reakpoints . Contract No. HHSO100201800015C No. Contract Percent Resistant Percent

(Tebipenem 0.6% of isolates with MIC ≥ 0.25 µg/mL) 0.25 ≥ MIC with isolates of 0.6% (Tebipenem

a This research was funded in part with Federal funds from DHS, ASPR, and BARDA under under BARDA and ASPR, DHS, from funds Federal with part in funded was research This 120 100 80 60 40 20 0

ACKNOWLEDGEMENT . SMX - TMP and levofloxacin including agents

97.1 Cefuroxime . agents oral all for rates susceptibility determine to used were Enterobacterales the

for criteria interpretive CLSI . criteria screening MIC CLSI with accordance

existing to resistance - co mediated - ESBL of era an in cUTIs for option oral new a represents 77.1 oxacin Levofl

in determined were phenotypes ESBL . carbapenems intravenous the as phenotype resistance of regardless µg/mL 03 . 0 of ,s MIC with coli . E Tebipenem . ) 2 (Table 90

66.3 MX P-S TM

well as SMX), - (TMP sulfamethoxazole - trimethoprim and fluoroquinolones

SMX - TMP and R - levofloxacin ESBL+, against activity maintained Tebipenem of phenotypes R - Oral

cephalosporins, the including UTIs treat to used routinely antibiotics oral

Amox-clav

20.6

. µg/mL 25 . 0 ≥ MICs exhibited coli . E of % 6 . 0 only but µg/mL various included study the in evaluated Antibiotics . guidelines CLSI with

12 . 0 of breakpoint a support data PK/PD preliminary but tebipenem, for available currently irfrantoin Nitrofur accordance in method microdilution broth the using tested centrally were 6.6

isolates All . instructions manufacturer’s to according Biotyper MALDI a

3 (Figure cefuroxime) and levofloxacin SMX, - TMP , clav - amox ( agents oral are breakpoints No . )

eipenem Tebi 0.6

using and tests biochemical standard using confirmed was identification a for observed was resistance - co high coli . E of phenotypes ESBL Among available currently

1.7 Piperacillin-tazobactam Species . study the in included were infection of cause probable reported

phenotypes both against µg/mL 015 . 0 was MIC modal The . ) 2 (Figure UTIs from

the as criteria local by significant be to determined isolates Only . UTIs

0.6 Ertapenem

phenotypes ESBL - non and ESBL both against activity similar exhibited Tebipenem coli . E of

uncomplicated and complicated both included and infections

IV acquired

- community and nosocomial both from were Isolates . ) 37 = (n catheter 0 penem Mero

. µg/mL 5 . 0 ≤ at inhibited isolates all Foley urethral and ), 111 = (n catheter ureteral ), 984 = (n tract urine/urinary

0 penem i Im

value MIC an with carbapenems iv to activity similar exhibited tebipenem and µg/mL 015 . 0 of 90 ; UTI with patients from collected were Isolates . US the of regions Census

The . ) 1 (Table meropenem and imipenem ertapenem, to susceptible carbapenem, oral

nine the across distributed geographically centers medical participating

from UTIs from

isolates coli . E UTI the of % 6 . 99 ≥ with active remained Carbapenems as reported being

47 from IA) Liberty, North Laboratories, (JMI Program Surveillance

E. coli coli E. of phenotypes ESBL 175 among agents IV and oral to Resistance 3: Figure

STEWARD the of part as collected were coli . E of isolates 131 , 1 of total A

respectively , % 5 . 33 and % 9 . 23 were SMX - TMP and levofloxacin for rates resistance .

Ceftriaxone 14.3 0.4 85.3 >8 ≤0.06 >8 - ≤0.06

Atlantic - Mid in % 2 . 49 to Central North West in % 3 . 7 from ranged National . ) 1 (Figure

METHODS Ceftazidime 8.1 2.8 89.1 8 0.25 >32 - 0.03

phenotypes ESBL of rate prevalence national the coli . E of isolates UTI Among and % 4 . 15 was

Aztreonam 9.3 3.6 87.1 8 0.12 >16 - ≤0.03

Amikacin 0.2 0.2 99.6 4 2 >32 - ≤0.25

CONCLUSIONS . organisms resistant - SMX - TMP and resistant

1.9 1.8 96.3 32 16 >64 - ≤4 Nitrofurantoin

- levofloxacin phenotypes, ESBL included that 2019 during US the

NA NA NA >8 0.5 >8 - ≤0.06 Mecillinam

in collected pathogens UTI contemporary against agents comparators

acid

and tebipenem of activity the evaluate to was study the of goal The 5.4 14.1 80.5 16 4 >32 - 0.5

clavulanic clavulanic - Amoxicillin 0.03 0.015 0.25 – 0.008 166 R - SMX - TMP + Levofloxacin . cUTI of treatment the for ertapenem IV to inferiority - non demonstrated

15.6 3.5 80.8 recently has that carbapenem oral an is Tebipenem . pathogens

Cefuroxime 0.015 0.25 – 0.008 377 R - SMX - TMP >64 4 >64 - ≤0.5 0.03

15.6 25.5 58.9 resistant by caused cUTIs for options tx newer for need unmet

the address would carbapenems the of potency and spectrum the 0.03 0.015 0.25 – 0.008 135 R - Levofloxacin and ESBL

33.5 66.5 >16 ≤0.12 >16 - ≤0.12 SMX - TMP

with agents Oral . enzymes carbapenemase than other lactamases - β to

0.015 0.25 – 0.008 270 R - Levofloxacin 0.03

stability inherent their of because carbapenems (IV) intravenous the are Levofloxacin 23.9 0.8 75.3 16 0.03 >32 - ≤0.015

coli . E producing - ESBL against active highly remain that agents only

0.03 0.015 0.5 – 0.008 175 ESBL Meropenem 0 0 100 0.03 ≤0.015 1 - ≤0.015

the that shown have studies surveillance Recent . effective less UTIs

Imipenem 0 0.1 99.9 ≤0.12 ≤0.12 2 - ≤0.12

0.015 0.015 0.12 – ≤0.004 958 ESBL non

treat to used agents oral available currently the of many render that

Ertapenem 0.1 0.3 99.6 0.03 ≤0.008 2 - ≤0.008

organisms producing - ESBL among resistance - co antimicrobial of levels

0.015 0.5 – ≤0.004 1133 All 0.015

0.015 0.015 0.5 - ≤0.004 Tebipenem

high the are concern Of . stay hospital of durations longer including

%R %I %S 90% 50% Range

risk, additional poses and lactams - β oral of use the compromises

Antimicrobial Agent Antimicrobial MIC MIC Range

90 50

N Phenotype coli E.

CLSI

uropathogens negative - gram among (ESBLs) lactamases - β spectrum

Tebipenem MIC (µg/mL) MIC Tebipenem

extended of prevalence increasing The . resistance of development

collected in the US during 2019 surveillance 2019 during US the in collected coli E.

and use widespread by eroded being is agents these of many of utility E. coli coli E. resistant drug - multi against tebipenem of Activity 2: Table from UTIs from

Table 1: Activity of tebipenem and comparator agents against 1,133 UTI isolates of of isolates UTI 1,133 against agents comparator and tebipenem of Activity 1: Table The . fluoroquinolones the and SMX - TMP cephalosporins, the including

antibiotics oral with managed historically been have pathogen,

Tebipenem MIC (µg/mL) MIC Tebipenem

UTI prevalent most the coli, . E by caused infections tract Urinary

≤0.004 0.008 0.5 0.25 0.12 0.06 0.03 0.015

0.00

0.10 0.31

0.57 0.73 1.14

1.71

INTRODUCTION

3.65

R = 30.2% = R - SMX - TMP 4.57

5.71

10.00

R = 25.4% = R - LEVO

R = 41.9% = R - SMX - TMP

R = 31.5% = R - SMX - TMP

ESBL = 23.8% = ESBL

R = 29.9% = R - LEVO

R = 19.8% = R - LEVO

East South Central South East

ESBL = 9.4% = ESBL

SMX - TMP and FQs the to resistance - co mediated ESBL of era an in cUTIs for option oral new a as ESBL = 12.0% = ESBL

West South Central South West

20.00

South Atlantic South no breakpoints are available, ≥99.7% of EC were inhibited by TBP at ≤0.12 µg/mL highlighting potential potential highlighting µg/mL ≤0.12 at TBP by inhibited were EC of ≥99.7% available, are breakpoints no

20.57 MIC at Percent values. Although Although values. MIC of comparison on based carbapenems IV to activity similar with carbapenem oral 90

resistance. TBP is an an is TBP resistance. - co by compromised not are and ESBLs to stability their to due EC against active

25.47

R = 50.0% = R - SMX - TMP 30.00 R to oral agents remains high, raising concerns on empiric use. Carbapenems remain remain Carbapenems use. empiric on concerns raising high, remains agents oral to R Conclusions:

SMX = 43.0% = SMX - TMP

R = 56.3% = R - LEVO

s of 0.03 µg/mL. 0.03 of s MIC with EC classes) (≥3 MDR and R - SMX - TMP 90

R = 22.8% = R - LEVO ESBL (n = 175) = (n ESBL ESBL = 49.2% = ESBL

R = 26.9% = R - SMX - TMP

R, R, - LEV against active was TBP S). (99.6% ETP and S) (100% MER TBP, for noted were respectively, ESBL = 12.7% = ESBL

Mid Atlantic Mid

no n-E SB L ( N = 958) = N ( L SB n-E no

40.00

R = 11.7% = R - LEVO

Mountain s of 0.03, 0.03 and 0.12 µg/mL, µg/mL, 0.12 and 0.03 0.03, of s MIC ≥66.3%. at rates R with EC ESBL against respectively, µg/mL, R = 31.1% = R - SMX - TMP 90

ESBL = 7.4% = ESBL

SMX were 32 and >16 >16 and 32 were SMX - TMP and LEV for s MIC The TBP. by inhibited were EC of 99.7% µg/mL 0.12 of 90 R = 14.6% = R - LEVO R = 27.3% = R - SMX - TMP

Pacific

ESBL = 7.3% = ESBL R = 21.7% = R - LEVO s of 0.03 µg/mL for meropenem (MER) and ertapenem (ETP). Using a tentative PK/PD cut off off cut PK/PD tentative a Using (ETP). ertapenem and (MER) meropenem for µg/mL 0.03 of s MIC with 90

West North Central North West ESBL = 12.1% = ESBL

50.00

was 0.015 µg/mL compared compared µg/mL 0.015 was MIC the and µg/mL ≤0.5 at TBP by inhibited were EC All carbapenems. 90

SMX = 25.0% = SMX - TMP

East North Central North East

SMX were: 15.6%, 23.9% and 33.5%, respectively. In contrast, low R was observed for the IV IV the for observed was R low contrast, In respectively. 33.5%, and 23.9% 15.6%, were: SMX - TMP R = 15.0% = R - LEVO

ESBL = 7.1% = ESBL Overall prevalence of ESBL EC from UTI was 15.4% and R to oral cefuroxime, levofloxacin and and levofloxacin cefuroxime, oral to R and 15.4% was UTI from EC ESBL of prevalence Overall Results:

New England New 60.00

the US Census regions, centrally tested, and susceptibility (S) interpreted according to CLSI criteria. CLSI to according interpreted (S) susceptibility and tested, centrally regions, Census US the

to TBP and comparators. Isolates were collected from medical centers geographically distributed across across distributed geographically centers medical from collected were Isolates comparators. and TBP to

R = 33.5% = R - SMX - TMP 1133 EC from UTIs in the 2019 STEWARD Surveillance Program were tested for susceptibility susceptibility for tested were Program Surveillance STEWARD 2019 the in UTIs from EC 1133 Methods:

65.71

70.00

assessed the activity of TBP against EC collected from UTIs in the US including isolates R to oral agents. oral to R isolates including US the in UTIs from collected EC against TBP of activity the assessed R = 23.9% = R - LEVO

69.73

ESBL = 15.4% = ESBL activity to IV carbapenems in clinical development for treating complicated UTIs (cUTI). This study study This (cUTI). UTIs complicated treating for development clinical in carbapenems IV to activity

National

and intravenous (IV) agents are often needed. Tebipenem (TBP) is an oral carbapenem with similar similar with carbapenem oral an is (TBP) Tebipenem needed. often are agents (IV) intravenous and

from UTIs from coli E.

sulfamethoxazole (TMP sulfamethoxazole - trimethoprim and SMX) making treatment of UTIs outside the hospital difficult difficult hospital the outside UTIs of treatment making SMX) -

from UTI in the USA in 2019 STEWARD Surveillance STEWARD 2019 in USA the in UTI from coli E. 1,133 among phenotypes

to the fluoroquinolones (FQs) (FQs) fluoroquinolones the to coresistance exhibit EC producing - ESBL antibiotics. oral available currently

ESBL phenotypes of of phenotypes ESBL - ESBL/non and tebipenem for distributions MIC 2: Figure

resistant resistant - SMX - TMP and levofloxacin ESBL, of prevalence regional and National 1: Figure lactamase (ESBL) continues to compromise the use of of use the compromise to continues (ESBL) lactamase - β - spectrum extended of prevalence increasing

is a predominant urinary tract infection (UTI) pathogen where where pathogen (UTI) infection tract urinary predominant a is (EC) coli Escherichia Background:

RESULTS ABSTRACT

Poster 1695 Poster JMI Laboratories, North Liberty, IA Liberty, North Laboratories, JMI MA, Cambridge, Therapeutics, Spero

mail: [email protected] mail: - E

1 2

Submission ID: 904232 ID: Submission

5139 - 564 (303) Phone:

, R.E. Mendes R.E. , Jain A. , Pucci M.J. , Cotroneo N. , Critchley I.A.

1 1 Number: Presentation 2 1 1

Cambridge, MA 02139 MA Cambridge,

October 2020 October collected from US medical centers during 2019 2019 during centers medical US from collected coli Escherichia of isolates infection

Floor 14

th

ID Week ID

675 Massachusetts Ave Massachusetts 675

drug resistant urinary tract tract urinary resistant drug - multi against activity with carbapenem oral An Tebipenem:

Ian A. Critchley A. Ian Spero Therapeutics Spero