Publications by authors named "Mark H Wilcox"

227 Publications

Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults.

Clin Infect Dis 2021 09;73(5):755-757

Department of Microbiology, Leeds Teaching Hospitals NHS Trust, and Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.

This clinical practice guideline is a focused update on management of Clostridioides difficile infection (CDI) in adults specifically addressing the use of fidaxomicin and bezlotoxumab for the treatment of CDI. This guideline was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). This guideline is intended for use by healthcare professionals who care for adults with CDI, including specialists in infectious diseases, gastroenterologists, hospitalists, pharmacists, and any clinicians and healthcare providers caring for these patients. The panel's recommendations for the management CDI are based upon evidence derived from topic-specific systematic literature reviews. Summarized below are the recommendations for the management of CDI in adults. The panel followed a systematic process which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation). A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text.
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http://dx.doi.org/10.1093/cid/ciab718DOI Listing
September 2021

Development and clinical validation of an automated cell cytotoxicity neutralization assay for detecting Clostridioides difficile toxins in clinically relevant stools samples.

Anaerobe 2021 Jul 20;71:102415. Epub 2021 Jul 20.

Pfizer Vaccines Research and Development, Pearl River, NY, USA. Electronic address:

Objectives: To improve the diagnostic accuracy of Clostridioides difficile infection, current U.S. and E.U. guidelines recommend multistep testing that detects the presence of C. difficile and toxin in clinically relevant stool samples to confirm active disease. An accepted gold standard to detect C. difficile toxins is the cell cytotoxicity neutralization assay (CCNA). Although highly sensitive, the traditional CCNA has limitations. One such limitation is the subjective interpretation of an analyst to recognize cytopathic effects in cultured cells exposed to a fecal sample containing toxin. To overcome this limitation, an automated CCNA was developed that replaces most human pipetting steps with robotics and incorporates CellTiterGlo® for a semi-quantitative, non-subjective measure of cell viability instead of microscopy.

Methods: To determine sample positivity and control for non-specific cytopathic effects, two thresholds were defined and validated by evaluating the sample with/without antitoxin antisera (sample-antitoxin/sample + antitoxin): 1) a >70% cell viability threshold was validated with samples containing anti-toxin, and 2) a >1.2-fold difference cut-off where sample results above the cut-off are considered positive.

Results: Assay validation demonstrated excellent accuracy, precision, and sample linearity with an LOD of 126.9 pg/mL toxin-B in stool. The positivity cut-offs were clinically validated by comparing 322 diarrheal stool sample results with those run in a predicate, microscopic readout-based CCNA. The automated CCNA demonstrated 96% sensitivity and 100% specificity compared with the predicate CCNA.

Conclusions: Overall, the automated CCNA provides a specific, sensitive, and reproducible tool to support determination of CDI epidemiology or the efficacy of interventions such as vaccines.
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http://dx.doi.org/10.1016/j.anaerobe.2021.102415DOI Listing
July 2021

Trehalose-Induced Remodelling of the Human Microbiota Affects Infection Outcome in an Colonic Model: A Pilot Study.

Front Cell Infect Microbiol 2021 2;11:670935. Epub 2021 Jul 2.

Healthcare Associated Infection Research Group, Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.

Within the human intestinal tract, dietary, microbial- and host-derived compounds are used as signals by many pathogenic organisms, including . Trehalose has been reported to enhance virulence of certain ribotypes; however, such variants are widespread and not correlated with clinical outcomes for patients suffering from infection (CDI). Here, we make preliminary observations on how trehalose supplementation affects the microbiota in an model and show that trehalose-induced changes can reduce the outgrowth of , preventing simulated CDI. Three clinically reflective human gut models simulated the effects of sugar (trehalose or glucose) or saline ingestion on the microbiota. Models were instilled with sugar or saline and further exposed to spores. The recovery of the microbiota following antibiotic treatment and CDI induction was monitored in each model. The human microbiota remodelled to utilise the bioavailable trehalose. Clindamycin induction caused simulated CDI in models supplemented with either glucose or saline; however, trehalose supplementation did not result in CDI, although limited spore germination did occur. The absence of CDI in trehalose model was associated with enhanced abundances of , and , and reduced abundances of and spp., compared with the other models. Functional analysis of the microbiota in the trehalose model revealed differences in the metabolic pathways, such as amino acid metabolism, which could be attributed to prevention of CDI. Our data show that trehalose supplementation remodelled the microbiota, which prevented simulated CDI, potentially due to enhanced recovery of nutritionally competitive microbiota against .
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http://dx.doi.org/10.3389/fcimb.2021.670935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284250PMC
July 2021

Performance of the Innova SARS-CoV-2 antigen rapid lateral flow test in the Liverpool asymptomatic testing pilot: population based cohort study.

BMJ 2021 07 6;374:n1637. Epub 2021 Jul 6.

Institute of Population Health Sciences, University of Liverpool, Liverpool, UK.

Objective: To assess the performance of the SARS-CoV-2 antigen rapid lateral flow test (LFT) versus polymerase chain reaction testing in the asymptomatic general population attending testing centres.

Design: Observational cohort study.

Setting: Community LFT pilot at covid-19 testing sites in Liverpool, UK.

Participants: 5869 asymptomatic adults (≥18 years) voluntarily attending one of 48 testing sites during 6-29 November 2020.

Interventions: Participants were tested using both an Innova LFT and a quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) test based on supervised self-administered swabbing at testing sites.

Main Outcome Measures: Sensitivity, specificity, and predictive values of LFT compared with RT-qPCR in an epidemic steady state of covid-19 among adults with no classic symptoms of the disease.

Results: Of 5869 test results, 22 (0.4%) LFT results and 343 (5.8%) RT-qPCR results were void (that is, when the control line fails to appear within 30 minutes). Excluding the void results, the LFT versus RT-qPCR showed a sensitivity of 40.0% (95% confidence interval 28.5% to 52.4%; 28/70), specificity of 99.9% (99.8% to 99.99%; 5431/5434), positive predictive value of 90.3% (74.2% to 98.0%; 28/31), and negative predictive value of 99.2% (99.0% to 99.4%; 5431/5473). When the void samples were assumed to be negative, a sensitivity was observed for LFT of 37.8% (26.8% to 49.9%; 28/74), specificity of 99.6% (99.4% to 99.8%; 5431/5452), positive predictive value of 84.8% (68.1% to 94.9%; 28/33), and negative predictive value of 93.4% (92.7% to 94.0%; 5431/5814). The sensitivity in participants with an RT-qPCR cycle threshold (Ct) of <18.3 (approximate viral loads >10 RNA copies/mL) was 90.9% (58.7% to 99.8%; 10/11), a Ct of <24.4 (>10 RNA copies/mL) was 69.4% (51.9% to 83.7%; 25/36), and a Ct of >24.4 (<10 RNA copies/mL) was 9.7% (1.9% to 23.7%; 3/34). LFT is likely to detect at least three fifths and at most 998 in every 1000 people with a positive RT-qPCR test result with high viral load.

Conclusions: The Innova LFT can be useful for identifying infections among adults who report no symptoms of covid-19, particularly those with high viral load who are more likely to infect others. The number of asymptomatic adults with lower Ct (indicating higher viral load) missed by LFT, although small, should be considered when using single LFT in high consequence settings. Clear and accurate communication with the public about how to interpret test results is important, given the chance of missing some cases, even at high viral loads. Further research is needed to understand how infectiousness is reflected in the viral antigen shedding detected by LFT versus the viral loads approximated by RT-qPCR.
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http://dx.doi.org/10.1136/bmj.n1637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259455PMC
July 2021

Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults.

Clin Infect Dis 2021 09;73(5):e1029-e1044

Department of Microbiology, Leeds Teaching Hospitals NHS Trust, and Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.

This clinical practice guideline is a focused update on management of Clostridioides difficile infection (CDI) in adults specifically addressing the use of fidaxomicin and bezlotoxumab for the treatment of CDI. This guideline was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). This guideline is intended for use by healthcare professionals who care for adults with CDI, including specialists in infectious diseases, gastroenterologists, hospitalists, pharmacists, and any clinicians and healthcare providers caring for these patients. The panel's recommendations for the management CDI are based upon evidence derived from topic-specific systematic literature reviews. Summarized below are the recommendations for the management of CDI in adults. The panel followed a systematic process which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation). A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text.
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http://dx.doi.org/10.1093/cid/ciab549DOI Listing
September 2021

Utility of Whole Genome Sequencing in Assessing and Enhancing Partner Notification of Neisseria gonorrhoeae Infection.

Sex Transm Dis 2021 Oct;48(10):773-780

Nuffield Department of Medicine.

Background: Gonorrhea is a sexually transmitted infection of global concern. We investigated whole-genome sequencing (WGS) as a tool to measure and enhance partner notification (PN) in gonorrhea management.

Methods: Between May and November 2018, all N. gonorrhoeae isolated from patients attending Leeds Sexual Health, United Kingdom, underwent WGS. Reports listing sequences within 20 single-nucleotide polymorphisms (SNPs) of study isolates within a database containing select isolates from April 1, 2016, to November 15, 2018, were issued to clinicians. The proportion of cases with a potential transmission partner identified by PN was determined from patient and PN data. The WGS reports were reviewed to identify additional cases within 6 SNPs or less and verified for PN concordance.

Results: Three hundred eighty isolates from 377 cases were successfully sequenced; 292 had traceable/contactable partners and 69 (18%) had a potential transmission partner identified by PN. Concordant PN and WGS links were identified in 47 partner pairs. Of 308 cases with no transmission partner by PN, 185 (60%) had a case within 6 SNPs or less; examination of these cases' PN data identified 7 partner pairs with previously unrecognized PN link, giving a total of 54 pairs; all had 4 or less SNP differences. The WGS clusters confirmed gaps in partner finding, at individual and group levels. Despite the clinic providing sexual health services to the whole city, 35 cases with multiple partners had no genetically related case, suggesting multiple undiagnosed infections.

Conclusions: Whole-genome sequencing could improve gonorrhea PN and control by identifying new links and clusters with significant gaps in partner finding.
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http://dx.doi.org/10.1097/OLQ.0000000000001419DOI Listing
October 2021

Antimicrobial resistance progression in the United Kingdom: A temporal comparison of Clostridioides difficile antimicrobial susceptibilities.

Anaerobe 2021 Aug 25;70:102385. Epub 2021 May 25.

Healthcare-Associated Infections Research Group, Molecular Gastroenterology, Leeds Institute for Biomedical and Clinical Sciences, University of Leeds, Old Medical School, Leeds General Infirmary, LS1 3EX, West Yorkshire, UK; Microbiology, Leeds Teaching Hospitals Trust, Leeds, UK.

Objectives: Clostridioides difficile (CD) is widely reported as one of the most prevalent multi-drug resistant (MDR) organisms. Assessment of temporally disparate isolate collections can give valuable epidemiological data to further the understanding of antimicrobial resistance progression.

Methods: A collection of 75 CD isolates (1980-86) was characterised by PCR ribotyping, cell cytotoxicity assay and susceptibility testing with a panel of 16 antimicrobials and compared to a modern surveillance collection consisting of 416 UK isolates (2012-2016). Agar-incorporation was performed to ascertain susceptibility data for vancomycin, metronidazole, rifampicin, fidaxomicin, moxifloxacin, clindamycin, imipenem, chloramphenicol, tigecycline, linezolid, ciprofloxacin, piperacillin/tazobactam, ceftriaxone, amoxicillin, tetracycline and erythromycin. Genomes were obtained using Illumina HiSeq3000 sequencing and assembled using CLC Genomics Workbench. Resistance genes were identified using the Comprehensive Antibiotic Research Database's Resistance Gene Identifier and ResFinder3.0.

Results: Twenty-six known and one previously unobserved ribotype (RT) were detected. RT015 and RT020 dominated; 21.3% and 17.3%, respectively. Three moxifloxacin resistant (16-32 mg/L) RT027 isolates were recovered, pre-dating the earliest reports of this phenotype/genotype. Phenotypic resistance was observed to moxifloxacin (9.3% of isolates), ciprofloxacin (100%), erythromycin (17.3%), tetracycline (9.3%), linezolid and chloramphenicol (4.0%). Phenotypic comparisons with modern strains revealed increasing minimum inhibitory concentrations (MIC), with MIC elevations of one doubling-dilution for the majority of compounds, excluding clindamycin and imipenem. Moxifloxacin MIC comparisons revealed a two doubling-dilution increase between temporal isolate collections. Historical genomes revealed twenty different resistance determinants, including ermB (8.0% of isolates), tetM (9.3%), cfr (5.3%) and gyrA substitution Thr-82→Ile (9.3%). Seventeen isolates (22.7%) were resistant to ≥3 compounds (MDR), demonstrating ten different combinations. Intra-RT diversity was observed.

Conclusions: Antibiotic resistance in CD has increased since the early 1980s, across the majority of classes. Moxifloxacin resistance determinants may pre-date its introduction.
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http://dx.doi.org/10.1016/j.anaerobe.2021.102385DOI Listing
August 2021

Global Landscape of Clostridioides Difficile Phylogeography, Antibiotic Susceptibility, and Toxin Polymorphisms by Post-Hoc Whole-Genome Sequencing from the MODIFY I/II Studies.

Infect Dis Ther 2021 Jun 22;10(2):853-870. Epub 2021 Mar 22.

BGI-Shenzhen, Shenzhen, China.

Introduction: Clostridioides (Clostridium) difficile infection, the leading cause of healthcare-associated diarrhea, represents a significant burden on global healthcare systems. Despite being a global issue, information on C. difficile from a global perspective is lacking. The aim of this study is to model the global phylogeography of clinical C. difficile.

Methods: Using samples collected from the MODIFY I and II studies (NCT01241552, NCT01513239), we performed whole-genome sequencing of 1501 clinical isolates including 37 novel sequence types (STs), representing the largest worldwide collection to date.

Results: Our data showed ribotypes, multi-locus sequence typing clades, and whole-genome phylogeny were in good accordance. The clinical C. difficile genome was found to be more conserved than previously reported (61% core genes), and modest recombination rates of 1.4-5.0 were observed across clades. We observed a significant continent distribution preference among five C. difficile clades (Benjamini-Hochberg corrected Fisher's exact test P < 0.01); moreover, weak association between geographic and genetic distance among ribotypes suggested sources beyond healthcare-related transmission. Markedly different trends of antibiotic susceptibility among lineages and regions were identified, and three novel mutations (in pyridoxamine 5'-phosphate oxidase family protein: Tyr130Ser, Tyr130Cys, and a promoter SNP) associated with metronidazole-reduced susceptibility were discovered on a nim-related gene and its promotor by genome-wide association study. Toxin gene polymorphisms were shown to vary within and between prevalent ribotypes, and novel severe mutations were found on the tcdC toxin regulator protein.

Conclusion: Our systematic characterization of a global set of clinical trial C. difficile isolates from infected individuals demonstrated the complexity of the genetic makeup of this pathogenic organism. The geographic variability of clades, variability in toxin genes, and mutations associated with antibiotic susceptibility indicate a highly complex interaction of C. difficile between host and environment. This dataset will provide a useful resource for validation of findings and future research of C. difficile.
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http://dx.doi.org/10.1007/s40121-021-00426-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116447PMC
June 2021

From the hospital toilet to the ward: A pilot study on microbe dispersal to multiple hospital surfaces following hand drying using a jet air dryer versus paper towels.

Infect Control Hosp Epidemiol 2021 Mar 17:1-4. Epub 2021 Mar 17.

Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom.

Using a bacteriophage to represent microbial contamination, we investigated virus transmission to the hospital environment following hand drying. The use of paper towels resulted in lower rates of virus contamination on hands and clothing compared with a jet air dryer and, consequently, lower contamination of multiple hospital surfaces.
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http://dx.doi.org/10.1017/ice.2021.43DOI Listing
March 2021

Biofilms harbour Clostridioides difficile, serving as a reservoir for recurrent infection.

NPJ Biofilms Microbiomes 2021 02 5;7(1):16. Epub 2021 Feb 5.

Healthcare-Associated Infections Group, Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds, LS1 9JT, UK.

C. difficile infection (CDI) is a worldwide healthcare problem with ~30% of cases failing primary therapy, placing a burden on healthcare systems and increasing patient morbidity. We have little understanding of why these therapies fail. Here, we use a clinically validated in vitro gut model to assess the contribution of biofilms towards recurrent disease and to investigate biofilm microbiota-C. difficile interactions. Initial experiments show that C. difficile cells became associated with the colonic biofilm microbiota and are not depleted by vancomycin or faecal microbiota transplant therapies. We observe that transferring biofilm encased C. difficile cells into a C. difficile naïve but CDI susceptible model induces CDI. Members of the biofilm community can impact C. difficile biofilm formation by acting either antagonistically or synergistically. We highlight the importance of biofilms as a reservoir for C. difficile, which can be a cause for recurrent infections.
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http://dx.doi.org/10.1038/s41522-021-00184-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864922PMC
February 2021

Safety and efficacy of omadacycline by BMI categories and diabetes history in two Phase III randomized studies of patients with acute bacterial skin and skin structure infections.

J Antimicrob Chemother 2021 04;76(5):1315-1322

Paratek Pharmaceuticals, Inc., King of Prussia, PA 19406, USA.

Objectives: The objectives of this post-hoc analysis were to examine the safety and efficacy of omadacycline by BMI categories and diabetes history in adults with acute bacterial skin and skin structure infections (ABSSSI) from two pivotal Phase III studies.

Patients And Methods: OASIS-1 (ClinicalTrials.gov identifier NCT02378480): patients were randomized 1:1 to IV omadacycline or linezolid for 7-14 days, with optional transition to oral medication. OASIS-2 (ClinicalTrials.gov identifier NCT02877927): patients received once-daily oral omadacycline or twice-daily oral linezolid for 7-14 days. Early clinical response (ECR) was defined as ≥20% reduction in lesion size 48-72 h after the first dose. Clinical success at post-treatment evaluation (PTE; 7-14 days after the last dose) was defined as symptom resolution such that antibacterial therapy was unnecessary. Safety was assessed by treatment-emergent adverse events and laboratory measures. Between-treatment comparisons were made with regard to WHO BMI categories and diabetes history.

Results: Patients were evenly distributed among healthy weight, overweight and obese groups. Clinical success for omadacycline-treated patients at ECR and PTE was similar across BMI categories. Outcomes by diabetes status were similar in omadacycline- and linezolid-treated patients: at ECR, clinical success rates were lower for those with diabetes; at PTE, clinical success was similar between treatment groups regardless of diabetes history. The safety of omadacycline and linezolid was largely similar across BMI groups and by diabetes history.

Conclusions: Omadacycline efficacy in patients with higher BMI and in patients with diabetes was consistent with results from two pivotal Phase III ABSSSI trials. Fixed-dose omadacycline is an appropriate treatment for ABSSSI in adults regardless of BMI.
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http://dx.doi.org/10.1093/jac/dkaa558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050767PMC
April 2021

Recontamination of Healthcare Surfaces by Repeated Wiping with Biocide-Loaded Wipes: "" as Best Practice in the Clinical Environment.

Int J Mol Sci 2020 Dec 18;21(24). Epub 2020 Dec 18.

School of Design, University of Leeds, Leeds LS2 9JT, UK.

The wiping of high-touch healthcare surfaces made of metals, ceramics and plastics to remove bacteria is an accepted tool in combatting the transmission of healthcare-associated infections (HCAIs). In practice, surfaces may be repeatedly wiped using a single wipe, and the potential for recontamination may be affected by various factors. Accordingly, we studied how the surface to be wiped, the type of fibre in the wipe and how the presence of liquid biocide affected the degree of recontamination. Experiments were conducted using metal, ceramic and plastic healthcare surfaces, and two different wipe compositions (hygroscopic and hydrophilic), with and without liquid biocide. Despite initially high removal efficiencies of >70% during initial wiping, all healthcare surfaces were recontaminated with , and when wiped more than once using the same wipe. Recontamination occurred regardless of the fibre composition of the wipe or the presence of a liquid biocide. The extent of recontamination by , and bacteria also increased when metal healthcare surfaces possessed a higher microscale roughness (<1 μm), as determined by Atomic Force Microscopy (AFM). The high propensity for healthcare surfaces to be re-contaminated following initial wiping suggests that a "One wipe, One surface, One direction, Dispose" policy should be implemented and rigorously enforced.
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http://dx.doi.org/10.3390/ijms21249659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766459PMC
December 2020

Perturbations of the gut microbiome in anti-CCP positive individuals at risk of developing rheumatoid arthritis.

Rheumatology (Oxford) 2021 07;60(7):3380-3387

Leeds Institute of Medical Research, University of Leeds, Leeds General Infirmary, Leeds, UK.

Objective: Individuals with newly diagnosed RA have a distinct microbiome when compared with healthy controls. However, little is known as to when these microbiome perturbations begin. Using a prospective at-risk cohort of individuals positive for anti-citrullinated protein (anti-CCP) antibody with new onset musculoskeletal symptoms, but without clinical arthritis, we investigated for the presence of a gut dysbiosis before the onset of RA.

Methods: The gut microbiota of 25 anti-CCP positive individuals without clinical synovitis were sequenced targeting the V4 region of the 16S rRNA gene. Using a publicly available database, a control population of 44 individuals, approximately matched in age, gender, diet and ethnicity was selected for comparison, using the same sequencing methodology. Median interval between sample collection and progression to RA was 188 days. Taxonomic analysis was performed using QIIME and MEGAN, and statistical analysis using R software.

Results: There were significant differences (P =0.01) at family level in gut microbiomes of anti-CCP positive individuals vs controls. The anti-CCP positive population had an overabundance of Lachnospiraceae, Helicobacteraceae, Ruminococcaceae, Erysipelotrichaceae and Bifidobacteriaceae, among others. Five individuals progressed to RA between sample collection and analysis. Clustering of the progressor population was observed on a phylogenetic network created using a probabilistic similarity index (Goodall's index).

Conclusions: Anti-CCP positive at-risk individuals without clinical synovitis appear to have a distinct gut microbiome compared with healthy controls. Phylogenetic clustering was observed in individuals who progressed to RA, suggesting that distinct taxa are associated with the development of RA many months before its onset.
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http://dx.doi.org/10.1093/rheumatology/keaa792DOI Listing
July 2021

An Analysis of Environmental Contamination During and After Treatment for Infection.

Open Forum Infect Dis 2020 Nov 17;7(11):ofaa362. Epub 2020 Aug 17.

Healthcare Associated Infection Research Group, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, United Kingdom.

Background: Lower spore counts in feces from infection (CDI) patients treated with fidaxomicin versus vancomycin have been observed. We aimed to determine whether environmental contamination is lower in patients treated with fidaxomicin compared with those treated with vancomycin/metronidazole.

Methods: The CDI cases were recruited at 4 UK hospitals (Leeds, Bradford, and London [2 centers]). Environmental samples (5 room sites) were taken pretreatment and at 2-3, 4-5, 6-8, and 9-12 days of treatment, end of treatment (EOT), and post-EOT. Fecal samples were collected at diagnosis and as often as produced thereafter. Swabs/feces were cultured for ; percentage of -positive samples and bioburden were compared between different treatment arms at each time point.

Results: Pre-EOT (n = 244), there was a significant reduction in environmental contamination (≥1 site positive) around fidaxomicin versus vancomycin/metronidazole recipients at days 4-5 (30% vs 50% recipients, = .04) and at days 9-12 (22% vs 49%, = .005). This trend was consistently seen at all other timepoints, but it was not statistically significant. No differences were seen between treatment groups post-EOT (n = 76). Fidaxomicin-associated fecal positivity rates and colony counts were consistently lower than those for vancomycin/metronidazole from days 4 to 5 of treatment (including post-EOT); however, the only significant difference was in positivity rate at days 9-12 (15% vs 55%, = .03).

Conclusions: There were significant reductions in recovery from both feces and the environment around fidaxomicin versus vancomycin/metronidazole recipients. Therefore, fidaxomicin treatment may lower the transmission risk by reducing excretion and environmental contamination.
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http://dx.doi.org/10.1093/ofid/ofaa362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651500PMC
November 2020

Optimization of an Assay To Determine Colonization Resistance to Clostridioides difficile in Fecal Samples from Healthy Subjects and Those Treated with Antibiotics.

Antimicrob Agents Chemother 2020 12 16;65(1). Epub 2020 Dec 16.

Heath Care Associated Infection Research Group, Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom

A healthy, intact gut microbiota is often resistant to colonization by gastrointestinal pathogens. During periods of dysbiosis, however, organisms such as can thrive. We describe an optimized colonization resistance assay for in stool (CRACS) and demonstrate the utility of this assay by assessing changes in colonization resistance following antibiotic exposure. Fecal samples were obtained from healthy volunteers ( = 6) and from healthy subjects receiving 5 days of moxifloxacin ( = 11) or no antibiotics ( = 10). Samples were separated and either not manipulated (raw) or sterilized (autoclaved or filtered) prior to inoculation with ribotype 027 spores and anaerobic incubation for 72 h. Different methods of storing fecal samples were also investigated in order to optimize the CRACS. In healthy, raw fecal samples, incubation with spores did not lead to increased total viable counts (TVCs) or cytotoxin detection. In contrast, increased TVCs and cytotoxin detection occurred in sterilized healthy fecal samples or those from antibiotic-treated individuals. The CRACS was functional with fecal samples stored at either 4°C or -80°C but not with those stored with glycerol (12% or 30% [vol/vol]). Our data show that the CRACS successfully models the loss of colonization resistance and subsequent proliferation and toxin production. The CRACS could be used as a proxy for infection in clinical studies or to determine if an individual is at risk of developing infection or other potential infections occurring due to a loss of colonization resistance.
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http://dx.doi.org/10.1128/AAC.01401-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927831PMC
December 2020

Is there a causal relationship between trehalose consumption and Clostridioides difficile infection?

Curr Opin Gastroenterol 2021 01;37(1):9-14

Healthcare-Associated Infections Group, Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds.

Purpose Of Review: Trehalose metabolism appears to play a role in the pathogenicity of some microbes. It has been claimed that trehalose consumption may be a risk factor for Clostridioides difficile infection (CDI), but the evidence for a causal link is contentious.

Recent Findings: Epidemic ribotypes of C. difficile harbour mutations or have acquired extra genes that mean these strains can utilize lower concentrations of bioavailable trehalose, providing a competitive metabolic advantage in some CDI animal models. By contrast, evidence has emerged to show that trehalose-induced microbiota changes can help protect/reduce CDI in other models. In addition, C. difficile trehalose metabolic variants are widespread among epidemic and nonepidemic ribotypes alike, and the occurrence of these trehalose variants was not associated with increase disease severity or mortality.

Summary: Currently, there is no proven causal association between the incidence or severity of human CDI and the presence of trehalose metabolism variants. Furthermore, microbial metabolism reduces trehalose bioavailability, potentially removing this competitive advantage for C. difficile trehalose metabolism variants. Taken together, trehalose consumed as part of a normal diet has no increased risk of CDI.
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http://dx.doi.org/10.1097/MOG.0000000000000695DOI Listing
January 2021

Tracking COVID-19 via sewage.

Curr Opin Gastroenterol 2021 01;37(1):4-8

Leeds Institute of Medical Research, University of Leeds, Leeds, UK.

Purpose Of Review: We discuss the potential role of the faecal chain in COVID-19 and highlight recent studies using waste water-based epidemiology (WBE) to track severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Recent Findings: WBE has been suggested as an adjunct to improve disease surveillance and aid early detection of circulating disease. SARS-CoV-2, the aetiological agent of COVID-19, is an enveloped virus, and as such, typically not associated with the waste water environment, given high susceptibility to degradation in aqueous conditions. A review of the current literature supports the ability to detect of SARS-CoV-2 in waste water and suggests methods to predict community prevalence based on viral quantification.

Summary: The summary of current practices shows that while the isolation of SARS-CoV-2 is possible from waste water, issues remain regarding the efficacy of virial concentration and subsequent quantification and alignment with epidemiological data.
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http://dx.doi.org/10.1097/MOG.0000000000000692DOI Listing
January 2021

Cost Consequences for the NHS of Using a Two-Step Testing Method for the Detection of with a Point of Care, Polymerase Chain Reaction Test as the First Step.

Diagnostics (Basel) 2020 Oct 14;10(10). Epub 2020 Oct 14.

NIHR Newcastle In Vitro Diagnostics Co-operative, Room M2.088, Translational and Clinical Research Institute, William Leech Building, Medical School, Newcastle University, Newcastle NE2 4HH, UK.

infection (CDI) is a common healthcare-associated infection. Current practice for diagnosing CDI in the Newcastle upon Tyne Hospitals NHS Foundation Trust involves a three-step, laboratory testing strategy using glutamate dehydrogenase (GDH) enzyme immunoassay (EIA), followed by a polymerase chain reaction (PCR) test then a toxin EIA. However, a PCR point of care test (POCT) for the tcdB gene for screening suspected CDI cases, may provide a more efficient way of facilitating an equally effective, two-step, testing strategy with a toxin EIA. This study evaluated the cost consequences of changing from the three-step to a two-step testing strategy. A cost-consequences model was developed to compare the costs and consequences of the two strategies. Uncertainties in the model inputs were investigated with one- and two-way sensitivity analysis. The two-step, POCT strategy was estimated to save £283,282 per 1000 hospitalized NHS patients with suspected infectious diarrhea. Sensitivity analysis indicated that the turnaround time for the POCT was the largest driver for cost savings. Providing the POCT has sufficiently high diagnostic accuracy for detecting , the two-step, POCT strategy for CDI identification is likely to be cost saving for NHS hospitals with an offsite laboratory.
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http://dx.doi.org/10.3390/diagnostics10100819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602277PMC
October 2020

Swab-yourself trial with economic monitoring and testing for infections collectively (SYSTEMATIC): Part 2. A diagnostic accuracy, and cost-effectiveness, study comparing rectal, pharyngeal and urogenital samples analysed individually, versus as a pooled specimen, for the diagnosis of gonorrhoea and chlamydia.

Clin Infect Dis 2020 Oct 12. Epub 2020 Oct 12.

Department of Clinical Microbiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Background: Sexual history does not accurately identify those with extragenital Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) so universal extragenital sampling is recommended. Nucleic acid amplification tests (NAATs) are expensive. If urogenital, plus rectal and pharyngeal, samples are analysed the diagnostic cost is trebled. Pooling samples into one NAAT container would cost the same as urogenital samples alone. We compared clinician triple samples analysed individually with self-taken pooled samples for diagnostic accuracy, and cost, in MSM and females.

Methods: Prospective, convenience, sample in UK sexual health clinic. Randomised order of clinician and self-samples from pharynx, rectum, plus first catch urine (FCU) in MSM and vulvovaginal swabs (VVS) in females, for NG and CT detection.

Results: Of 1793 participants (1284 females, 509 MSM), 116 had NG detected (75 urogenital, 83 rectum, 72 pharynx). 276 had CT detected (217 urogenital, 249 rectum, 63 pharynx).There was no difference in sensitivities between clinician triple samples and self-pooled specimens for NG (99.1%, 98.3%) but clinician samples analysed individually identified 3% more chlamydia infections than pooled (99.3%, 96.0%; p=0.027). However, pooled specimens identified more infections than VVS/FCU alone. Pooled specimens missed 2 NG and 11 CT infections, whereas VVS/FCU missed 41 NG and 58 CT infections. Self-taken pooled specimens were the most cost-effective.

Conclusions: Just FCU/VVS testing missed many infections. Self-taken pooled samples were as sensitive as clinician triple samples for identifying NG, but clinician samples analysed individually identified 3% more CT infections than pooled. The extragenital sampling was achievable at no additional diagnostic cost to the FCU/VVS.

Trial Registration: ClinicalTrials.gov NCT02371109.
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http://dx.doi.org/10.1093/cid/ciaa1546DOI Listing
October 2020

Multicenter Prevalence Study Comparing Molecular and Toxin Assays for Clostridioides difficile Surveillance, Switzerland.

Emerg Infect Dis 2020 10;26(10):2370-2377

Public health authorities in the United States and Europe recommend surveillance for Clostridioides difficile infections among hospitalized patients, but differing diagnostic algorithms can hamper comparisons between institutions and countries. We compared surveillance based on detection of C. difficile by PCR or enzyme immunoassay (EIA) in a nationwide C. difficile prevalence study in Switzerland. We included all routinely collected stool samples from hospitalized patients with diarrhea in 76 hospitals in Switzerland on 2 days, 1 in winter and 1 in summer, in 2015. EIA C. difficile detection rates were 6.4 cases/10,000 patient bed-days in winter and 5.7 cases/10,000 patient bed-days in summer. PCR detection rates were 11.4 cases/10,000 patient bed-days in winter and 7.1 cases/10,000 patient bed-days in summer. We found PCR used alone increased reported C. difficile prevalence rates by <80% compared with a 2-stage EIA-based algorithm.
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http://dx.doi.org/10.3201/eid2610.190804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510716PMC
October 2020

Eravacycline, a novel tetracycline derivative, does not induce Clostridioides difficile infection in an in vitro human gut model.

J Antimicrob Chemother 2021 01;76(1):171-178

Healthcare-Associated Infections Group, Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds LS1 9JT, UK.

Objectives: The approval of new antibiotics is essential to combat infections caused by antimicrobial-resistant pathogens; however, such agents should be tested to determine their effect on the resident microbiota and propensity to select for opportunistic pathogens, such as Clostridioides difficile. Eravacycline is a new antibiotic for the treatment of complicated intra-abdominal infections. Here, we determined the effects of eravacycline compared with moxifloxacin on the microbiota and if these were conducive to induction of C. difficile infection (CDI).

Methods: We seeded in vitro chemostat models, which simulate the physiological conditions of the human colon, with a human faecal slurry and instilled gut-reflective concentrations of either eravacycline or moxifloxacin.

Results: Eravacycline instillation was associated with decreased Bifidobacterium, Lactobacillus and Clostridium species, which recovered 1 week after exposure. However, Bacteroides spp. levels decreased to below the limit of detection and did not recover prior to the end of the experiment. Post-eravacycline, a bloom of aerobic bacterial species occurred, including Enterobacteriaceae, compared with pre-antibiotic, which remained high for the duration of the experiment. These changes in microbiota were not associated with induction of CDI, as we observed a lack of C. difficile spore germination and thus no toxin was detected. Moxifloxacin exposure sufficiently disrupted the microbiota to induce simulated CDI, where C. difficile spore germination, outgrowth and toxin production were seen.

Conclusions: These model data suggest that, despite the initial impact of eravacycline on the intestinal microbiota, similar to clinical trial data, this novel tetracycline has a low propensity to induce CDI.
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http://dx.doi.org/10.1093/jac/dkaa386DOI Listing
January 2021

Swab-yourself trial with economic monitoring and testing for infections collectively (SYSTEMATIC): Part 1. A diagnostic accuracy, and cost-effectiveness, study comparing clinician-taken versus self-taken rectal and pharyngeal samples for the diagnosis of gonorrhoea and chlamydia.

Clin Infect Dis 2020 Sep 2. Epub 2020 Sep 2.

Department of Clinical Microbiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Background: Urogenital testing misses extragenital Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT). Extragenital self-sampling is frequently undertaken despite no robust RCT evidence of efficacy. We compared clinician-taken rectal and pharyngeal samples with self-taken samples for diagnostic accuracy and cost in MSM and females.

Methods: Prospective, convenience, sample in UK sexual health clinic. Randomised order of clinician and self-samples from pharynx and rectum, plus first catch urine (MSM) and vulvovaginal swabs (females), for NG/CT detection.

Results: Of 1793 participants (1284 females, 509 MSM), 116 had NG detected (75 urogenital site, 83 rectum, 72 pharynx); 9.4% infected females and 67.3% MSM were urogenital negative. 276 had CT detected (217 urogenital site, 249 rectum, 63 pharynx); 13.1% infected females and 71.8% MSM were urogenital negative. Sexual history did not identify those with rectal infections. Clinician-rectal and self-rectal positive percent agreements (PPA) for NG detection were 92.8% and 97.6%; clinician-rectal, and self-rectal PPA for CT detection were 95.6% and 97.2%. There was no difference in diagnostic accuracy between clinician and self-taken samples.Clinicians performed swabs quicker than participants so costs were lower. However, in asymptomatic people, non-qualified clinicians would oversee self-swabbing and these costs would be lower than clinician's.

Conclusions: There was no difference in diagnostic accuracy of clinician compared with self-taken extragenital samples. Sexual history did not identify those with rectal infections so individuals should have extragenital clinician, or self-taken, samples. Clinician swabs cost less than self-swabs but in asymptomatic people, or doing home testing, their costs would be lower than clinician swabs.

Trial Registration: ClinicalTrials.gov NCT02371109.
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http://dx.doi.org/10.1093/cid/ciaa1266DOI Listing
September 2020

Shedding of SARS-CoV-2 in feces and urine and its potential role in person-to-person transmission and the environment-based spread of COVID-19.

Sci Total Environ 2020 Dec 31;749:141364. Epub 2020 Jul 31.

Centre for Environmental Biotechnology, School of Natural Sciences, Bangor University, Bangor, Gwynedd LL57 2UW, UK; School of Ocean Sciences, Bangor University, Menai Bridge, Anglesey LL59 5AB, UK.

The recent detection of SARS-CoV-2 RNA in feces has led to speculation that it can be transmitted via the fecal-oral/ocular route. This review aims to critically evaluate the incidence of gastrointestinal (GI) symptoms, the quantity and infectivity of SARS-CoV-2 in feces and urine, and whether these pose an infection risk in sanitary settings, sewage networks, wastewater treatment plants, and the wider environment (e.g. rivers, lakes and marine waters). A review of 48 independent studies revealed that severe GI dysfunction is only evident in a small number of COVID-19 cases, with 11 ± 2% exhibiting diarrhea and 12 ± 3% exhibiting vomiting and nausea. In addition to these cases, SARS-CoV-2 RNA can be detected in feces from some asymptomatic, mildly- and pre-symptomatic individuals. Fecal shedding of the virus peaks in the symptomatic period and can persist for several weeks, but with declining abundances in the post-symptomatic phase. SARS-CoV-2 RNA is occasionally detected in urine, but reports in fecal samples are more frequent. The abundance of the virus genetic material in both urine (ca. 10-10 gc/ml) and feces (ca. 10-10 gc/ml) is much lower than in nasopharyngeal fluids (ca. 10-10 gc/ml). There is strong evidence of multiplication of SARS-CoV-2 in the gut and infectious virus has occasionally been recovered from both urine and stool samples. The level and infectious capability of SARS-CoV-2 in vomit remain unknown. In comparison to enteric viruses transmitted via the fecal-oral route (e.g. norovirus, adenovirus), the likelihood of SARS-CoV-2 being transmitted via feces or urine appears much lower due to the lower relative amounts of virus present in feces/urine. The biggest risk of transmission will occur in clinical and care home settings where secondary handling of people and urine/fecal matter occurs. In addition, while SARS-CoV-2 RNA genetic material can be detected by in wastewater, this signal is greatly reduced by conventional treatment. Our analysis also suggests the likelihood of infection due to contact with sewage-contaminated water (e.g. swimming, surfing, angling) or food (e.g. salads, shellfish) is extremely low or negligible based on very low predicted abundances and limited environmental survival of SARS-CoV-2. These conclusions are corroborated by the fact that tens of million cases of COVID-19 have occurred globally, but exposure to feces or wastewater has never been implicated as a transmission vector.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836549PMC
December 2020

Efficacy of bezlotoxumab in trial participants infected with Clostridioides difficile strain BI associated with poor outcomes.

Clin Infect Dis 2020 Jul 31. Epub 2020 Jul 31.

Merck & Co., Inc., Kenilworth, NJ, USA.

Background: Bezlotoxumab reduced rates of recurrent Clostridioides difficile infection (rCDI) versus placebo in MODIFY I/II trial participants receiving antibacterial drug treatment for CDI. A secondary objective of MODIFY I/II was to assess bezlotoxumab's efficacy against C. difficile strains associated with increased rates of morbidity and mortality.

Methods: In this post-hoc analysis of pooled MODIFY I/II data, efficacy endpoints were assessed in participants infected with restriction endonuclease analysis (REA) BI and non-BI strains of C. difficile at study entry. Treatment outcomes were compared between participants receiving bezlotoxumab (alone or with actoxumab: B, B+A) and those receiving no bezlotoxumab (placebo or actoxumab: P, A).

Results: From 2559 randomized participants, C. difficile was isolated from 1588 (67.2%) baseline stool samples. Participants with BI strains (n=328) were older and had more risk factors for rCDI than non-BI strain participants (n=1260). There were no differences in initial clinical cure rate between BI and non-BI strains in either group. The rCDI rates for BI strains treated with bezlotoxumab was lower than for the no bezlotoxumab group (B, B+A vs P, A: 23.6% vs 43.9%) and was also lower for the non-BI strains (B, B+A vs P, A: 21.4% vs 36.1%). Rates of 30-day CDI-associated re-hospitalization were greater with BI versus non-BI strains in both groups.

Conclusions: Infection with BI strains of C. difficile predicted poor outcomes in the MODIFY I/II trials. Bezlotoxumab (B, B+A) treatment was effective both in BI and non-BI subpopulations.
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http://dx.doi.org/10.1093/cid/ciaa1035DOI Listing
July 2020

In vitro activity of eravacycline against common ribotypes of Clostridioides difficile.

J Antimicrob Chemother 2020 10;75(10):2879-2884

University of Houston College of Pharmacy, Houston, TX, USA.

Background: Eravacycline is a novel synthetic fluorocycline antibacterial approved for complicated intra-abdominal infections.

Objectives: The purpose of this study was to assess the in vitro activities of eravacycline and comparator antibiotics against contemporary clinical isolates of Clostridioides difficile representing common ribotypes, including isolates with decreased susceptibility to metronidazole and vancomycin.

Methods: Clinical C. difficile strains from six common or emerging ribotypes were used to test the in vitro activities of eravacycline and comparator antibiotics (fidaxomicin, vancomycin and metronidazole) by broth microdilution. In addition, MBC experiments, time-kill kinetic studies and WGS experiments were performed.

Results: A total of 234 isolates were tested, including ribotypes RT001 (n = 37), RT002 (n = 41), RT014-020 (n = 39), RT027 (n = 42), RT106 (n = 38) and RT255 (n = 37). MIC50/90 values were lowest for eravacycline (≤0.0078/0.016 mg/L), followed by fidaxomicin (0.016/0.063 mg/L), metronidazole (0.25/1.0 mg/L) and vancomycin (2.0/4.0 mg/L). MBCs were lower for eravacycline compared with vancomycin for all ribotypes tested. Both vancomycin and eravacycline demonstrated bactericidal killing, including for epidemic RT027. The presence of the tetM or tetW resistance genes did not affect the MIC of eravacycline.

Conclusions: This study demonstrated potent in vitro activity of eravacycline against a large collection of clinical C. difficile strains that was not affected by ribotype, susceptibility to vancomycin or the presence of certain tet resistance genes. Further development of eravacycline as an antibiotic to be used in patients with Clostridioides difficile infection is warranted.
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http://dx.doi.org/10.1093/jac/dkaa289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678891PMC
October 2020

ribotypes 001 and 126 were predominant in Tehran healthcare settings from 2004 to 2018: a 14-year-long cross-sectional study.

Emerg Microbes Infect 2020 Dec;9(1):1432-1443

Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

infection (CDI) remains a major healthcare problem worldwide, however, little is known about CDI epidemiology in Iran. Between December 2004 and November 2018, 3649 stool samples were collected from patients in 69 hospitals and medical centres in Tehran and were cultured for the presence of ; isolates were characterized by PCR ribotyping and toxin genes detection. A total of 582 isolates were obtained and the overall CDI prevalence was 15.9%; 290 (49.8%) cases were healthcare-associated (HA) and 292 (50.2%) cases were community-associated (CA). Of these, DNA of 513 isolates submitted for ribotyping. The ribotype and/or WEBRIBO type could be assessed in 366 (62.9%) isolates. The most frequent RTs were 001 ( = 75, 12.9%), 126 ( = 65, 11.2%) and 084 ( = 19, 3.3%); the toxin gene profile ( = 112, 19.2%) was the most common. Fifteen isolates (2.6%) did not carry any toxin genes. There was no difference between frequently found RTs in HA-CDI and CA-CDI, except for RT 029 which was more likely to be associated with healthcare origin (12/15, -value = 0.02). No isolate of RTs 027 or 078 was identified. Importantly, RTs 031, 038, 039, 084, 085 reported previously as RTs with an absence of toxin genes, revealed the presence of toxin genes in our study. Using Simpson's reciprocal index of diversity, we found that RT diversity decreased as the prevalence of the RT 084 increased ( = -0.78, -value = 0.041). Different patterns in CDI epidemiology underscore the importance of local surveillance and infection control measures in Tehran healthcare settings.
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http://dx.doi.org/10.1080/22221751.2020.1780949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473134PMC
December 2020

Activity of Omadacycline, a New Tetracycline Analog, and Comparators against Clostridioides difficile.

Antimicrob Agents Chemother 2020 07 22;64(8). Epub 2020 Jul 22.

University of Houston College of Pharmacy, Houston, Texas, USA

Omadacycline is a potent aminomethylcycline with activity against Gram-positive, Gram-negative, and anaerobic bacteria. Preliminary data demonstrated that omadacycline has activity against ; however, large-scale studies have not been done. The purpose of this study was to assess the susceptibility of omadacycline and comparators on a large biobank of clinical isolates. susceptibility to omadacycline and comparators (fidaxomicin, metronidazole, and vancomycin) was assessed using the broth microdilution method. Minimum bactericidal concentrations (MBCs) and time-kill assays were assessed for pharmacodynamics analysis, and whole-genome sequencing was performed in a subset of isolates to assess distribution of MICs and resistance determinants. Two hundred fifty clinical isolates collected between 2015 and 2018 were tested for susceptibility of omadacycline and comparators. Ribotypes included F001 ( = 5), F002 ( = 56), F014-020 ( = 66), F017 ( = 8), F027 ( = 53), F106 ( = 45), and F255 ( = 17). Omadacycline demonstrated potent activity with an MIC range of 0.016 to 0.13 μg/ml, an MIC of 0.031 μg/ml, and an MIC of 0.031 μg/ml. No difference was observed for omadacycline MIC and MIC values stratified by ribotype, disease severity, or vancomycin susceptibility. Bactericidal activity was confirmed in time-kill studies. No difference was observed in MIC based on phylogeny. Further development of omadacycline as an intravenous and oral antibiotic directed toward infection is warranted.
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http://dx.doi.org/10.1128/AAC.00522-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526832PMC
July 2020

The Efficacy and Safety of Fecal Microbiota Transplant for Recurrent Infection: Current Understanding and Gap Analysis.

Open Forum Infect Dis 2020 May 11;7(5):ofaa114. Epub 2020 Apr 11.

Department of Medicine, Division of Gastroenterology, Loyola University Chicago, Chicago, Illinois, USA.

The leading risk factor for () infection (CDI) is broad-spectrum antibiotics, which lead to low microbial diversity, or dysbiosis. Current therapeutic strategies for CDI are insufficient, as they do not address the key role of the microbiome in preventing spore germination into toxin-producing vegetative bacteria, which leads to symptomatic disease. Fecal microbiota transplant (FMT) appears to reduce the risk of recurrent CDI through microbiome restoration. However, a wide range of efficacy rates have been reported, and few placebo-controlled trials have been conducted, limiting our understanding of FMT efficacy and safety. We discuss the current knowledge gaps driven by questions around the quality and consistency of clinical trial results, patient selection, diagnostic methodologies, use of suppressive antibiotic therapy, and methods for adverse event reporting. We provide specific recommendations for future trial designs of FMT to provide improved quality of the clinical evidence to better inform treatment guidelines.
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http://dx.doi.org/10.1093/ofid/ofaa114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184446PMC
May 2020

Genetic Association Reveals Protection against Recurrence of Infection with Bezlotoxumab Treatment.

mSphere 2020 05 6;5(3). Epub 2020 May 6.

Merck & Co., Inc., Kenilworth, New Jersey, USA

Bezlotoxumab is a human monoclonal antibody against toxin B, indicated to prevent recurrence of infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP and the HLA alleles and , located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II). infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds toxin B and is indicated for the prevention of recurrent infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of infection recurrence.
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http://dx.doi.org/10.1128/mSphere.00232-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203456PMC
May 2020

Ultrasensitive Clostridioides difficile Toxin Testing for Higher Diagnostic Accuracy.

J Clin Microbiol 2020 05 26;58(6). Epub 2020 May 26.

Healthcare Associated Infections Research Group, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, United Kingdom

Currently available diagnostic tests for infection (CDI) lack specificity or sensitivity, which has led to guideline recommendations for multistep testing algorithms. Ultrasensitive assays for detection of toxins provide measurements of disease-specific markers at very low concentrations. These assays may show improved accuracy compared to that of current testing methods and offer a potential standalone solution for CDI diagnosis, although large studies of clinical performance and accuracy are lacking.
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http://dx.doi.org/10.1128/JCM.01913-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269404PMC
May 2020
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