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Assessment of Eravacycline against a Recent Global Collection of 4,462 Clinical Isolates (2013-2014) Contact: C-619 I. Morrissey1, J. Sutcliffe2, M. Hackel3, S. Hawser1* Dr. S. Hawser 1 IHMA Europe Sàrl, Epalinges, Switzerland. IHMA Europe Sàrl 2Tetraphase Pharmaceuticals, Watertown, USA ICAAC/ICC [email protected] 17-21 September, 2015 3International Health Management Associates, Inc., Schaumburg, USA San Diego, CA *Presenting Author Abstract Results Conclusions

Background: Eravacycline is a novel, fully synthetic fluorocycline with Table 1. Summary of Enterobacteriaceae species and geographical origin TableMethods 2. Summary MIC data and susceptibility for all Enterobacteriaceae (n = 4,462) Table 5. Summary MIC data for eravacycline against individualResults species of • Against a total of 4,462 broad-spectrum activity available in intravenous and oral formulations for the Number of isolates from country: treatment of multidrug-resistant (MDR) infections, including MDR Gram-negative Percentage MIC (µg/ml) Enterobacteriaceae from Europe and the USA Enterobacteriaceae clinical isolates, Organism Grand Total CLSI Breakpoints [S|I|R] bacteria. Eravacycline has completed enrollment in Phase 3 studies for the AT BE CZ DK FR DE EL HU IE IT LV NL PL PT RO RU RS ES SE CH TR UK AllEUR USA Antibiotic (µg/ml) SIRMIC MIC Min Max eravacycline exhibited the lowest MIC90 treatment of complicated intra-abdominal infections (cIAI) and complicated 50 90 Europe USA Citrobacter freundii 2 23 2192 2 32137286 urinary tract infections (cUTI).The current study assessed the activity of Aztreonam <=4 | 8 | >=16 84.7 1.3 14.1 <= 0.5 > 16 <= 0.5 > 16 Organism of 2 µg/ml (equal to cefepime and NMIC 50 MIC 90 NMIC 50 MIC 90 eravacycline against 4,462 Enterobacteriaceae collected worldwide. Citrobacter koseri 193 322 3 3269218 Cefepime <=8 | 16 | >=32 94.8 1.5 3.7 <= 0.25 2 <= 0.25 > 16 ). Methods: A total of 4,462 Enterobacteriaceae clinical isolates (collected from Citrobacter freundii 149 0.25 0.5 137 0.25 0.5 aerogenes 15 215 2 15 2 15151596349 499 2013-2014) were tested. MICs were determined by CLSI broth microdilution. Ceftazidime <=4 | 8 | >=16 85.3 1.1 13.5 <= 0.5 > 16 <= 0.5 > 16 Citrobacter koseri 149 0.25 0.25 69 0.25 0.25 • Eravacycline had a lower MIC Quality control testing was performed on each day of testing as specified by the Enterobacter asburiae 3 3 Ceftriaxone <=1 | 2 | >=4 80.3 2.0 17.7 <= 0.5 32 <= 0.5 > 32 CLSI. Susceptibility was assessed using CLSI breakpoints except for tigecycline Enterobacter aerogenes 150 0.5 0.5 349 0.5 1 distribution than or Enterobacter cloacae 151515 15 15 1415 15 1514 148 347 495 No Breakpoints Defined - - - 1 > 4 <= 0.12 > 4 where FDA breakpoints were used. Results Enterobacter cloacae 148 0.5 1 347 0.5 1 tigecycline, with 64% of isolates having Results: Results are shown in the following Table: 15 1615 15 15 1 1615 15 15 15 153 349 502 Eravacycline No Breakpoints Defined - - - 0.5 2 0.06 16 Escherichia coli 153 0.12 0.25 349 0.12 0.25 an eravacycline MIC ≥2-fold lower than MIC (µg/ml) <=4 | 8 | >=16 91.5 1.0 7.5 0.5 4 <= 0.25 > 8 %S* %I %R 151515 15 15 1515 15 1515 150 347 497 MIC MIC 50 90 Imipenem <=1 | 2 | >=4 72.0 16.8 11.3 0.5 4 <= 0.25 > 8 Klebsiella oxytoca 150 0.25 0.25 347 0.25 0.5 tigecycline. Eravacycline 0.5 2 - - - 151515 15 14 1514 14 1515 35 497 Tetracycline 2 > 8 59.8 6.6 33.6 <=2 | 4 | >=8 86.8 1.9 11.3 <= 0.25 > 4 <= 0.25 > 4 Klebsiella pneumoniae 147 0.5 1 350 0.5 1 Morganella morganii 15 15211 15 19 1 25 1 95 67 216 • Eravacycline activity was similar against Tigecycline 0.5 2 91.1 7.3 1.6 Pip/Taz <=16/4 | 32/4-64/4 | >=128/4 87.4 9.0 3.6 2 32 <= 0.5 > 64 Morganella morganii 149 1 2 67 2 4 Aztreonam ≤ 0.5 > 16 84.7 1.3 14.1 15 151515 15 1515 15 1515 150 258 408 isolates from the USA and Europe. Cefepime ≤ 0.25 2 94.8 1.5 3.7 Tetracycline <=4 | 8 | >=16 59.8 6.6 33.6 2 > 8 <= 0.25 > 8 Proteus mirabilis 150 2 2 258 1 2 Ceftazidime ≤ 0.5 > 16 85.3 1.1 13.5 Proteus vulgaris 119 152 1 15151 215 776 209 Tigecycline <=2 | 4 | >=8 * 91.1 7.3 1.6 0.5 2 <= 0.015 32 Proteus vulgaris 149 1 1 60 1 1 • Data from the recently completed Phase Ceftriaxone ≤ 0.5 32 80.3 2.0 17.7 Providencia rettgeri 21114731 11 3414 31 3813 51 Colistin 1 >4 - - - *, FDA breakpoints were used for tigecycline; S, I, R, percent of isolates susceptible, intermediate or resistant, respectively; Providencia rettgeri 38 2 2 13 2 2 3 trials will be used in determining the Gentamicin 0.5 4 91.5 1.0 7.5 Providencia stuartii 327 429318 2 11338 5727 84 Pip/Taz, piperacillin/tazobactam Providencia stuartii 57 1 4 27 1 4 clinical breakpoints. Imipenem 0.5 4 72.0 16.8 11.3 Levofloxacin ≤ 0.25 > 4 86.8 1.9 11.3 Serratia marcescens 15 1515 15 15 1515 15 15 15 150 347 497 Serratia marcescens 150 1 2 347 1 2 Table 3. Summary MIC data and susceptibility for Enterobacteriaceae from the • Eravacycline exhibited excellent activity Piperacillin/tazobactam 2 32 87.4 9.0 3.6 Total 15 28 82 1 187 215 97 39 1 184 1 41 77 110 92 116 3 212 18 16 100 104 1739 2723 4462 *%S, I, R; percent susceptible, intermediate or resistant USA (n = 2,723) against the majority of isolates and AT, Austria; BE, Belgium; CZ, Czech Republic; DK, Denmark; FR, France; DE, Germany; EL, Greece; HU, Hungary; IE, Republic of Ireland; IT, Italy; LV, Latvia; NL, Netherlands; Conclusions: Against a total of 4,462 Enterobacteriaceae clinical isolates, CLSI Breakpoints [S|I|R] Percentage MIC (µg/ml) PL, Poland; PT, Portugal; RO, Romania; RU, Russia; RS, Republic of Serbia; ES, Spain; SE, Sweden; CH, Switzerland; TR, Turkey; UK, United Kingdom. Antibiotic shows promise for the treatment of (µg/ml) SIRMIC MIC Min Max eravacycline exhibited the lowest MIC90 of 2 µg/ml (equal to cefepime and 50 90 Figure 3: Comparison between tigecycline MIC and eravacycline MIC (all isolates) tigecycline). Eravacycline exhibited excellent activity against the majority of infections caused by Aztreonam <=4 | 8 | >=16 81.9 1.6 16.5 <= 0.5 > 16 <= 0.5 > 16 isolates and shows promise for the treatment of infections caused by Figure 1. Cumulative percentage MIC distribution for eravacycline, tetracycline and tigecycline against 60% Enterobacteriaceae. Enterobacteriaceae. Data from the recently completed Phase 3 trials will be Enterobacteriaceae from the USA (n=2,723) Cefepime <=8 | 16 | >=32 91.8 2.0 6.2 <= 0.25 4 <= 0.25 > 16 56% used in determining the clinical breakpoints. Ceftazidime <=4 | 8 | >=16 82.4 1.3 16.4 <= 0.5 > 16 <= 0.5 > 16 50% 100 Ceftriaxone <=1 | 2 | >=4 76.5 2.1 21.4 <= 0.5 > 32 <= 0.5 > 32 e Colistin No Breakpoints Defined - - - 1 > 4 <= 0.12 > 4 v References i s Introduction t 80 e

a 40%

Eravacycline No Breakpoints Defined - - - 0.5 2 0.06 16 t l 35% a u Eravacycline is a novel, fully synthetic fluorocycline antibiotic with l 1. CLSI, 2015. Methods for Dilution Antimicrobial

Gentamicin <=4 | 8 | >=16 89.2 0.9 9.9 1 8 <= 0.25 > 8 o m

60 s broad-spectrum activity available in intravenous and oral formulations i Susceptibility Tests for Bacteria That Grow u

f 30%

C Imipenem <=1 | 2 | >=4 63.5 20.2 16.3 1 4 <= 0.25 > 8 o for the treatment of multidrug-resistant (MDR) infections, including Eravacycline Aerobically; Approved Standard-Eighth Edition t 40 e n those caused by MDR Gram-negative bacteria. Eravacycline was Levofloxacin*, FDA breakpoints were used <=2 | for 4 | >=8 tigecycline; S, I,86.6 R, percent 2.1 of isolates 11.3 susceptible, <= 0.25 intermediate > 4 <= or 0.25 resistant, > 4 g M07-A10. Clinical and Laboratory Standards e Tetracycline a t c 20%

investigated in Phase 3 studies for the treatment of complicated intra- respectively; Pip/Taz, piperacillin/tazobactam n r 20 Pip/Taz <=16/4 | 32/4-64/4 | >=128/4 86.5 8.8 4.7 2 32 <= 0.5 > 64 Institute (CLSI), Wayne, PA 19087-1898 USA. e e abdominal infections (cIAI) and complicated urinary tract infections Tigecycline c P Tetracycline <=4 | 8 | >=16 57.1 7.8 35.1 4 > 8 0.5 > 8 r 0 e 2. CLSI, 2015. Performance Standards for (cUTI). p 7% Tigecycline <=2 | 4 | >=8 * 89.5 8.9 1.6 1 4 <= 0.015 32 10% Antimicrobial Susceptibility Testing; Informational 2% Supplement-Twenty-Second Edition M100-S25. The current study assessed the activity of eravacycline against a large *, FDA breakpoints were used for tigecycline; S, I, R, percent of isolates susceptible, intermediate or resistant, respectively; 0% 0% Clinical and Laboratory Standards Institute (CLSI), collection of recent clinical isolates of Enterobacteriaceae from both the MIC (µg/ml) Pip/Taz, piperacillin/tazobactam USA and Europe. ≤0.5 1 2 4 8 Wayne, PA 19087-1898 USA. Tigecycline MIC/Eravacycline MIC 3. http://www.accessdata.fda.gov/drugsatfda_docs/la Figure 2. Cumulative percentage MIC distribution for eravacycline, tetracycline and tigecycline against Table 4. Summary MIC data and susceptibility for Enterobacteriaceae from Europe bel/2010/021821s021lbl.pdf Enterobacteriaceae from Europe (n=1,739) (n = 1,739)

CLSI Breakpoints [S|I|R] Percentage MIC (µg/ml) Methods Antibiotic 100 (µg/ml)

e SIRMIC MIC Min Max A total of 4,462 Enterobacteriaceae clinical isolates (collected from 50 90 • A breakdown of the 4,462 Enterobacteriaceae collected by country of origin is v i 2013-2014) were tested. The majority were from body fluid sources t 80 86.5 1.1 12.5 <= 0.5 > 16 <= 0.5 > 16 shown in Table 1. a Aztreonam <=4 | 8 | >=16 Acknowledgment l

(n = 1277, 27.6% of total), genito-urinary sources (n = 1113, 24%), u Cefepime <=8 | 16 | >=32 96.7 1.1 2.2 <= 0.25 1 <= 0.25 > 16 • Summary susceptibility and MIC data for eravacycline and comparators gastro-intestinal sources (n = 1,094, 23.7%), respiratory sources (n = m 60

u against all isolates combined and those from Europe and the USA are shown Ceftazidime <=4 | 8 | >=16 87.2 1.1 11.7 <= 0.5 > 16 <= 0.5 > 16 This study was supported by a grant from Tetraphase C 545, 11.8%) and skin (n = 359, 7.8%). The remainder were from in Tables 2 to 4. Pharmaceuticals. t 40 Eravacycline Ceftriaxone <=1 | 2 | >=4 82.7 1.9 15.4 <= 0.5 32 <= 0.5 > 32 other sources that included blood, bone, head/ear/nose/throat, lymph, n e Tetracycline - - - 1 >4 <=0.12 >4 • A comparison of the activity of eravacycline against specific members of the muscle and medical devices (catheters, tubes). c 20 Colistin No Breakpoints Defined r Enterobacteriaceae from Europe and the USA are shown in Table 5. e Tigecycline Eravacycline No Breakpoints Defined - - - 0.5 2 0.06 8 Minimum inhibitory concentration (MIC) endpoints were determined P 0 • Eravacycline, tigecycline and tetracycline MIC distributions for isolates from Gentamicin <=4 | 8 | >=16 93.0 1.0 6.0 0.5 2 <= 0.25 > 8 by broth microdilution according to CLSI guidelines (1). the USA and Europe are shown in Figures 1 and 2. Imipenem <=1 | 2 | >=4 77.3 14.6 8.1 0.5 2 <= 0.25 > 8 • A direct comparison of tigecycline versus eravacycline MIC is shown in Figure Quality control testing was performed each day of testing as specified Levofloxacin <=2 | 4 | >=8 87.0 1.8 11.3 <= 0.25 > 4 <= 0.25 > 4 MIC (µg/ml) 3. by the CLSI using Escherichia coli ATCC 25922 and ATCC 35218. Pip/Taz <=16/4 | 32/4-64/4 | >=128/4 88.0 9.1 2.9 2 32 <= 0.5 > 64 Printed by 61.6 5.9 32.6 2 > 8 <= 0.25 > 8 Antibiotic susceptibility was determined using CLSI 2015 breakpoints Tetracycline <=4 | 8 | >=16 (2), with the exception of tigecycline where FDA breakpoints were Tigecycline <=2 | 4 | >=8 * 92.2 6.3 1.5 0.5 2 0.03 16 used (3). *, FDA breakpoints were used for tigecycline; S, I, R, percent of isolates susceptible, intermediate or resistant, respectively; Pip/Taz, piperacillin/tazobactam