34 2.56-3.07 44-47 (67-87)

Elimination (U/F) 16% / 28.4% 16%/47.7% < 15% / 59% 5-12% / 20-35%

T1/2 (Hr) 26-48 18-36 18-37 13-17 (15-21)

Agwuk KN. J Antimicrob Chemother. 2006; 58: 256-65. Zhanel GG. Drugs. 2016; 76: 567-88.

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Eravacycline - Microbiology

Zhanel GG. Drugs. 2016; 76: 567-88. Grossman TH, et al. AntimicrobAgents Chemother. 2012; 56:2559-2664.

Organism Erava, MIC90 Tige, MIC90 Mero, MIC 90

A. baumannii 1 (≤ 0.0015-8) 4 1 (0.25-2)

P. Aeruginosa 16 32 8

E. coli- ESBL

0.5 (≤ 0.015-4)0.5 (0.03-2)

0.51

0.120.12

K. pneumoniae- ESBL- CRE

1 (0.03-16)1 (0.13-8)2 (0.13-16)

242

0.030.06> 16

Steno 1 (≤ 0.015-8) 8 128

MSSAMRSA

0.12 (≤ 0.015-0.5)0.12 (≤ 0.015-4)

0.50.5

0.1232

E. faecalis- VRE

0.06 (≤ 0.015-0.12)0.06 (≤ 0.015-0.12)

0.250.25

>32>32

E. faecium- VRE

0.06 (≤ 0.015-0.5)0.06 (≤ 0.015-0.25)

0.250.12

>32>32

• Activity against F. tularensis, Y. pestis, B. mallei/pseudomallei

EravacyclineTrial N Treatment Regimen Clinical response in

MITT at TOC, %(n)Clinical Response for ME group, % (n)

EOT Visit TOC Visit LFU visit

Ignite 1 – cIAI541

ERV 1mg/kg q12hERT 1g q24h

87 (230/270)88.8 (238/268)

--

91.4 (181/198)95 (189/199)

--

Ignite 2 – cUTI- IV d1-3- PO switch

option d4-7

908

ERV 1.5mg/kg q24h- PO ERV 200mg q12h

LVX 750mg IV q24h- PO LVX 750mg q24h

60 (180/298)

67 (202-302)

- IV only subset- 54.4 (31/57) ERV

- 42.2 (27/64) LVX- ?PO Absorption (fed/fast)

Ignite 3 – cUTI- IV x 5d, then PO LVX switch

1205ERV 1.5mg/kg q24h

ERT 1g q24h

84.8 (363/428)

94.8 (382/403)

Ignite 4 - cIAI500

ERV 1mg/kg q12hMEM 1g q8h

TBD

Solomkin J, et al. JAMA Surg. 2017;152:224-232. IGNITE 2/3 Results at:https://decisionresourcesgroup.com/drg-blog/tetraphase-reports-negative-results-eravacycline-cuti-trial-2/IGNITE 4 Methods at: https://clinicaltrials.gov/ct2/show/NCT02784704?term=eravacycline&rank=6

• Ignite 2/3 (cUTI) failed to meet non-inferiority• NDA submitted 02/2018 for cIAI, PDUFA date 8/28/2018

Cefiderocol

• Catechol-substituted siderophore cephalosporin

• Enhanced GNR activity, incl. MDR/XDR organisms

• Linear PK – 2g q8h over 3hr

• Studies:

– APEKs-cUTI vs. Imipenem

• Composite clinical/micro curewas 72.6% vs 54.6%

– CREDIBLE-CR, phase 3 vs. BATSaisho Y. Antimicrob Agents Chemother. 2018; 62(3): e2163-17Trial data available at: https://www.prnewswire.com/news-releases/shionogi-announces-positive-top-line-results-for-cefiderocol-pivotal-cuti-clinical-trial-300389912.html

Cefiderocol

Enterobacteriaceae

P. aeruginosa

Hackel MA. Antimicrob Agents Chemother. 2018; 62(2). E01968-17 Ito-Horiyama T. Antimicrob Agents Chemother. 2016; 60(7). 4384-6.

Aztreonam-Avibactam• Aztreonam = monobactam, stable against MBLs

• Avibactam = misses MBLs, inhibits wide range of class A, C, D enzymes (incl. KPC and OXA-48 like carbapenemase)

– Extends activity to Stenotrophomonas maltophila

– No significant improvement in P. aeruginosa activity

• Studies:

– REJUVINATE – Phase 2a for cIAI vs. meropenem

– REVISIT – Phase 3 for serious GNR infections vs. meropenem +/-colistin (incl. MBL-producers)

https://clinicaltrials.gov/ct2/show/NCT02655419https://clinicaltrials.gov/ct2/show/NCT03329092?term=aztreonam+avibactam&rank=1

Aztreonam-Avibactam

Karlowsky JA. AntimicrobAgent Chemother. 2017; 61(9): e00472-17

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Fosfomycin IV (Zolyd®)

• Epoxide class – inhibits early cell wall synthesis

• Broad gram-negative and –positive activity

– Incl. MRSA, VRE, ESBL, AmpC, CRE

– Rapid resistance may occur, combo therapy encouraged

• PO form limited absorption, approved for cystitis

– IV dosing 4g q6h (up to 24g/day) – renally adjusted

• ZEUS study – compared to TZP for cUTI (7-14 days)

– Composite clinical/micro cure – 65% fosfo vs. 55% TZP

Kaye KS. ID Week 2017.Patel SS. Drugs. 1997; 53(4): 637-56.

Fosfomycin IV (Zolyd®)

Summary of Resistant GN ActivitiesAntibiotic ESBL KPC MBL AmpC OXA-48 P. Aeruginosa A. Baumannii Stenotrophomonas

Ceftolozane / tazobactam

Limited X X Limited X ✔✔✔✔ X X

Ceftazidime / Avibactam

✔✔✔✔ ✔✔✔✔ X ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ X X

Aztreonam / Avibactam

✔✔✔✔✔✔✔✔

✔✔✔✔ ✔✔✔✔ ✔✔✔✔ Limited X ✔✔✔✔

Imipenem / Relebactam

✔✔✔✔ ✔✔✔✔ X ✔✔✔✔ Limited ✔✔✔✔ X X

Meropenem / Vaborbactam ✔✔✔✔ ✔✔✔✔ X ✔✔✔✔ X X X X

Eravacycline ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ X ✔✔✔✔ ✔✔✔✔

Plazomicin ✔✔✔✔ ✔✔✔✔ X ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ X

Cefidericol ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ ✔✔✔✔ ✔✔✔✔

PIPELINE – GRAM POSITIVES

Iclaprim

• Selective inhibitor of DHFR (like TMP)

– Designed to bind in TMP resistance (incl. F98Y & I100L)

• IV only, flat dosing 80mg q12h over 2h (250-500mL NS/D5W)

– Initial dosing in ASSIST-1/2 studies weight based (0.8mg/kg q12h)

– ↑ AUC/MIC (+28%) & T > MIC (+32%), avoids Cmax >800 ng/mL

• Linear PK and good tissue distribution (ELF = 20-40x)

– < 2% excreted unchanged in urine/feces, mostly metabolized in liver

• No significant CYP interactions or renal K+ excretionHuang DB. Open Forum Infect Dis. 2018; 5(2): ofy 003.

Iclaprim

Organism Iclaprim, MIC 50/90 TMP, MIC 50/90 TMP-SMZ, MIC 50/90 Vanc, MIC 50/90

S. aureus- MRSA

0.06 / 0.120.06 / 0.5

1 / 22 / 8

0.06 / 0.120.06 / 0.25

1 / 11 / 1

β-heme strep 0.06 / 0.25 1 / 2 0.12 / 0.25 0.25 / 0.5

S. pneumoniae 0.06 / 2 2 / 64 0.25 / 8 0.25 / 0.5

PneumocystisEC50 = 20.3

Icla/SMZ = 13.2/66- EC50 = 51.4/257 -

• Active against DAP, LZD, and VAN resistant S. aureusHuang DB. Open Forum Infect Dis. 2018; 5(2): ofy 003. Huang DB. Diagn Microbiol Infect Dis. 2018; 90(4): 329-34.Lodise TP. AntimicrobAgent Chemother. 2017; 62(2): e01184-17. Aliouat EM. Eur J Clin Microbiol Infect Dis. 2018; 37(3):409-15.

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Iclaprim

Huang DB. Open Forum Infect Dis. 2018; 5(2): ofy 003.

Indication Phase Drug/Dose Year Clinical Cure-TOC Early Clinical Response

HABP2

Icla 0.8 mg/kg q12hIcla 1.2 mg/kg q8hVanc 1g q12h

2007-0874% (17/23)63% (15/24)52.2% (12/23)

**comparable 28-daymortality; 8.7% / 12.5% / 21.7%**

cSSSI2

Icla 0.8 mg/kg q12hIcla 1.6 mg/kg q12hVanc 1g q12h

2006-0792.9% (26/28)90.3% (28/31)92.9% (26/28)

cSSSIASSIST-1

3Icla 0.8 mg/kg q12hLZD 600mg IV q12h

2007-0883.1% (207/249)88.7% (220/248)

Diff. -5.6% (95% CI, -11.7% -0.6%). Non-Inf. Margin -10%

cSSSIASSIST-2

3Icla 0.8 mg/kg q12hLZD 600mg IV q12h

2007-0881.3% (204/251)81.9% (199/243)

Diff. -0.6% (95% CI, -7.7% -6.5%). Non-Inf. Margin -10%

ABSSSIREVIVE-1

3Icla 80mg q12hVanco 15mg/kg q12h

2016-1780.9% (241/295)81% (243/300)

ABSSSIREVIVE-2

3Icla 80mg q12hVanco 15mg/kg q12h

2016-1778.3% (231/295)76.7% (234/305)

Safety: Common (>5%) TEAEs were headache, nausea, fatigue, vomiting. Rare/Serious = QTc prolongation

Omadacycline

• Aminomethylcycline (tetracycline-like)

• Potent GP, atypicals, GN, and some anaerobes

– Active with ribosomal protection mutations [Tet(O/M)] and several efflux pumps [Tet(K)]

• IV/PO formulations – 100mg IV / 300mg PO (BE ~35%)

– IV Cmax=1.8 mg/L (PO=0.5 mg/L); IV/PO AUC=8.8 mg h/L; T1/2=17h

• TEAEs = nausea, headache, vomiting, dizziness

Villano S. Future Microbiol. 2016; 11(11): 1421-34.

Omadacycline

OASIS OPTIC

Study design Double-blind, multicenter RCT

Population Adults with ABSSSI (N=627) Adults with CABP: PORT Risk Class II-IV (N=774)

Treatment • OMC: 100 mg IV q12h x 2 doses �

100 mg IV q24h � 300 mg q24h• LZD: 600 mg IV q12h � 600 po

q12hDuration: 7-14 days

• OMC: 100 mg IV q12h x 2 doses �

100 mg IV q24h � 300 mg q24h• MOX: 400 mg q12hDuration: 7-14 days

Primary Outcome Early clinical response (ECR) Survival, no rescue antibiotics, and symptomatic improvement at ECR

Results ECR: 86.1% vs. 83.6% (95% CI: -3.2, 8.2)PTE: 96.3% vs. 93.5% (95% CI: -1.0, 6.9)TEAE’s: 48.3% vs. 45.7%

ECR: 81.1% vs. 82.7% (95% CI: -7.1, 3.8)PTE: 92.9% vs. 90.4% (95% CI: -1.7, 6.8)TEAE’s: 41.1% vs. 48.5%

Conclusion Non-inferior and well-tolerated

O’Riordan WA. 27th Annual ECCMID. 2017. Stets R. IDWeek 2017. Villano S. Future Microbiol. 2016; 11(11): 1421-34.

MIC90‘s (mg/L)• S. pneumoniae=0.06

• MDR=0.06

• MRSA=0.12

• E. faecalis=0.5

• E. faecium=0.12

• VRE=0.12-0.25

• BHS=0.12-0.25

• Legionella=0.25

• Enteric GNRs ≥ 8

Lefamulin

• “Novel” class – Pleuromutilin, from basidiomycetes-1951

– Inhibits protein synthesis via binding at 23S rRNA of the 50S subunit

• Excellent GP, atypical, and some GN coverage– Target ABSSSI and CABP, MDR N. gonorrhea (in vitro)

• Dosing 150mg IV q12h or 600mg PO q12h– ~25% absorbed orally, large Vd (~200L), T1/2 = 6-9h

– ELF ~6x free serum levels (adipose & muscle 80-100% serum)

Rubino CM. AntimicrobAgents Chemother. 2015; 59(1): 282-288 Wicha WW. ECCMID: 2017; Vienna, Austria. P1336Zeitlinger M. J Antimicrob Chemother. 2016; 71(4): 1022-6.

Lefamulin

OrganismLEF, MIC 90

DOX, MIC 90

LZD,MIC 90

AZI, MIC 90

CRO,MIC 90

MRSA 0.25 1 1 >4 -

β-heme streptococci 0.03 8 1 >4 -

E. faecium 4 >8 1 >4 -

S. pneumoniae 0.25 8 1 >4 1

VGS 0.5 >8 1 >4

H. influenzae 2 0.5 - 2 < 0.12

M. catarrhalis 0.25 0.25 - < 0.5 0.5

C. trachomatis 0.04 0.02 > 12.8 0.2 -

M. genitalium 0.063 1 - > 16 -

N. gonorrhoeae 0.5 4 - 0.5 0.03

• Phase 3 – CABP (LEAP 1)

– Vs. Moxifloxacin +/- Linezolid

– N=551

– 10 Endpoint = Early Response

• 87.3% LEF vs. 90.2% Moxi

– Some QTc prolongation and LFT abnormalities, similar to moxi

• Phase 2 – ABSSSI– Comparable to vanco for ECR

Paukner S. AntimicrobAgents Chemother. 2013; 57(9): 4489-95. File T. ECCMID: 2018; Madrid, Spain. P0277Paukner S. AntimicrobAgents Chemother. 2018; 62(5): e02380-17. File T. ECCMID: 2018; Madrid, Spain P0276Rubino CM, et al. AntimicrobAgents Chemother. 2015;59:282–288.

PIPELINE – ANTIFUNGALS

6/19/2018

9

AntifungalsAgent Stage Class Spectrum Comments

VT-1598Pre

CYP-51 inhibitor (ergosterol)Candida (incl. fluc-R), endemics, mold (incl. mucor)

QIDP for coccidiomycosisC. auris activity

VT-11612

CYP-51 inhibitor (ergosterol)Candida, Cocci, Trichophyton,Rhizopus arrihizus

QIDP status for tinea pedis & vulvovaginal candida

VT-1129 Pre CYP-51 inhibitor (ergosterol) Candida, Cryptococcus In vivo crypto meningitis

SCY-078 2-3 Glucan-synthase inhibitor

Candida (incl. FKS mutants and C. auris), Aspergillus spp., Scedosporium

QIDP for IC/IA infectionsSemi-synthetic enfumafunginIV & PO formulation

CD-101 2 BDG synthetase inhibitor (echinocandin)

Candida (similar to micafungin),Aspergillus, C. auris (similar to anidulafungin)

QIDP vulvovaginal candidaQweek dosing? (T1/2 ~80h)

AX001 (aka E1210)

2Glycosylphosphadidylinositolbiosynthesis inhibitor

Candida, Aspergillus, Fusarium, Scedosporium (inactive against C. krusei and Mucor)

QIDP IC, IA, Cocci, and rare molds

F901318 1 Pyrimidine synthesis inhibitorMolds/endemic fungi (no candida or mucor activity)

QIDP status, azole-resistant mold activity

MAT2203 2 ergosterol – cochleate AmB POCandida, Molds, Endemic Fungi QIDP for IC, IA, and prophyWeiderholdNP. Int J Antimicrob Agents. 2018; epub

Honorable MentionsAgent Stage Class Spectrum Comments

Cadazolid 3Oxazolidinone-quinolone hybrid

C. difficile Suppresses toxin/spore. 1/2 phase 3’s didn’t meet endpoint

Murepavadin 2 Peptide mimetic Pseudomonas – incl. CRPA Phase 2 as part of combo therapy

Afabacin 2Benzofurannaphthyridine

S. aureus – incl. MRSA, VRSA, LZD-R, DAP-R

IV and PO formulations. Phase II ABSSSI showed non-inferiority

Solithromycin3

Fluoroketolide S. pneumoniae, atypicals, Chlamydia, N. gonorrhea

Phase 3 CABP trials met non-inferiority vs. Moxi.

Imipenem-relebactam

3Carbapenem+ BLI

GNRs – CRE (KPC), and Imi-R Pseudomonas

Phase 2 completed, non-inferior. Phase 3 underway, RESTORE 1/2

Ceftobiprole 3 Cephalosporin MRSA and PseudomonasQIDP for S. aureus bacteremia, ABSSSI, and CABP

Fusidic Acid3

Fusidane – elongation factor G

GPs – incl. MRSAPhase 3 non-inferior to linezolid for ABSSSI

Ridinilazole 2 Bis-benzimidazole C. difficile Phase 2 – superiority to PO vanco

LYS228 2 Monobactam GNRs – CRE (incl. MBLs/SBLs) Stable against most CRE

Available at: http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development

Conclusions

• More antimicrobials in pipeline now vs. past several decades

• Novel classes/mechanisms lagging behind modifications in existing classes, but are on the horizon

• Resistance is inevitable, even to new agents

– Optimize current use

– Good stewardship of current/new agents

Questions