In vitro susceptibility of clinical Clostridioides difficile isolates to ridinilazole and ibezapolstat in Israel, 2020-2022

In vitro susceptibility of clinical Clostridioides difficile isolates to ridinilazole and ibezapolstat in Israel, 2020-2022 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article In vitro susceptibility of clinical Clostridioides difficile isolates to ridinilazole and ibezapolstat in Israel, 2020-2022 Orna Schwartz, Maya Azrad, Avi Peretz This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5818289/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Mar, 2025 Read the published version in BMC Gastroenterology → Version 1 posted 4 You are reading this latest preprint version Abstract Background Even though they constitute a risk factor, antibiotics are still the current primary treatment of C. difficile infection. Due to C. difficile 's rapid development of resistance and high recurrences rates, there is an unmet need for new antimicrobials. In the current study, we assessed the in vitro susceptibility of clinical isolates from Israel to two recently developed antibiotics, ridinilazole and ibezpolstat, and to currently used antibiotics. Methods We collected 313 C. difficile isolates from several medical centers across Israel, that were recovered from patients of both community and hospital facilities. Isolates were typed to different strains (strain type-ST) by multi-locus sequencing typing (MLST). Susceptibility to metronidazole and vancomycin was determined by Etest; susceptibility to fidaxomicin, ridinilazole and ibezpolstat was determined by agar dilution. Results The most prevalent STs were ST42, with 39 (12.5%) isolates and ST2, with 36 isolates (11.5%). Resistance rate to metronidazole and vancomycin was low (2.2%, 1.6%, respectively). Ridinilazole (RDZ) MIC ranged between 0.06 to 0.5 mg/L, and the MIC 50/90 were 0.25/0.5 mg/L. Ibezpolstat (IBZ) had an MIC 50/90 of 4 mg/L. No significant differences were noted in MIC of different strains. Conclusions We demonstrated a potent in vitro activity of RDZ and IBZ against 313 C. difficile isolates, belonging to different STs. These two antimicrobials may serve as a treatment for C. difficile infection, as they have an excellent activity against C. difficile on one hand, and minimal effect on gut microbiome, on the other hand. C. difficile Antibiotic susceptibility Fidaxomicin Ridinilazole Ibezpolstat Strains MLST Figures Figure 1 Figure 2 Background Clostridioides difficile ( C. difficile ) is a Gram-positive, anaerobic bacterium which causes significant diarrheal illness, both in healthcare and community facilities ( 1 ). Since 2011, Emerging Infections Program (EIP) of the Centers for Disease Control and Prevention (CDC) has been monitoring C. difficile infection (CDI) in 10 US sites. A recent study which used the EIP data, reported on a 24% decrease in the total burden of CDI in the US between the years 2011 and 2017. Nevertheless, there was no changes in the high burden of first recurrences and of CDI-associated in-hospital mortality ( 2 ). CDI onset begins with ingestion of spores, followed by their germination in the gut, which results in bacterial colonization and proliferation. Then, toxins produced by the bacteria disrupt the gut epithelial integrity, induce cytotoxic effects on intestinal cells and stimulate an inflammatory response ( 1 ). The main risk factor for developing CDI is antibiotic administration as it induces dysbiosis, i.e., alteration of the gut microbiome composition, which results in germination of C. difficile spores ( 3 ). Another potential outcome of dysbiosis is an increased ratio of primary-to-secondary bile acids. As primary bile acids promote spore germination while secondary bile acids inhibit C. difficile growth, this shift also contributes to CDI development ( 3 ). Even though they constitute a risk factor, antibiotics are currently the primary treatment for CDI. The main options in use are fidaxomicin (FDX) and vancomycin (VAN); metronidazole may be given when the previous two antibiotics are not available ( 4 ). Although MTZ and VAN are effective against vegetative C. difficile cells, their use still induces gut microbiome disruption, which may lead to further C. difficile spore germination and disease recurrence ( 5 ). FDX advantages over VAN and MTZ, are the lower concentration needed for treatment, longer duration of effect, and reduced disease recurrence rate ( 6 ). Additionally, FDX use has been associated with less microbiome dysbiosis ( 6 ). In recent years, several new C. difficile strains have emerged, with some of them being resistant to antibiotics in clinical use. Additionally, up to 30% of treated patients may experience recurrent CDI due to persistence of antibiotic-resistant spores ( 7 ). Thus, new alternatives are required. One of the newest developed antibiotics for CDI treatment is ridinilazole (RDZ), a narrow-spectrum antibiotic. RDZ is a a bis-benzimidazole antibiotic with a bacterricidal activity that is mediated by its interaction with AATTT-rich sequences in C. difficile DNA minor groove, leading to interference with cell division and apparently with ATP production ( 8 ). In addition to its high inhibitory activity against several C. difficile strains, both in vitro and in vivo ( 9 , 10 ), RDZ reduced CDI recurrence rate from 17.3–8.1%, compared to VAN ( p = 0.0002) ( 8 ). In contrast to VAN, RDZ did not impact the gut microbiome( 11 , 12 ) and had no effect on secondary bile acids ( 12 ). In line with these reports, two clinical trials (NCT03595553 and CT03595566) comparing the efficacy of RDZ vs. VAN, found better conservation of gut microbiome with RDZ ( 8 ). RDZ treatment in a phase 3 superiority trial was associated with less recurrence cases and increased secondary bile acids levels ( 8 ). Recently, a phase 3 study of RDZ has been terminated; due to the insuperiority of RDZ on VAN in sustained clinical response (73%, and 70.7%, respectively), the drug company which developed RDZ stated on rethinking( 8 ) Ibezapolstat (IBZ) is another treatment recently developed for CDI. This narrow-spectrum antibiotic binds and inhibits DNA polymerase IIIC (DNA pol IIIC), which is unique to Gram-positive bacteria with a low G + C content. IBZ has been tested in clinical trials and has exhibited several advantages, including minimal adverse effects, good pharmacokinetics, a favourable secondary-to-primary bile acid ratio and limited damage to the gut microbiome ( 13 ). Murray et al. reported on the potent activity of IBZ against 104 C. difficile isolates ( 14 ). Recently, phase 2b clinical trial of ibezapolstat has been completed. To the best of our knowledge, there are no data regarding susceptibility of clinical C. difficile strains to RDZ and IBZ in Israel. Additionally, since antibiotic susceptibility testing for C. difficile is not routinely evaluated by clinical laboratories, there are limited data on susceptibility rates to the currently used treatments. Therefore, this study aims to assess the susceptibility of different clinical strains, collected from several areas in Israel between 2020 and 2022, to RDZ, IBZ, FDX, MTZ and VAN. Methods Study isolates The study included 313 C. difficile isolates that were recovered from stool samples of patients diagnosed with CDI and hospitalized in one of four medical centres in Israel between 2020 and 2022. CDI was confirmed with the GeneXpert C. difficile BT PCR assay (Cepheid, Sunnyvale, CA, USA) which identifies toxin B and binary toxin genes, and tcd C deletion (independent identification of the epidemic Nap1/027 strain). Community-acquired CDI (CA-CDI) was defined as CDI that developed within 48 hours of admission, while hospital-acquired CDI (HA-CDI) was defined as CDI that developed > 48 h after admission. The four participating medical centres are located in different geographic areas of Israel: North - Tzafon Medical Center, Poriya and W. Hirsch Regional Microbiology Laboratory Clalit Health Services, Haifa, Center - Edith Wolfson Medical Center, Holon, and South - Soroka University Medical Center, Be'er Sheva. The local Ethics (Helsinki) Committee of each medical centre approved the study (POR-0085-15, WOMC-0115-20, SOR-0307-20). The need for informed consent was waived. Multi-locus sequence typing (MLST) DNA was extracted from study isolates using the MagCore® Genomic DNA Bacterial Kit (ATRIDAB.V, Amersfoort, Netherlands) with the MagCore® automated extraction instrument (RBCBioscience, New Taipei, Taiwan), according to the manufacturer’s instructions. Following whole-genome sequencing of DNA samples, the sequences of seven housekeeping genes ( adk , atp A, dxr , gly A, rec A, sod A, and tpi ) of each isolate were uploaded to the C. difficile MLST database ( https://pubmlst.org/organisms/clostridioides-difficile ), in order to determine the sequence type (ST), as previously described ( 15 ). Bacterial isolation and identification Stool samples were inoculated on a selective growth agar medium, chromID™ C. difficile (CDIF) (BioMérieux, Durham, NC), and incubated for 48 h, at 37°C, in a Bactron EZ 300 anaerobic chamber (Sheldon manufacturing, Cornelius, USA). Identification of C. difficile colonies was based on colonies' asymmetrical shape and black color. The Bruker Biotyper system (Bruker Daltonics, Bremen, Germany), that is based on matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry, was used for definitive. All isolates were stored at -80°C until further analysis. Antimicrobial susceptibility testing Susceptibility testing for MTZ and VAN Susceptibility to MTZ and VAN was assessed using the Etest technique, which determines the minimum inhibitory concentration (MIC). Several C. difficile colonies were suspended in thioglycollate broth medium (Becton Dickinson, Heidelberg, Germany) to achieve 1.0 McFarland standards. Then, bacterial suspensions were inoculated on Brucella blood agar (Hy Laboratories, Rehovot, Israel) and a gradient Etest strip (bioMérieux, Durham, NC) of VAN or MTZ was added. The agar plates were incubated at 37°C under anaerobic conditions for 48 h. Following incubation, the MIC was visually determined and isolates were classified as susceptible or resistant according to breakpoints of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines ( 16 ). Susceptibility testing for FDX, RDZ and IBZ Susceptibility to FDX, RDZ and IBZ in accordance with the procedures of the Clinical and Laboratory Standards Institute (CLSI-M11-9th ) ( 17 ). Brucella agar supplemented with 5% defibrinated sheep blood (Hy Laboratories) was mixed with FDX (Sigma-Aldrich, Missouri, US), RDZ or IBZ (MedChemExpress LLC, NJ, USA) by first dissolving the antibiotics in dimethyl sulfoxide (DMSO) and then further diluting it with distilled water to various concentrations. The agar plates were mixed with the different dilutions of each antibiotic, yielding the following ranges of final concentrations: FDX 0.03-32 mg/L, RDZ-0.03-0.5 mg/L, and IBZ- 0.5-8 mg/L. Several C. difficile colonies were inoculated in thioglycollate broth medium (Becton Dickinson) to 0.5 McFarland turbidity, and then placed as spots on the antibiotics-supplemented agar plates. Plates were incubated at 35°C, under anaerobic conditions, for 48 h. After incubation, plates were visually screened for bacterial growth, and MIC was determined as the lowest antibiotic concentration that inhibited bacterial growth. Results The study included 313 isolates, recovered from 187 patients with HA-CDI and 126 patients with CA-CDI. ST distribution ST was determined for 90.1% (282/313) of the isolates, while the rest of isolates remained unclassified. Isolates were categorized into ten major groups, with each group containing at least seven isolates (Table 1 ). An additional group, called "others", included 108 (34.5%) isolates had STs shared by fewer than seven isolates (Supplemental Table 1). Table 1 Distribution of ST among study isolates ST Clade n (%) ST42 1 39 (12.5) ST2 1 36 (11.5) ST104 1 23 (7.3) ST11 5 21 (6.7) ST3 1 13 (4.2) ST34 1 9 (2.9) ST54 1 9 (2.9) ST55 1 9 (2.9) ST37 4 8 (2.6) ST13 1 7 (2.2) Others 1, 2, 3, 4 108 (34.5) Unclassified N.A. 31 (9.9) The most prevalent STs were ST42 (n = 39; 12.5%) and ST2 (n = 36; 11.5%). Most isolates (274/282; 97.2%) belonged to Clade 1, one isolate with ST1 belonged to Clade 2, 2 isolates with ST5 belonged to Clade 3, 9 isolates (8 ST37 and 1 ST39), belonged to Clade 4 and 21 isolates of ST11, belonged to Clade 5. The "Others" group included isolates from Clades 1–4 (Table 1 ). One hypervirulent strain (0.3%), belonged to ST1, was found. Overall, the same STs were found among both CA and HA isolates, however, their distributions differed (Fig. 1 ). For example, among HA isolates, ST42 (13.9%) was the most common strain, while ST2 was the most (13.5%) frequent ST among CA isolates. ST37 was more frequent detected among HA isolates compared to CA isolates (3.7%, 0.8%, respectively). Susceptibility of study isolates Bacterial susceptibility to MTZ, VAN, FDX and to the new antimicrobials RDX and IBZ was assessed (Table 2 , Fig. 2 ). The MIC of MTZ were in the range of 0.016-256 mg/L and MIC 50/90 were 0.19/0.38 mg/L. Resistance rate to MTZ was low (2.2%). The MIC 50 of VAN was 0.5 mg/L, the MIC 90 was 0.75 mg/L, and the resistance rate was low (1.6%). The geometric MIC means of both MTZ and VAN were quite high (6 mg/L and 2.5 mg/L, respectively). FDX MIC was in the range of 0.03-16 mg/L and MIC 50/90 was 0.25/0.5 mg/L. Twenty three (7.35%) isolates were resistant to FDX. RDX MIC ranged between 0.06 mg/L and 0.5 mg/L, and the MIC 50/90 was 0.25/0.5 mg/L. IBZ had an MIC 50/90 of 4 mg/L. Table 2 Antimicrobial susceptibility of study isolates Antimicrobial agent MIC Range (mg/L) MIC 50 (mg/L) MIC 90 (mg/L) Geometric MIC mean (mg/L) % Resistance Metronidazole 0.016-256 0.19 0.38 6 2.2 Vancomycin 0.064-256 0.5 0.75 2.5 1.9 Fidaxomicin 0.03-16 0.25 0.5 0.81 7.35 Ridinilazole 0.06–0.5 0.25 0.5 0.32 N.A. Ibezapolstat 0.5-8 4 4 3.1 N.A. Different STs had no major differences in MIC to the different antibiotics, including RDX and IBZ (Table 3 ). Furthermore, when we compared the MIC 50 /90 and geometric mean MIC values for RDZ and IBZ between MTZ-susceptible and MTZ-resistant strains, as well as between VAN-susceptible and VAN-resistant strains, no differences were observed; similar result was seen for FDX- susceptible and FDX-resistant strains (Table 4 ). We also compared our results with data from all studies that tested the in vitro activity of RDZ and/or IBZ (Table 5 ). RDZ MIC in the current analysis were among the highest reported values. In most studies, RDZ had a lower MIC 90, compared to MTZ and VAN. When compared to the newest antibiotic in use, RDZ had either lower or equal MIC 90 . Table 3 Antibiotic susceptibility of study isolates, with relation to ST Strains MIC (µg/mL) MTZ VAN FDX RDZ IBZ ST2 Range 0.032-1 0.094-2 0.03-16 0.12–0.5 2–4 (n = 36) MIC 50 MIC 90 0.125 0.25 0.5 0.75 0.25 0.25 0.25 0.5 4 4 ST3 Range 0.023-0.2 0.25–0.75 0.03-16 0.12–0.25 1–4 (n = 13 MIC 50 MIC 90 0.094 0.25 0.75 0.75 0.12 0.25 0.25 0.5 4 4 ST11 Range 0.016-256 0.064-256 0.03-16 0.12–0.5 2–4 (n = 21) MIC 50 MIC 90 0.094 0.25 0.75 1 0.12 0.25 0.5 0.5 2 4 ST13 Range 0.125–0.25 0.5–0.75 0.06-16 0.12–0.5 2–4 (n = 7) MIC 50 MIC 90 0.19 0.25 0.5 0.75 0.25 0.25 0.5 0.5 4 4 ST34 Range 0.032–0.38 0.5-3 0.06-8 0.06–0.5 2–4 (n = 9) MIC 50 MIC 90 0.19 0.38 0.75 0.75 0.25 0.25 0.25 0.5 4 4 ST37 Range 0.016-256 0.5–0.75 0.06–0.25 0.06–0.5 1–4 (n = 8) MIC 50 MIC 90 0.19 0.75 0.75 0.75 0.25 0.25 0.25 0.5 4 4 ST42 Range 0.016-256 0.25-56 0.03-4 0.06–0.5 0.5-4 (n = 39) MIC 50 MIC 90 0.25 0.75 0.75 0.75 0.25 0.25 0.25 0.5 4 4 ST54 Range 0.023–0.38 0.38-1 0.06–0.25 0.12–0.5 1–4 (n = 9) MIC 50 MIC 90 0.19 0.25 0.75 1 0.25 0.25 0.25 0.5 2 4 ST55 Range 0.064–0.38 0.5–0.75 0.12–0.25 0.25–0.5 4–8 (n = 9) MIC 50 MIC 90 0.125 0.25 0.75 0.75 0.25 0.25 0.25 0.5 4 4 ST104 Range 0.023-1 0.38-1 0.03-16 0.06–0.5 1–4 (n = 23) MIC 50 MIC 90 0.19 0.25 0.5 1 0.25 0.5 0.25 0.5 2 4 Unclassified Range 0.047-256 0.125-2 0.06-16 0.06–0.5 1–4 (n = 31) MIC 50 MIC 90 0.19 0.25 0.5 0.75 0.25 8 0.5 0.5 2 4 Others Range 0.016-256 0.125-256 0.03-16 0.06–0.5 0.5-8 (n = 108) MIC 50 MIC 90 0.19 0.38 0.75 0.75 0.25 0.25 0.25 0.5 2 4 Table 4 Susceptibility of study isolates to RDZ and IBZ, with relation to their susceptibility to MTZ, VAN and FDX Antimicrobial agent RDZ IBZ MIC 50 MIC 90 Geometric MIC mean MIC 50 MIC 90 Geometric MIC mean (mg/L) Metronidazole-S Metronidazole-R 0.5 0.5 0.5 0.5 0.313 0.41 4 4 4 4 3.07 3 Vancomycin-S 0.25 0.5 0.314 4 4 3.07 Vancomycin-R 0.5 0.5 0.374 4 4 3.2 Fidaxomicin-S 0.25 0.5 0.31 4 4 3.06 Fidaxomicin-R 0.5 0.5 0.37 4 4 3.21 Table 5 Summary of reported data regarding C. difficile susceptibility to MTZ, VAN, FDX, RDZ and IBZ Reference (Geographic area) No. of isolates MIC (µg/mL) IBZ RDZ FDX VAN MTZ Dvoskin et al., 2012 (USA) 36 23 Range MIC 50 MIC 90 Not shown 2 4 N.D. N.D. N.D. N.D. Goldstein et al., 2013 50 Range N.D. 0.125-0.5 0.06-1 1–8 0.25-8 (USA) 34 MIC 50 MIC 90 0.25 0.25 0.25 0.5 1 4 0.5 2 Corbett at al., 2015 82 Range N.D. 0.06–0.125 0.008–0.125 0.5-4 0.125-8 (UK) 37 MIC 50 MIC 90 0.125 0.125 0.03 0.06 1 2 2 8 Freeman et al., 2016 107 Range N.D. 0.015-0.5 0.004–0.125 0.5-8 < 0.125-2 (Europe) 38 MIC 50 MIC 90 0.03 0.125 0.06 0.125 1 2 0.2 2 Snydman et al., 2017 200 Range N.D. 0.12–0.5 0.015-1 0.25-4 0.12-2 (US) 39 MIC 50 MIC 90 0.12 0.25 0.03 0.125 1 2 0.25 1 Snydman et al., 2018 44 *Range N.D. 0.06–0.5 0.06-1 1–4 0.12-4 (US) 11 MIC 50 MIC 90 0.12 0.25 0.12 0.5 1 2 0.5 2 45 #Range 0.06–0.5 0.06-1 0.5-2 0.12-2 MIC 50 MIC 90 0.12 0.5 0.25 0.5 1 2 0.25 1 van Eijk, et al., 2019 (the Netherlands) 33 363 Range MIC 50 MIC 90 0.5-4 2 4 N.D. N.D. N.D. N.D. Murray et al., 2020 (USA) 14 104 Range MIC 50 MIC 90 1–8 4 4 N.D. 0.015-1 0.12 0.25 0.5-4 1 2 0.25-16 0.5 1 Collins et al., 2021 (Japan, China, South Korea) 30 140 Range N.D. 0.03–0.25 0.125 0.25 0.015–0.25 0.125 0.25 0.06-4 1 2 0.06–0.5 0.25 0.25 MIC 50 MIC 90 Snydman et al., 2023 300 Range N.D. 0.3–0.5 0.03–0.5 0.25-4 0.12-4 (US) 29 MIC 50 MIC 90 0.25 0.25 0.25 0.5 2 2 0.5 1 Bassères et al., 2024 (US) 32 100 Range MIC 50 MIC 90 - 4 8 N.D. - 0.5 1 - 2 4 - 0.25 4 The current study 313 Range 0.5-8 0.06–0.5 0.03-16 0.064-256 0.016-256 (Israel) MIC 50 MIC 90 4 4 0.25 0.5 0.25 0.5 0.5 0.75 0.19 0.38 N.D., not detected IBZ MIC 50 / 90 in the current study were similar to those reported in a recent study from the USA (Table 5 ). Out of the four studies evaluating IBZ, only two, including the current study, tested other antibiotics as well. In these two studies, IBZ MIC 90 was higher than the VAN, MTZ and FDX MIC 90 . Discussion The current study investigated the susceptibility of 313 C. difficile isolates collected from patients across Israel, to the recently developed antimicrobials RDZ and IBZ, as well as to currently used antibiotics. ST distribution ST42 and ST2 were the predominant (12.5%, 11.5%, respectively) STs in the current study. ST42 which correlates to Ribotype106/RT106, has been reported worldwide. In the US, RT106 became the second most detected strain in 2012 and the most prevalent strain in 2016 ( 18 , 19 ). This strain produces both toxins A and B, but not the binary toxin. Additionally, it showed high resistance to erythromycin, clindamycin, fluoroquinolones, and third-generation cephalosporins. Most RT106 isolates are susceptible to metronidazole and vancomycin ( 19 ). Regarding ST2, a study performed in a Chinese hospital found ST2 to be the second-most-prevalent ST (10, 11.11%) among the 90 isolated strains ( 20 ). Similar to RT106/ST42, ST2 is toxins A and B producer ( 20 ). A recent study from Germany that characterized C. difficile isolates recovered from various environmental samples, also found ST2 to be the second-most-prevalent (14/166, 8%) ST ( 21 ). Although the contribution of environmental bacteria to CDI is not fully understood, the similar prevalence of ST2 in both clinical and environmental isolates suggests that the environmental strains constitute a source for both CA- and HA-CDI. Interestingly, a previous study conducted by our group, which characterized 70 C. difficile isolates during the years 2016–2018, reported ST4 (22.5%) and ST37 (12.7%) were the most common STs ( 22 ). Although this study was performed in one geographic area in Israel, the different distribution of STs as compared to the current study suggest the epidemiology of CDI have been changing in Israel. Additionally, studies from other Middle East countries reported different strain distribution; for example, An Iranian study which investigated 65 isolates in 2020, found that RT001/ST3 (32.3%) and RT126/ST11 (9.2%) were the most prevalent strains ( 23 ). In Lebanon, two strains were the dominant in 2018- RT014/ST2 (16.8%), which is similar to our results, and RT002/ST8 (9.3%) ( 24 ). Thus, C. difficile strains' distribution differs in different geographic areas and different periods. Among our HA isolates, ST42 was more common than ST2. In contrast, the opposite order was seen among CA-CDI isolates, where ST2 was the most detected strain, followed by ST42. Several studies suggested that RT014/RT020/ST2 has a community origin ( 25 , 26 ), a hypothesis that was strengthened by the current results. Furthermore, RT014/ST2 isolates have been recovered from various environmental sources including wastewater ( 27 ), parks and homes ( 28 ), another strengthening evidence for a community origin for this strain. Susceptibility of study isolates to antibiotics in clinical use Resistance rates to MTZ and VAN were low (2.2% and 1.6%, respectively). A previous study by our group, which characterized 70 isolates from north Israel, reported on higher (17.1%) resistance rate to MTZ and a similar resistance rate (1.4%) to VAN ( 22 ). As mentioned earlier, these changes may indicate on the evolving epidemiology of C. difficile in Israel. Lower resistance rates to both MTZ (0.3%) and VAN (0.7%) were reported in a recent US study of 300 C. difficile isolates ( 29 ). Collins et al, who investigated the susceptibility of 140 C. difficile isolates from Japan, China and South Korea, to various antibiotics, did not find any isolates resistant to either MTZ or VAN ( 30 ). Our low resistance rates might result from decreased use of MTZ and VAN in recent years, due to the introduction of FDX into clinical use. FDX MIC 50 in the current study was low (0.25 µg/mL). However, high FDX MICs were detected (the highest MIC was 32 µg/mL), as compared to MICs reported in recent studies (see Table 5 ). Although there is no clinical breakpoint for FDX, using the 0.5 mg/L cut-off proposed by EUCAST suggests that there are already FDX-resistant strains in Israel. Yet, according to a recent systematic review and meta-analysis of 1184 isolates, the resistance rate to FDX based on a breakpoint of ≥ 8 mg/L, was 0.08% ( 31 ). Thus, FDX susceptibility should be further monitored for early recognition of resistant strains and treatment failure. Susceptibility of study isolates to RDZ and IBZ Overall, low MIC to RDZ and IBZ were observed. Additionally, their activities were efficient against all STs and against isolates with different susceptibilities to MTZ/VAN/FDX. Specifically for IBZ, our results strengthen previous reports according to which the activity of IBZ was not different against different ribotypes or strains with different MTZ/VAN/FDX susceptibility patterns ( 32 , 33 ). When comparing the present results with recent studies that investigated RDZ susceptibility, the MICs in the current study were among the highest reported values. For example, most studies reported on MIC 90 of 0.25 mg/L and lower, while in the current study, the MIC 90 was 0.5 mg/L. Currently, there are no breakpoints for this new antimicrobial and further studies should be performed to gain sufficient and a comprehensive data regarding C. difficile susceptibility to RDZ. Comparison of RDZ activity to that of other antibiotics showed that the RDX MIC 90 was generally lower or similar to the MIC 90 of FDX and always lower than those of VAN and MTZ. Furthermore, RDZ was shown to have lesser activity against Gram-negative anaerobes and Gram-positive aerobes, as compared to FDX, VAN and MTZ ( 34 ). Thus, the superiority of RDZ over the currently used antibiotics is expressed not only by its increased potency against C. difficile , but also by its reduced effect on the gut microbiome. It should be noted that RDZ's manufacturer has stopped clinical trials due to the non-superiority of RDZ on VAN in sustained clinical response and consider changes in this molecule ( 35 ). The IBZ MIC 50 and MIC 90 for isolates in the current study aligned with those previously reported by others. However, only few studies reported on in vitro susceptibility of C. difficile to this antimicrobial. Thus, additional studies are needed in order to have a good comparison of susceptibility of isolates from different geographic areas. Of note, IBZ had a wider MIC range and higher values of MIC 50/90 , as compared to RDZ, which may indicate increased potency of RDZ as compared to IBZ. However, our study is the only study that tested both RDZ and IBZ activity and thus we do not have previous data to compare with, and this issue should be further investigated. IBZ MIC was also higher than those of FDX, MTZ and VAN. However, the main advantages of IBZ include minimal adverse effects and limited interruption to gut microbiome ( 13 ), which outweigh the high dose requirement. Conclusions This study demonstrated the potent in vitro activity of RDZ and IBZ against 313 C. difficile isolates belonging to different STs and clades. So far, the two antimicrobials has proved to be ideal for CDI treatment, with excellent activity against C. difficile and minimal impact on bacterial species that constitute the gut microbiome. Abbreviations CA: community-acquired; CDI: C. difficile infection; FDX: fidaxomicin; HA: hospital-acquired; IBZ: ibezpolstat; MALDI-TOF: matrix-assisted laser desorption ionization-time of flight; MIC: minimum inhibitory concentration; MLST: multi-locus sequencing typing; MTZ: metronidazole; RDZ: ridinilazole; ST: sequence type; VAN: vancomycin Declarations Ethics approval and consent to participate: The local Ethics (Helsinki) Committee of each medical centre approved the study (POR-0085-15, WOMC-0115-20, SOR-0307-20). The need for informed consent was waived. Clinical trial number : not applicable Consent for publication: Not applicable Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions: OS collected the data, performed the experiments, analysed results and wrote the manuscript. MA and AP were major contributors in result analysis and the manuscript writing. All authors read and approved the final manuscript. Acknowledgements: Not applicable. References Gawey BJ, Khanna S. Clostridioides difficile Infection: Landscape and Microbiome Therapeutics. Gastroenterol Hepatol (N Y). 2023;19(6), 319–328. Guh AY, Mu Y, Winston LG, Johnston H, Olson D, Farley MM, et al. Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes . New England Journal of Medicine. 2020;382(14):1320–30. Seekatz AM, Safdar N, Khanna S. The role of the gut microbiome in colonization resistance and recurrent Clostridioides difficile infection. Therap Adv Gastroenterol. 2022; 15:17562848221134396. van Prehn J, Reigadas E, Vogelzang EH, Bouza E, Hristea A, Guery B, et al. European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin Microbiol Infect. 2021;27 Suppl 2:S1-S21.5. Chilton CH, Pickering DS, Freeman J. Microbiologic factors affecting Clostridium difficile recurrence. Clin Microbiol Infect. 2018;24(5):476–482. Zhanel GG, Walkty AJ, Karlowsky JA. Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection. Can J Infect Dis Med Microbiol. 2015;26(6):305–312. Gonzales-Luna AJ, Carlson TJ, Garey KW. Emerging Options for the Prevention and Management of Clostridioides difficile Infection. Drugs. 2023 Feb 1;83(2):105–116. Okhuysen PC, Ramesh MS, Louie T, Kiknadze N, Torre-Cisneros J, de Oliveira CM, et al. A Randomized, Double-Blind, Phase 3 Safety and Efficacy Study of Ridinilazole Versus Vancomycin for Treatment of Clostridioides difficile Infection: Clinical Outcomes With Microbiome and Metabolome Correlates of Response. Clin Infect Dis. 2024;78(6):1462–1472. Weiss W, Pulse M, Vickers R. In vivo assessment of smt 19969 in a hamster model of clostridium difficile infection. Antimicrob Agents Chemother. 2014;58(10):5714–5718. Baines SD, Crowther GS, Freeman J, Todhunter S, Vickers R, Wilcox MH. SMT19969 as a treatment for Clostridium difficile infection: An assessment of antimicrobial activity using conventional susceptibility testing and an in vitro gut model. J Antimicrob Chemother. 2015;70(1):182–189. Snydman DR, McDermott LA, Thorpe CM, Chang J, Wick J, Walk ST, et al. Antimicrobial susceptibility and ribotypes of Clostridium difficile isolates from a Phase 2 clinical trial of ridinilazole (SMT19969) and vancomycin. J Antimicrob Chemother. 2018;73(8):2078–2084. Qian X, Yanagi K, Kane A V., Alden N, Lei M, Snydman DR, et al. Ridinilazole, a narrow spectrum antibiotic for treatment of Clostridioides difficile infection, enhances preservation of microbiota-dependent bile acids. Am J Physiol Gastrointest Liver Physiol. 2020;319(2):G227–G237 Garey KW, Mcpherson J, Dinh AQ, Hu C, Jo J, Wang W, et al. Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial. Clin Infect Dis. 2022;75(7):1164–1170. Murray B, Wolfe C, Marra A, Pillar C, Shinabarger D. In vitro activity of the novel antibacterial agent ibezapolstat (ACX-362E) against Clostridioides difficile. J Antimicrob Chemother. 2020;75(8):2149–2155. Griffiths D, Fawley W, Kachrimanidou M, Bowden R, Crook DW, Fung R, et al. Multilocus sequence typing of Clostridium difficile. J Clin Microbiol. 2010;48(3):770–8. EUCAST breakpoints 2020. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 10.0, 2020. http://www.eucast.org. Breakpoint tables for interpretation of MICs and zone diameters Version 100. 2020; Meng X, Huang X, Peng Z, Wang Y, Liu S, Zeng C, et al. Antibiotic Resistances and Molecular Characteristics of Clostridioides difficile in ICUs in a Teaching Hospital From Central South China. Front Med (Lausanne) . 2021;8:745383. Roxas BAP, Roxas JL, Claus-Walker R, Harishankar A, Mansoor A, Anwar F, et al. Phylogenomic analysis of Clostridioides difficile ribotype 106 strains reveals novel genetic islands and emergent phenotypes. Sci Rep. 2020;10(1):22135. Carlson TJ, Blasingame D, Gonzales-Luna AJ, Alnezary F, Garey KW. Clostridioides difficile ribotype 106: A systematic review of the antimicrobial susceptibility, genetics, and clinical outcomes of this common worldwide strain. Anaerobe. 2020;62:102142. Cui Y, Zhang C, Jia Q, Gong X, Tan Y, Hua X, et al. An epidemiological surveillance study (2021–2022): detection of a high diversity of Clostridioides difficile isolates in one tertiary hospital in Chongqing, Southwest China. BMC Infect Dis. 2023;23(1):703. Blau K, Berger FK, Mellmann A, Gallert C. Clostridioides difficile from Fecally Contaminated Environmental Sources: Resistance and Genetic Relatedness from a Molecular Epidemiological Perspective. Microorganisms. 2023;11(10):2497. Rohana H, Azrad M, Nitzan O, Adler A, Binyamin D, Koren O, et al. Characterization of clostridioides difficile strains, the disease severity, and the microbial changes they induce. J Clin Med. 2020;9(12):4099. Baghani A, Mesdaghinia A, Kuijper EJ, Aliramezani A, Talebi M, Douraghi M. High prevalence of Clostridiodes diffiicle PCR ribotypes 001 and 126 in Iran. Sci Rep. 2020;10(1):4658. Berger FK, Rasheed SS, Araj GF, Mahfouz R, Rimmani HH, Karaoui WR, et al. Molecular characterization, toxin detection and resistance testing of human clinical Clostridium difficile isolates from Lebanon. Int J Med Microbiol. 2018;308(3):358–363. Cheknis A, Johnson S, Chesnel L, Petrella L, Sambol S, Dale SE, et al. Molecular epidemiology of Clostridioides (Clostridium) difficile strains recovered from clinical trials in the US, Canada and Europe from 2006-2009 to 2012-2015. Anaerobe. 2018 Oct 1;53:38–42. Hong S, Putsathit P, George N, Hemphill C, Huntington PG, Korman TM, et al. Laboratory-based surveillance of clostridium difficile infection in australian health care and community settings, 2013 to 2018. J Clin Microbiol. 2020 1;58(11):e01552–20. Romano V, Pasquale V, Krovacek K, Mauri F, Demarta A, Dumontet S. Toxigenic clostridium difficile PCR ribotypes from wastewater treatment plants in Southern Switzerland. Appl Environ Microbiol. 2012;78(18): 6643–6646. Jahangir Alam M, Walk ST, Endres BT, Basseres E, Khaleduzzaman M, Amadio J, et al. Community environmental contamination of toxigenic Clostridium difficile. Open Forum Infect Dis. 2017;4(1). Snydman DR, McDermott LA, Thorpe CM, Goldstein EJC, Schuetz AN, Johnson S, et al. A US-based national surveillance study for the susceptibility and epidemiology of Clostridioides difficile isolates with special reference to ridinilazole: 2020–2021. Antimicrob Agents Chemother. 2023;1;67(10):e0034923. Collins DA, Wu Y, Tateda K, Kim HJ, Vickers RJ, Riley T V. Evaluation of the antimicrobial activity of ridinilazole and six comparators against Chinese, Japanese and South Korean strains of Clostridioides difficile. Antimicrob Chemother. 2021;76(4):967–972. Sholeh M, Krutova M, Forouzesh M, Mironov S, Sadeghifard N, Molaeipour L, et al. Antimicrobial resistance in Clostridioides (Clostridium) difficile derived from humans: A systematic review and meta-analysis. Antimicrob Resist Infect Control. 2020;9(1):158. Bassères E, Eubank TA, Begum K, Alam MJ, Jo J, Le TM, et al. Antibacterial activity of ibezapolstat against antimicrobial-resistant clinical strains of Clostridioides difficile . Antimicrob Agents Chemother. 2024;68(3):e0162123. Van Eijk E, Boekhoud IM, Kuijper EJ, Bos-Sanders IMJG, Wright G, Smits WK. Genome Location Dictates the Transcriptional Response to PolC Inhibition in Clostridium difficile. Van Eijk E, Boekhoud IM, Kuijper EJ, Bos-Sanders IMJG, Wright G, Smits WK. Genome Location Dictates the Transcriptional Response to PolC Inhibition in Clostridium difficile. Antimicrob Agents Chemother. 2019;63(2):e01363–18. Goldstein EJC, Citron DM, Tyrrell KL, Merriam CV. Comparative in vitro activities of SMT19969, a new antimicrobial agent, against Clostridium difficile and 350 gram-positive and gram-negative aerobic and anaerobic intestinal flora isolates. Antimicrob Agents Chemother . 2013;57(10):4872–4876. Gancarz D. Summit Therapeutics Provides Update on Ridinilazole Check Point Threat Extraction secured this document [Internet]. Available from: https://www.summittxinc.com Additional Declarations No competing interests reported. Supplementary Files SupplementalTable1.docx Cite Share Download PDF Status: Published Journal Publication published 31 Mar, 2025 Read the published version in BMC Gastroenterology → Version 1 posted Editorial decision: Revision requested 29 Jan, 2025 Editor assigned by journal 29 Jan, 2025 Submission checks completed at journal 15 Jan, 2025 First submitted to journal 13 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5818289","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":402538800,"identity":"6b12f1a5-6b00-417d-b2bb-5b8460308dd6","order_by":0,"name":"Orna Schwartz","email":"","orcid":"","institution":"Bar Ilan University","correspondingAuthor":false,"prefix":"","firstName":"Orna","middleName":"","lastName":"Schwartz","suffix":""},{"id":402538801,"identity":"d20e94e8-e589-478c-908c-64b55ba97b66","order_by":1,"name":"Maya Azrad","email":"","orcid":"","institution":"Tzafon Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Maya","middleName":"","lastName":"Azrad","suffix":""},{"id":402538802,"identity":"ddb0d724-d60f-4f78-b6a5-fcaa9962ab0e","order_by":2,"name":"Avi Peretz","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYBADOQSTmbmBCA0JDMY8CC2MxGlJ7EHwCGjhn9187MPHH3Xp+/lPJ35g+GWT2MBOQIvEnWPJM2cksOX2MJzdLMHYl5bYQNBhN3KMmXkSeHJ7GHu3MTD2HDYm6Bf5G/mfmf8kSKTzMPMSqcXgRg4zM0OCQQIPG1ALw4/DcgS1GN45ZszYk5Zg2HOGd7NEYkOaHBshLXK3mx8z/LCpk2fvP7vxw4c/Njz8/IcP4NXCIIHMSWxjYGDDrx5dC8MfgupHwSgYBaNgBAIA/4Q/HN8L/1sAAAAASUVORK5CYII=","orcid":"","institution":"Bar Ilan University","correspondingAuthor":true,"prefix":"","firstName":"Avi","middleName":"","lastName":"Peretz","suffix":""}],"badges":[],"createdAt":"2025-01-13 08:53:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5818289/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5818289/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12876-025-03800-7","type":"published","date":"2025-03-31T15:57:40+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":74243344,"identity":"56770628-455e-4cd5-91ef-3341aa584ce9","added_by":"auto","created_at":"2025-01-20 09:41:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46105,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eC. difficile\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e sequence types (STs) among study isolates.\u003c/strong\u003e \u003cem\u003eC. difficile\u003c/em\u003e isolates were typed by MLST. The figure presents the distribution of STs among \u003cem\u003eC. difficile\u003c/em\u003e isolates that were recovered from stool samples of patients with (a) HA-CDI (n=187), (b) CA-CDI (n=126).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5818289/v1/c4c8a994ebd83e5c4516f353.png"},{"id":74241483,"identity":"2f05ce3e-b460-49b1-95c1-a0e263dc0931","added_by":"auto","created_at":"2025-01-20 09:33:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51163,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of MIC values of study isolates to different antibiotics. \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eC. difficile\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e susceptibility to antibiotics was determined by the E test or by agar dilution methods\u003c/strong\u003e. The figure presents the distribution of MIC values of all study isolates to the following antibiotics (a) metronidazole, (b) vancomycin, (c) fidaxomicin, (d) ridinilazol and (e) ibezpolstat. The dashed line represent the breakpoints for resistance determination (MIC \u0026gt;2 mg/l for MTZ and VAN, and MIC \u0026gt;0.5 mg/L for FDX).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5818289/v1/6f6f781c401d7258b3c22111.png"},{"id":80082265,"identity":"c00126c8-26bb-4e52-9568-5df0f6d7276a","added_by":"auto","created_at":"2025-04-07 16:08:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1408087,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5818289/v1/abfd2524-fb21-4ad1-a624-ed644180658f.pdf"},{"id":74244046,"identity":"746401f5-8f71-40e1-80ce-2b9e0beb0439","added_by":"auto","created_at":"2025-01-20 09:49:17","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14257,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5818289/v1/97d04f4c38e8a70b0358f90a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"In vitro susceptibility of clinical Clostridioides difficile isolates to ridinilazole and ibezapolstat in Israel, 2020-2022","fulltext":[{"header":"Background","content":"\u003cp\u003e \u003cem\u003eClostridioides difficile\u003c/em\u003e (\u003cem\u003eC. difficile\u003c/em\u003e) is a Gram-positive, anaerobic bacterium which causes significant diarrheal illness, both in healthcare and community facilities (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSince 2011, Emerging Infections Program (EIP) of the Centers for Disease Control and Prevention (CDC) has been monitoring \u003cem\u003eC. difficile\u003c/em\u003e infection (CDI) in 10 US sites. A recent study which used the EIP data, reported on a 24% decrease in the total burden of CDI in the US between the years 2011 and 2017. Nevertheless, there was no changes in the high burden of first recurrences and of CDI-associated in-hospital mortality (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCDI onset begins with ingestion of spores, followed by their germination in the gut, which results in bacterial colonization and proliferation. Then, toxins produced by the bacteria disrupt the gut epithelial integrity, induce cytotoxic effects on intestinal cells and stimulate an inflammatory response (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The main risk factor for developing CDI is antibiotic administration as it induces dysbiosis, i.e., alteration of the gut microbiome composition, which results in germination of \u003cem\u003eC. difficile\u003c/em\u003e spores (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Another potential outcome of dysbiosis is an increased ratio of primary-to-secondary bile acids. As primary bile acids promote spore germination while secondary bile acids inhibit \u003cem\u003eC. difficile\u003c/em\u003e growth, this shift also contributes to CDI development (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEven though they constitute a risk factor, antibiotics are currently the primary treatment for CDI. The main options in use are fidaxomicin (FDX) and vancomycin (VAN); metronidazole may be given when the previous two antibiotics are not available (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Although MTZ and VAN are effective against vegetative \u003cem\u003eC. difficile\u003c/em\u003e cells, their use still induces gut microbiome disruption, which may lead to further \u003cem\u003eC. difficile\u003c/em\u003e spore germination and disease recurrence (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). FDX advantages over VAN and MTZ, are the lower concentration needed for treatment, longer duration of effect, and reduced disease recurrence rate (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Additionally, FDX use has been associated with less microbiome dysbiosis (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn recent years, several new \u003cem\u003eC. difficile\u003c/em\u003e strains have emerged, with some of them being resistant to antibiotics in clinical use. Additionally, up to 30% of treated patients may experience recurrent CDI due to persistence of antibiotic-resistant spores (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Thus, new alternatives are required. One of the newest developed antibiotics for CDI treatment is ridinilazole (RDZ), a narrow-spectrum antibiotic. RDZ is a a bis-benzimidazole antibiotic with a bacterricidal activity that is mediated by its interaction with AATTT-rich sequences in \u003cem\u003eC. difficile\u003c/em\u003e DNA minor groove, leading to interference with cell division and apparently with ATP production (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn addition to its high inhibitory activity against several \u003cem\u003eC. difficile\u003c/em\u003e strains, both \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), RDZ reduced CDI recurrence rate from 17.3\u0026ndash;8.1%, compared to VAN (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0002) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In contrast to VAN, RDZ did not impact the gut microbiome(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) and had no effect on secondary bile acids (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In line with these reports, two clinical trials (NCT03595553 and CT03595566) comparing the efficacy of RDZ vs. VAN, found better conservation of gut microbiome with RDZ (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). RDZ treatment in a phase 3 superiority trial was associated with less recurrence cases and increased secondary bile acids levels (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Recently, a phase 3 study of RDZ has been terminated; due to the insuperiority of RDZ on VAN in sustained clinical response (73%, and 70.7%, respectively), the drug company which developed RDZ stated on rethinking(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIbezapolstat (IBZ) is another treatment recently developed for CDI. This narrow-spectrum antibiotic binds and inhibits DNA polymerase IIIC (DNA pol IIIC), which is unique to Gram-positive bacteria with a low G\u0026thinsp;+\u0026thinsp;C content. IBZ has been tested in clinical trials and has exhibited several advantages, including minimal adverse effects, good pharmacokinetics, a favourable secondary-to-primary bile acid ratio and limited damage to the gut microbiome (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Murray et al. reported on the potent activity of IBZ against 104 \u003cem\u003eC. difficile\u003c/em\u003e isolates (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Recently, phase 2b clinical trial of ibezapolstat has been completed.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, there are no data regarding susceptibility of clinical \u003cem\u003eC. difficile\u003c/em\u003e strains to RDZ and IBZ in Israel. Additionally, since antibiotic susceptibility testing for \u003cem\u003eC. difficile\u003c/em\u003e is not routinely evaluated by clinical laboratories, there are limited data on susceptibility rates to the currently used treatments. Therefore, this study aims to assess the susceptibility of different clinical strains, collected from several areas in Israel between 2020 and 2022, to RDZ, IBZ, FDX, MTZ and VAN.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy isolates\u003c/h2\u003e \u003cp\u003eThe study included 313 \u003cem\u003eC. difficile\u003c/em\u003e isolates that were recovered from stool samples of patients diagnosed with CDI and hospitalized in one of four medical centres in Israel between 2020 and 2022. CDI was confirmed with the GeneXpert \u003cem\u003eC. difficile\u003c/em\u003e BT PCR assay (Cepheid, Sunnyvale, CA, USA) which identifies toxin B and binary toxin genes, and \u003cem\u003etcd\u003c/em\u003eC deletion (independent identification of the epidemic Nap1/027 strain). Community-acquired CDI (CA-CDI) was defined as CDI that developed within 48 hours of admission, while hospital-acquired CDI (HA-CDI) was defined as CDI that developed\u0026thinsp;\u0026gt;\u0026thinsp;48 h after admission.\u003c/p\u003e \u003cp\u003eThe four participating medical centres are located in different geographic areas of Israel: North - Tzafon Medical Center, Poriya and W. Hirsch Regional Microbiology Laboratory Clalit Health Services, Haifa, Center - Edith Wolfson Medical Center, Holon, and South - Soroka University Medical Center, Be'er Sheva. The local Ethics (Helsinki) Committee of each medical centre approved the study (POR-0085-15, WOMC-0115-20, SOR-0307-20). The need for informed consent was waived.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMulti-locus sequence typing (MLST)\u003c/h3\u003e\n\u003cp\u003eDNA was extracted from study isolates using the MagCore\u0026reg; Genomic DNA Bacterial Kit (ATRIDAB.V, Amersfoort, Netherlands) with the MagCore\u0026reg; automated extraction instrument (RBCBioscience, New Taipei, Taiwan), according to the manufacturer\u0026rsquo;s instructions. Following whole-genome sequencing of DNA samples, the sequences of seven housekeeping genes (\u003cem\u003eadk\u003c/em\u003e, \u003cem\u003eatp\u003c/em\u003eA, \u003cem\u003edxr\u003c/em\u003e, \u003cem\u003egly\u003c/em\u003eA, \u003cem\u003erec\u003c/em\u003eA, \u003cem\u003esod\u003c/em\u003eA, and \u003cem\u003etpi\u003c/em\u003e) of each isolate were uploaded to the \u003cem\u003eC. difficile\u003c/em\u003e MLST database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmlst.org/organisms/clostridioides-difficile\u003c/span\u003e\u003cspan address=\"https://pubmlst.org/organisms/clostridioides-difficile\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), in order to determine the sequence type (ST), as previously described (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eBacterial isolation and identification\u003c/h3\u003e\n\u003cp\u003eStool samples were inoculated on a selective growth agar medium, chromID\u0026trade; \u003cem\u003eC. difficile\u003c/em\u003e (CDIF) (BioM\u0026eacute;rieux, Durham, NC), and incubated for 48 h, at 37\u0026deg;C, in a Bactron EZ 300 anaerobic chamber (Sheldon manufacturing, Cornelius, USA). Identification of \u003cem\u003eC. difficile\u003c/em\u003e colonies was based on colonies' asymmetrical shape and black color. The Bruker Biotyper system (Bruker Daltonics, Bremen, Germany), that is based on matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry, was used for definitive. All isolates were stored at -80\u0026deg;C until further analysis.\u003c/p\u003e\n\u003ch3\u003eAntimicrobial susceptibility testing\u003c/h3\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSusceptibility testing for MTZ and VAN\u003c/h2\u003e \u003cp\u003eSusceptibility to MTZ and VAN was assessed using the Etest technique, which determines the minimum inhibitory concentration (MIC). Several \u003cem\u003eC. difficile\u003c/em\u003e colonies were suspended in thioglycollate broth medium (Becton Dickinson, Heidelberg, Germany) to achieve 1.0 McFarland standards. Then, bacterial suspensions were inoculated on Brucella blood agar (Hy Laboratories, Rehovot, Israel) and a gradient Etest strip (bioM\u0026eacute;rieux, Durham, NC) of VAN or MTZ was added. The agar plates were incubated at 37\u0026deg;C under anaerobic conditions for 48 h. Following incubation, the MIC was visually determined and isolates were classified as susceptible or resistant according to breakpoints of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSusceptibility testing for FDX, RDZ and IBZ\u003c/h2\u003e \u003cp\u003eSusceptibility to FDX, RDZ and IBZ in accordance with the procedures of the Clinical and Laboratory Standards Institute (CLSI-M11-9th ) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Brucella agar supplemented with 5% defibrinated sheep blood (Hy Laboratories) was mixed with FDX (Sigma-Aldrich, Missouri, US), RDZ or IBZ (MedChemExpress LLC, NJ, USA) by first dissolving the antibiotics in dimethyl sulfoxide (DMSO) and then further diluting it with distilled water to various concentrations. The agar plates were mixed with the different dilutions of each antibiotic, yielding the following ranges of final concentrations: FDX 0.03-32 mg/L, RDZ-0.03-0.5 mg/L, and IBZ- 0.5-8 mg/L.\u003c/p\u003e \u003cp\u003eSeveral \u003cem\u003eC. difficile\u003c/em\u003e colonies were inoculated in thioglycollate broth medium (Becton Dickinson) to 0.5 McFarland turbidity, and then placed as spots on the antibiotics-supplemented agar plates. Plates were incubated at 35\u0026deg;C, under anaerobic conditions, for 48 h. After incubation, plates were visually screened for bacterial growth, and MIC was determined as the lowest antibiotic concentration that inhibited bacterial growth.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe study included 313 isolates, recovered from 187 patients with HA-CDI and 126 patients with CA-CDI.\u003c/p\u003e\n\u003ch3\u003eST distribution\u003c/h3\u003e\n\u003cp\u003eST was determined for 90.1% (282/313) of the isolates, while the rest of isolates remained unclassified. Isolates were categorized into ten major groups, with each group containing at least seven isolates (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). An additional group, called \"others\", included 108 (34.5%) isolates had STs shared by fewer than seven isolates (Supplemental Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of ST among study isolates\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39 (12.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36 (11.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23 (7.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21 (6.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (2.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (2.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1, 2, 3, 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e108 (34.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnclassified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN.A.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31 (9.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe most prevalent STs were ST42 (n\u0026thinsp;=\u0026thinsp;39; 12.5%) and ST2 (n\u0026thinsp;=\u0026thinsp;36; 11.5%). Most isolates (274/282; 97.2%) belonged to Clade 1, one isolate with ST1 belonged to Clade 2, 2 isolates with ST5 belonged to Clade 3, 9 isolates (8 ST37 and 1 ST39), belonged to Clade 4 and 21 isolates of ST11, belonged to Clade 5. The \"Others\" group included isolates from Clades 1\u0026ndash;4 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). One hypervirulent strain (0.3%), belonged to ST1, was found.\u003c/p\u003e \u003cp\u003eOverall, the same STs were found among both CA and HA isolates, however, their distributions differed (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). For example, among HA isolates, ST42 (13.9%) was the most common strain, while ST2 was the most (13.5%) frequent ST among CA isolates. ST37 was more frequent detected among HA isolates compared to CA isolates (3.7%, 0.8%, respectively).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSusceptibility of study isolates\u003c/h2\u003e \u003cp\u003eBacterial susceptibility to MTZ, VAN, FDX and to the new antimicrobials RDX and IBZ was assessed (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The MIC of MTZ were in the range of 0.016-256 mg/L and MIC\u003csub\u003e50/90\u003c/sub\u003e were 0.19/0.38 mg/L. Resistance rate to MTZ was low (2.2%). The MIC\u003csub\u003e50\u003c/sub\u003e of VAN was 0.5 mg/L, the MIC\u003csub\u003e90\u003c/sub\u003e was 0.75 mg/L, and the resistance rate was low (1.6%). The geometric MIC means of both MTZ and VAN were quite high (6 mg/L and 2.5 mg/L, respectively). FDX MIC was in the range of 0.03-16 mg/L and MIC\u003csub\u003e50/90\u003c/sub\u003e was 0.25/0.5 mg/L. Twenty three (7.35%) isolates were resistant to FDX. RDX MIC ranged between 0.06 mg/L and 0.5 mg/L, and the MIC\u003csub\u003e50/90\u003c/sub\u003e was 0.25/0.5 mg/L. IBZ had an MIC\u003csub\u003e50/90\u003c/sub\u003e of 4 mg/L.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAntimicrobial susceptibility of study isolates\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntimicrobial agent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC Range (mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGeometric MIC mean (mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e% Resistance\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetronidazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.016-256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVancomycin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.064-256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFidaxomicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.03-16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRidinilazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.A.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIbezapolstat\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.A.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDifferent STs had no major differences in MIC to the different antibiotics, including RDX and IBZ (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Furthermore, when we compared the MIC\u003csub\u003e50\u003c/sub\u003e/90 and geometric mean MIC values for RDZ and IBZ between MTZ-susceptible and MTZ-resistant strains, as well as between VAN-susceptible and VAN-resistant strains, no differences were observed; similar result was seen for FDX- susceptible and FDX-resistant strains (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). We also compared our results with data from all studies that tested the \u003cem\u003ein vitro\u003c/em\u003e activity of RDZ and/or IBZ (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). RDZ MIC in the current analysis were among the highest reported values. In most studies, RDZ had a lower MIC\u003csub\u003e90,\u003c/sub\u003e compared to MTZ and VAN. When compared to the newest antibiotic in use, RDZ had either lower or equal MIC\u003csub\u003e90\u003c/sub\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAntibiotic susceptibility of study isolates, with relation to ST\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStrains\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC (\u0026micro;g/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMTZ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVAN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFDX\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRDZ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIBZ\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eST2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.032-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.094-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.03-16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.12\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;36)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eST3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.023-0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25\u0026ndash;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.03-16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.12\u0026ndash;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eST11\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.016-256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.064-256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.03-16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.12\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;21)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eST13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.125\u0026ndash;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u0026ndash;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06-16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.12\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;7)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eST34\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.032\u0026ndash;0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eST37\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.016-256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u0026ndash;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u0026ndash;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;8)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eST42\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.016-256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25-56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.03-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5-4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eST54\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.023\u0026ndash;0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.38-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u0026ndash;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.12\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eST55\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.064\u0026ndash;0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u0026ndash;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u0026ndash;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.25\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eST104\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.023-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.38-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.03-16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;23)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUnclassified\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.047-256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.125-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06-16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;31)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOthers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.016-256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.125-256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.03-16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5-8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;108)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSusceptibility of study isolates to RDZ and IBZ, with relation to their susceptibility to MTZ, VAN and FDX\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAntimicrobial agent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRDZ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIBZ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGeometric MIC mean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGeometric MIC mean\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e(mg/L)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMetronidazole-S\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMetronidazole-R\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.313\u003c/p\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.07\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVancomycin-S\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.314\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVancomycin-R\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.374\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFidaxomicin-S\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFidaxomicin-R\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of reported data regarding \u003cem\u003eC. difficile\u003c/em\u003e susceptibility to MTZ, VAN, FDX, RDZ and IBZ\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e(Geographic area)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of isolates\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC (\u0026micro;g/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIBZ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRDZ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFDX\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eVAN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMTZ\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDvoskin et al., 2012\u003c/p\u003e \u003cp\u003e(USA) \u003csup\u003e36\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNot shown\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGoldstein et al., 2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.125-0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.06-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.25-8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(USA) \u003csup\u003e34\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorbett at al., 2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u0026ndash;0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.008\u0026ndash;0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.125-8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(UK) \u003csup\u003e37\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFreeman et al., 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.015-0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.004\u0026ndash;0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.125-2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(Europe) \u003csup\u003e38\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSnydman et al., 2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.015-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.12-2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(US) \u003csup\u003e39\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSnydman et al., 2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e*Range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.06-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.12-4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e(US) \u003csup\u003e11\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e#Range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.06-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.12-2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evan Eijk, et al., 2019 (the Netherlands) \u003csup\u003e33\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e363\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5-4\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMurray et al., 2020 (USA) \u003csup\u003e14\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u0026ndash;8\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.015-1\u003c/p\u003e \u003cp\u003e0.12\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5-4\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.25-16\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCollins et al., 2021\u003c/p\u003e \u003cp\u003e(Japan, China, South Korea) \u003csup\u003e30\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.03\u0026ndash;0.25\u003c/p\u003e \u003cp\u003e0.125\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.015\u0026ndash;0.25\u003c/p\u003e \u003cp\u003e0.125\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.06-4\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSnydman et al., 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.03\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.12-4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(US) \u003csup\u003e29\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBass\u0026egrave;res et al., 2024\u003c/p\u003e \u003cp\u003e(US) \u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN.D.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe current study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e313\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.03-16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.064-256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.016-256\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(Israel)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMIC\u003csub\u003e90\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eN.D., not detected\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIBZ MIC\u003csub\u003e50\u003c/sub\u003e/\u003csub\u003e90\u003c/sub\u003e in the current study were similar to those reported in a recent study from the USA (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Out of the four studies evaluating IBZ, only two, including the current study, tested other antibiotics as well. In these two studies, IBZ MIC\u003csub\u003e90\u003c/sub\u003e was higher than the VAN, MTZ and FDX MIC\u003csub\u003e90\u003c/sub\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe current study investigated the susceptibility of 313 \u003cem\u003eC. difficile\u003c/em\u003e isolates collected from patients across Israel, to the recently developed antimicrobials RDZ and IBZ, as well as to currently used antibiotics.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eST distribution\u003c/h2\u003e \u003cp\u003eST42 and ST2 were the predominant (12.5%, 11.5%, respectively) STs in the current study. ST42 which correlates to Ribotype106/RT106, has been reported worldwide. In the US, RT106 became the second most detected strain in 2012 and the most prevalent strain in 2016 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). This strain produces both toxins A and B, but not the binary toxin. Additionally, it showed high resistance to erythromycin, clindamycin, fluoroquinolones, and third-generation cephalosporins. Most RT106 isolates are susceptible to metronidazole and vancomycin (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding ST2, a study performed in a Chinese hospital found ST2 to be the second-most-prevalent ST (10, 11.11%) among the 90 isolated strains (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Similar to RT106/ST42, ST2 is toxins A and B producer (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). A recent study from Germany that characterized \u003cem\u003eC. difficile\u003c/em\u003e isolates recovered from various environmental samples, also found ST2 to be the second-most-prevalent (14/166, 8%) ST (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Although the contribution of environmental bacteria to CDI is not fully understood, the similar prevalence of ST2 in both clinical and environmental isolates suggests that the environmental strains constitute a source for both CA- and HA-CDI.\u003c/p\u003e \u003cp\u003eInterestingly, a previous study conducted by our group, which characterized 70 \u003cem\u003eC. difficile\u003c/em\u003e isolates during the years 2016\u0026ndash;2018, reported ST4 (22.5%) and ST37 (12.7%) were the most common STs (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Although this study was performed in one geographic area in Israel, the different distribution of STs as compared to the current study suggest the epidemiology of CDI have been changing in Israel. Additionally, studies from other Middle East countries reported different strain distribution; for example, An Iranian study which investigated 65 isolates in 2020, found that RT001/ST3 (32.3%) and RT126/ST11 (9.2%) were the most prevalent strains (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). In Lebanon, two strains were the dominant in 2018- RT014/ST2 (16.8%), which is similar to our results, and RT002/ST8 (9.3%) (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Thus, \u003cem\u003eC. difficile\u003c/em\u003e strains' distribution differs in different geographic areas and different periods.\u003c/p\u003e \u003cp\u003eAmong our HA isolates, ST42 was more common than ST2. In contrast, the opposite order was seen among CA-CDI isolates, where ST2 was the most detected strain, followed by ST42. Several studies suggested that RT014/RT020/ST2 has a community origin (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), a hypothesis that was strengthened by the current results. Furthermore, RT014/ST2 isolates have been recovered from various environmental sources including wastewater (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), parks and homes (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), another strengthening evidence for a community origin for this strain.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSusceptibility of study isolates to antibiotics in clinical use\u003c/h2\u003e \u003cp\u003eResistance rates to MTZ and VAN were low (2.2% and 1.6%, respectively). A previous study by our group, which characterized 70 isolates from north Israel, reported on higher (17.1%) resistance rate to MTZ and a similar resistance rate (1.4%) to VAN (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). As mentioned earlier, these changes may indicate on the evolving epidemiology of \u003cem\u003eC. difficile\u003c/em\u003e in Israel. Lower resistance rates to both MTZ (0.3%) and VAN (0.7%) were reported in a recent US study of 300 \u003cem\u003eC. difficile\u003c/em\u003e isolates (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Collins et al, who investigated the susceptibility of 140 \u003cem\u003eC. difficile\u003c/em\u003e isolates from Japan, China and South Korea, to various antibiotics, did not find any isolates resistant to either MTZ or VAN (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Our low resistance rates might result from decreased use of MTZ and VAN in recent years, due to the introduction of FDX into clinical use.\u003c/p\u003e \u003cp\u003eFDX MIC\u003csub\u003e50\u003c/sub\u003e in the current study was low (0.25 \u0026micro;g/mL). However, high FDX MICs were detected (the highest MIC was 32 \u0026micro;g/mL), as compared to MICs reported in recent studies (see Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Although there is no clinical breakpoint for FDX, using the 0.5 mg/L cut-off proposed by EUCAST suggests that there are already FDX-resistant strains in Israel. Yet, according to a recent systematic review and meta-analysis of 1184 isolates, the resistance rate to FDX based on a breakpoint of \u0026ge;\u0026thinsp;8 mg/L, was 0.08% (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Thus, FDX susceptibility should be further monitored for early recognition of resistant strains and treatment failure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSusceptibility of study isolates to RDZ and IBZ\u003c/h2\u003e \u003cp\u003eOverall, low MIC to RDZ and IBZ were observed. Additionally, their activities were efficient against all STs and against isolates with different susceptibilities to MTZ/VAN/FDX. Specifically for IBZ, our results strengthen previous reports according to which the activity of IBZ was not different against different ribotypes or strains with different MTZ/VAN/FDX susceptibility patterns (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWhen comparing the present results with recent studies that investigated RDZ susceptibility, the MICs in the current study were among the highest reported values. For example, most studies reported on MIC\u003csub\u003e90\u003c/sub\u003e of 0.25 mg/L and lower, while in the current study, the MIC\u003csub\u003e90\u003c/sub\u003e was 0.5 mg/L. Currently, there are no breakpoints for this new antimicrobial and further studies should be performed to gain sufficient and a comprehensive data regarding \u003cem\u003eC. difficile\u003c/em\u003e susceptibility to RDZ.\u003c/p\u003e \u003cp\u003eComparison of RDZ activity to that of other antibiotics showed that the RDX MIC\u003csub\u003e90\u003c/sub\u003e was generally lower or similar to the MIC\u003csub\u003e90\u003c/sub\u003e of FDX and always lower than those of VAN and MTZ. Furthermore, RDZ was shown to have lesser activity against Gram-negative anaerobes and Gram-positive aerobes, as compared to FDX, VAN and MTZ (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Thus, the superiority of RDZ over the currently used antibiotics is expressed not only by its increased potency against \u003cem\u003eC. difficile\u003c/em\u003e, but also by its reduced effect on the gut microbiome. It should be noted that RDZ's manufacturer has stopped clinical trials due to the non-superiority of RDZ on VAN in sustained clinical response and consider changes in this molecule (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe IBZ MIC\u003csub\u003e50\u003c/sub\u003e and MIC\u003csub\u003e90\u003c/sub\u003e for isolates in the current study aligned with those previously reported by others. However, only few studies reported on \u003cem\u003ein vitro\u003c/em\u003e susceptibility of \u003cem\u003eC. difficile\u003c/em\u003e to this antimicrobial. Thus, additional studies are needed in order to have a good comparison of susceptibility of isolates from different geographic areas.\u003c/p\u003e \u003cp\u003eOf note, IBZ had a wider MIC range and higher values of MIC\u003csub\u003e50/90\u003c/sub\u003e, as compared to RDZ, which may indicate increased potency of RDZ as compared to IBZ. However, our study is the only study that tested both RDZ and IBZ activity and thus we do not have previous data to compare with, and this issue should be further investigated.\u003c/p\u003e \u003cp\u003eIBZ MIC was also higher than those of FDX, MTZ and VAN. However, the main advantages of IBZ include minimal adverse effects and limited interruption to gut microbiome (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), which outweigh the high dose requirement.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study demonstrated the potent \u003cem\u003ein vitro\u003c/em\u003e activity of RDZ and IBZ against 313 \u003cem\u003eC. difficile\u003c/em\u003e isolates belonging to different STs and clades. So far, the two antimicrobials has proved to be ideal for CDI treatment, with excellent activity against \u003cem\u003eC. difficile\u003c/em\u003e and minimal impact on bacterial species that constitute the gut microbiome.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCA: community-acquired; CDI: \u003cem\u003eC. difficile\u003c/em\u003e infection; FDX: fidaxomicin; HA: hospital-acquired; IBZ: ibezpolstat; MALDI-TOF: matrix-assisted laser desorption ionization-time of flight; MIC: minimum inhibitory concentration; MLST: multi-locus sequencing typing; MTZ: metronidazole; RDZ: ridinilazole; ST: sequence type; VAN: vancomycin\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e The local Ethics (Helsinki) Committee of each medical centre approved the study (POR-0085-15, WOMC-0115-20, SOR-0307-20). The need for informed consent was waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e: not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e \u0026nbsp;OS collected the data, performed the experiments, analysed results and wrote the manuscript. MA and AP were major contributors in result analysis and the manuscript writing. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNot applicable.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGawey BJ, Khanna S. Clostridioides difficile Infection: Landscape and Microbiome Therapeutics. Gastroenterol Hepatol (N Y). 2023;19(6), 319\u0026ndash;328. \u003c/li\u003e\n\u003cli\u003eGuh AY, Mu Y, Winston LG, Johnston H, Olson D, Farley MM, et al. Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes . New England Journal of Medicine. 2020;382(14):1320\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eSeekatz AM, Safdar N, Khanna S. The role of the gut microbiome in colonization resistance and recurrent Clostridioides difficile infection. 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Drugs. 2023 Feb 1;83(2):105\u0026ndash;116. \u003c/li\u003e\n\u003cli\u003eOkhuysen PC, Ramesh MS, Louie T, Kiknadze N, Torre-Cisneros J, de Oliveira CM, et al. A Randomized, Double-Blind, Phase 3 Safety and Efficacy Study of Ridinilazole Versus Vancomycin for Treatment of Clostridioides difficile Infection: Clinical Outcomes With Microbiome and Metabolome Correlates of Response. Clin Infect Dis. 2024;78(6):1462\u0026ndash;1472. \u003c/li\u003e\n\u003cli\u003eWeiss W, Pulse M, Vickers R. In vivo assessment of smt 19969 in a hamster model of clostridium difficile infection. Antimicrob Agents Chemother. 2014;58(10):5714\u0026ndash;5718. \u003c/li\u003e\n\u003cli\u003eBaines SD, Crowther GS, Freeman J, Todhunter S, Vickers R, Wilcox MH. SMT19969 as a treatment for Clostridium difficile infection: An assessment of antimicrobial activity using conventional susceptibility testing and an in vitro gut model. 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Clin Infect Dis. 2022;75(7):1164\u0026ndash;1170.\u003c/li\u003e\n\u003cli\u003eMurray B, Wolfe C, Marra A, Pillar C, Shinabarger D. In vitro activity of the novel antibacterial agent ibezapolstat (ACX-362E) against Clostridioides difficile. J Antimicrob Chemother. 2020;75(8):2149\u0026ndash;2155.\u003c/li\u003e\n\u003cli\u003eGriffiths D, Fawley W, Kachrimanidou M, Bowden R, Crook DW, Fung R, et al. Multilocus sequence typing of Clostridium difficile. J Clin Microbiol. 2010;48(3):770\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eEUCAST breakpoints 2020. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 10.0, 2020. http://www.eucast.org. Breakpoint tables for interpretation of MICs and zone diameters Version 100. 2020; \u003c/li\u003e\n\u003cli\u003eMeng X, Huang X, Peng Z, Wang Y, Liu S, Zeng C, et al. Antibiotic Resistances and Molecular Characteristics of Clostridioides difficile in ICUs in a Teaching Hospital From Central South China. \u003cem\u003eFront Med (Lausanne)\u003c/em\u003e. 2021;8:745383. \u003c/li\u003e\n\u003cli\u003eRoxas BAP, Roxas JL, Claus-Walker R, Harishankar A, Mansoor A, Anwar F, et al. Phylogenomic analysis of Clostridioides difficile ribotype 106 strains reveals novel genetic islands and emergent phenotypes. Sci Rep. 2020;10(1):22135. \u003c/li\u003e\n\u003cli\u003eCarlson TJ, Blasingame D, Gonzales-Luna AJ, Alnezary F, Garey KW. Clostridioides difficile ribotype 106: A systematic review of the antimicrobial susceptibility, genetics, and clinical outcomes of this common worldwide strain. Anaerobe. 2020;62:102142. \u003c/li\u003e\n\u003cli\u003eCui Y, Zhang C, Jia Q, Gong X, Tan Y, Hua X, et al. An epidemiological surveillance study (2021\u0026ndash;2022): detection of a high diversity of Clostridioides difficile isolates in one tertiary hospital in Chongqing, Southwest China. BMC Infect Dis. 2023;23(1):703. \u003c/li\u003e\n\u003cli\u003eBlau K, Berger FK, Mellmann A, Gallert C. Clostridioides difficile from Fecally Contaminated Environmental Sources: Resistance and Genetic Relatedness from a Molecular Epidemiological Perspective. Microorganisms. 2023;11(10):2497. \u003c/li\u003e\n\u003cli\u003eRohana H, Azrad M, Nitzan O, Adler A, Binyamin D, Koren O, et al. Characterization of clostridioides difficile strains, the disease severity, and the microbial changes they induce. J Clin Med. 2020;9(12):4099. \u003c/li\u003e\n\u003cli\u003eBaghani A, Mesdaghinia A, Kuijper EJ, Aliramezani A, Talebi M, Douraghi M. High prevalence of Clostridiodes diffiicle PCR ribotypes 001 and 126 in Iran. Sci Rep. 2020;10(1):4658. \u003c/li\u003e\n\u003cli\u003eBerger FK, Rasheed SS, Araj GF, Mahfouz R, Rimmani HH, Karaoui WR, et al. Molecular characterization, toxin detection and resistance testing of human clinical Clostridium difficile isolates from Lebanon. Int J Med Microbiol. 2018;308(3):358\u0026ndash;363. \u003c/li\u003e\n\u003cli\u003eCheknis A, Johnson S, Chesnel L, Petrella L, Sambol S, Dale SE, et al. Molecular epidemiology of Clostridioides (Clostridium) difficile strains recovered from clinical trials in the US, Canada and Europe from 2006-2009 to 2012-2015. Anaerobe. 2018 Oct 1;53:38\u0026ndash;42. \u003c/li\u003e\n\u003cli\u003eHong S, Putsathit P, George N, Hemphill C, Huntington PG, Korman TM, et al. Laboratory-based surveillance of clostridium difficile infection in australian health care and community settings, 2013 to 2018. J Clin Microbiol. 2020 1;58(11):e01552\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eRomano V, Pasquale V, Krovacek K, Mauri F, Demarta A, Dumontet S. Toxigenic clostridium difficile PCR ribotypes from wastewater treatment plants in Southern Switzerland. Appl Environ Microbiol. 2012;78(18): 6643\u0026ndash;6646. \u003c/li\u003e\n\u003cli\u003eJahangir Alam M, Walk ST, Endres BT, Basseres E, Khaleduzzaman M, Amadio J, et al. Community environmental contamination of toxigenic Clostridium difficile. Open Forum Infect Dis. 2017;4(1). \u003c/li\u003e\n\u003cli\u003eSnydman DR, McDermott LA, Thorpe CM, Goldstein EJC, Schuetz AN, Johnson S, et al. A US-based national surveillance study for the susceptibility and epidemiology of Clostridioides difficile isolates with special reference to ridinilazole: 2020\u0026ndash;2021. Antimicrob Agents Chemother. 2023;1;67(10):e0034923. \u003c/li\u003e\n\u003cli\u003eCollins DA, Wu Y, Tateda K, Kim HJ, Vickers RJ, Riley T V. Evaluation of the antimicrobial activity of ridinilazole and six comparators against Chinese, Japanese and South Korean strains of Clostridioides difficile. Antimicrob Chemother. 2021;76(4):967\u0026ndash;972.\u003c/li\u003e\n\u003cli\u003eSholeh M, Krutova M, Forouzesh M, Mironov S, Sadeghifard N, Molaeipour L, et al. Antimicrobial resistance in Clostridioides (Clostridium) difficile derived from humans: A systematic review and meta-analysis. Antimicrob Resist Infect Control. 2020;9(1):158. \u003c/li\u003e\n\u003cli\u003eBass\u0026egrave;res E, Eubank TA, Begum K, Alam MJ, Jo J, Le TM, et al. Antibacterial activity of ibezapolstat against antimicrobial-resistant clinical strains of Clostridioides difficile . Antimicrob Agents Chemother. 2024;68(3):e0162123. \u003c/li\u003e\n\u003cli\u003eVan Eijk E, Boekhoud IM, Kuijper EJ, Bos-Sanders IMJG, Wright G, Smits WK. Genome Location Dictates the Transcriptional Response to PolC Inhibition in Clostridium difficile. Van Eijk E, Boekhoud IM, Kuijper EJ, Bos-Sanders IMJG, Wright G, Smits WK. Genome Location Dictates the Transcriptional Response to PolC Inhibition in Clostridium difficile. Antimicrob Agents Chemother. 2019;63(2):e01363\u0026ndash;18. \u003c/li\u003e\n\u003cli\u003eGoldstein EJC, Citron DM, Tyrrell KL, Merriam CV. Comparative in vitro activities of SMT19969, a new antimicrobial agent, against Clostridium difficile and 350 gram-positive and gram-negative aerobic and anaerobic intestinal flora isolates. \u003cem\u003eAntimicrob Agents Chemother\u003c/em\u003e. 2013;57(10):4872\u0026ndash;4876.\u003c/li\u003e\n\u003cli\u003eGancarz D. Summit Therapeutics Provides Update on Ridinilazole Check Point Threat Extraction secured this document [Internet]. Available from: https://www.summittxinc.com\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"C. difficile, Antibiotic susceptibility, Fidaxomicin, Ridinilazole, Ibezpolstat, Strains, MLST","lastPublishedDoi":"10.21203/rs.3.rs-5818289/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5818289/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEven though they constitute a risk factor, antibiotics are still the current primary treatment of \u003cem\u003eC. difficile\u003c/em\u003e infection. Due to \u003cem\u003eC. difficile\u003c/em\u003e's rapid development of resistance and high recurrences rates, there is an unmet need for new antimicrobials. In the current study, we assessed the in vitro susceptibility of clinical isolates from Israel to two recently developed antibiotics, ridinilazole and ibezpolstat, and to currently used antibiotics.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe collected 313 \u003cem\u003eC. difficile\u003c/em\u003e isolates from several medical centers across Israel, that were recovered from patients of both community and hospital facilities. Isolates were typed to different strains (strain type-ST) by multi-locus sequencing typing (MLST). Susceptibility to metronidazole and vancomycin was determined by Etest; susceptibility to fidaxomicin, ridinilazole and ibezpolstat was determined by agar dilution.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe most prevalent STs were ST42, with 39 (12.5%) isolates and ST2, with 36 isolates (11.5%). Resistance rate to metronidazole and vancomycin was low (2.2%, 1.6%, respectively). Ridinilazole (RDZ) MIC ranged between 0.06 to 0.5 mg/L, and the MIC\u003csub\u003e50/90\u003c/sub\u003e were 0.25/0.5 mg/L. Ibezpolstat (IBZ) had an MIC\u003csub\u003e50/90\u003c/sub\u003e of 4 mg/L. No significant differences were noted in MIC of different strains.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWe demonstrated a potent \u003cem\u003ein vitro\u003c/em\u003e activity of RDZ and IBZ against 313 \u003cem\u003eC. difficile\u003c/em\u003e isolates, belonging to different STs. These two antimicrobials may serve as a treatment for \u003cem\u003eC. difficile\u003c/em\u003e infection, as they have an excellent activity against \u003cem\u003eC. difficile\u003c/em\u003e on one hand, and minimal effect on gut microbiome, on the other hand.\u003c/p\u003e","manuscriptTitle":"In vitro susceptibility of clinical Clostridioides difficile isolates to ridinilazole and ibezapolstat in Israel, 2020-2022","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-20 09:33:12","doi":"10.21203/rs.3.rs-5818289/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-29T14:02:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-29T13:53:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-15T14:10:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Gastroenterology","date":"2025-01-13T08:44:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ed93a5ff-9c36-4a25-899e-c153b714bb45","owner":[],"postedDate":"January 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-07T16:04:34+00:00","versionOfRecord":{"articleIdentity":"rs-5818289","link":"https://doi.org/10.1186/s12876-025-03800-7","journal":{"identity":"bmc-gastroenterology","isVorOnly":false,"title":"BMC Gastroenterology"},"publishedOn":"2025-03-31 15:57:40","publishedOnDateReadable":"March 31st, 2025"},"versionCreatedAt":"2025-01-20 09:33:12","video":"","vorDoi":"10.1186/s12876-025-03800-7","vorDoiUrl":"https://doi.org/10.1186/s12876-025-03800-7","workflowStages":[]},"version":"v1","identity":"rs-5818289","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5818289","identity":"rs-5818289","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}