REVISED ABSTRACT Background: Omadacycline (OMC) is the first of a new class of tetracyclines, the aminomethylcyclines, and is being developed as a once-daily.

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REVISED ABSTRACT Background: Omadacycline (OMC) is the first of a new class of tetracyclines, the aminomethylcyclines, and is being developed as a once-daily oral and IV treatment for acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP). The objective of the present study was to evaluate the bactericidal activity of OMC compared with other antibacterial agents. Materials/methods: Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) were determined against 85 bacterial isolates following CLSI guidelines. A subset of isolates was further investigated with time-kill studies (TK), where bactericidal activity was defined as a 3-log reduction in viable count (99.9% kill) over 24 hours. Results: OMC showed low MICs against the test isolates, including antibiotic-resistant strains. MBC data indicated bactericidal activity against streptococci, M. catarrhalis, and H. influenzae but bacteriostatic activity against enterococci, S. aureus, and E. coli. TK studies generally confirmed the MBC data with omadacycline being rapidly bactericidal against H. influenzae and S. pneumoniae. Bactericidal activity was species and strain dependent, and time to achieve 99.9% killing for these isolates varied between 3.1 to 20.4 hours. Conclusion: Omadacycline demonstrated good activity against the pathogens tested with particularly strong bactericidal activity against H. influenzae, M. catarrhalis, and S. pneumoniae. The spectrum and rapidity of the bactericidal activity of omadacycline was comparable to tigecycline. The inhibitory and bactericidal activity of omadacycline was not affected by resistance to other antimicrobials. Table 1: Isolates Tested PEN-S, penicillin susceptible; PEN-R, penicillin resistant; ESBL, extended spectrum beta-lactamase; MSSA, methicillin susceptible S. aureus; CA-MRSA, community-acquired methicillin resistant S. aureus Omadacycline was bactericidal against S. pneumoniae, H. influenzae, and M. catarrhalis and bacteriostatic against enterococci, S. aureus, and most E. coli isolates. The extent and rapidity of the bactericidal activity of omadacycline was comparable to tigecycline and doxycycline. The inhibitory and bactericidal activity of omadacycline was not affected by other phenotypes of resistance included in this study. References and Acknowledgment 1.CLSI, Performance Standards for Antimicrobial Susceptibility Testing; Informational Supplement-Twenty-Second Edition M100-S25. Clinical and Laboratory Standards Institute (CLSI), Wayne, PA USA 2.CLSI, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved standard- Tenth Edition; M07-A10. Clinical and Laboratory Standards Institute (CLSI), Wayne, PA USA 3.CLSI, Methods for Determining Bactericidal Activity of Antimicrobial Agents; Approved Guideline. M26-A. Vol 19 No.18. Clinical and Laboratory Standards Institute (CLSI), Wayne, PA This study was supported by a grant from Paratek Pharmaceuticals Bactericidal activity of omadacycline, a novel aminomethylcycline Stephen Hawser 1*, Coralie Siegmund 1, Pauline Jeandey 1, Eric Genet 1, Sophie Magnet 1, Ian Morrissey 1, Ken Tanaka 2 1 IHMA Europe Sàrl, 9A Route de la Corniche, 1066 Epalinges, Switzerland; 2 Paratek Pharmaceuticals, 75 Park Plaza, 4 th Floor, Boston MA 02116, USA P1322 CONCLUSION INTRODUCTION Paratek Pharmaceuticals is developing the aminomethylcycline antibiotic omadacycline (OMC), as a once-daily oral and IV therapy for serious community-acquired infections. Omadacycline is currently in Phase 3 clinical development for acute bacterial skin and skin structure infections (ABSSSI) and for moderate to severe community-acquired bacterial pneumonia (CABP). In this study we investigated the bactericidal activity of omadacycline in vitro against bacterial pathogens involved in CABP and ABSSSI, including resistant isolates.  Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and time-kill kinetics (TKK) were performed in line with CLSI susceptibility testing standards methodology (1, 2, 3).  MICs were determined against 85 isolates (see Table 1) by broth microdilution methodology (final volume 100 µL).  For MBCs the number of colony forming unit (CFU) was determined in each well of the MIC microtiter plate containing antibiotic concentration greater or equal to the MIC.  Prior to performing TKK, MICs were determined using macrobroth dilution methodology in line with CLSI standards (1, 2). The test volume was 10 ml with shaking (200 rpm) to emulate the conditions used in the time-kill experiments.  TKK were performed in presence of antibiotic concentration equal to 4x and 16x MIC by determination of CFU of samples taken at time 0, 2, 4, 6 and 24 hours.  Bactericidal activity was defined by at least 99.9% of killing, i.e ≥3 log reduction of the initial inoculum. METHODS SpeciesPhenotype Isolates tested for MIC and MBC Isolates tested for TKK E. coli ESBL-negative61 ESBL-positive71 M. catarrhalis- 102 H. influenzae -112 S. aureus MSSA71 CA-MRSA71 S. pyogenes 122 S. pneumoniae PEN-S61 PEN-R51 E. faecalis -70 E. faecium -70 Total 8512 The quality control organisms E. coli ATCC 25922, H. influenzae ATCC 49247, S. aureus ATCC 29213, S. pneumoniae ATCC 49619, and E. faecalis ATCC were also tested.  Omadacycline showed very good inhibitory activity against the majority of pathogens tested. The most potent activity was against M. catarrhalis, S. aureus, S. pneumoniae, S. pyogenes, and enterococci with MIC 90 range of mg/L (Table 2).  MBC data showed bactericidal activity of omadacycline against M. catarrhalis, H. influenzae, S. pneumoniae, and S. pyogenes (Table 3).  Omadacycline displayed a rapid bactericidal activity against H. influenzae and S. pneumoniae in TKK experiments at concentrations equal to 4x MIC, although the rapidity of killing was isolate dependent (Tables 3-4, Figures 1- 4) and a slow bactericidal activity against M. catarrhalis at concentration equal to 16x MIC (Tables 3 -4, Figure 5 - 6).  Omadacycline did not display bactericidal activity against S. pyogenes in time-kill experiments contradictory to MBC data (Table 2-3). This discrepancy could be due to the difference in methodology between MBC and TKK.  Omadacycline was bacteriostatic against enterococci, S. aureus, and most E.coli isolates (Tables 3 - 4). RESULTS Table 2. Summary of MIC data for omadacycline and comparators against 85 isolates. MIC 50 /MIC 90 (mg/L) Species (number of isolates)OMCTIGDOXTSXAZILZD S. pneumoniae (n=11)0.03/ / /42/80.12/>320.5/2 S. pyogenes (n=12)0.06/ / /0.061/1 M. catarrhalis (n=10)0.12/ / / /0.03NT H. influenzae (n=11)1/10.25/0.50.5/12/81/2NT E. coli (n=13)2/40.25/0.58/6464/>64NT Enterococci (n=14)0.12/ /0.128/1632/64>32/>321/2 S. aureus (n=14)0.25/ /0.12≤0.03/0.121/>322/2 Table 3. Summary of MBC data for omadacycline and comparators against 85 isolates. MBC 50 /MBC 90 (mg/L) Species (number of isolates)OMCTIGDOXTSXAZILZD S. pneumoniae (n=11)0.06/ / /162/162/>322/8 S. pyogenes (n=12)0.25/20.12/12/80.12/10.25/14/16 M. catarrhalis (n=10)2/81/41/160.5/20.03/0.064/16 H. influenzae (n=11)4/162/1632/648/32 NT E. coli (n=13)>16/>16 64/>64>64/>64NT Enterococci (n=14)>16/>16 >64/>64 >32/>32NT S. aureus (n=14)16/>162/>1616/320.06/8>32/>3264/128 Table 4. Summary of time-kill data for omadacycline and comparators against 12 isolates. OMC, omadacycline; DOX, doxycycline; TIG, tigecycline; TSX, trimethoprim-sulfamethoxazole; LZD, linezolid; AZI, azithromycin; NT, not tested; a --Not Achieved; PEN-S, penicillin susceptible; PEN-R, penicillin resistant; ESBL, extended spectrum beta-lactamase; MSSA, Methicillin susceptible S. aureus; CA-MRSA, community-acquired methicillin resistant S. aureus. Time to kill 99.9% (3 log) 4xMIC/16xMIC (h) Isolate (resistance phenotype)OMCTIG DOXTSXAZI LZD S. pneumoniae (PEN-S) 3.7/3.11.9/ /5.424/21.221/3.88.3/3.7 S. pneumoniae (PEN-R) 21.5/ /1222/ /21.921/19.422/21 S. pyogenes /-- a S. pyogenes /-- a M. catarrhalis /-- a -- a /5.7NT/NT M. catarrhalis a / a / a /22.6--/-- a 20.7/19.2NT/NT H. influenzae / / / /-- a 7.8/3.4NT/NT H. influenzae /3.32.6/1.43.4/3.312/131.4/1.4NT/NT E. coli (ESBL-) 5.9/3.1--/-- a 1.6/1.6NT/NT E. coli (ESBL+) --/-- a 20.9/20.8--/-- a NT/NT S. aureus (MSSA) --/-- a 18/17.5--/-- a S. aureus (CA-MRSA) --/-- a 15.1/13--/-- a OMC, omadacycline; DOX, doxycycline; TIG, tigecycline; TSX, trimethoprim-sulfamethoxazole; LZD, linezolid; AZI, azithromycin; NT, not tested. Figure 1. Time-kill of omadacycline and comparators against S. pneumoniae OMC, omadacycline; DOX, doxycycline; TIG, tigecycline; TSX, trimethoprim-sulfamethoxazole; LZD, linezolid; AZI, azithromycin. Figure 2. Time-kill of omadacycline and comparators against S. pneumoniae OMC, omadacycline; DOX, doxycycline; TIG, tigecycline; TSX, trimethoprim-sulfamethoxazole; LZD, linezolid; AZI, azithromycin. Figure 3. Time-kill of omadacycline and comparators against H. influenzae OMC, omadacycline; DOX, doxycycline; TIG, tigecycline; TSX, trimethoprim-sulfamethoxazole; LZD, linezolid; AZI, azithromycin. Figure 4. Time-kill of omadacycline and comparators against H. influenzae OMC, omadacycline; DOX, doxycycline; TIG, tigecycline; TSX, trimethoprim-sulfamethoxazole; LZD, linezolid; AZI, azithromycin. Figure 5. Time-kill of omadacycline and comparators against M. catarrhalis OMC, omadacycline; DOX, doxycycline; TIG, tigecycline; TSX, trimethoprim-sulfamethoxazole; LZD, linezolid; AZI, azithromycin. Figure 6. Time-kill of omadacycline and comparators against M. catarrhalis OMC, omadacycline; DOX, doxycycline; TIG, tigecycline; TSX, trimethoprim-sulfamethoxazole; LZD, linezolid; AZI, azithromycin.