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ETX0282, a Novel Oral Agent Against Multidrug-Resistant Enterobacteriaceae Thomas Durand-Réville 02 June 2017 - ASM Microbe 2017 (Session #113) Disclosures • Thomas Durand-Réville: Full-time Employee; Self; Entasis Therapeutics. 2 The cefpodoxime proxetil/ETX0282 combination addresses a significant unmet medical need Unmet need: Lack of effective, oral agents for treatment of MDR UTIs • There is an unmet need for new treatments due to increasing incidence of UTI due to MDR Gram-negative bacteria not covered by available oral therapies (fluoroquinolones, TMP-SMX) • Uncomplicated UTI patients (typically treated in the community) require hospitalization for I.V. treatment when infected with MDR strains • 95% of community UTIs are caused by Enterobacteriaceae, ~75% by E. coli Our vision: An oral BL/BLI combination to treat MDR Enterobacteriaceae • Oral and BID administration providing well tolerated and convenient dosing • Outpatient setting: First-line treatment for UTI and avoid Prodrug Active Agent hospitalization β-lactamase ETX0282 ETX1317 inhibitor (BLI) • Hospital setting: Oral step-down resulting in a reduced length Cefpodoxime Cefpodoxime of hospitalization β-lactam (BL) proxetil (CPDP) (CPD) * Foxman, B. Urinary Tract Infection Syndromes: Occurrence, Recurrence, Bacteriology, Risk Factors, and Disease Burden. Infect. Dis. Clin. N. Am. 2014, (28): 1-13 3 MDR Gram-negative uropathogens are rapidly emerging and spreading globally 1.8% 2.0% 7.5% 3.0% % Resistance E.E. coli coli (HAIs, 2011-2014, USA) 13.3% KlebsiellaKlebsiella spp. spp. ESBL CRE FQ-R MDR ProteusProteus spp. spp. P.P. aeruginosa aeruginosa E. coli 13.4 0.7 33.0 7.5 EnterobacterEnterobacter spp.spp. Klebsiella spp. 20.0 8.7 ND 14.2 72.4% OtherOther Enterobacter spp. 28.5 4.1 ND 7.9 CDDEP Resistance Map, CDC Antibiotic Resistance Atlas A new orally-bioavailable, broad spectrum BLI is needed N = 216,645 global UTI isolates (2009-2014) * Zowawi, H.M., et al. The emerging threat of multidrug-resistant Gram-negative bacteria in urology. Nat. Rev. Urol. 2015, 12(12): 570-584. 4 Diazabicyclooctenones: the next generation β-lactamase inhibitors Optimize β-lactamase inhibition Optimize ADME and MIC by exploring substitutions properties and around core and activating groups oral bioavailability In vivo ETX2514 (IV) ETX1317 activation ETX0282 (PO) Class A, C and D BLI Class A, C and D BLI (liver) Oral prodrug Restores β-lactam activity in A. Restores β-lactam activity in baumannii, P. aeruginosa, Gram-negative bacteria Enterobacteriaceae 5 ETX1317 displays broad spectrum inhibition of serine β-lactamases and E. coli PBP2 E. coli W3110 (ΔampC) total cell membrane extract (competition with Bocillin FL) β-lactamase inhibition (IC50, µM) ETX1317 AZT MEC PEN Class A Class C Class D 0 10µM 100µM 100µM 100µM Compound AmpC 1a CTX-M-15 SHV-5 KPC-2 TEM-1 P99 OXA-24/40 OXA-48 P. aeruginosa 1b avibactam 0.009 0.23 0.18 6.9 0.52 0.12 32 0.88 2 3 ETX2514 0.001 0.004 0.002 0.001 0.006 0.001 0.28 0.005 ETX1317 0.002 0.036 0.043 0.003 0.16 0.024 0.54 0.077 4 AZT: aztreonam, MEC: mecillinam, PEN: penicillin G • ETX1317 is a broad spectrum serine β-lactamase inhibitor • ETX1317 inhibits E. coli PBP2 which results in intrinsic antibacterial activity 6 ETX1317 restores activity of multiple β-lactams against K. pneumoniae strain MIC (mg/L) for single agents and combinations ETX1317 Cefpodoxime Cefuroxime Tigemonam Faropenem Cefixime Loracarbef K. pneumoniae + ETX1317* + ETX1317* + ETX1317* + ETX1317* + ETX1317* + ETX1317* SHV-18, OXA-2, 32 16 0.25 32 4 32 0.5 8 0.5 8 ≤0.06 32 0.125 OKP-6 (ATCC 700603) *ETX1317 tested at a fixed concentration of 4 mg/L in combinations • A series of β-lactams from different chemical subclasses were tested in combination with ETX1317 • Cefpodoxime selected as partner based on microbiological data, PK profile and dosage 7 Session 198 - AAID11, “New Antimicrobial CPD/ETX1317 has excellent microbiological profile Agents: New Beta-lactams and New Beta- against Enterobacteriaceae lactamase Inhibitors” SATURDAY – Poster 279, S. McLeod, et al. Activity vs. ~900 global, diverse, ESBL-enriched Enterobacteriaceae isolates (from UTI in 2013-2015) MIC MIC CLSI 50 90 Breakpoint Compound (mg/L) (mg/L) (mg/L) CPD >32 >32 2 ETX1317 2 32 ND CPD/ETX1317* ≤0.015 0.03 ND LVX 16 32 2 TZP* 16 >32 16 *BLIs tested at a fixed concentration of 4 mg/L in combinations LVX: levofloxacin; TZP: piperacillin/tazobactam 8 Session 198 - AAID11, “New Antimicrobial Consistent CPD/ETX1317 activity across the different Agents: New Beta-lactams and New Beta- Enterobacteriaceae pathogens and different serine β-lactamases lactamase Inhibitors” SATURDAY – Poster 279, S. McLeod, et al. Activity vs. ~900 global, diverse, ESBL-enriched Enterobacteriaceae isolates (from UTI in 2013-2015) Bacterial All E. coli K. pneumoniae K. oxytoca Citrobacter spp. E. aerogenes E. cloaceae Proteus spp. species N 911 301 253 53 120 40 51 93 MIC50 (mg/L) ≤0.015 ≤0.015 ≤0.015 ≤0.015 0.06 ≤0.015 ≤0.015 ≤0.015 MIC90(mg/L) 0.03 ≤0.015 0.03 0.125 0.06 0.06 0.25 0.12 β-lactamase Not None or wildtype De-repressed Plasmid All ESBL KPC OXA-48-like MBL class classified OSBL AmpC AmpC AmpC N 911 7 15 621 18 30 98 69 25 28 MIC50(mg/L) ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 MIC90(mg/L) 0.03 0.03 0.03 0.03 0.03 0.06 0.03 0.06 0.06 >32 9 Session 198 - AAID11, “New Antimicrobial Liver S9 incubations demonstrate consistent conversion of Agents: New Beta-lactams and New Beta- ETX0282 to ETX1317 in vitro lactamase Inhibitors” SATURDAY – Poster 278, J. O'Donnell, et al. o in vitro S9 stability (T1/2 in minutes, 37 C) Buffer Rat Intestinal (RI) Rat Liver (SL) Dog Intestinal (DI) Dog Liver (DL) Human Intestinal (HI) Human Liver (HL) pH 7.4 S9 S9 S9 S9 S9 S9 ETX0282 186 240 32 186 30 163 39 HL ETX1317 formation DL RL M • ETX0282 is predominantly stable in the presence µ HI of buffer and intestinal S9 DI • More rapid conversion of ETX0282 into ETX1317 RI Concentration, Concentration, by rat, dog and human liver S9 enzymes Buffer Time, min 10 Session 198 - AAID11, “New Antimicrobial ETX0282 delivers high bioavailability in preclinical species Agents: New Beta-lactams and New Beta- lactamase Inhibitors” SATURDAY – Poster 278, J. O'Donnell, et al. ETX0282 PO Pharmacokinetics (ETX1317 concentrations) Species Dose Eq. Cmax AUC T1/2 Oral Bioavailability (n=3) (mg/kg) (µg/mL) (µg.h/mL) (hr) F% Rat 10 5.8 ± 0.2 7.0 ± 0.6 1.1 ± 0.3 98 Dog 1 1.27 ± 0.02 2.7 ± 0.2 1.3 ± 0.6 97 100000 Rat 100000 Dog 10000 10000 • Excellent bioavailability achieved 1000 1000 in both rats and dogs 100 100 • PK profile similar to cefpodoxime 10 10 proxetil Concentration, ng/mL Concentration, 1 1 0 5 10 0 5 10 15 Time, hr Time, hr 11 Session 198 - AAID11, “New Antimicrobial CPDP/ETX0282 combination is orally efficacious against Agents: New Beta-lactams and New Beta- MDR E. coli in murine studies lactamase Inhibitors” SATURDAY – Poster 278, J. O'Donnell, et al. Neutropenic mouse thigh model (PO) 10.86 MDR E. coli (AmpC, CTX-M-14): 10.24 9.56 • Levofloxacin resistant (MIC > 4 mg/L) • Cefpodoxime resistant (MIC > 64 mg/L) • Meropenem (MIC = 0.03 mg/L) Stasis 6.63 • ETX1317 (MIC = 0.5 mg/L) Log(CFU/g) 5.77 5.59 • Cefpodoxime/ETX1317 (MIC ≤ 0.03 mg/L) 5.52 5.17 ETX0282 + CPDP 50 mg/kg • In vivo oral efficacy also observed for CPDP/ETX0282 combination against 4 other MDR Enterobacteriaceae isolates (including K. pneumoniae CRE strain where ETX1317 MIC > 32 mg/L) 12 CPDP/ETX0282 represents the first, new oral BL/BLI combination for the treatment of MDR Gram-negative uropathogens in decades • ETX1317 potently restores the activity of CPD against ESBL-producing, carbapenem- resistant, fluoroquinolone-resistant and colistin-resistant Enterobacteriaceae • The prodrug ETX0282 demonstrates high bioavailability of ETX1317 following oral administration in preclinical species with similar ADME attributes as CPDP • The promising activity of CPDP/ETX0282 in vitro and in vivo warrants further preclinical evaluation of the combination 13 Acknowledgements • Pharmaron • IHMA, Inc. • NeoSome Life Sciences, LLC 14.
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    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
  • Extended Spectrum Beta-Lactamases

    Extended Spectrum Beta-Lactamases

    Extended spectrum beta-lactamases A. Beta-lactam antibiotics a. Structure b. Types c. Action d. Mechanism of resistances B. Beta-lactamases a. Classical beta-lactamases b. Extended spectrum beta-lactamases (ESBL) c. Non-TEM, non-SBV ESBL d. Inhibitor Resistant TEM (IRT) C. Definition, classification and properties of ESBL D. Epidemiology and risk factors E. Laboratory detection and identification of ESBLs a. Screening, phenotypic and genotypic methods b. Co-production of ESBL and AmpC beta-lactamases F. Beta-lactamase inhibitors G. Multiple drug resistance H. Treatment options against ESBL producers A. Beta-lactam antibiotics A β-lactam (beta-lactam) ring is a four-membered cyclic amide consisting of three carbon atoms and one nitrogen atom. It is named so, because the nitrogen atom is attached to the β-carbon relative to the carbonyl (C=O). Antibiotics possessing this structure are called beta-lactam antibiotics. Penams contain a β-lactam ring fused to a 5- membered ring, where one of the atoms in the ring is a sulfur and the ring is fully saturated. A carbapenam is a β-lactam compound that is a saturated carbapenem. They exist primarily as biosynthetic intermediates on the way to the carbapenem antibiotics. A clavam is a molecule similar to a penam, but with an oxygen atom substituted for the sulfur. Thus, they are also known as oxapenams. Carbapenems are very similar to the penams, but the sulfur atom of the unsaturated structure is replaced with a carbon atom. Penem is a type of unsaturated β-lactam, which is similar in structure to carbapenems but penems have a sulfur atom instead of carbon.