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(12) Patent Application Publication (10) Pub. No.: US 2017/0211121 A1 Stern Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0211121 A1 Stern Et Al US 20170211121A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0211121 A1 Stern et al. (43) Pub. Date: Jul. 27, 2017 (54) METHODS FOR RAPID ANTIBOTC filed on Feb. 23, 2016, provisional application No. SUSCEPTIBILITY TESTING 62/326,545, filed on Apr. 22, 2016, provisional ap plication No. 62/338,376, filed on May 18, 2016, (71) Applicant: SeLux Diagnostics, Inc., Cambridge, provisional application No. 62/370,579, filed on Aug. MA (US) 3, 2016, provisional application No. 62/383, 198, filed on Sep. 2, 2016. (72) Inventors: Eric Stern, Cambridge, MA (US); Aleksandar Vacic, Cambridge, MA (US); Benjamin Spears, Cambridge, Publication Classification MA (US); Kelly Flentie, Cambridge, (51) Int. C. MA (US); Alec Flyer, Cambridge, MA CI2O 1/18 (2006.01) (US) CI2O 1/02 (2006.01) (52) U.S. C. (21) Appl. No.: 15/464,240 CPC ............... CI2O 1/18 (2013.01); C12O I/025 (2013.01); G0IN 24.58/00 (2013.01); G0IN (22) Filed: Mar. 20, 2017 2333/195 (2013.01); G0IN 2500/10 (2013.01) Related U.S. Application Data (63) Continuation of application No. PCT/US 17/14343, (57) ABSTRACT filed on Jan. 20, 2017. The present invention relates, in part, to methods and kits for (60) Provisional application No. 62/281,698, filed on Jan. rapidly determining antimicrobial Susceptibility of microor 21, 2016, provisional application No. 62/298,821, ganisms. Patent Application Publication Jul. 27, 2017. Sheet 2 of 49 US 2017/0211121 A1 3. 48 as ca s sistsa sassic Patent Application Publication Jul. 27, 2017 Sheet 3 of 49 US 2017/0211121 A1 & 8 s: i. 8xx w & 8. 3 - 3. t w s 8: & 8.3 peoid 33:3S piepies 3.8f3 30E 8A:isod-to-338 it Patent Application Publication Jul. 27, 2017 Sheet 4 of 49 US 2017/0211121 A1 fitekine tex AS esti ck:s FG. 4 Patent Application Publication Jul. 27, 2017 Sheet 5 of 49 US 2017/0211121 A1 OO x Fast-AS to Overnight 5. D.O. O. O Clindamycin Conc. (ugiml) F.G. 5 Patent Application Publication Jul. 27, 2017 Sheet 6 of 49 US 2017/0211121 A1 150 « Fast-AST to Overnight 100, 50 2 3. 4. Ceftazidine Conc. (ig/ml.) F.G. 6 Patent Application Publication Jul. 27, 2017. Sheet 7 of 49 US 2017/0211121 A1 axis ked %{}{}{}} %{}{}{} %{}{} to 3.03;0 se%gy Patent Application Publication Jul. 27, 2017. Sheet 8 of 49 US 2017/0211121 A1 Susceptible (29213) Resistant (43300 4. Pseudomonas aeruginosa Susceptible (27853) 2 imipenen isks AA 208)int (BAA 32 32 Escherichia caii, anpiciin Susceptible (25922) 4 4 Resistani (35238) 32 32 FIG. 8 Patent Application Publication Jul. 27, 2017 Sheet 9 of 49 US 2017/0211121 A1 2- Starting 05 106 107 108 109 010 S. aureus CFUlm. FIG. 9 Patent Application Publication Jul. 27, 2017. Sheet 10 of 49 US 2017/0211121 A1 & Patent Application Publication Jul. 27, 2017. Sheet 11 of 49 US 2017/0211121 A1 Patent Application Publication Jul. 27, 2017. Sheet 12 of 49 US 2017/0211121 A1 FIG. 12A F.G. 12B F.G. 12C Patent Application Publication Jul. 27, 2017. Sheet 13 of 49 US 2017/0211121 A1 rig: xacii |-|--Reference Results (CSON) F.G. 13A Drug Vancomycin FIG. 13B Patent Application Publication Jul. 27, 2017. Sheet 14 of 49 US 2017/0211121 A1 -- Reference Results (CLSOIN) 0.25 05 || 1 || 2 | 4 || 8 -- F.G. 13C Patent Application Publication Jul. 27, 2017 Sheet 15 of 49 US 2017/0211121 A1 Drug Apicii ---------------------------------------------------------------------------------------------------------Reference Results (CLSION) F.G. 14A Drug Ciprofloxacin reference Resuits (CLS O'N) S0.25 0.5 2 4 8 CA 00 FIG, 14B Patent Application Publication Jul. 27, 2017. Sheet 16 of 49 US 2017/0211121 A1 Drug tripeners. Reference Resuits CS 8 ---------------------------------------- F.G. 14C Brug: Gentaticis. Reference Resuits 8 CSION) 4 -eeeeeeeeeeeeeeeeeeeeeeeee ---------- re-eeeeeeeeee-ee ------------------------------- Patent Application Publication Jul. 27, 2017. Sheet 17 of 49 US 2017/0211121 A1 1.5 . M b x 8 o S N N. Run number (temporal, over 1 month) FIG. 15 Patent Application Publication Jul. 27, 2017. Sheet 19 of 49 US 2017/0211121 A1 {}{}{}{}{}} {}{}{}{}} {{}{}{}{} {{}{}{}; {{}}? Patent Application Publication Jul. 27, 2017. Sheet 22 of 49 US 2017/0211121 A1 {}{}{}{}{}; {}{}{}{}} Ü{{}{}{} cy Kid c c g {{}{}{}}} {{}{}{} Yy 83.83$80s 8Agee Patent Application Publication Jul. 27, 2017. Sheet 23 of 49 US 2017/0211121 A1 ? 83.8388:0:8A388 Patent Application Publication Jul. 27, 2017. Sheet 24 of 49 US 2017/0211121 A1 {}{}{}{}} {}{}{}{} {{}{}{} 83.8388 (E8Aege Patent Application Publication Jul. 27, 2017. Sheet 26 of 49 US 2017/0211121 A1 {{}}? {}{}{}{}; {}{}{}{} 83.8388,0888 Patent Application Publication Jul. 27, 2017. Sheet 27 of 49 US 2017/0211121 A1 ||||||||||||ç.§§|-Ž?$ {{}}? {}{}{}{}; {}{}{}{}; {{}}} 8383S3308Agee Patent Application Publication Jul. 27, 2017. Sheet 28 of 49 US 2017/0211121 A1 Vidi {}{}{}{} {}{}{}}} 83.33S3:08.88 Patent Application Publication Jul. 27, 2017. Sheet 29 of 49 US 2017/0211121 A1 Sub-culture FAS Patent Application Publication Jul. 27, 2017. Sheet 30 of 49 US 2017/0211121 A1 Patent Application Publication Jul. 27, 2017. Sheet 31 of 49 US 2017/0211121 A1 6. 50 u 30 2. 1. ( OE-00 007 2E-G 3. Eif 400-Gi 5.0-07 6.0-07 Saifetis CF FG. 29 40 Y 20 t COS+7 2: 3.007 . SES-07 $3.7 Ecoli Ci F.G. 30 Patent Application Publication Jul . 27, 2017. Sheet 33 Of 49 US 2017/0211121 A1 Jul. 27, 2017. Sheet 34 of 49 US 2017/0211121 A1 Patent Application Publication Jul. 27, 2017. Sheet 35 of 49 US 2017/0211121 A1 {{}{}; {}{}{}{}{}} Patent Application Publication Jul. 27, 2017. Sheet 36 of 49 US 2017/0211121 A1 Patent Application Publication Jul. 27, 2017. Sheet 37 of 49 US 2017/0211121 A1 O 899 3 }}}}}{{{1}--~~~~ ->*,** 90+3096 Patent Application Publication Jul. 27, 2017. Sheet 38 of 49 US 2017/0211121 A1 O99'9|- {}{}{}{}{}; {}{}{}{}; {{}}}, {{}} Patent Application Publication Jul. 27, 2017. Sheet 39 of 49 US 2017/0211121 A1 {}{}{}{}{}; 0000;†were X?03~~~~~X,33~~~~(}}--~~~~ {}{}{}{}{}} {{}{}{}; {}{}{}; {{}} Patent Application Publication Jul. 27, 2017. Sheet 40 of 49 US 2017/0211121 A1 00 E. Co. NS-8i 0. - OE-08 Bacteria Concentration -o- EC2 F.G. 38 Patent Application Publication Jul. 27, 2017. Sheet 41 of 49 US 2017/0211121 A1 '88teria” ce with side a s X ray fesistant: I rity susceptise: iividing : iaiets Acces x - k x : x &8 : ::: &: i: 388x3 - or x x facifix . x- . was 4x 38 : : to A. 3x ' s Fiatentous SA ratic approaches2.f3 the 'esistant SA FIG. 39 Patent Application Publication Jul. 27, 2017. Sheet 42 of 49 US 2017/0211121 A1 8:8; 83: i: t: it: *::::::::x:y: traps $&rix: tickxistics: wi: ;33-8s :::::: iii.33&ts as waii: 88say &: fixty8::s ::::: fiat 8::s 8ixx's six:8:8: :::::::::sts: 33cteria to 3888 FIG. 40 Patent Application Publication Jul. 27, 2017. Sheet 43 of 49 US 2017/0211121 A1 Patent Application Publication Jul. 27, 2017. Sheet 44 of 49 US 2017/0211121 A1 2. s: s: S3 Ampieir Cortc. gfrni FG. 42 Patent Application Publication Jul. 27, 2017. Sheet 45 of 49 US 2017/0211121 A1 3. 2 O,1. O.E+00 5.E+05 1.E+06 2.E+06 2.E+06 3.E+06 E. coli CFU/mL. Patent Application Publication Jul. 27, 2017. Sheet 46 of 49 US 2017/0211121 A1 -O- Ceftazidime an e a 3 O Xa Cin 9. A Vanco mycin g 9 2 (5 O O a 0 10 - 1 Antibiotic C on c. (gfm L.) FG. 44 Patent Application Publication Jul. 27, 2017. Sheet 47 of 49 US 2017/0211121 A1 --- A . : rt r ( i \, : x- as go ses ca xw 8: Patent Application Publication Jul. 27, 2017. Sheet 48 of 49 US 2017/0211121 A1 Fictioai Cationic SitiaCe Protective she Polymer matrix core Encapsulated species FG. 46A Patent Application Publication Jul. 27, 2017. Sheet 49 of 49 US 2017/0211121 A1 i. 20 E 10 Oy1 1. N. N FE 8. i O2 in O ? 1000 Catalyst Concentration pii C 30 -KY- RP -- Nailab8 is 2 & Clostricium difficie Fox: A pg/ml) FG. 46C US 2017/0211121 A1 Jul. 27, 2017 METHODS FOR RAPID ANTIBOTC include signaling agents (e.g., Europium compounds) that SUSCEPTIBILITY TESTING are bound to microorganisms non-specifically rather than specifically (e.g., via chemically conserved groups or bio RELATED APPLICATIONS chemically conserved binding sites on microorganisms), thereby expanding the generalization of the present inven 0001. This application is a continuation of International tion to any microorganism and allowing onset of an appro Patent Application No. PCT/US 17/14343 filed Jan. 20, priate treatment without first needing to identify the particu 2017. PCT/US 17/14343 designates the United States and lar infectious microorganism. Also, the present invention claims priority to and benefit of U.S. Provisional Patent permits signal amplification Such that microbes may be Application No. 62/281,698, filed Jan. 21, 2016; U.S. Pro rapidly detected at lower concentrations, e.g., from a dilute visional Patent Application No. 62/298,821, filed Feb. 23, culture of microorganisms or via a patient’s biological 2016; U.S. Provisional Patent Application No. 62/326,545, sample. Additionally, the present invention may use Euro filed Apr. 22, 2016; U.S. Provisional Patent Application No. pium formulations as chemical moiety, thereby expanding 62/338,376, filed May 18, 2016; U.S. Provisional Patent the dynamic range of the methods and allowing for more Application No. 62/370,579, filed Aug. 3, 2016; and U.S. accurate determinations from a range of microbial samples.
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