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View U.S. Patent Application Publication No. US-2020-0056988 1111111111111111 IIIIII IIIII 1111111111 11111 11111 111111111111111 IIIII IIIII IIIIII IIII 11111111 US 20200056988Al c19) United States c12) Patent Application Publication c10) Pub. No.: US 2020/0056988 Al Butz et al. (43) Pub. Date: Feb. 20, 2020 (54) METHOD OF DETERMINING THE Publication Classification EFFICACY OF ANTIMICROBIALS (51) Int. Cl. GOIN 2113504 (2006.01) (71) Applicant: Wisconsin Alumni Research GOIN 33/497 (2006.01) Foundation, Madison, WI (US) (52) U.S. Cl. CPC ....... GOIN 2113504 (2013.01); GOIN 33/497 (72) Inventors: Daniel Elmer Butz, Madison, WI (US); (2013.01) Ann P. O'Rourke, Madison, WI (US); Mark E. Cook, Madison, WI (US) (57) ABSTRACT A method of determining efficacy of an antimicrobial treat­ ment in a subject includes calculating a breath delta value (21) Appl. No.: 16/540,627 (BDV) for each of at least six breath samples acquired from the subject over a 24 hour period starting from when the subject has been administered the antimicrobial treatment, (22) Filed: Aug. 14, 2019 calculating a mean standard deviation of BDV (SD BDV) across the six or more breath samples; and determining that the antimicrobial treatment is effective when the SD BDV is Related U.S. Application Data less than or equal to 0.46, or determining that the antimi­ crobial treatment is ineffective when the SD BDV is greater (60) Provisional application No. 62/764,874, filed on Aug. than 0.46. Also included are methods of treating a subject in 16, 2018. need of antimicrobial treatment. r Ass~sse~.f~;·el;~!~i!lt;·~n~~·~1)···· i ,, --~----·--··--···············r··············•······-·······•_.•.•.•.•_.•.•.•.•_J________ ___.........,., ; Excluded (no:299) r- ➔@!~;;;:~=:· ~··· Consented for partidpatfon {ir=32) Wi!hdrawn: • Exdusionary Criteria (ri=3) • Withdrawn by lnve.stigator(n"'2) Analyzed {n:=27) , Excluded from analysis {inadequate breath samples} {n=7} • 20 Subjects Anaiyze<l: o 13 Male; 7 Femi.lie o 76.2% Caucasian: VU% African American: 9.5% Other o 19% 18-35 yfo; 33_3% 36-54 yfo; 33.3% 55-73 yfo: i4.3 74+ yto Patent Application Publication Feb. 20, 2020 Sheet 1 of 7 US 2020/0056988 Al 4.0 Infection Progression Y'ancom::cln q ....... .~ .. ,-.•.•··········· .................. 3.0 BDV rises and variance increases Ce,,,p;m,:, , ·if ./ . ***~ * .... '!ti-.,.•:,$' 2.0 'Iii::./ .~ •: ... ·.·•,•:::::::•· * ,..············::·.•·· ~--···O) g!?~P.Q.J~J?JQ Ir.e~trn~ot . BDV variance decreases! :A} Blue"' "Safe Zone" B) Infection Onset ·~ BDV fails below --3,0 -4.0 FIG. 1 '···Assessed for ;§gib1li!y {n<~3i} .. I ............ ' I e, ct,,Jod (~,.,i I 1 [~1f~~~~::::'.~ ~,rt, ........, Consented for participation {n=32) Wilhdrawn: • Exduskmmy Criteria (rr=3) • Withdrawn by lnvesllgalor (!F2) I !"fi~i~d~0iiti·~~~-;~~is (inadequate breath \ samples} (n=7) l • 20 Subjects Analyzed: o 13 Male. 7 Female o 16.2% Caucasian; 14.3% tv."rican American: 9.5% Othar ,:~,1:;;'~~~::'~,:::·,'.:'.'.'.: I FIG. 2 Patent Application Publication Feb. 20, 2020 Sheet 2 of 7 US 2020/0056988 Al b a !CU admitted no- untreated infection treated infection infection FIG. 3 00-004 3 ,. • ::i s.o ... o.1s 3 s 2.5 ~-/~\! 'ii "' 2 .n"' a; 1.5 5.0. "0.38 -~After treatment > 0 ···•··Before treatmet)t IS '-'- 53.1% decrease in S.D. 3 0.5 0 0 1 2 3 4 s 6 7 Time since €r:roliment FIG. 4 O!J-004 3.5 s.o. "0.18 3 ?-- J .5 2.5 ~_,/ \ 'ii 2 "'ro ..0 [) 1.5 SJ). "0.38 -·After treatment > 0 1 ·• Before treatment IS 'ii 53.1% t!ecras~ In 5.D. o 0.5 0 0 1 2 3 4 6 7 ffme since enrollment FIG. 5 Patent Application Publication Feb. 20, 2020 Sheet 3 of 7 US 2020/0056988 Al 00--007 2.5 2 S.O. ~ 0.1S /·,.)~ ..., .... After treatment •. !3efon~ treatment 0 0 1 2 3 4 5 6 FIG. 6 00-011 3.S 3 ··'··After treatment .,. Before treatment 0 0 .1 2 3 4 5 6 7 Time since enroi!ment FIG. 7 02-002 3 2..5 2 --After treatment s.o." 0.46 •·"·· Before treatment 1 z 7 Time since enrollment {d) FIG. 8 Patent Application Publication Feb. 20, 2020 Sheet 4 of 7 US 2020/0056988 Al 02-003 2.5 43.9% de(N,i.!Se 1!'1 S.D. 2 LS ~ •""~After tre<1tment > 1 0 · Before treatment ro ~ 0.5 0 0 ❖ 0 .j. 2 3 4 5 6 Time since enmHmwt (d) FIG, 9 02-004 0 ·0.2 0.2 0.4 0.6 0.8 1 t2 1.4 LG LS -04 54.9% decrease In S.t) . ·0.6 .£ S.O. »O-!>il ~ ·0.8 11> ....... After treatment J:l .. 1 w"" > •··'··Before treatment o ·1.2 ,!!l oi -1.4 0 .. 1.6 ·l.8 Time since enrollment {d) FIG. 10 02-006 3 2.5 S.D. :0.27 IV .E 2 1, V, 15 1.5 ... ..-After treatment ,l; > S.l). "'0.49 0 1 ·•· Before tre<1tment .a 44.7% detrnas;; in SJ). ~ 0.5 0 0 0.5 1 1.5 2 2.5 3 3.5 4 T!me since enrollmeilt FIG. 11 Patent Application Publication Feb. 20, 2020 Sheet 5 of 7 US 2020/0056988 Al 04-004 2 S.D •.«0.$1 21.8% dea~ase lfi 5.D. :LS w .s (LJ 1 V, SJ'.l."0.40 (G ·"~·After treatment .0,_ <:;; ::,, o.s ··•· -Before tis!.itment 0 fl ~ 0 0 0 1 l 3 4 5 7 -{J.5 Time since enrollment FIG. 12 04-007 3 2.5 'l.' 2 ,!::, ·a; if> 1.5 S.D. ~o.86 -"-After treatment J:,"' n. 7% decrease in :LO. b 1 > ·· Before ueatment 0 s O,S ·-a; CJ 0 0 0.5 1 1.5 2 £ ,..;;C 3 -05 T1me since enrollment FIG. 13 Patent Application Publication Feb. 20, 2020 Sheet 6 of 7 US 2020/0056988 Al 4.0 3.0 Cefuroxime ::rn Day 1 Day2 Day3 Day4 Day5 Day7 Daya Day9 Day iO FIG. 14 4.0 'Ctlfuroxfrrie 3.0 2,0 LD + BAL: Klebsiarla oxytoca: endogenous flora; Aclnetobacter baumanlilca Blood: + Fungai: Aspergrnus No fumigalus B!ood: growth No SAL: No -z.o growth 9ro\11lh Day 1 Day2 Day 3 Day4 Day 5 Day6 Day8 Day 10 FIG. 15 Patent Application Publication Feb. 20, 2020 Sheet 7 of 7 US 2020/0056988 Al Cefepime /\...,.__,,_,.;"'-.,.1,-.,,.,'¼;.,. ,-""•.•;,.•··'''•, ... 1.0 r·--,,,,' " f\/~\_./ . ~ . •.• ' i i, ..,J. \ ✓ \/ k Urine: No g,o.-.-th + Blood; Streptococcus coM!eila!JJs + BAL: S!aphyloooccus aureus + Brach line: Sttaptocoocus COn$tellus Day 1 Day2 Day3 Day4 Day5 Day6 Day? Daya Day9 Day 10 FIG. 16 US 2020/0056988 Al Feb.20,2020 1 METHOD OF DETERMINING THE [0006] In addition, U.S. Pat. No. 8,512,676 describes the EFFICACY OF ANTIMICROBIALS use of oscillation modes in breath isotope ratio data to identify an "unhealthy" state in an organism. Changes in the CROSS-REFERENCE TO RELATED frequency and/or amplitude of the oscillation modes can be APPLICATIONS correlated with the health of an individual. Advantageously, advances in cavity ringdown spectrometry allow for the [0001] This application claims priority to U.S. Provisional continuous collection of breath isotope data which permits Application 62/764,874 filed on Aug. 16, 2018, which is the identification of oscillatory patterns within the breath incorporated herein by reference in its entirety. isotope data. The identified oscillation modes are particu­ larly useful in determining the transition from a healthy to an FIELD OF THE DISCLOSURE infected state in an organism within the short-term infection [0002] The present disclosure is related markers for deter­ period, e.g., 30 minutes to 2 hours. mining the efficacy of antimicrobials, and novel methods for [0007] What is needed are improved markers for the administering antibiotics, particularly to subjects in a sur­ response of subjects to antimicrobial treatment, particularly gical ICU setting. acute surgical and trauma subjects admitted to the ICU. BRIEF SUMMARY BACKGROUND [0008] In one aspect, a method of determining efficacy of [0003] Infections remain a leading cause of morbidity and an antimicrobial treatment in a subject comprises mortality in the intensive care unit (ICU). In the United [0009] calculating a breath delta value (BDV) for each of States, infectious complications develop in up to 28% of at least six breath samples acquired from the subject over a patients admitted to the ICU and require mechanical venti­ 24 hour period starting from when the subject has been lation. The current standard of care for detecting infections administered the antimicrobial treatment, wherein BDV is relies heavily on the physician to make decisions bedside, determined according to monitoring trending vitals signs and laboratory work. Hos­ pital mortality for severe infection ranges from 18% to 28% in adults and remains the leading cause of death in adult 13 12 13 12 13 ( C/ C sample- C/ c PDE) surgical ICU patients. Assessing the efficacy of antimicro­ EDV=OC= 13 C/l2CPDE xlOOO bial treatment in acute systemic inflammation and severe infection, is vital to improved patient outcomes. Moreover, unnecessary empiric antibiotic treatment is undesirable [0010] wherein PDB is a Pee Dee Belenmite reference because of the risk of antibiotic-resistant bacterial strains. standard, and BDV is expressed as parts per mil (%0); [0004] A noninvasive, non-doping, rapid stable isotope [0011] calculating a mean standard deviation of BDV (SD method to discern the onset of the catabolic state by detect­ BDV) across the six or more breath samples; and [0012] determining that the antimicrobial treatment is ing isotopic changes in the exhaled CO2 in breath was described in issued U.S.
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