ASM Microbe 2019 | Poster Saturday-AAR-777 Table 1 MIC distributions of tebipenem tested against surveillance Enterobacterales isolates Table 2 MIC distributions of tebipenem tested against specific phenotypes

Monitoring the In Vitro Activity of Tebipenem, an Orally Available Species No. and cumulative % of isolates inhibited at MIC (μg/mL) of: Phenotypic organism group (no. No. and cumulative % of isolates inhibited at MIC (μg/mL) of: MIC50 MIC90 MIC MIC (no. of isolates) ≤0.004 0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4a 8a >8a of isolates) ≤0.004 0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4a 8a >8a 50 90 Enterobacterales 2 113 174 161 195 229 125 18 0 1 3 2 8 6 10 4 Carbapenem Agent, against a Current Collection of Surveillance 0.06 0.25 ESBL-phenotype E. coli (20)b 0.015 0.03 (1,031) 0.2 11.2 28.0 43.6 62.6 84.8 96.9 98.6 98.6 98.7 99.0 99.2 100.0 30.0 80.0 100.0 1 67 30 4 1 61 20 E. coli (102) 0.008 0.015 Non-ESBL-phenotype E. coli (82) 0.008 0.015 Enterobacterales Clinical Isolates (2018) 1.0 66.7 96.1 100.0 1.2 75.6 100.0 1 36 17 1 C. koseri (55) 0.008 0.015 ESBL-phenotype Klebsiella spp. 12 10 0 0 0 0 0 0 0 0 3 1.8 67.3 98.2 100.0 0.03 >8 Rodrigo E. Mendes, Helio S. Sader, Paul R. Rhomberg, Jill Lindley, Holly K. Huynh, Robert K. Flamm (25)b 48.0 88.0 88.0 88.0 88.0 88.0 88.0 88.0 88.0 88.0 100.0 4 32 11 2 0 0 0 0 0 0 1 C. freundii (50) 0.015 0.03 ESBL-phenotype carbapenem- 12 10 8.0 72.0 94.0 98.0 98.0 98.0 98.0 98.0 98.0 98.0 100.0 0.015 0.03 JMI Laboratories, North Liberty, Iowa, USA susceptible Klebsiella spp. (22)b 54.5 100.0 K. pneumoniae 1 42 34 4 1 0 0 0 0 0 0 3 0.015 0.03 Non-ESBL-phenotype Klebsiella 1 40 30 4 1 (85) 1.2 50.6 90.6 95.3 96.5 96.5 96.5 96.5 96.5 96.5 96.5 100.0 0.015 0.03 spp. (76) 1.3 53.9 93.4 98.7 100.0 – Quality control strains were tested before and concomitantly with selected 10 6 K. oxytoca (16) 0.015 0.03 1 1 3 2 isolates, and bacterial inoculum density was monitored by counting the number of 62.5 100.0 ESBL-phenotype P. mirabilis (7)b 0.12 Introduction 14.3 28.6 71.4 100.0 colony-forming units present in the inoculum material E. aerogenes 15 44 35 9 2 0.03 0.12 Complicated and uncomplicated urinary tract infections (UTIs) are frequent in any (105) 14.3 56.2 89.5 98.1 100.0 Non-ESBL-phenotype P. mirabilis 4 14 36 36 6 • – Interpretations of MIC values obtained from clinical isolates used CLSI M100 0.12 0.25 given population (96) 4.2 18.8 56.2 93.8 100.0 (2019) breakpoint criteria, as available 5 27 25 26 9 5 0 0 0 2 0 4 E. cloacae (103) 0.03 0.25 • Current guidelines recommend that empiric antibiotic therapy for UTIs should be based • The ESBL phenotype was defined for Escherichia coli, Klebsiella pneumoniae, 4.9 31.1 55.3 80.6 89.3 94.2 94.2 94.2 94.2 96.1 96.1 100.0 Levofloxacin-susceptible 1 93 157 148 179 191 103 16 0 1 1 0 4 on local resistance data, drug availability, drug intolerance/allergy, and patient history c 0.06 0.25 Klebsiella oxytoca, and Proteus mirabilis as an isolate that displayed MIC values M. morganii 2 7 45 47 6 Enterobacterales (894) 0.1 10.5 28.1 44.6 64.7 86.0 97.5 99.3 99.3 99.4 99.6 99.6 100.0 0.12 0.25 – Nitrofurantoin or trimethoprim-sulfamethoxazole (TMP-SMX), if local resistance ≥2 µg/mL for ceftriaxone, ceftazidime, and/or aztreonam (107) 1.9 8.4 50.5 94.4 100.0 Levofloxacin-non-susceptible 1 20 17 13 15 37 22 2 0 0 2 2 4 ≤20% can be used empirically for uncomplicated cystitis, while fluoroquinolones, 0.12 0.25 5 15 39 38 6 Enterobacterales (135) 0.7 15.6 28.1 37.8 48.9 76.3 92.6 94.1 94.1 94.1 95.6 97.0 100.0 ceftriaxone, aminoglycosides, and carbapenems are appropriate for pyelonephritis P. mirabilis (103) 0.12 0.25 4.9 19.4 57.3 94.2 100.0 Trimethoprim-sulfamethoxazole- 1 88 141 141 180 190 98 14 0 0 1 0 1 and complicated UTIs 0.06 0.25 1 19 23 4 1 0 1 susceptible Enterobacterales (855)d 0.1 10.4 26.9 43.4 64.4 86.7 98.1 99.8 99.8 99.8 99.9 99.9 100.0 However, managing such infections is challenged by the dissemination of isolates P. rettgeri (49) 0.12 0.25 • 2.0 40.8 87.8 95.9 98.0 98.0 100.0 producing extended-spectrum -lactamases (ESBLs) and displaying cross-resistance Trimethoprim-sulfamethoxazole- 1 25 33 20 15 39 27 4 0 1 2 2 7 β 0.06 0.25 2 15 25 8 resistant Enterobacterales (176) 0.6 14.8 33.5 44.9 53.4 75.6 90.9 93.2 93.2 93.8 94.9 96.0 100.0 to fluoroquinolones, aminoglycosides, and folate pathway inhibitors in the hospital Results P. stuartii (50) 0.12 0.25 and community settings 4.0 34.0 84.0 100.0 Overall, tebipenem showed MIC and MIC results of 0.06 µg/mL and 0.25 µg/mL, ESBL, extended-spectrum β-lactamase • 50 90 a Meropenem-nonsusceptible. S. marcescens 1 8 42 35 10 4 0 0 1 1 1 b • Carbapenem agents represent good options for treating these patients with UTIs, who respectively, against all isolates in the study (Table 1) 0.12 0.25 The ESBL phenotype was defined for E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis as isolates that displayed MIC values of ≥2 µg/mL for ceftriaxone, ceftazidime, and/or aztreonam. (103) 1.0 8.7 49.5 83.5 93.2 97.1 97.1 97.1 98.1 99.0 100.0 c Isolates with MIC results of ≤2 µg/mL. usually have a spectrum of illness severity, comorbidities, and clinical histories, and d – These tebipenem (MIC50/90, 0.06/0.25 µg/mL) MIC results were similar to Isolates with MIC results of ≤2/38 µg/mL. an oral carbapenem option would provide additional benefits a Meropenem-nonsusceptible. meropenem (MIC50/90, 0.06/0.12 µg/mL) Tebipenem, the active metabolite of tebipenem-pivoxil (SPR859), is an oral • – Isolates displaying tebipenem MIC values of >2 µg/mL were meropenem- carbapenem introduced in Japan (2009) for pediatric respiratory and otolaryngologic nonsusceptible (Table 1) infections The lowest tebipenem MIC values (0.008 µg/mL) were obtained against Citrobacter SPR994 is a novel tebipenem formulation (tebipenem-pivoxil hydrobromide) that is • 50 • koseri and E. coli, followed by Citrobacter freundii, K. pneumoniae, and K. oxytoca under clinical development for treatment of UTIs (MIC , 0.015 µg/mL) (Table 1) Acknowledgements 50 This study evaluated the tebipenem activity and spectrum against targeted • A tebipenem MIC value of 0.03 µg/mL was obtained against Enterobacter cloacae Enterobacterales species • 50 This study and presentation were sponsored by Spero Therapeutics. and Enterobacter aerogenes (Table 1), while the MIC value of 0.12 µg/mL was Figure 1 Antimicrobial activity 50 100 observed for other species tested (Proteus spp., Morganella morganii, Providencia of comparator agents tested spp., and Serratia marcescens) against Enterobacterales and 90 Agents other than carbapenems did not show high activity against Enterobacterales, • Enterobacterales displaying an except for piperacillin-tazobactam (91.0% susceptible) and the aminoglycosides 80 Materials and Methods (92.5–99.2% susceptible) (Figure 1) extended-spectrum β-lactamase References Carbapenems, amikacin, and tigecycline showed susceptibility rates >80% when Surveillance isolates • phenotype 70 Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment tested against Enterobacterales isolates, meeting the MIC criteria for ESBL phenotype of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious • Enterobacterales isolates included in this study were collected as part of the SENTRY (Figure 2) 60 Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Antimicrobial Surveillance Program Clin Infect Dis 2011; 52:e103. • Tebipenem MIC50 values within ±1 doubling dilution were obtained against the • A total of 1,031 isolates composed of target numbers of randomly selected species respective species of isolates with and without an ESBL phenotype (Table 2) 50 Khawcharoenporn T, Vasoo S, Singh K. Urinary Tract Infections due to Multidrug-Resistant recovered from documented infections during 2018 were included (Table 1) Enterobacteriaceae: Prevalence and Risk Factors in a Chicago Emergency Department. Emerg • Similar MIC50 results were observed for tebipenem when tested against Med Int 2013; 2013:258517.

Preference was given to isolates recovered from urinary tract samples (669 isolates; % susceptible • Enterobacterales isolates showing nonsusceptible or susceptible phenotypes for 40 United States Food and Drug Administration (2019). FDA-Recognized antimicrobial susceptibility 64.9%), but those recovered from bloodstream infections (186 isolates; 18.0%) and lower levofloxacin or trimethoprim-sulfamethoxazole (Table 2) test interpretive criteria. Available at https://www.fda.gov/drugs/development-resources respiratory tract of patients with pneumonia (176 isolates; 17.1%) were included, as well 30 /tigecycline-injection-products. Accessed April 2019. • Isolates were collected in 113 medical centers located in 26 countries and 9 US census divisions: the United States (674 isolates [65.4%] from 62 medical centers), 20 Europe (262 isolates [25.4%] from 32 medical centers), Latin America (44 isolates [4.3%] from 8 medical centers), and the Asia-Pacific region (51 isolates [4.9%] from 10 11 medical centers) Conclusions 0 0 0 0 Contact • Bacterial species were initially identified by the submitting laboratories and confirmed • Tebipenem showed broad-spectrum and potent activity against this current and by JMI Laboratories using standard microbiology methods and matrix-assisted laser targeted collection of Enterobacterales clinical isolates and inhibited all but 14 desorption ionization-time of flight mass spectrometry (Bruker Daltonics, Bremen, isolates (98.6%) at ≤0.5 µg/mL Ampicillin Cefazolin Amikacin Germany) Ceftazidime CeftriaxoneMeropenem Ertapenem Gentamicin Tigecycline Tebipenem was most active against E. coli, K. pneumoniae, K. oxytoca, C. koseri, Levofloxacin Nitrofurantoin • Oral cefuroxime and C. freundii (MIC , 0.008–0.015 µg/mL) followed by Enterobacter spp., Proteus Antimicrobial susceptibility testing 50 Parenteral cefuroxime spp., M. morganii, Providencia spp., and S. marcescens (MIC50, 0.03–0.12 µg/mL) Piperacillin-tazobactam Rodrigo E Mendes, PhD To obtain a PDF of this poster: • Susceptibility testing was performed for tebipenem and comparator agents by Amoxicillin-clavulanic acid • ESBL phenotype and/or nonsusceptibility to levofloxacin and/or trimethoprim- JMI Laboratories Scan the QR code or visit https://www reference broth microdilution method 345 Beaver Kreek Centre, Suite A sulfamethoxazole did not adversely affect tebipenem activity Trimethoprim-sulfamethoxazole .jmilabs.com/data/posters/ASM-Microbe19 – 96-well frozen-form broth microdilution panels with cation-adjusted Mueller-Hinton North Liberty, IA 52317 These data suggest that tebipenem may be a convenient oral option for treating UTIs -tebipenem-Enterobacterales.pdf broth (CAMHB) were manufactured by JMI Laboratories (North Liberty, Iowa, USA) • Enterobacterales Enterobacterales with an ESBL phenotype Phone: (319) 665-3370 caused by carbapenem-susceptible Enterobacterales isolates and warrant its clinical per the Clinical and Laboratory Standards Institute (CLSI) specifications described Fax: (319) 665-3371 Charges may apply. No personal development in the M07 (2018) document Email: [email protected] information is stored.

ASM Microbe 2019, June 20–24, 2019, San Francisco, California