In Vitro Activity of Eravacycline and Comparators Against Staphylococcus Aureus and Enterococci, Including Methicillin-Resistant And

Home , Eravacycline

Poster # 1358 In vitro activity of eravacycline and comparators against Staphylococcus aureus and enterococci, including methicillin-resistant and

vancomycin-resistant subgroups, collected from European hospitals in 2015 Contact: 1 2 1 1 3 3 Tetraphase Pharmaceuticals Medical Information (TPMI) Ian Morrissey , Matteo Bassetti , Sophie Magnet , Stephen Hawser , Melanie Olesky , Corey Fyfe [email protected] 1IHMA Europe Sarl, Monthey, Switzerland; 2Univ. of Udine, Udine, Italy; 3Tetraphase Pharmaceuticals, Watertown, MA 617-715-3600

Introduction Results

The European Centre for Disease Prevention and Control (ECDC) • Clinical isolates were comparably represented among diverse geograph- Table 1. Antimicrobial activity of ERV and comparator agents against Table 2. Antimicrobial activity of ERV and comparator agents against Figure 3. MIC distribution for eravacycline, minocycline and tigecycline against estimates ~ 37,000 deaths per year in Europe to be attributed to acquired ic locations throughout Europe (Fig. 1), with the largest numbers isolated Staphylococcus spp., including resistant strains, collected from Europe in 2015 Enterococcus spp., including resistant strains, collected from Europe in 2015 MSSA (N=105) and MRSA isolates (N=104) healthcare-associated infections, with Gram-positive organisms such from France (16%), Italy (15%), Spain (12%), and Germany (11%). Organism/Antimicrobial Tested MIC (mg/L) EUCAST Organism/Antimicrobial Tested MIC (mg/L) EUCAST DZ^ as Staphylococcus aureus, Enterococcus spp. and coagulase-negative (No. Tested) MIC50 MIC90 MIN MAX %S %I %R (No. Tested) MIC50 MIC90 MIN MAX %S %I %R 1 a Enterococcus a ϭϬϬ staphylococci among the contributable pathogens. While the percentage Figure 1. Isolate distribution (%) by country of origin for the 998 isolates All Staphylococcus spp. (N=544) All spp. (N=454) of methicillin-resistant Staphylococcus aureus (MRSA) has stabilized/ Amoxicillin-clavulanate >1 >1 ͠ 0.06 >1 ------Amoxicillin-clavulanate 1 > 1 ͠ 0.12 > 1 100 0 0 collected in 2015 in Europe Azithromycin >4 >4 ͠ 0.25 >4 44.3 0.2 55.5 Ampicillin 1 > 8 ͠ 0.25 > 8 67.2 0.4 32.4 ϱϬ 2 decreased, it remains ~17% in EU/EAA countries. However, the proportion Clindamycin 0.06 >2 ͠ 0.03 >2 77.2 1.1 21.7 Daptomycin 2 4 0.12 8 ------of MRSA typically associated with healthcare-associated infections has Daptomycin 0.25 0.5 ͠ 0.06 >2 99.6 -- 0.4 Eravacycline 0.03 0.06 0.015 1 ------Ϭ Levofloxacin 2 > 8 0.25 > 8 52 -- 48 2 Eravacycline 0.06 0.25 ̤ 0.008 2 ------Ϭ͘Ϭϭϱ Ϭ͘Ϭϯ Ϭ͘ϬϲΎ Ϭ͘ϭϮ Ϭ͘Ϯϱ Ϭ͘ϱ EƵŵďĞƌŽĨ/ƐŽůĂƚĞƐ increased in the community-onset setting. The occurrence of vancomycin- dƵƌŬĞǇ h< KƚŚĞƌΎ ĞůŐŝƵŵ Gentamicin 0.25 >8 ͠ 0.06 >8 67.3 -- 32.7 Linezolid 1 1 0.5 4 100 -- 0 Minocycline 8 > 8 0.03 > 8 ------D/;ŵŐͬ>Ϳ resistant Enterococcus faecium at 8.3% has shown an increasing trend ^ǁŝƚǌĞƌůĂŶĚ ϯй ϯй ϯй ϵй ƌŽĂƚŝĂ Levofloxacin 4 >4 0.06 >4 44.1 3.9 52 ͠ ^ƉĂŝŶ ǌĞĐŚZĞƉƵďůŝĐ Penicillin 2 > 8 ͠ 0.06 > 8 ------2 Ϯй ϯй Linezolid 1 2 ͠ 0.5 >4 99.5 -- 0.6 Zs D/E d' among almost half of EU/EAA countries. In a recent report by the World Tetracycline 32 > 32 0.12 > 32 ------ϭϮй ϰй Minocycline 0.12 0.25 ͠ 0.06 4 98.4 1.5 0.2 Tigecycline 0.12 0.12 0.03 8 98.9 0.4 0.7 Health Organization (WHO), both MRSA and vancomycin-resistant ĞŶŵĂƌŬ Oxacillin >2 >2 ͠ 0.06 >2 ------Vancomycin 1 2 ͠ 0.25 > 16 95.6 -- 4.4 D^^ ϯй Penicillin >2 >2 ͠ 0.12 >2 ------enterococci (VRE) have been designated as high priority (tier 2) global Enterococcus faecalis, VSE (N=281) Tetracycline 0.25 4 ͠ 0.06 >16 82.4 3.9 13.8 ϭϬϬ 3 Amoxicillin-clavulanate 1 1 0.12 > 1 100 0 0 pathogens for which new antibiotics are urgently needed within Europe. Tigecycline 0.12 0.25 0.03 1 99.8 -- 0.2 ͠ WŽƌƚƵŐĂů Ampicillin 1 1 ͠ 0.25 > 8 98.9 0 1.1 Vancomycin 1 2 ͠ 0.25 4 ------ϱϬ ϱй Daptomycin 1 2 0.12 8 ------Eravacycline (ERV) is a novel, fully-synthetic ﬂ uorocycline antibiotic &ƌĂŶĐĞ MSSA (N=105) Eravacycline 0.06 0.06 0.015 0.12 ------ϭϲй Amoxicillin-clavulanate >1 >1 0.25 >1 ------being developed for the treatment of serious infections, including those Levofloxacin 1 > 8 0.25 > 8 72.6 -- 27.4 Ϭ Azithromycin 0.5 >4 ͠ 0.25 >4 88.6 1.0 10.5

Linezolid 1 1 0.5 2 100 -- 0 EƵŵďĞƌŽĨ/ƐŽůĂƚĞƐ чϬ͘Ϭϭϱ Ϭ͘Ϭϯ Ϭ͘ϬϲΎ Ϭ͘ϭϮ Ϭ͘Ϯϱ Ϭ͘ϱ caused by multidrug-resistant (MDR) pathogens. ERV is in phase 3 Clindamycin 0.06 0.12 ͠ 0.03 0.25 100 0 0 Minocycline 8 > 8 ͠ 0.03 > 8 ------Daptomycin 0.25 0.5 0.12 0.5 100 -- 0 D/;ŵŐͬ>Ϳ clinical development for the treatment of complicated intra-abdominal Penicillin 2 4 0.5 > 8 ------Eravacycline 0.06 0.06 ̤ 0.008 0.12 ------Tetracycline > 32 > 32 0.12 > 32 ------Zs D/E d' infections (cIAI) and complicated urinary tract infections (cUTI), including Gentamicin 0.25 0.5 0.06 1 100 -- 0 EĞƚŚĞƌůĂŶĚƐ ͠ Tigecycline 0.12 0.25 0.03 8 98.9 0.7 0.4 pyelonephritis. ϱй Levofloxacin 0.12 0.5 0.06 >4 90.5 0 9.5 Vancomycin 1 2 0.5 2 100 -- 0 *For minocycline, the lowest range tested was 0.06 mg/L Linezolid 1 2 ͠ 0.5 2 100 -- 0 Enterococcus faecium, VSE (N=143) Minocycline 0.12 0.12 0.06 0.25 100 0 0 Previous global surveillance studies of eravacycline have demonstrated ͠ Amoxicillin-clavulanate > 1 > 1 ͠ 0.12 > 1 100 0 0 4 Oxacillin 0.25 0.5 0.12 0.5 100 -- 0 potent in vitro activity against specifi c Gram-positive pathogens. /ƚĂůǇ 'ĞƌŵĂŶǇ Ampicillin > 8 > 8 ͠ 0.25 > 8 11.2 1.4 87.4 Penicillin 1 >2 ͠ 0.12 >2 23.8 -- 76.2 Figure 4. MIC distribution for eravacycline, minocycline and tigecycline against ϭϱй ϭϭй Daptomycin 4 4 0.12 4 ------The purpose of this study was to demonstrate the in vitro activity of ,ƵŶŐĂƌǇ 'ƌĞĞĐĞ Tetracycline 0.25 0.25 ͠ 0.06 >16 99.1 0 1.0 Eravacycline 0.03 0.06 0.015 0.25 ------all VSE (N=434) and VRE isolates (N=20) eravacycline and comparators against S. aureus, Enterococcus spp. and ϯй ϯй Tigecycline 0.12 0.25 0.06 0.25 100 -- 0 Levofloxacin > 8 > 8 0.5 > 8 15.4 -- 84.6 Vancomycin 1 1 ͠ 0.25 2 100 -- 0 Linezolid 1 2 0.5 4 100 -- 0 coagulase-negative staphylococci, including resistant phenotypes, isolated MRSA (N=104) Minocycline 0.06 > 8 0.06 > 8 ------s^ from patients in Europe during 2015. UK, United Kingdom; *Countries includes as “Other” (Austria, Ireland, Poland, Romania, and Russia) had 10 or less isolates Amoxicillin-clavulanate >1 >1 1 >1 ------Penicillin > 8 > 8 ͠ 0.06 > 8 ------ϯϬϬ Azithromycin >4 >4 ͠ 0.25 >4 33.7 0 66.4 Tetracycline 0.25 > 32 0.12 > 32 ------ϮϬϬ Clindamycin 0.12 >2 ͠ 0.03 >2 58.7 0 41.4 Tigecycline 0.06 0.12 0.03 8 99.3 0 0.7 Daptomycin 0.25 0.5 0.25 1 100 -- 0 Vancomycin 0.5 1 ͠ 0.25 2 100 -- 0 ϭϬϬ b • Most isolates were collected from genito-urinary and respiratory sources, Eravacycline 0.06 0.06 0.015 0.25 ------VRE (N=20) Ϭ Gentamicin 0.25 0.5 0.12 >8 96.2 -- 3.9 Amoxicillin-clavulanate > 1 > 1 1 > 1 100 0 0 followed by blood, other body fl uid and gastro-intestinal sources (Fig. 2). Ϭ͘Ϭϭϱ чϬ͘ϬϯΎ Ϭ͘Ϭϲ Ϭ͘ϭϮ Ϭ͘Ϯϱ Ϭ͘ϱ ϭ Ϯ ϰ шϴ Levofloxacin >4 >4 0.06 > 4 16.4 1.9 81.7 Ampicillin > 8 > 8 1 > 8 15 0 85 EƵŵďĞƌŽĨ/ƐŽůĂƚĞƐ Linezolid 1 2 1 2 100 -- 0 Daptomycin 2 4 1 4 ------D/;ŵŐͬ>Ϳ Methods Minocycline 0.12 0.12 0.06 0.5 100 0 0 Eravacycline 0.03 0.06 0.03 1 ------Figure 2. Isolate counts by source of infection (N=992) ͠ Zs D/E d' Oxacillin >2 >2 1 >2 1 -- 99 Levofloxacin > 8 > 8 0.5 > 8 10 -- 90 A total of 998 staphylococci (N=544) and enterococci (N=454) clinical Penicillin >2 >2 ͠ 0.12 >2 1.9 -- 98.1 Linezolid 1 1 1 1 100 -- 0 Tetracycline 0.25 0.5 ͠ 0.06 >16 95.2 0 4.8 Minocycline 0.06 8 0.06 > 8 ------sZ isolates, collected from various body sites from hospitals in Europe in 2015, ϯϱϬ Tigecycline 0.25 0.25 0.06 0.5 100 -- 0 Penicillin > 8 > 8 2 > 8 ------ϮϬ ϯϭϮ Tetracycline 0.25 > 32 0.25 > 32 ------were tested. Vancomycin 1 1 ͠ 0.25 1 100 -- 0 ϭϱ ϯϬϬ Staphylococcus epidermidis (N=148) Tigecycline 0.06 0.25 0.06 1 95 0 5 ϮϳϬ ϭϬ Amoxicillin-clavulanate >1 >1 ͠ 0.06 >1 ------Vancomycin > 16 > 16 > 16 > 16 0 -- 100 ϱ • Azithromycin >4 >4 ͠ 0.25 >4 41.2 0 58.8 a Breakdowns by country and site of infection are given in Figures 1 and 2, ϮϱϬ Includes E. avium (2), E. casseliflavus (1), E. durans (1), E. faecalis (284), E. faecium (160), E. gallinarum (3), E. hirae (1), E. raffi nosus (2) Ϭ Clindamycin 0.06 >2 ͠ 0.03 >2 66.2 3.4 30.4 respectively. bIncludes vancomycin-resistant E. faecalis (N=3) and vancomycin-resistant E. faecium (17) Ϭ͘Ϭϯ Ϭ͘Ϭϲ Ϭ͘ϭϮ Ϭ͘Ϯϱ Ϭ͘ϱ ϭ Ϯ ϰ шϴ Daptomycin 0.5 0.5 ͠ 0.06 1 100 -- 0 EƵŵďĞƌŽĨ/ƐŽůĂƚĞƐ ϮϬϬ ϭϳϴ Eravacycline 0.06 0.25 0.008 1 ------VSE, vancomycin-sensitive enterococci; VRE, vancomycin-resistant enterococci; “--” represents lack of an established breakpoint • Minimal inhibitory concentration (MIC) endpoints were determined by ̤ D/;ŵŐͬ>Ϳ ϭϰϭ Gentamicin 0.12 >8 ͠ 0.06 >8 52.7 -- 47.3 Zs D/E d' broth microdilution according to CLSI guidelines.5 ϭϱϬ Levofloxacin 2 > 4 0.12 >4 39.2 11.5 49.3 Linezolid ͠ 0.5 1 ͠ 0.5 >4 98.7 -- 1.4 • The in vitro activity (as measured by MIC values) for ERV against S. EƵŵďĞƌŽĨ/ƐŽůĂƚĞƐ ϵϭ 90 VRE isolates consisted of vancomycin-resistant E. faecalis (N=3) and E. faecium (N=17); *For minocycline, the lowest range tested • Quality control testing was performed each day of testing as specifi ed ϭϬϬ Minocycline 0.12 0.5 ͠ 0.06 4 98 1.4 0.7 aureus, including MRSA, was 4-fold more potent than tigecycline (TGC) was 0.03 mg/L Oxacillin 2 >2 ͠ 0.06 >2 22.3 -- 77.7 and 2-fold more potent than minocycline (MIN). ERV exhibited up to by the CLSI using E. faecalis ATCC 29212 and S. aureus ATCC 29213. ϱϬ Penicillin >2 >2 ͠ 0.12 >2 ------Tetracycline 1 8 ͠ 0.06 >16 75 10.8 14.2 4-fold greater activity than TGC, >64-fold greater activity than MIN, and • Antibiotic susceptibility was determined using EUCAST version 6.0 Tigecycline 0.12 0.25 0.03 0.5 100 -- 0 Ϭ 6 Vancomycin 2 2 0.5 2 100 -- 0 at least 16-fold greater activity than vancomycin against enterococci. All Conclusions breakpoints . ŽĚǇ&ůƵŝĚ ůŽŽĚ 'ĂƐƚƌŽŝŶƚĞƐƚŝŶĂů;'/Ϳ 'ĞŶŝƚĂůͬhƌŝŶĂƌǇ;'hͿ ZĞƐƉŝƌĂƚŽƌǇ Staphylococcus haemolyticus (N=135) S. aureus, 99% of VSE and 95% of VRE were TGC-susceptible. Fig. 3 and Amoxicillin-clavulanate >1 >1 0.12 >1 ------Fig. 4 show MIC distributions for ERV, MIN and TGC. ERV demonstrated potent in vitro activity against Staphylococcus spp. and Note: Throat infection source (N=6) not included in chart. Azithromycin >4 >4 ͠ 0.25 >4 18.5 0 81.5 Enterococcus spp., including resistant phenotypes, collected from European Body fl uid includes bile and fl uids from abdominal, peritoneal and pleural cavities. Clindamycin 0.06 >2 ͠ 0.03 >2 83.7 0 16.3 • While staphylococci combined had varied susceptibilities to Daptomycin 0.5 0.5 0.12 1 100 -- 0 countries in 2015. Overall, eravacycline MIC90 values for S. aureus and Eravacycline 0.12 0.25 0.015 2 ------comparators, MSSA were ~≥90% susceptible to most agents except enterococci isolates were 0.06 mg/L and its activity was unaffected by • Tables 1 and 2 show MIC data for staphylococci and enterococci, Gentamicin 8 >8 ͠ 0.06 >8 27.4 -- 72.6 penicillin (24% susceptible) and MRSA were poorly susceptible to Levofloxacin >4 >4 0.06 >4 18.5 0.7 80.7 MRSA or VRE phenotypes. ERV shows promising activity against S. aureus respectively. Linezolid 1 1 ͠ 0.5 2 100 -- 0 most agents except gentamicin (96% susceptible), tetracyclines and enterococci, including resistant phenotypes, in patients from Europe. Minocycline 0.25 0.25 ͠ 0.06 1 95.6 4.4 0 (≥95% susceptible), daptomycin (100% susceptible), linezolid (100% – ERV MIC values were 0.06/0.25 mg/L for all staphylococci Oxacillin >2 >2 ͠ 0.06 >2 17.8 -- 82.2 50/90 susceptible) and vancomycin (100% susceptible). VS E. faecalis were combined and were 0.06/0.06 mg/L for both methicillin-sensitive S. Penicillin >2 >2 ͠ 0.12 >2 ------References Tetracycline 1 >16 0.12 >16 68.2 2.2 29.6 ≥90% susceptible to most agents, except levofl oxacin (73%). VS E. 1. ECDC: http://ecdc.europa.eu/en/Pages/home.aspx. Accessed on 21MAR2017 aureus (MSSA) and MRSA Tigecycline 0.25 0.5 0.06 1 99.3 -- 0.7 faecium and VRE showed reduced susceptibilities to ampicillin (11-15%) 2. ECDC 2015 Antimicrobial resistance surveillance in Europe Report. Accessed at http://ecdc.europa.eu/en/Pages/home.aspx Vancomycin 2 2 0.5 4 100 -- 0 3. World Health Organization; 2017: http://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf. – MIC values for ERV against all enterococci combined, VS and levofl oxacin (10-15%). 50/90 aIncludes S. aureus (209), S. capitis (4), S. epidermidis (148), S. haemolyticus (135), S. hominis (16), S. lugdunensis (9), S. pasteuri (1), S. 4. Bassetti et al., Poster #1820 presented at IDWeek, 26-30 October 2016, New Orleans, LA, USA (vancomycin-susceptible) E. faecium, and VRE strains were 0.03/0.06 saprophyticus (13), S. schleiferi (1), S. sciuri (2), S. simulans (2), S. warneri (2), CoNSA, non-speciated (1), non-speciated (1) 5. CLSI, 2015. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; ApprovedStandard-Eighth Edition M07-A10. Clinical and Laboratory Standards Institute (CLSI), Wayne, PA 19087-1898USA. MSSA, methicillin-sensitive S. aureus; MRSA, methicillin-resistant S. aureus; “--” represents lack of an established breakpoint mg/L and were 0.06/0.06 mg/L for VS E. faecalis. 6. EUCAST version 6.0. Breakpoint tables for interpretation of MICs and zone diameters.

27th ECCMID, 22 – 25 April 2017, Vienna, Austria