Ridinilazole: A novel, narrow-spectrum antimicrobial agent targeting Clostridium (Clostridioides) difficile

Clostridium (Clostridioides) difficile infection (CDI) remains an urgent threat to patients in health systems worldwide. Recurrent CDI occurs in up to 30% of cases due to sustained dysbiosis of the gut microbiota which normally protects against CDI. Associated costs of initial and recurrent episodes of CDI impose heavy financial burdens on health systems. Vancomycin and metronidazole have been the mainstay of therapy for CDI for many years; however, these agents continue to cause significant disruption to the gut microbiota and thus carry a high risk of recurrence for CDI patients. Treatment regimens are now turning towards novel narrow spectrum antimicrobial agents which target C. difficile while conserving the commensal gut microbiota, thus significantly reducing risk of recurrence. One such agent, fidaxomicin, has been in therapeutic use for several years and is now recommended as a first-line treatment for CDI, as it is superior to vancomycin in reducing risk of recurrence. Another narrow spectrum agent, ridnilazole, was recently developed and is undergoing evaluation of its potential clinical utility. This review aimed to summarize experimental reports of ridinilazole and assess its potential as a first-line agent for treatment of CDI. Reported results from in vitro assessments, and from hamster models of CDI, show potent activity against C. difficile, non-inferiority to vancomycin for clinical cure and non-susceptibility among most gut commensal bacteria. Phase I and II clinical trials have been completed with ridinilazole showing high tolerability and efficacy in treatment of CDI, and superiority over vancomycin in reducing recurrence of CDI within 30 days of treatment completion. Phase III trials are currently underway, the results of which may prove its potential to reduce recurrent CDI and lessen the heavy health and financial burden C. difficile imposes on patients and healthcare systems

Microbiological evaluation of the ability of the DEKO-190 Washer/Disinfector to remove Clostridium difficile spores from bedpan surfaces

BACKGROUND: Clostridium difficile is a major nosocomial pathogen causing mild diarrhoea to life-threatening pseudomembranous colitis, and its spores frequently contaminate hospital environments and equipment. Washer/Disinfectors (WDs) are commonly used to clean and decontaminate soiled equipment in health care facilities. This study aimed to evaluate the effectiveness of the DEKO-190 WD in removing C. difficile spores from bedpans. METHODS: Plastic carriers were inoculated with suspensions of C. difficile spores in autoclaved (sterile) human faeces. The carriers were then taped to a sterile plastic bedpan which was subjected to short, long or intensive wash cycles in the WD using one of two test detergents: Formula A (generic) and Formula B (highly alkaline). Mean log10 reductions in spores were calculated for each wash cycle. RESULTS: Mean log10 reductions were 3.21(SEM ± 0.20) and 2.82 (±0.13) for Formula A and B, respectively, for the short cycle. The mean log10 reductions using the long wash cycle were 3.65 (±0.44) using Formula A and 5.30 (±0.43) using Formula B, while log10 reductions were 3.37 (±0.58) (Formula A) and 4.64 (±0.47) (Formula B) for the intensive cycle. Washing with the DEKO-190 significantly reduced spore concentrations on carrier surfaces on a bedpan. Spore counts were most effectively reduced when carriers were washed on a long or intensive wash cycle using an alkaline detergent

Ariel - Volume 12 Number 2

Executive Editors David G. Polin Larry H. Pastor Business Manager Alex Macones Jean Lien Editorial Page Editor Deepak Kapoor Sports Editor Todd Hoover Photography Editors Lois Leach Ken Yonemur

Genome analysis of Clostridium difficile PCR ribotype 014 lineage in Australian pigs and humans reveals a diverse genetic repertoire and signatures of long-range interspecies transmission

Clostridium difficile PCR ribotype (RT) 014 is well-established in both human and porcine populations in Australia, raising the possibility that C. difficile infection (CDI) may have a zoonotic or foodborne etiology. Here, whole genome sequencing and high-resolution core genome phylogenetics were performed on a contemporaneous collection of 40 Australian RT014 isolates of human and porcine origin. Phylogenies based on MLST (7 loci, STs 2, 13, and 49) and core orthologous genes (1260 loci) showed clustering of human and porcine strains indicative of very recent shared ancestry. Core genome single nucleotide variant (SNV) analysis found 42 % of human strains showed a clonal relationship (separated by ≤ 2 SNVs in their core genome) with one or more porcine strains, consistent with recent inter-host transmission. Clones were spread over a vast geographic area with 50 % of the human cases occurring without recent healthcare exposure. These findings suggest a persistent community reservoir with long-range dissemination, potentially due to agricultural recycling of piggery effluent. We also provide the first pan-genome analysis for this lineage, characterizing its resistome, prophage content, and in silico virulence potential. The RT014 is defined by a large “open” pan-genome (7587 genes) comprising a core genome of 2296 genes (30.3 % of the total gene repertoire) and an accessory genome of 5291 genes. Antimicrobial resistance genotypes and phenotypes varied across host populations and ST lineages and were characterized by resistance to tetracycline [tetM, tetA(P), tetB(P) and tetW], clindamycin/erythromycin (ermB), and aminoglycosides (aph3-III-Sat4A-ant6-Ia). Resistance was mediated by clinically important mobile genetic elements, most notably Tn6194 (harboring ermB) and a novel variant of Tn5397 (harboring tetM). Numerous clinically important prophages (Siphoviridae and Myoviridae) were identified as well as an uncommon accessory gene regulator locus (agr3). Conservation in the pathogenicity locus and S-layer correlated with ST affiliation, further extending the concept of clonal C. difficile lineages. This study provides novel insights on the genetic variability and strain relatedness of C. difficile RT014, a lineage of emerging One Health importance. Ongoing molecular and genomic surveillance of strains in humans, animals, food, and the environment is imperative to identify opportunities to reduce the overall CDI burden

Global Software Innovators Strengthening the Software Innovation Capacity of Europe and Korea

Global entrepreneurial talent management is a key challenge for the software sector internationally where competition for high-end skills is intense. SMEs are at a significant disadvantage when competing with major multinationals to access these skills. The Information and Communications Technology sector accounts for 5% of all employment in the EU and there are 900,000 vacancies in this sector in 2017 [1], however over 50% of senior ICT managers believe graduates lack the necessary combination of technical, business and interpersonal skills [2]. In addition, only 4 in 1000 women work in the ICT sector [3]. To address these challenges, HubLinked, an EU-funded Knowledge Alliance partnership of 11 industry and HE partners in the EU and Korea, is developing an integrated curriculum for industry-oriented, internationalised, innovation focused and interdisciplinary Computer Science degrees (“CSI4”). CSI4 features Global Labs, where teams of students work across timezones to prototype software, an internationalization-at-home experience which mimics working in a global ICT campany

Evaluation of the antimicrobial activity of ridinilazole and six comparators against Chinese, Japanese and South Korean strains of Clostridioides difficile

BACKGROUND: Clostridioides difficile is the most common cause of antimicrobial-associated diarrhoea in high-income countries. Fluoroquinolone resistance enabled the emergence and intercontinental spread of the epidemic ribotype (RT) 027 strain of C. difficile in the early 2000s. Despite frequent inappropriate antimicrobial use in Asia, RT 027 is rarely isolated in the region, but the often fluoroquinolone- and clindamycin-resistant RT 017 strain predominates. OBJECTIVES: This study evaluated the antimicrobial activity of ridinilazole, a novel antimicrobial agent with highly specific activity for C. difficile, against clinical strains of C. difficile from Asia. METHODS: C. difficile strains from Japan (n = 64), South Korea (n = 32) and China (n = 44) were tested by the agar dilution method for susceptibility to ridinilazole, metronidazole, vancomycin, clindamycin, moxifloxacin, rifaximin and fidaxomicin. RESULTS: All strains were susceptible to ridinilazole, with low MICs (0.03-0.25 mg/L). Several strains showed multiresistance profiles, particularly RT 017 (100% clindamycin resistant, 91.3% moxifloxacin resistant, 82.6% rifaximin resistant) and RT 369 (94.4% clindamycin resistant, 100% moxifloxacin resistant). Rifaximin resistance was absent in all strains from Japan. Multiresistance to clindamycin, moxifloxacin and rifaximin was found in 19 RT 017 strains (from China and South Korea), 2 RT 001 strains (South Korea) and 1 RT 046 strain (South Korea). CONCLUSIONS: Ridinilazole showed potent activity against a range of Asian C. difficile strains, which otherwise frequently displayed resistance to several comparator antimicrobial agents. Ongoing surveillance of antimicrobial resistance profiles is required to monitor and control the spread of resistant strains

Clostridium difficile ribotype 017–characterization, evolution and epidemiology of the dominant strain in Asia

Clostridium difficile ribotype (RT) 017 is an important toxigenic C. difficile RT which, due to a deletion in the repetitive region of the tcdA gene, only produces functional toxin B. Strains belonging to this RT were initially dismissed as nonpathogenic and circulated largely undetected for almost two decades until they rose to prominence following a series of outbreaks in the early 2000s. Despite lacking a functional toxin A, C. difficile RT 017 strains have been shown subsequently to be capable of causing disease as severe as that caused by strains producing both toxins A and B. While C. difficile RT 017 strains can be found in almost every continent today, epidemiological studies suggest that the RT is endemic in Asia and that the global spread of this MLST clade 4 lineage member is a relatively recent event. C. difficile RT 017 transmission appears to be mostly from human to human with only a handful of reports of isolations from animals. An important feature of C. difficile RT 017 strains is their resistance to several antimicrobials and this has been documented as a possible factor driving multiple outbreaks in different parts of the world. This review summarizes what is currently known regarding the emergence and evolution of strains belonging to C. difficile RT 017 as well as features that have allowed it to become an RT of global importance

Recurrence of Clostridium difficile infection in the Western Australian population

Clostridium difficile, the most common cause of hospital-associated diarrhoea in developed countries, presents major public health challenges. The high clinical and economic burden from C. difficile infection (CDI) relates to the high frequency of recurrent infections caused by either the same or different strains of C. difficile. An interval of 8 weeks after index infection is commonly used to classify recurrent CDI episodes. We assessed strains of C. difficile in a sample of patients with recurrent CDI in Western Australia from October 2011 to July 2017. The performance of different intervals between initial and subsequent episodes of CDI was investigated. Of 4612 patients with CDI, 1471 (32%) were identified with recurrence. PCR ribotyping data were available for initial and recurrent episodes for 551 patients. Relapse (recurrence with same ribotype (RT) as index episode) was found in 350 (64%) patients and reinfection (recurrence with new RT) in 201 (36%) patients. Our analysis indicates that 8- and 20-week intervals failed to adequately distinguish reinfection from relapse. In addition, living in a non-metropolitan area modified the effect of age on the risk of relapse. Where molecular epidemiological data are not available, we suggest that applying an 8-week interval to define recurrent CDI requires more consideration

Establishing Research Competitiveness in Biophysical Sciences in Maine

The Maine EPSCoR Research Infrastructure Improvement award is designed to enhance Maine\u27s competitiveness in molecular biophysical sciences through a partnership between the University of Maine and Maine\u27s non-profit research organizations. The proposed Biophysical Sciences Institute brings together University of Maine faculty in physics, chemistry, biology, mathematics, and spatial engineering, with biomedical researchers at the Jackson Laboratory and Maine Medical Center Research Institute. Maine EPSCoR proposes to hire additional tenure-track faculty in the fields of biophysics and advanced optics, biochemistry, structural biology, applied mathematics, computer science, image analysis and visualization, and material science. The new and existing investigators will form research teams to develop new measurement techniques, new sensors, and innovative approaches to data processing and interpretation in intracellular structures and dynamics, functional materials as a means to manipulate cellular reactions, and biocomputing. In addition to establishing the institute, Maine EPSCoR will integrate research and education through improvements to graduate training

Genomic epidemiology and transmission dynamics of recurrent Clostridioides difficile infection in Western Australia

Recurrent cases of Clostridioides difficile infection (rCDI) remain one of the most common and serious challenges faced in the management of CDI. The accurate distinction between a relapse (caused by infection with the same strain) and reinfection (caused by a new strain) has implications for infection control and prevention, and patient therapy. Here, we used whole-genome sequencing to investigate the epidemiology of 94 C. difficile isolates from 38 patients with rCDI in Western Australia. The C. difficile strain population comprised 13 sequence types (STs) led by ST2 (PCR ribotype (RT) 014, 36.2 %), ST8 (RT002, 19.1 %) and ST34 (RT056, 11.7 %). Among 38 patients, core genome SNP (cgSNP) typing found 27 strains (71%) from initial and recurring cases differed by ≤ 2 cgSNPs, suggesting a likely relapse of infection with the initial strain, while eight strains differed by ≥ 3 cgSNPs, suggesting reinfection. Almost half of patients with CDI relapse confirmed by WGS suffered episodes that occurred outside the widely used 8-week cut-off for defining rCDI. Several putative strain transmission events between epidemiologically unrelated patients were identified. Isolates of STs 2 and 34 from rCDI cases and environmental sources shared a recent evolutionary history, suggesting a possible common community reservoir. For some rCDI episodes caused by STs 2 and 231, within-host strain diversity was observed, characterised by loss/gain of moxifloxacin resistance. Genomics improves discrimination of relapse from reinfection and identifies putative strain transmission events among patients with rCDI. Current definitions of relapse and reinfection based on the timing of recurrence need to be reconsidered