Methods Revised Abstract Methods Results TP-271 is a Potent, Broad-Spectrum Fluorocycline with...
1
Methods Revised Abstract Methods Results TP-271 is a Potent, Broad-Spectrum Fluorocycline with Activity Against Community-Acquired Bacterial Respiratory and Biothreat P T. GROSSMAN 1 , C.FYFE 1 , W. O’BRIEN 1 , M. HACKEL 2 , J. SUTCLIFFE 1 1 Tetraphase Pharmaceuticals, Inc., Watertown, MA, 2 International Health Management Associates, Inc. 52 nd Annual ICAAC 9 - 12 September, 2012 San Francisco, CA Conclusions Poster F-1525 Background: TP-271 is a novel, fully synthetic fluorocycline antibiotic in preclinical development for IV/oral treatment of respiratory infections caused by susceptible and multidrug-resistant (MDR) public health and biothreat pathogens. Method: In vitro susceptibility testing against recent isolates was done according to CLSI guidelines. Tetracycline-specific resistance and ESβL genes were detected by PCR. Results: TP-271 was potent against Streptococcus spp., Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis isolates and Gram-positive pathogens vancomycin-resistant Enterococcus faecium and Enterococcus faecalis (see Tables). The MIC 50/90 values of TP-271 against ESβL + Escherichia coli (n=34) and Klebsiella pneumoniae (n=48) were 1/ 2, and 1/ 4 g/ml, respectively. Against other Enterobacteriaceae, the MIC 50 and MIC 90 values of TP-271 were 0.25 – 4 and 1-8 µg/ml, respectively. The MIC 50/90 values against Acinetobacter baumannii (n=54), Acinetobacter lwoffi (n=29), and Stenotrophomonas maltophiliia (n=35) were 0.13/1, 0.063/0.5, 0.25/2 µg/ml, respectively. The MIC 50/90 values against biothreat pathogens Yersinia pestis (n=30), Bacillus anthracis (n=30), Francisella tularensis (n=27), Burkholderia mallei (n=30) and Burkholderia pseudomallei (n=30) were 0.12/0.25, ≤0.008/≤0.008, 0.25/0.5, 0.06/0.12, and 1/4 µg/ml, respectively. Conclusions: TP-271 is active against community-acquired respiratory and biothreat pathogens, and problematic multidrug-resistant (MDR) pathogens. Susceptibility testing. All minimal inhibitory concentration (MIC) assays were performed as per CLSI guidelines [1]. Testing of public health pathogens was performed at Tetraphase Pharmaceuticals, Inc. and International Health Management Associates (IHMA) using recent clinical isolates obtained from Eurofins Medinet and IHMA. Testing of biothreat agents was performed at United States Army Medical Research Institute for Infectious Diseases (USAMRIID). Genotypic characterization of ESβL-producing isolates was done by standard PCR methodology and sequence confirmation. 1 Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Nineth Edition. CLSI document M07-A9.. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2012. Results • TP-271, a novel fully synthetic tetracycline, exhibits excellent potency against key MDR public health respiratory pathogens, including S. pneumoniae, MRSA, S. pyogenes, H. influenzae and M. catarrhalis. • pestis, B. anthracis, F. tularensis, B. mallei, and B. pseudomallei, supporting its potential for the treatment of biothreat infections. • The broad spectrum potency of TP-271 is demonstrated by good activity against difficult-to-treat MDR Gram-negatives and Gram-positive pathogens including VRE. TP-271 Table 2. Determination of MIC 50 and MIC 90 values for Gram-positive & respiratory pathogens Table 1. Determination of MIC 50 and MIC 90 values for biothreat pathogens Contact: Leland Webster Tetraphase Pharmaceuticals [email protected] Table 3. Determination of MIC 50 and MIC 90 values for Gram-negative pathogens Organism MIC 50 /MIC 90 (µg/ml) (range) N TP-271 Tetracycl ine Tigecyclin e Macrolide a Fluoroquinolo ne b Linezolid Vancomycin Streptococcus pneumoniae 137 ≤0.016/ ≤0.016 1/>32 c ≤0.016/ ≤0.016 4/>32 1/1 1/1 c 0.25/0.5 c ≤0.016- ≤0.016 ≤0.016- >32 ≤0.016- ≤0.016 ≤0.016->32 0.25-32 0.13-2 ≤0.016-0.5 S. pneumoniae penicillin-R d 58 ≤0.016/ ≤0.016 32/>32 ≤0.016/ ≤0.016 >32/>32 1/1 1/1 0.25/0.5 ≤0.016- ≤0.016 0.031->32 ≤0.016- ≤0.016 ≤0.016->32 0.5-1 0.5-2 0.25-0.5 S. pneumoniae macrolide-R 58 ≤0.016/ ≤0.016 32/>32 ≤0.016/ ≤0.016 >32/>32 1/1 1/1 0.25/0.5 ≤0.016- ≤0.016 0.13->32 ≤0.016- ≤0.016 1->32 0.25-32 0.25-2 0.13-0.5 Streptococcus pyogenes 64 ≤0.016/ ≤0.016 0.25/>32 ≤0.016/ ≤0.016 0.063/4 0.5/1 1/2 0.5/0.5 ≤0.016- ≤0.016 0.13->32 ≤0.016- 0.063 ≤0.016->32 0.25-2 0.5-2 0.25-0.5 Streptococcus agalactiae 30 ≤0.031/0.063 32/32 0.031/0.03 1 ≤0.13/>4 1/1 1/2 ≤0.5/≤0.5 ≤0.031-0.063 ≤2->32 ≤0.016- 0.063 ≤0.13->4 0.5-2 1-2 ≤0.5-≤0.5 Streptococcus anginosus 73 ≤0.031/ ≤0.031 16/32 ≤0.016/0.0 31 ≤0.12/>4 m 0.5/1 1/2 ≤0.5/1 ≤0.03-0.063 ≤2->32 ≤0.016- 0.25 ≤0.12->4 ≤0.12-1 ≤0.25-2 ≤0.5-1 Staphylococcus aureus 155 0.06/0.25 ≤2/32 0.12/0.25 >4/>4 >4/>4 2/4 1/1 ≤0.03-1 0.063->32 ≤0.016-0.5 0.25->4 ≤0.13->4 0.5-64 ≤0.5-8 S. aureus (MRSA) 124 0.063/0.13 ≤2-32 0.13/0.25 >4/>4 >4/>4 2/4 1/1 ≤0.016-1 0.063->32 ≤0.016-0.5 0.25->4 ≤0.13->4 1-64 ≤0.5-8 S. aureus (MRSA) PVL+ 25 0.063/0.12 ≤2/≤2 0.12/0.12 >4/>4 2/>4 2/2 1/1 0.063-0.12 ≤2-16 0.063-0.25 1->4 ≤0.13->4 1-4 ≤0.5-1 S. aureus (MSSA) 31 0.12/0.25 ≤2/≤2 0.12/0.25 1/>4 0.25/0.5 2/4 1/1 ≤0.031-0.25 ≤2-32 0.03-0.25 0.5->4 ≤0.13->4 0.5-4 ≤0.5-1 Staphylococcus epidermidis 62 0.063/0.5 ≤2/>32 0.25/0.5 >4/>4 0.25/>4 2/2 2/2 ≤0.03-1 ≤2->32 0.06-1 ≤0.13->4 ≤0.13->4 1-4 ≤0.5-2 S. epidermidis methicillin-S 32 0.063/0.25 ≤2/32 0.12/0.25 0.5/>4 0.25/0.5 2/2 2/2 ≤0.03-0.5 ≤2->32 0.06-0.5 ≤0.13->4 ≤0.13->4 1-4 ≤0.5-2 S. epidermidis methicillin-R 30 0.25/0.5 ≤2/>32 0.5/0.5 >4/>4 >4/>4 2/2 2/2 0.06-1 ≤2->32 0.06-1 0.25->4 ≤0.13->4 1-2 1-2 Enterococcus faecalis 113 ≤0.031/0.063 >32/>32 0.12/0.25 >4/>4 g 2/>4 2/2 2/>16 ≤0.031-0.5 0.13->32 ≤0.016-1 0.5->4 1->4 ≤0.25-32 ≤0.5->16 E. faecalis (VRE) 37 ≤0.031/0.063 32/>32 0.12/0.25 >4/>4 h >4/>4 2/2 >16/>16 ≤0.03-0.25 ≤2->32 0.03-1 4->4 1->4 ≤0.25-4 >16->16 E. faecalis (VSE) 68 ≤0.031/0.063 >32/>32 0.12/0.25 >4/>4 i 2/>4 2/4 1/2 ≤0.03-0.5 0.13->32 ≤0.016-1 0.5->4 1->4 0.5-32 1-4 Enterococcus faecium 81 ≤0.031/ ≤0.031 ≤2/>32 0.06/0.25 ≤0.13/>4 j >4/>4 2/4 >16/>16 ≤0.031-0.063 ≤2->32 ≤0.03-1 4->4 0.25->4 0.5->4 ≤0.5->16 E. faecium ≤0.031/ 16/>32 0.06/0.25 >4/>4 k >4/>4 2/4 >16/>16 Results Organism N MIC 50 /MIC 90 (µg/ml) (range) TP-271 Doxycycline Ciprofloxaci n Yersinia pestis 30 0.12/0.25 0.5/1 0.03/0.06 0.015-0.5 0.06-2 0.015-0.06 Bacillus anthracis 30 ≤0.008/ ≤0.008 ≤0.008/≤0.008 0.12/0.25 ≤0.008- ≤0.008 ≤0.008-0.015 0.03-0.25 Francisella tularensis 27 0.25/0.5 0.12/0.25 0.06/0.5 0.03-2 0.015-1 0.015-8 TP-271 Doxycycline Azithromycin Burkholderia mallei 30 0.06/0.12 0.03/0.12 1/2 ≤0.008-1 ≤0.008-1 0.25-2 TP-271 Doxycycline Ceftazidime These studies were funded in part by NIAID Partnership Grant # 1R01AI093484 – 01 and NIAID Contract #: HHSN272201100028C awarded to CUBRC and Tetraphase Pharmaceuticals Organism MIC 50 /MIC 90 (g/ml) (range) N TP-271 Tetracycl ine Tigecycli ne Carbapene m a Fluoroquinolo ne b 3rd Gen Ceph c Pipericili n/ Tazobactam Aminoglycosi de d Klebsiella pneumoniae ESBL 48 1/4 8/>32 0.5/1 0.13/>32 32/>32 >32/>32 >128/>128 16/>32 0.25-32 1->32 0.25-16 0.031- >32 0.031->32 2->32 0.5->128 0.5->32 Klebsiella oxytoca 41 0.25/2 ≤4/>32 0.5/1 ≤1/≤1 ≤0.25/>4 ≤2/>32 2/64 ≤2/>32 0.031-8 ≤4->32 0.063-4 ≤1-1 ≤0.25->4 ≤2->32 ≤1->64 ≤2->32 Klebsiella oxytoca ESBL 11 0.5/2 >32/>32 0.25/0.5 0.063/0. 25 0.5/>32 >32/>32 8/>32 >32/>32 0.031-8 0.5->32 0.063-1 0.031-1 0.031->32 4->32 0.5->32 0.5->32 Escherichia coli ESBL 34 1/2 >32/>32 0.13/0.5 0.031/0. 13 16/>32 >32/>32 8/>128 4/>32 0.031-4 2->32 0.063-1 ≤0.016-1 0.031->32 0.5->32 1->128 1->32 Enterobacter cloacae 44 1/4 ≤4/>32 1/2 ≤1/>8 ≤0.25/>4 ≤2/>32 8/>64 ≤2/>16 0.25-16 ≤4->32 0.25-8 ≤1->8 ≤0.25->4 ≤2->32 ≤1->64 ≤2->16 Enterobacter spp. AmpC + 15 1/8 8/>32 1/4 >8/>8 >4/>4 >32/>32 >64/>64 16/>16 0.25-16 ≤4 - >32 0.5-4 2->8 ≤0.25 - >4 >32->32 16->64 ≤2 - >16 Enterobacter aerogenes 30 0.5/1 ≤4/16 0.5/2 ≤1/≤1 ≤0.25/1 ≤2/>32 4/>64 ≤2/≤2 0.25-4 ≤4->32 0.25-2 ≤1-≤1 ≤0.25->4 ≤2->32 2->64 ≤2-8 Citrobacter freundii 30 0.25/1 ≤4/≤4 0.5/1 ≤1/≤1 ≤0.25/2 2/>32 2/>64 ≤2/≤2 0.12-2 ≤4->32 0.25-2 ≤1-8 ≤0.25-4 ≤2->32 ≤1->64 ≤2->16 Proteus mirabilis 20 4/8 >32/>32 4/8 8/8 0.13/32 0.031/0.03 1 0.5/1 2/8 2-8 32->32 2-8 4-16 0.063-32 ≤0.016- 0.13 0.25-2 0.5->32 Proteus vulgaris 30 2/4 8/32 2/4 ≤1/≤1 ≤0.25/≤0.25 ≤2/>32 ≤1/≤1 ≤2/≤2 0.25-4 ≤4->32 0.5-4 ≤1-≤1 ≤0.25-4 ≤2->32 ≤1->64 ≤2->16 Serratia marcescens 30 2/2 32/>32 1/2 ≤1/≤1 ≤0.25/0.5 ≤2/≤2 2/16 ≤2/≤2 0.5-8 ≤4->32 0.5-4 ≤1-≤1 ≤0.25-2 ≤2->32 ≤1->64 ≤2->16 Salmonella spp. 35 0.5/2 ≤4/>32 0.5/2 ≤1/≤1 ≤0.25/0.5 ≤2/2 2/16 ≤2/≤2 0.12-16 ≤4->32 0.12-2 ≤1-≤1 ≤0.25->4 ≤2->32 ≤1-64 ≤2->16 Shigella spp. 18 0.13/0.5 ≤4/>32 0.5/1 ≤1/≤1 ≤0.25/≤0.25 ≤2/≤2 2/8 ≤2/≤2 ≤0.031-2 ≤4->32 0.12-2 ≤1-≤1 ≤0.25->4 ≤2->32 ≤1->64 ≤2->16 Morganella morganii 30 4/8 32/>32 2/8 ≤1/≤1 ≤0.25/>4 4/16 ≤1/32 ≤2/>16 1-16 ≤4->32 1-8 ≤1-2 ≤0.25->4 ≤2->32 ≤1->64 ≤2->16 Providencia stuartii 30 4/8 >32/>32 4/8 ≤1/≤1 4/>4 ≤2/>16 4/64 4/>16 0.13->16 ≤4>32 0.13-16 ≤1-≤1 ≤0.25->4 ≤2->16 ≤1-64 ≤2->16 Pseudomonas aerguinosa 35 32/>32 >32/>32 16/32 1/32 2/>32 8/>32 16/>128 8/>32 4->32 32->32 1->32 0.5-32 0.25->32 1->32 2->128 0.5->32 Acinetobacter baumannii 54 0.13/1 16/>32 0.5/4 4/>32 8/32 N/D e N/D 32/>32 ≤0.016-2 0.25->32 ≤0.016-8 0.13->32 0.063->32 1->32 Acinetobacter lwoffii 30 0.063/0.1 2 ≤4/≤4 0.25/1 ≤1/≤1 ≤0.25/≤0.25 8/>16 ≤1/16 ≤2/≤2 ≤0.031- 0.5 ≤4-16 ≤0.031-2 ≤1->8 ≤0.25-4 ≤2->16 ≤1->64 ≤2->16 Stenotrophomonas maltophilia 35 0.25/2 16/32 0.5/4 >32/>32 1/16 >32/>32 64/>128 >32/>32 ≤0.016-32 0.5->32 0.031-4 2->32 0.13-32 8->32 8->128 1->32 a imipenem or meropenem; b levofloxacin or ciprofloxacin; c ceftriaxone, cefotaxime or ceftazidime; d gentamicin or tobramycin; e not done OH O HO O N H H OH NH 2 O O H F N H O N H 3 C H
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Transcript of Methods Revised Abstract Methods Results TP-271 is a Potent, Broad-Spectrum Fluorocycline with...
MethodsRevised Abstract
Methods
Results
TP-271 is a Potent, Broad-Spectrum Fluorocycline with Activity Against Community-Acquired Bacterial Respiratory and Biothreat Pathogens
T. GROSSMAN1, C.FYFE1, W. O’BRIEN1, M. HACKEL2, J. SUTCLIFFE1 1Tetraphase Pharmaceuticals, Inc., Watertown, MA, 2 International Health Management Associates, Inc.
52nd Annual ICAAC9 - 12 September, 2012
San Francisco, CA
Conclusions
Poster F-1525
Background: TP-271 is a novel, fully synthetic fluorocycline antibiotic in preclinical development for IV/oral treatment of respiratory infections caused by susceptible and multidrug-resistant (MDR) public health and biothreat pathogens. Method: In vitro susceptibility testing against recent isolates was done according to CLSI guidelines. Tetracycline-specific resistance and ESβL genes were detected by PCR.
Results: TP-271 was potent against Streptococcus spp., Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis isolates and Gram-positive pathogens vancomycin-resistant Enterococcus faecium and Enterococcus faecalis (see Tables). The MIC50/90 values of TP-271 against ESβL+ Escherichia coli (n=34) and Klebsiella pneumoniae (n=48) were 1/ 2, and 1/ 4 g/ml, respectively. Against other Enterobacteriaceae, the MIC50 and MIC90 values of TP-271 were 0.25 – 4 and 1-8 µg/ml, respectively. The MIC50/90 values against Acinetobacter baumannii (n=54), Acinetobacter lwoffi (n=29), and Stenotrophomonas maltophiliia (n=35) were 0.13/1, 0.063/0.5, 0.25/2 µg/ml, respectively. The MIC50/90 values against biothreat pathogens Yersinia pestis (n=30), Bacillus anthracis (n=30), Francisella tularensis (n=27), Burkholderia mallei (n=30) and Burkholderia pseudomallei (n=30) were 0.12/0.25, ≤0.008/≤0.008, 0.25/0.5, 0.06/0.12, and 1/4 µg/ml, respectively.
Conclusions: TP-271 is active against community-acquired respiratory and biothreat pathogens, and problematic multidrug-resistant (MDR) pathogens.
Susceptibility testing. All minimal inhibitory concentration (MIC) assays were performed as per CLSI guidelines [1]. Testing of public health pathogens was performed at Tetraphase Pharmaceuticals, Inc. and International Health Management Associates (IHMA) using recent clinical isolates obtained from Eurofins Medinet and IHMA. Testing of biothreat agents was performed at United States Army Medical Research Institute for Infectious Diseases (USAMRIID). Genotypic characterization of ESβL-producing isolates was done by standard PCR methodology and sequence confirmation.1Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Nineth Edition. CLSI document M07-A9.. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2012.
Results
• TP-271, a novel fully synthetic tetracycline, exhibits excellent potency against key MDR public health respiratory pathogens, including S. pneumoniae, MRSA, S. pyogenes, H. influenzae and M. catarrhalis.
• TP-271 also exhibits potent activity against five important biothreat agents: Y. pestis, B. anthracis, F. tularensis, B. mallei, and B. pseudomallei, supporting its potential for the treatment of biothreat infections.
• The broad spectrum potency of TP-271 is demonstrated by good activity against difficult-to-treat MDR Gram-negatives and Gram-positive pathogens including VRE.
OH O HO O
NHH
H3C CH3
OH
NH2
OO H
F
NH
O
NH3C
HTP-271
Table 2. Determination of MIC50 and MIC90 values for Gram-positive & respiratory pathogens
Table 1. Determination of MIC50 and MIC90 values for biothreat pathogens
Contact:Leland Webster
Tetraphase [email protected]
Table 3. Determination of MIC50 and MIC90 values for Gram-negative pathogens
Organism
MIC50/MIC90 (µg/ml)
(range)
N TP-271 Tetracycline Tigecycline Macrolidea Fluoroquinoloneb Linezolid Vancomycin
Streptococcus pneumoniae 137
≤0.016/≤0.016 1/>32c ≤0.016/≤0.016 4/>32 1/1 1/1c 0.25/0.5c
≤0.016-≤0.016 ≤0.016->32 ≤0.016-≤0.016 ≤0.016->32 0.25-32 0.13-2 ≤0.016-0.5S. pneumoniae penicillin-Rd 58
≤0.016/≤0.016 32/>32 ≤0.016/≤0.016 >32/>32 1/1 1/1 0.25/0.5≤0.016-≤0.016 0.031->32 ≤0.016-≤0.016 ≤0.016->32 0.5-1 0.5-2 0.25-0.5
S. pneumoniae macrolide-R 58
≤0.016/≤0.016 32/>32 ≤0.016/≤0.016 >32/>32 1/1 1/1 0.25/0.5≤0.016-≤0.016 0.13->32 ≤0.016-≤0.016 1->32 0.25-32 0.25-2 0.13-0.5
Streptococcus pyogenes 64
≤0.016/≤0.016 0.25/>32 ≤0.016/≤0.016 0.063/4 0.5/1 1/2 0.5/0.5≤0.016-≤0.016 0.13->32 ≤0.016-0.063 ≤0.016->32 0.25-2 0.5-2 0.25-0.5
Streptococcus agalactiae 30
≤0.031/0.063 32/32 0.031/0.031 ≤0.13/>4 1/1 1/2 ≤0.5/≤0.5≤0.031-0.063 ≤2->32 ≤0.016-0.063 ≤0.13->4 0.5-2 1-2 ≤0.5-≤0.5
Streptococcus anginosus 73
≤0.031/≤0.031 16/32 ≤0.016/0.031 ≤0.12/>4m 0.5/1 1/2 ≤0.5/1≤0.03-0.063 ≤2->32 ≤0.016-0.25 ≤0.12->4 ≤0.12-1 ≤0.25-2 ≤0.5-1
Staphylococcus aureus 155
0.06/0.25 ≤2/32 0.12/0.25 >4/>4 >4/>4 2/4 1/1≤0.03-1 0.063->32 ≤0.016-0.5 0.25->4 ≤0.13->4 0.5-64 ≤0.5-8
S. aureus (MRSA) 124
0.063/0.13 ≤2-32 0.13/0.25 >4/>4 >4/>4 2/4 1/1≤0.016-1 0.063->32 ≤0.016-0.5 0.25->4 ≤0.13->4 1-64 ≤0.5-8
S. aureus (MRSA) PVL+ 25
0.063/0.12 ≤2/≤2 0.12/0.12 >4/>4 2/>4 2/2 1/10.063-0.12 ≤2-16 0.063-0.25 1->4 ≤0.13->4 1-4 ≤0.5-1
S. aureus (MSSA) 31
0.12/0.25 ≤2/≤2 0.12/0.25 1/>4 0.25/0.5 2/4 1/1≤0.031-0.25 ≤2-32 0.03-0.25 0.5->4 ≤0.13->4 0.5-4 ≤0.5-1
Staphylococcus epidermidis 62
0.063/0.5 ≤2/>32 0.25/0.5 >4/>4 0.25/>4 2/2 2/2≤0.03-1 ≤2->32 0.06-1 ≤0.13->4 ≤0.13->4 1-4 ≤0.5-2
S. epidermidis methicillin-S 32
0.063/0.25 ≤2/32 0.12/0.25 0.5/>4 0.25/0.5 2/2 2/2≤0.03-0.5 ≤2->32 0.06-0.5 ≤0.13->4 ≤0.13->4 1-4 ≤0.5-2
S. epidermidis methicillin-R 30
0.25/0.5 ≤2/>32 0.5/0.5 >4/>4 >4/>4 2/2 2/20.06-1 ≤2->32 0.06-1 0.25->4 ≤0.13->4 1-2 1-2
Enterococcus faecalis 113
≤0.031/0.063 >32/>32 0.12/0.25 >4/>4g 2/>4 2/2 2/>16≤0.031-0.5 0.13->32 ≤0.016-1 0.5->4 1->4 ≤0.25-32 ≤0.5->16
E. faecalis (VRE) 37
≤0.031/0.063 32/>32 0.12/0.25 >4/>4h >4/>4 2/2 >16/>16≤0.03-0.25 ≤2->32 0.03-1 4->4 1->4 ≤0.25-4 >16->16
E. faecalis (VSE) 68
≤0.031/0.063 >32/>32 0.12/0.25 >4/>4i 2/>4 2/4 1/2≤0.03-0.5 0.13->32 ≤0.016-1 0.5->4 1->4 0.5-32 1-4
Enterococcus faecium 81
≤0.031/≤0.031 ≤2/>32 0.06/0.25 ≤0.13/>4j >4/>4 2/4 >16/>16≤0.031-0.063 ≤2->32 ≤0.03-1 4->4 0.25->4 0.5->4 ≤0.5->16
E. faecium (VRE) 45
≤0.031/≤0.031 16/>32 0.06/0.25 >4/>4k >4/>4 2/4 >16/>16≤0.031-0.031 ≤2->32 ≤0.03-0.5 0.25->4 >4->4 0.5->4 16->16
E. faecium (VSE) 36
≤0.031/≤0.031 ≤2/>32 0.06/0.25 >4/>4l >4/>4 2/4 0.5/1≤0.03-0.06 ≤2->32 ≤0.03-1 ≤0.13->4 0.25->4 1-4 0.5-4
Haemophilus influenzae 65
0.031/0.13 0.5/4 0.063/0.25 8/8 ≤0.016/0.031 8/16 >32/>32e
≤0.016-0.25 0.13-16 ≤0.016-0.5 0.063-16 ≤0.016-0.13 4-32 16->32Moraxella
catarrhalis 57≤0.016/≤0.016 0.5/32 ≤0.016/0.031 0.063/0.25 0.031/0.063 8/8 >32/>32f
≤0.016-0.031 0.13->32 ≤0.016-0.13 ≤0.016-4 0.031-0.13 2-32 16->32aerythromycin, azithromycin or clarithromycin; bciprofloxacin or levofloxacin; c126 S. pneumoniae isolates; dpenicillin MIC ≥2 µg/ml; e51 H. influenzae isolates; f 43 M. catarhalis isolates; g 74 E. faecalis isolates; h 30 E. faecalis isolates; i 36 E. faecalis isolates; j 67 E. faecalis isolates; k 32 E. faecium isolates; l 35 E. faecium isolates; m 51 S. anginosus isolates
Results
Organism NMIC50/MIC90 (µg/ml)
(range)TP-271 Doxycycline Ciprofloxacin
Yersinia pestis 30
0.12/0.25 0.5/1 0.03/0.060.015-0.5 0.06-2 0.015-0.06
Bacillus anthracis 30
≤0.008/≤0.008 ≤0.008/≤0.008 0.12/0.25≤0.008-≤0.008 ≤0.008-0.015 0.03-0.25
Francisella tularensis 27
0.25/0.5 0.12/0.25 0.06/0.50.03-2 0.015-1 0.015-8
TP-271 Doxycycline AzithromycinBurkholderia
mallei 300.06/0.12 0.03/0.12 1/2≤0.008-1 ≤0.008-1 0.25-2
TP-271 Doxycycline CeftazidimeBurkholderia pseudomallei 30
1/4 1/8 2/20.25-8 0.06-16 0.25-32
These studies were funded in part by NIAID Partnership Grant # 1R01AI093484 – 01 and
NIAID Contract #: HHSN272201100028C awarded to CUBRC and Tetraphase Pharmaceuticals
Organism
MIC50/MIC90 (mg/ml) (range)
N TP-271 Tetracycline Tigecycline Carbapenema Fluoroquinoloneb 3rd Gen Cephc Pipericilin/ Tazobactam Aminoglycosided
Klebsiella pneumoniae ESBL 48
1/4 8/>32 0.5/1 0.13/>32 32/>32 >32/>32 >128/>128 16/>320.25-32 1->32 0.25-16 0.031->32 0.031->32 2->32 0.5->128 0.5->32
Klebsiella oxytoca 41
0.25/2 ≤4/>32 0.5/1 ≤1/≤1 ≤0.25/>4 ≤2/>32 2/64 ≤2/>320.031-8 ≤4->32 0.063-4 ≤1-1 ≤0.25->4 ≤2->32 ≤1->64 ≤2->32
Klebsiella oxytoca ESBL 11
0.5/2 >32/>32 0.25/0.5 0.063/0.25 0.5/>32 >32/>32 8/>32 >32/>320.031-8 0.5->32 0.063-1 0.031-1 0.031->32 4->32 0.5->32 0.5->32
Escherichia coli ESBL 34
1/2 >32/>32 0.13/0.5 0.031/0.13 16/>32 >32/>32 8/>128 4/>320.031-4 2->32 0.063-1 ≤0.016-1 0.031->32 0.5->32 1->128 1->32
Enterobacter cloacae 44
1/4 ≤4/>32 1/2 ≤1/>8 ≤0.25/>4 ≤2/>32 8/>64 ≤2/>160.25-16 ≤4->32 0.25-8 ≤1->8 ≤0.25->4 ≤2->32 ≤1->64 ≤2->16
Enterobacter spp. AmpC+ 151/8 8/>32 1/4 >8/>8 >4/>4 >32/>32 >64/>64 16/>16
0.25-16 ≤4 - >32 0.5-4 2->8 ≤0.25 - >4 >32->32 16->64 ≤2 - >16Enterobacter
aerogenes 300.5/1 ≤4/16 0.5/2 ≤1/≤1 ≤0.25/1 ≤2/>32 4/>64 ≤2/≤20.25-4 ≤4->32 0.25-2 ≤1-≤1 ≤0.25->4 ≤2->32 2->64 ≤2-8
Citrobacter freundii 30
0.25/1 ≤4/≤4 0.5/1 ≤1/≤1 ≤0.25/2 2/>32 2/>64 ≤2/≤20.12-2 ≤4->32 0.25-2 ≤1-8 ≤0.25-4 ≤2->32 ≤1->64 ≤2->16
Proteus mirabilis 20
4/8 >32/>32 4/8 8/8 0.13/32 0.031/0.031 0.5/1 2/82-8 32->32 2-8 4-16 0.063-32 ≤0.016-0.13 0.25-2 0.5->32
Proteus vulgaris 30
2/4 8/32 2/4 ≤1/≤1 ≤0.25/≤0.25 ≤2/>32 ≤1/≤1 ≤2/≤20.25-4 ≤4->32 0.5-4 ≤1-≤1 ≤0.25-4 ≤2->32 ≤1->64 ≤2->16
Serratia marcescens 30
2/2 32/>32 1/2 ≤1/≤1 ≤0.25/0.5 ≤2/≤2 2/16 ≤2/≤20.5-8 ≤4->32 0.5-4 ≤1-≤1 ≤0.25-2 ≤2->32 ≤1->64 ≤2->16
Salmonella spp. 350.5/2 ≤4/>32 0.5/2 ≤1/≤1 ≤0.25/0.5 ≤2/2 2/16 ≤2/≤2
0.12-16 ≤4->32 0.12-2 ≤1-≤1 ≤0.25->4 ≤2->32 ≤1-64 ≤2->16
Shigella spp. 180.13/0.5 ≤4/>32 0.5/1 ≤1/≤1 ≤0.25/≤0.25 ≤2/≤2 2/8 ≤2/≤2≤0.031-2 ≤4->32 0.12-2 ≤1-≤1 ≤0.25->4 ≤2->32 ≤1->64 ≤2->16
Morganella morganii 30
4/8 32/>32 2/8 ≤1/≤1 ≤0.25/>4 4/16 ≤1/32 ≤2/>161-16 ≤4->32 1-8 ≤1-2 ≤0.25->4 ≤2->32 ≤1->64 ≤2->16
Providencia stuartii 30
4/8 >32/>32 4/8 ≤1/≤1 4/>4 ≤2/>16 4/64 4/>160.13->16 ≤4>32 0.13-16 ≤1-≤1 ≤0.25->4 ≤2->16 ≤1-64 ≤2->16
Pseudomonas aerguinosa 35
32/>32 >32/>32 16/32 1/32 2/>32 8/>32 16/>128 8/>324->32 32->32 1->32 0.5-32 0.25->32 1->32 2->128 0.5->32
Acinetobacter baumannii 54
0.13/1 16/>32 0.5/4 4/>32 8/32N/De N/D
32/>32≤0.016-2 0.25->32 ≤0.016-8 0.13->32 0.063->32 1->32
Acinetobacter lwoffii 30
0.063/0.12 ≤4/≤4 0.25/1 ≤1/≤1 ≤0.25/≤0.25 8/>16 ≤1/16 ≤2/≤2≤0.031-0.5 ≤4-16 ≤0.031-2 ≤1->8 ≤0.25-4 ≤2->16 ≤1->64 ≤2->16
Stenotrophomonas maltophilia 35
0.25/2 16/32 0.5/4 >32/>32 1/16 >32/>32 64/>128 >32/>32≤0.016-32 0.5->32 0.031-4 2->32 0.13-32 8->32 8->128 1->32
aimipenem or meropenem; blevofloxacin or ciprofloxacin; cceftriaxone, cefotaxime or ceftazidime; dgentamicin or tobramycin; e not done
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