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Jo J, Hu C, Horvath TD, Haidacher SJ, Begum K, Alam MJ, Garey KW. Phase I trial comparing bile acid and short-chain fatty acid alterations in stool collected from human subjects treated with omadacycline or vancomycin. Antimicrob Agents Chemother 2025; 69:e0125124. [PMID: 39819014 PMCID: PMC11823362 DOI: 10.1128/aac.01251-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 12/06/2024] [Indexed: 01/19/2025] Open
Abstract
Omadacycline, an aminomethylcycline tetracycline, has a low propensity to cause Clostridioides difficile infection (CDI) in clinical trials. Omadacycline exhibited a reduced bactericidal effect compared with vancomycin on key microorganisms implicated in bile acid homeostasis and short-chain fatty acids (SCFAs), key components of CDI pathogenesis. The purpose of this study was to assess bile acid and SCFA changes in stool samples from healthy volunteers given omadacycline or vancomycin. Stool samples were collected daily from 16 healthy volunteers, who were given oral omadacycline or vancomycin for 10 days. Daily stool samples were assessed for bile acids and SCFA concentrations using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bile acids changed significantly over time for all subjects (P < 0.01 for each bile acid), with vancomycin causing a larger change in the primary bile acids, cholic acid (P < 0.001) and chenodeoxycholic acid (P < 0.001), and a reduced change in the secondary bile acid, lithocholic acid (P < 0.001). The secondary bile acid ursodeoxycholic acid was reduced less by vancomycin than by omadacycline (P < 0.001). All SCFA concentrations were reduced from baseline with a larger effect observed with vancomycin for isobutyric acid (P = 0.0034), propionic acid (P = 0.0012), and acetic acid (P = 0.047). Microbial changes associated with the use of vancomycin versus omadacycline were also associated with changes in bile acid homeostasis and SCFA concentrations. Oral omadacycline produced a distinctive metabolomic profile compared with vancomycin when administered to healthy subjects. The metabolic findings help further our understanding of the lower CDI risk properties of omadacycline and warrant phase 2 investigations using omadacycline as a CDI antibiotic. IMPORTANCE The purpose of this study was to assess bile acid and SCFA changes in stool samples obtained from healthy volunteers given omadacycline or vancomycin. Stool samples were collected daily from 16 healthy volunteers given a 10-day oral course of omadacycline or vancomycin. Vancomycin caused a larger change in the primary bile acids and SCFA concentrations compared with omadacycline. The metabolic findings help further our understanding of the mechanistic basis for the lower-risk properties of omadacycline causing CDI and warrant phase 2 investigations using omadacycline as a CDI antibiotic. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT06030219.
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Affiliation(s)
- Jinhee Jo
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - Chenlin Hu
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - Thomas D. Horvath
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Microbiome Center, Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Sigmund J. Haidacher
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Microbiome Center, Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Khurshida Begum
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - M. Jahangir Alam
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - Kevin W. Garey
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
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Alshannaq AF, Kates AE, Keating JA, Mckinley LL, Dixon JW, Safdar N. Diverse Sources and Latent Reservoirs of Community-Associated Clostridioides difficile Infection. Clin Infect Dis 2025; 80:37-42. [PMID: 39215602 DOI: 10.1093/cid/ciae429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 07/30/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024] Open
Abstract
Clostridioides difficile is a spore-forming, toxin-producing, anaerobic bacterium that infects the human gastrointestinal tract, causing diarrhea and life-threatening colitis. Clostridioides difficile epidemiology continues to evolve, and it is recognized as a major community-associated (CA) pathogen in addition to its established role in causing healthcare-associated (HA) infection. While current surveillance and prevention measures mainly focus on healthcare-associated C. difficile infections (HA-CDI), much less is known about the factors that drive CA-CDI. This review highlights the potential contribution of reservoirs, including asymptomatic carriers, to CA C. difficile transmission. The reservoirs discussed in this review provide potential avenues for research to better understand and reduce CA transmission of C. difficile.
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Affiliation(s)
- Ahmad F Alshannaq
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Ashley E Kates
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Department of Medicine, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA
| | - Julie A Keating
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Department of Medicine, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA
| | - Linda L Mckinley
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Department of Medicine, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA
| | - Jonah W Dixon
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Department of Medicine, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA
| | - Nasia Safdar
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Department of Medicine, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA
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Allegretti JR, Kelly CR, Louie T, Fischer M, Hota S, Misra B, Van Hise NW, Yen E, Bullock JS, Silverman M, Davis I, McGill SK, Pardi DS, Orenstein R, Grinspan A, El-Nachef N, Feuerstadt P, Borody TJ, Khanna S, Budree S, Kassam Z. Safety and Tolerability of CP101, a Full-Spectrum, Oral Microbiome Therapeutic for the Prevention of Recurrent Clostridioides difficile Infection: A Phase 2 Randomized Controlled Trial. Gastroenterology 2025; 168:357-366.e3. [PMID: 39366468 DOI: 10.1053/j.gastro.2024.09.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 09/09/2024] [Accepted: 09/26/2024] [Indexed: 10/06/2024]
Abstract
BACKGROUND & AIMS Recurrent Clostridioides difficile infections (CDIs) remain common. While novel microbiome therapeutics gain approval, the efficacy of a full-spectrum, oral microbiome therapeutic is unknown. This study aimed to determine the safety and efficacy of CP101, an orally administered microbiome therapeutic, to restore a diverse microbiome and prevent recurrent CDI in a broad population. METHODS We conducted a multicenter, phase 2, double-blind, randomized, placebo-controlled trial in adults with recurrent CDI. Participants with one or more CDI recurrences and diagnosis by polymerase chain reaction or toxin enzyme immunoassay for the qualifying episode were included. Participants were randomized 1:1 to receive a single oral dose of either CP101 (∼6 × 1011 colony-forming units of lyophilized microbial cells) or placebo after standard-of-care antibiotics. The primary efficacy endpoint was the proportion of participants without CDI recurrence through week 8. Safety, efficacy, and microbiome endpoints were evaluated through weeks 8 and 24. RESULTS A total of 198 participants were analyzed: CP101 (n = 102) and placebo (n = 96). Overall, 27.5% had a first recurrence, and 62.7% were diagnosed by polymerase chain reaction-based testing. The proportion without CDI recurrence through week 8 was significantly higher in the CP101 group compared to the placebo group (74.5% [76 of 102] vs 61.5% [59 of 96], respectively; P = .0488), with durable efficacy observed through week 24 (73.5% [75 of 102] vs 59.4% [57 of 96], respectively; P = .0347). Similar efficacy was observed regardless of diagnostic modality or number of CDI recurrences. Rapid and durable increase in microbiome diversity was observed in the CP101 group compared to the placebo group. The incidence of adverse events was similar between the 2 groups. CONCLUSIONS CP101 was superior to placebo in reducing recurrent CDI with a safety profile similar to placebo. (ClinicalTrials.gov, Number NCT03110133).
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Affiliation(s)
- Jessica R Allegretti
- Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Colleen R Kelly
- Division of Gastroenterology, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Thomas Louie
- Department of Medicine and Microbiology, University of Calgary, Calgary, Alberta, Canada
| | - Monika Fischer
- Division of Gastroenterology, Indiana University, Indianapolis, Indiana
| | - Susy Hota
- Division of Infectious Disease, University Health Network, Toronto, Ontario, Canada
| | | | | | - Eugene Yen
- Division of Gastroenterology, Northwestern Medical Group, Chicago, Illinois
| | | | - Michael Silverman
- St. Joseph's Health Care, Western University, London, Ontario, Canada
| | - Ian Davis
- Dalhousie University, Halifax, Nova Scotia, Canada
| | - Sarah K McGill
- Division of Gastroenterology, University of North Carolina Hospitals, Chapel Hill, North Carolina
| | - Darrell S Pardi
- Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota
| | - Robert Orenstein
- Division of Infectious Disease, Mayo Clinic, Scottsdale, Arizona
| | - Ari Grinspan
- Division of Gastroenterology, Mount Sinai Hospital, New York, New York
| | - Najwa El-Nachef
- Division of Gastroenterology, University of California San Francisco, San Francisco, California
| | - Paul Feuerstadt
- Division of Gastroenterology, Yale University, New Haven, Connecticut
| | - Thomas J Borody
- Center for Digestive Diseases, Sydney, New South Wales, Australia
| | - Sahil Khanna
- Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota
| | | | - Zain Kassam
- Innovate Calgary, University of Calgary, Calgary, Alberta, Canada
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Chen IW, Kao CL, Hung KC. Re: 'The effect of antibiotic therapy for Clostridioides difficile infection on mortality and other patient-relevant outcomes' by Stabholz et al. Clin Microbiol Infect 2025; 31:308-309. [PMID: 38331255 DOI: 10.1016/j.cmi.2024.01.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 01/31/2024] [Indexed: 02/10/2024]
Affiliation(s)
- I-Wen Chen
- Department of Anesthesiology, Chi Mei Medical Center, Liouying, Tainan City, Taiwan
| | - Chia-Li Kao
- Department of Anesthesiology, E-Da Hospital, I-Shou University, Kaohsiung City, Taiwan
| | - Kuo-Chuan Hung
- Department of Anesthesiology, Chi Mei Medical Center, Tainan City, Taiwan.
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Turello LA, Consul A, Yip C, Shen S, Seymour C, Geurink C, Alvarado I, Abel-Santos E. Differential gene expression analysis shows that cephalosporin resistance is intrinsic to Clostridioides difficile strain 630. J Antibiot (Tokyo) 2025; 78:113-125. [PMID: 39672901 PMCID: PMC12021185 DOI: 10.1038/s41429-024-00795-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 10/15/2024] [Accepted: 11/22/2024] [Indexed: 12/15/2024]
Abstract
Clostridioides difficile infection (CDI) is the most common nosocomial infection in the US. CDI has become a growing concern due to C. difficile's resistance to several antibiotics, including cephalosporins. Furthermore, patients administered cephalosporins are at higher risk of contracting CDI. Cephalosporins are β-lactam antibiotics, which prevent bacterial cell wall synthesis by inhibiting penicillin-binding proteins (PBPs). β-lactam-resistant bacteria evade these antibiotics by producing β-lactamases or by harboring low-affinity PBPs. A genomic analysis of C. difficile strain 630 identified 31 putative β-lactam resistance genes. Upon cefoxitin exposure, few C. difficile strain 630 putative antibiotic-resistant genes were overexpressed. Most notably, the β-lactamase blaCDD gene was upregulated approximately 600-fold, as previously reported. Deletion of the blaCDD locus did not change in cephalosporin susceptibility. Deletion of the second most upregulated gene, the PBP vanY, was also ineffective at decreasing cephalosporin resistance. Cefoxitin exposure of the C. difficile strain 630ΔblaCDD mutant did not increase upregulation of other putative antibiotic resistance genes compared to wildtype C. difficile strain 630. Transcriptomic analyses of wildtype C. difficile strain 630 exposed to cephradine, cefoxitin, ceftazidime, or cefepime revealed the shared upregulation of a putative heterodimeric ABC transporter encoded by loci CD630_04590 (ABC transporter ATP-binding protein) and CD630_04600 (ABC transporter permease). These genes are genomically located directly downstream of blaCDD (CD630_04580). The deletion mutant CD630_04600 remained resistant to a number of antibiotics. Thus, even though blaCDD, CD630_04590, and CD630_04600 are all upregulated when exposed to cephalosporins, they do not seem to be involved in antibiotic resistance in C. difficile strain 630.
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Affiliation(s)
- Lara A Turello
- Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV, USA
| | - Amber Consul
- Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV, USA
| | - Christopher Yip
- Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV, USA
| | - Shirley Shen
- Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas, Las Vegas, NV, 89154-4004, USA
| | - Cale Seymour
- Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV, USA
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Corey Geurink
- Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas, Las Vegas, NV, 89154-4004, USA
| | - Israel Alvarado
- Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV, USA
- School of Medicine, Ponce Health Sciences University, Saint Louis, MO, 63103, USA
| | - Ernesto Abel-Santos
- Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV, USA.
- Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas, Las Vegas, NV, 89154-4004, USA.
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Schley K, Heinrich K, Moïsi JC, Häckl D, Obermüller D, Brestrich G, von Eiff C, Weinke T. Costs and Outcomes of Clostridioides difficile Infections in Germany: A Retrospective Health Claims Data Analysis. Infect Dis Ther 2025; 14:91-104. [PMID: 39565511 PMCID: PMC11782737 DOI: 10.1007/s40121-024-01075-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 10/31/2024] [Indexed: 11/21/2024] Open
Abstract
INTRODUCTION Health claims data are a valuable resource for health services research, enabling analysis of the costs of hospitalizations, outpatient visits, procedures, and medications, and providing an improved understanding of the economic burden and underlying cost drivers for a given health condition. Since no recent data were available from Germany on the medical costs and clinical outcomes of Clostridioides difficile infections (CDI), this study assessed the economic burden of CDI and all-cause mortality in adults in Germany. METHODS A retrospective cohort study was conducted using a large, anonymized administrative health claims research database from Germany from which an age- and sex-representative sample of 4 million insured persons covered by approximately 60 statutory health insurances was extracted. Propensity score matching was conducted on age, sex, comorbidities, and antibiotic use to identify four matched controls (i.e., patients without CDI) for every eligible adult patient with CDI (i.e., case) in the study cohort. Costs, healthcare resource utilization, and CDI-attributable all-cause mortality were assessed. RESULTS Overall, there were 15,342 CDI cases in the study cohort. One-year mortality in CDI cases (45.7%) was more than fourfold that of matched non-CDI controls (11.0%). In the year following the index date, average mortality-adjusted medical costs per person-time for CDI cases were almost fivefold that of matched non-CDI controls, representing a cost difference of €31,459, mainly driven by inpatient treatment. Overall excess costs for CDI cases were estimated at approximately €1.6 billion within 1 year after diagnosis. CONCLUSIONS CDI in Germany is associated with a high clinical and economic burden, including significantly higher mortality, costs, and healthcare resource utilization, in patients with CDI versus their matched patients without CDI. This has important implications for patients, healthcare providers, and the healthcare system.
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Affiliation(s)
- Katharina Schley
- Pfizer Pharma GmbH, Friedrichstrasse 110, 10117, Berlin, Germany.
| | - Kirstin Heinrich
- Pfizer Inc., Patient and Health Impact, New York, NY, 10017, USA
| | - Jennifer C Moïsi
- Pfizer Vaccines, Medical Development and Scientific/Clinical Affairs, 23 Av du Dr Lannelongue, 75014, Paris, France
| | | | - Dominik Obermüller
- InGef-Institute for Applied Health Research Berlin GmbH, Otto-Ostrowski-Str. 5, 10249, Berlin, Germany
| | - Gordon Brestrich
- Pfizer Pharma GmbH, Friedrichstrasse 110, 10117, Berlin, Germany
| | | | - Thomas Weinke
- Ernst Von Bergmann Klinikum, Charlottenstraße 72, 14467, Potsdam, Germany
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Donskey CJ, Dubberke ER, Klein NP, Liles EG, Szymkowiak K, Wilcox MH, Lawrence J, Bouguermouh S, Zhang H, Koury K, Bailey R, Smith HM, Lockhart S, Lamberth E, Kalina WV, Pride MW, Webber C, Anderson AS, Jansen KU, Gruber WC, Kitchin N. CLOVER (CLOstridium difficile Vaccine Efficacy tRial) Study: A Phase 3, Randomized Trial Investigating the Efficacy and Safety of a Detoxified Toxin A/B Vaccine in Adults 50 Years and Older at Increased Risk of Clostridioides difficile Infection. Clin Infect Dis 2024; 79:1503-1511. [PMID: 39180325 PMCID: PMC11650871 DOI: 10.1093/cid/ciae410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 05/20/2024] [Accepted: 08/13/2024] [Indexed: 08/26/2024] Open
Abstract
BACKGROUND Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention. METHODS This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N = 17 535) to receive 3 PF-06425090 or placebo doses (0, 1, and 6 months). Primary end points were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary end points), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability and safety were assessed. RESULTS The primary end point was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE) = 31.0% (96.4% confidence interval [CI], -38.7% to 66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE = 28.6% (96.4% CI, -28.4% to 61.0%)]. Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P = .02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE = 100%; 95% CI, 59.6% to 100.0%) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE = 100%; 95% CI, 54.8% to 100.0%). Local reactions were more frequent in PF-06425090 recipients, and systemic events were generally similar between groups; most were mild to moderate. Adverse event rates were similar between groups. CONCLUSIONS Three PF-06425090 doses were safe and well tolerated. Although the primary end point was not met, PF-06425090 reduced symptom duration, CDI that required medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden. CLINICAL TRIALS REGISTRATION NCT03090191.
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Affiliation(s)
- Curtis J Donskey
- Geriatric Research Education and Clinical Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA
| | - Erik R Dubberke
- Division of Infectious Diseases, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Nicola P Klein
- Kaiser Permanente Vaccine Study Center, Oakland, California, USA
| | | | | | - Mark H Wilcox
- Leeds Teaching Hospitals NHS Trust and Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
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Yu H, Alfred T, Zhou J, Judy J, Olsen MA. Incidence, healthcare and out-of-pocket costs, and mortality of Clostridioides difficile infection among US adults aged 18 to 64 years. ANTIMICROBIAL STEWARDSHIP & HEALTHCARE EPIDEMIOLOGY : ASHE 2024; 4:e215. [PMID: 39758881 PMCID: PMC11696600 DOI: 10.1017/ash.2024.400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 01/07/2025]
Abstract
Objective To estimate incidence and healthcare costs and mortality associated with Clostridioides difficile infection (CDI) among adults <65 years old. Design Retrospective cohort study. Patients First CDI episodes among commercially insured US patients 18-64 years old were identified from a large claims database. CDI+ patients were propensity score-matched (PSM) 1:1 with CDI- controls using clinically relevant variables including comorbidities. Methods Annual CDI incidence was calculated by age group and year (2015-2019). Healthcare utilization, costs, and mortality were analyzed by age group, acquisition (healthcare and community), and hospitalization status by calculating CDI-excess costs and mortality as the difference between PSM CDI+ and CDI- individuals. Results In 50-64- and 18-49-year-olds, respective CDI incidence per 100,000 person-years decreased from 217 and 113 cases in 2015 to 167 and 87 cases in 2019. Most cases (76.5%-86.9%) were community-associated. The costs and mortality analyses included 6,332 matched CDI+/- 50-64-year-olds and 6,667 CDI+/- 18-49-year-olds. Among 50-64-year-olds, mean 2-month healthcare and patients' out-of-pocket costs were $11,634 and $573 higher, respectively, in the CDI+ versus CDI- group. Among 18-49-year-olds, 2-month costs were $7,826 and $642 higher. Healthcare costs were higher for healthcare- versus community-associated CDI. At the 12-month follow-up, mortality was significantly higher in the CDI+ versus CDI- groups for both 50-64-year-olds (4.2% vs 2.0%; P < .001) and 18-49-year-olds (1.2% vs 0.6%; P < .001). Mortality rates were higher for hospitalized versus nonhospitalized CDI+ patients. Conclusions Prevention of CDI among adults 18-64 years old may significantly reduce costs and mortality.
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Affiliation(s)
- Holly Yu
- Health Economics and Outcomes Research, Pfizer Inc, Collegeville, PA, USA
| | - Tamuno Alfred
- Statistical Research and Data Science Center, Pfizer Inc, New York, NY, USA
| | - Jingying Zhou
- Statistical Data Sciences & Analytics, Pfizer Inc, Peapack, NJ, USA
| | - Jennifer Judy
- Evidence Generation Platform, Real World Evidence, Pfizer Inc, New York, NY, USA
| | - Margaret A. Olsen
- Departments of Medicine and Surgery, Washington University School of Medicine, St. Louis, MO, USA
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Bejcek A, Ancha A, Lewis M, Beaver R, Tecson K, Bomar J, Johnson C. Antibiotic use and risk of Clostridioides difficile infection in patients with inflammatory bowel disease. J Gastroenterol Hepatol 2024; 39:2417-2423. [PMID: 39148287 DOI: 10.1111/jgh.16720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 06/23/2024] [Accepted: 07/30/2024] [Indexed: 08/17/2024]
Abstract
BACKGROUND AND AIM Patients with inflammatory bowel disease (IBD) have an increased risk of Clostridioides difficile infection (CDI) compared with those without IBD, which is worsened with antibiotic usage. While prior studies have shown a correlation between CDI development and certain classes of antibiotics, the IBD population has not been well represented. This study evaluates the rates of CDI with outpatient antibiotic use in patients with IBD. METHODS We conducted a retrospective cohort study composed of patients with IBD and compared the incidence of CDI in patients who received an outpatient prescription for antibiotics (6694 patients) against those without prescriptions (6025 patients) from 2014 to 2020 at our institution. We compared CDI rates based on nine antibiotic classes: penicillins, cephalosporins, sulfonamides, tetracyclines, macrolides, quinolones, clindamycin, metronidazole, and nitrofurantoin. RESULTS The risk of CDI was low (0.7%) but significantly higher for those with antibiotic exposure (0.9% vs 0.5%, P = 0.005) and had a positive correlation with a smoking history. The increased risk of CDI in the IBD population was attributable to the clindamycin and metronidazole classes (odds ratio = 4.7, 95% confidence interval: 1.9-11.9, P = 0.001; odds ratio = 3.6, 95% confidence interval: 2.1-6.2, P < 0.0001, respectively). CONCLUSIONS The use of clindamycin or metronidazole prescribed in an outpatient setting was associated with a statistically significant increased risk of CDI in patients with IBD. Although the association between clindamycin and CDI is a well-established and common finding, the association between metronidazole and CDI is unique in this study.
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Affiliation(s)
- Alexis Bejcek
- Division of Gastroenterology, Department of Medicine, Baylor Scott & White Medical Center, Temple, Texas, USA
| | - Anupama Ancha
- Division of Internal Medicine, Department of Medicine, Baylor Scott & White Medical Center, Temple, Texas, USA
| | - Megan Lewis
- Division of Gastroenterology, Department of Medicine, Baylor Scott & White Medical Center, Temple, Texas, USA
| | - Ryan Beaver
- Division of Infectious Diseases, Department of Medicine, Baylor Scott & White Medical Center, Temple, Texas, USA
| | - Kristen Tecson
- Baylor Scott & White Research Institute, Baylor Scott & White Health, Dallas, Texas, USA
| | - Jaccallene Bomar
- Baylor Scott & White Research Institute, Baylor Scott & White Health, Dallas, Texas, USA
| | - Christopher Johnson
- Division of Gastroenterology, Department of Medicine, Baylor Scott & White Medical Center, Temple, Texas, USA
- Department of Medicine, Baylor College of Medicine, Temple, Texas, USA
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Herrera G, Castañeda S, Arboleda JC, Pérez-Jaramillo JE, Patarroyo MA, Ramírez JD, Muñoz M. Metagenome-assembled genomes (MAGs) suggest an acetate-driven protective role in gut microbiota disrupted by Clostridioides difficile. Microbiol Res 2024; 285:127739. [PMID: 38763016 DOI: 10.1016/j.micres.2024.127739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/20/2024] [Accepted: 04/22/2024] [Indexed: 05/21/2024]
Abstract
Clostridioides difficile may have a negative impact on gut microbiota composition in terms of diversity and abundance, thereby triggering functional changes supported by the differential presence of genes involved in significant metabolic pathways, such as short-chain fatty acids (SCFA). This work has evaluated shotgun metagenomics data regarding 48 samples from four groups classified according to diarrhea acquisition site (community- and healthcare facility-onset) and positive or negative Clostridioides difficile infection (CDI) result. The metagenomic-assembled genomes (MAGs) obtained from each sample were taxonomically assigned for preliminary comparative analysis concerning differences in composition among groups. The predicted genes involved in metabolism, transport, and signaling remained constant in microbiota members; characteristic patterns were observed in MAGs and genes involved in SCFA butyrate and acetate metabolic pathways for each study group. A decrease in genera and species, as well as relative MAG abundance with the presence of the acetate metabolism-related gene, was evident in the HCFO/- group. Increased antibiotic resistance markers (ARM) were observed in MAGs along with the genes involved in acetate metabolism. The results highlight the need to explore the role of acetate in greater depth as a potential protector of the imbalances produced by CDI, as occurs in other inflammatory intestinal diseases.
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Affiliation(s)
- Giovanny Herrera
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
| | - Sergio Castañeda
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
| | - Juan Camilo Arboleda
- Unidad de Bioprospección and Estudio de Microbiomas, Programa de Estudio y Control de Enfermedades Tropicales (PECET), Sede de Investigación Universitaria, Universidad de Antioquia, Medellín, Colombia; Semillero de Investigación en Bioinformática - GenomeSeq, Seccional Oriente, Universidad de Antioquia, Medellín, Colombia; Grupo de Fundamentos y Enseñanza de la Física y las Sistemas Dinámicas, Instituto de Biología, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, Colombia
| | - Juan E Pérez-Jaramillo
- Unidad de Bioprospección and Estudio de Microbiomas, Programa de Estudio y Control de Enfermedades Tropicales (PECET), Sede de Investigación Universitaria, Universidad de Antioquia, Medellín, Colombia; Semillero de Investigación en Bioinformática - GenomeSeq, Seccional Oriente, Universidad de Antioquia, Medellín, Colombia
| | - Manuel Alfonso Patarroyo
- Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Bogotá, Colombia; Microbiology Department, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá D.C. 111321, Colombia; Health Sciences Faculty, Universidad de Ciencias Aplicadas y Ambientales (U.D.C.A), Bogotá, Colombia
| | - Juan David Ramírez
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia; Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia; Molecular Microbiology Laboratory, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Marina Muñoz
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia; Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia; Instituto de Biotecnología-UN (IBUN), Universidad Nacional de Colombia, Bogotá, Colombia.
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11
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Leal J, Shen Y, Faris P, Dalton B, Sabuda D, Ocampo W, Bresee L, Chow B, Fletcher JR, Henderson E, Kaufman J, Kim J, Raman M, Kraft S, Lamont NC, Larios O, Missaghi B, Holroyd-Leduc J, Louie T, Conly J. Effectiveness of Bio-K+ for the prevention of Clostridioides difficile infection: Stepped-wedge cluster-randomized controlled trial. Infect Control Hosp Epidemiol 2024; 45:443-451. [PMID: 38073551 PMCID: PMC11007362 DOI: 10.1017/ice.2023.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 05/20/2023] [Accepted: 07/08/2023] [Indexed: 04/10/2024]
Abstract
OBJECTIVE To evaluate the impact of administering probiotics to prevent Clostridioides difficile infection (CDI) among patients receiving therapeutic antibiotics. DESIGN Stepped-wedge cluster-randomized trial between September 1, 2016, and August 31, 2019. SETTING This study was conducted in 4 acute-care hospitals across an integrated health region. PATIENTS Hospitalized patients, aged ≥55 years. METHODS Patients were given 2 probiotic capsules daily (Bio-K+, Laval, Quebec, Canada), containing 50 billion colony-forming units of Lactobacillus acidophilus CL1285, L. casei LBC80R, and L. rhamnosus CLR2. We measured hospital-acquired CDI (HA-CDI) and the number of positive C. difficile tests per 10,000 patient days as well as adherence to administration of Bio-K+ within 48 and 72 hours of antibiotic administration. Mixed-effects generalized linear models, adjusted for influenza admissions and facility characteristics, were used to evaluate the impact of the intervention on outcomes. RESULTS Overall adherence of Bio-K+ administration ranged from 76.9% to 84.6% when stratified by facility and periods. Rates of adherence to administration within 48 and 72 hours of antibiotic treatment were 60.2% -71.4% and 66.7%-75.8%, respectively. In the adjusted analysis, there was no change in HA-CDI (incidence rate ratio [IRR], 0.92; 95% confidence interval [CI], 0.68-1.23) or C. difficile positivity rate (IRR, 1.05; 95% CI, 0.89-1.24). Discharged patients may not have received a complete course of Bio-K+. Our hospitals had a low baseline incidence of HA-CDI. Patients who did not receive Bio-K+ may have differential risks of acquiring CDI, introducing selection bias. CONCLUSIONS Hospitals considering probiotics as a primary prevention strategy should consider the baseline incidence of HA-CDI in their population and timing of probiotics relative to the start of antimicrobial administration.
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Affiliation(s)
- Jenine Leal
- Infection Prevention and Control, Alberta Health Services, Alberta, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
| | - Ye Shen
- Infection Prevention and Control, Alberta Health Services, Alberta, Canada
| | - Peter Faris
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Analytics, Alberta Health Services, Alberta, Canada
| | - Bruce Dalton
- Pharmacy Services, Alberta Health Services, Calgary, Alberta, Canada
| | - Deana Sabuda
- Pharmacy Services, Alberta Health Services, Calgary, Alberta, Canada
| | - Wrechelle Ocampo
- O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
- W21 Research and Innovation Centre, University of Calgary and Alberta Health Services, Calgary, Alberta, Canada
| | - Lauren Bresee
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
| | - Blanda Chow
- Infection Prevention and Control, Alberta Health Services, Alberta, Canada
| | - Jared R. Fletcher
- Department of Health and Physical Education, Mount Royal University, Calgary, Alberta, Canada
| | - Elizabeth Henderson
- Infection Prevention and Control, Alberta Health Services, Alberta, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
| | - Jaime Kaufman
- W21 Research and Innovation Centre, University of Calgary and Alberta Health Services, Calgary, Alberta, Canada
| | - Joseph Kim
- Infection Prevention and Control, Alberta Health Services, Alberta, Canada
- Department of Medicine, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada
| | - Maitreyi Raman
- Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Scott Kraft
- W21 Research and Innovation Centre, University of Calgary and Alberta Health Services, Calgary, Alberta, Canada
| | - Nicole C. Lamont
- W21 Research and Innovation Centre, University of Calgary and Alberta Health Services, Calgary, Alberta, Canada
| | - Oscar Larios
- Infection Prevention and Control, Alberta Health Services, Alberta, Canada
- Department of Medicine, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary and Alberta Health Services, Calgary, Alberta, Canada
| | - Bayan Missaghi
- Infection Prevention and Control, Alberta Health Services, Alberta, Canada
- Department of Medicine, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada
- Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Jayna Holroyd-Leduc
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
- Department of Medicine, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada
| | - Thomas Louie
- Infection Prevention and Control, Alberta Health Services, Alberta, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Medicine, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada
| | - John Conly
- Infection Prevention and Control, Alberta Health Services, Alberta, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
- Department of Medicine, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada
- Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary and Alberta Health Services, Calgary, Alberta, Canada
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12
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Stabholz Y, Paul M. The effect of antibiotic therapy for Clostridioides difficile infection on mortality and other patient-relevant outcomes: a systematic review and meta-analysis. Clin Microbiol Infect 2024; 30:51-58. [PMID: 37690610 DOI: 10.1016/j.cmi.2023.09.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 08/28/2023] [Accepted: 09/03/2023] [Indexed: 09/12/2023]
Abstract
BACKGROUND Current practice guidelines favour fidaxomicin over vancomycin and exclude metronidazole from the recommended standard regimen for Clostridioides difficile infection (CDI), based on lower recurrence rates with fidaxomicin, giving little weight to mortality or the clinical implications of recurrences. OBJECTIVES To compile the effects of metronidazole, glycopeptides (vancomycin or teicoplanin), and fidaxomicin for CDI on mortality and other patient-relevant outcomes. DATA SOURCES PubMed, the Cochrane Library, ClinicalTrials.gov, conference proceedings, and Google Scholar, until August 2023. STUDY ELIGIBILITY CRITERIA Randomized controlled trials (RCTs). PARTICIPANTS Adult patients experiencing primary or recurrent CDI. INTERVENTIONS Glycopeptides versus fidaxomicin or metronidazole (comparators). ASSESSMENT OF RISK OF BIAS We used the Risk of Bias 2 (RoB 2) tool for randomized trials, focusing on the outcome of all-cause mortality. METHODS OF DATA SYNTHESIS Random effects meta-analyses were performed for dichotomous outcomes. Outcomes were summarized preferentially for all randomly assigned patients. RESULTS Thirteen trials were included. There was no significant difference in all-cause mortality (risk ratio [RR] < 1 favouring the comparator) between vancomycin and fidaxomicin (RR 0.86, 95% CI 0.64-1.14, 8 RCTs, 1951 patients) or metronidazole (RR 0.78, 95% CI 0.46-1.32, 4 RCTs, 808 patients), with low and very low certainty of evidence, respectively. No significant difference in initial treatment failure between fidaxomicin and vancomycin was found, however, initial treatment failure was higher with metronidazole (RR 1.58, 95% CI 1.10-2.27, 5 RCTs, 843 patients). No study reported on symptomatic recurrence necessitating re-treatment among all randomly assigned patients. Among initially cured patients, symptomatic recurrence necessitating re-treatment was lower with fidaxomicin than with vancomycin (RR 0.54, 95% CI 0.42-0.71, 6 RCTs, 1617 patients). None of the studies reported on other CDI complications or the burden of infection on daily activities. CONCLUSIONS Setting patient-relevant outcomes for CDI independently of the RCT definitions and results might lead to less confidence in the guidance for CDI management.
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Affiliation(s)
- Yoav Stabholz
- Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel; Department of Internal Medicine B, Rambam Health Care Campus, Haifa, Israel.
| | - Mical Paul
- Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel; Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
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13
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Reigadas E, Vázquez-Cuesta S, Bouza E. Economic Burden of Clostridioides difficile Infection in European Countries. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1435:1-12. [PMID: 38175468 DOI: 10.1007/978-3-031-42108-2_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Clostridioides difficile infection (CDI) remains a considerable challenge to healthcare systems worldwide. Although CDI represents a significant burden on healthcare systems in Europe, few studies have attempted to estimate the consumption of resources associated with CDI in Europe. The reported extra costs attributable to CDI vary widely according to the definitions, design, and methodologies used, making comparisons difficult to perform. In this chapter, the economic burden of healthcare facility-associated CDI in Europe will be assessed, as will other less explored areas such as the economic burden of recurrent CDI, community-acquired CDI, pediatric CDI, and CDI in outbreaks.
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Affiliation(s)
- Elena Reigadas
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | | | - Emilio Bouza
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- CIBER de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
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14
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Feuerstadt P, Allegretti JR, Dubberke ER, Guo A, Harvey A, Yang M, Garcia-Horton V, Fillbrunn M, Tillotson G, Bancke LL, LaPlante K, Garey KW, Khanna S. Efficacy and Health-Related Quality of Life Impact of Fecal Microbiota, Live-jslm: A Post Hoc Analysis of PUNCH CD3 Patients at First Recurrence of Clostridioides difficile Infection. Infect Dis Ther 2024; 13:221-236. [PMID: 38236515 PMCID: PMC10828144 DOI: 10.1007/s40121-023-00907-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 12/14/2023] [Indexed: 01/19/2024] Open
Abstract
INTRODUCTION Clostridioides difficile infection (CDI) causes symptoms of varying severity and negatively impacts patients' health-related quality of life (HRQL). Despite antibiotic treatment, recurrence of CDI (rCDI) is common and imposes clinical and economic burdens on patients. Fecal microbiota, live-jslm (REBYOTA [RBL]) is newly approved in the USA for prevention of rCDI following antibiotic treatments. We analyzed efficacy and HRQL impact of RBL vs. placebo in patients at first rCDI using data from the phase 3 randomized, double-blind placebo-controlled clinical trial, PUNCH CD3. METHODS This post hoc analysis included patients at first rCDI fromPUNCH CD3. Treatment success (i.e., absence of diarrhea within 8 weeks post-treatment) was analyzed adjusting for baseline patient characteristics. HRQL was measured using the Clostridioides difficile Quality of Life Survey (Cdiff32); absolute scores and change from baseline in total and domain (physical, mental, and social) scores were summarized and compared between arms. Analyses were conducted for the trial's blinded phase only. RESULTS Among 86 eligible patients (32.8% of the overall trial population, RBL 53 [61.6%], placebo 33 [38.4%]), RBL-treated patients had significantly lower odds of recurrence (i.e., greater probability of treatment success) at week 8 vs. placebo (odds ratio 0.35 [95% confidence interval 0.13, 0.98]). Probability of treatment success at week 8 was 81% for RBL and 60% for placebo, representing 21% absolute and 35% relative increases for RBL (crude proportions 79.2% vs. 60.6%; relative risk 0.53, p = 0.06). Additionally, RBL was associated with significantly higher Cdiff32 total (change score difference 13.5 [standard deviation 5.7], p < 0.05) and mental domain (16.2 [6.0], p < 0.01) scores vs. placebo from baseline to week 8. CONCLUSION Compared to placebo, RBL demonstrated a significantly higher treatment success in preventing further rCDI and enhanced HRQL among patients at first recurrence, establishing RBL as an effective treatment to prevent further recurrences in these patients. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT03244644.
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Affiliation(s)
- Paul Feuerstadt
- Yale University School of Medicine, New Haven, CT, USA.
- PACT-Gastroenterology Center, 2200 Whitney Avenue Suite 330 & 360, Hamden, CT, 06518, USA.
| | | | | | - Amy Guo
- Ferring Pharmaceuticals, Inc, Parsippany, NJ, USA
| | - Adam Harvey
- Rebiotix, a Ferring Company, Roseville, MN, USA
| | - Min Yang
- Analysis Group, Inc., Boston, MA, USA
- University of Texas at Austin, Austin, TX, USA
| | | | | | | | | | - Kerry LaPlante
- University of Rhode Island, Kingston, RI, USA
- Warren Alpert Medical School of Brown University, Providence, RI, USA
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15
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Ribis JW, Melo L, Shrestha S, Giacalone D, Rodriguez EE, Shen A, Rohlfing A. Single-spore germination analyses reveal that calcium released during Clostridioides difficile germination functions in a feedforward loop. mSphere 2023; 8:e0000523. [PMID: 37338207 PMCID: PMC10449524 DOI: 10.1128/msphere.00005-23] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/21/2023] [Indexed: 06/21/2023] Open
Abstract
Clostridioides difficile infections begin when its metabolically dormant spores germinate in response to sensing bile acid germinants alongside amino acid and divalent cation co-germinants in the small intestine. While bile acid germinants are essential for C. difficile spore germination, it is currently unclear whether both co-germinant signals are required. One model proposes that divalent cations, particularly Ca2+, are essential for inducing germination, while another proposes that either co-germinant class can induce germination. The former model is based on the finding that spores defective in releasing large stores of internal Ca2+ in the form of calcium dipicolinic acid (CaDPA) cannot germinate when germination is induced with bile acid germinant and amino acid co-germinant alone. However, since the reduced optical density of CaDPA-less spores makes it difficult to accurately measure their germination, we developed a novel automated, time-lapse microscopy-based germination assay to analyze CaDPA mutant germination at the single-spore level. Using this assay, we found that CaDPA mutant spores germinate in the presence of amino acid co-germinant and bile acid germinant. Higher levels of amino acid co-germinants are nevertheless required to induce CaDPA mutant spores to germinate relative to WT spores because CaDPA released by WT spores during germination can function in a feedforward loop to potentiate the germination of other spores within the population. Collectively, these data indicate that Ca2+ is not essential for inducing C. difficile spore germination because amino acid and Ca2+ co-germinant signals are sensed by parallel signaling pathways. IMPORTANCE Clostridioides difficile spore germination is essential for this major nosocomial pathogen to initiate infection. C. difficile spores germinate in response to sensing bile acid germinant signals alongside co-germinant signals. There are two classes of co-germinant signals: Ca2+ and amino acids. Prior work suggested that Ca2+ is essential for C. difficile spore germination based on bulk population analyses of germinating CaDPA mutant spores. Since these assays rely on optical density to measure spore germination and the optical density of CaDPA mutant spores is reduced relative to WT spores, this bulk assay is limited in its capacity to analyze germination. To overcome this limitation, we developed an automated image analysis pipeline to monitor C. difficile spore germination using time-lapse microscopy. With this analysis pipeline, we demonstrate that, although Ca2+ is dispensable for inducing C. difficile spore germination, CaDPA can function in a feedforward loop to potentiate the germination of neighboring spores.
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Affiliation(s)
- John W. Ribis
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA
- Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Luana Melo
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Shailab Shrestha
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA
- Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - David Giacalone
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA
- Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA
| | | | - Aimee Shen
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Amy Rohlfing
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA
- Tufts University, Boston, Massachusetts, USA
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16
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Barbosa MLL, Albano MO, Martins CDS, Warren CA, Brito GADC. Role of probiotics in preventing Clostridioides difficile infection in older adults: an integrative review. Front Med (Lausanne) 2023; 10:1219225. [PMID: 37636573 PMCID: PMC10450140 DOI: 10.3389/fmed.2023.1219225] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/21/2023] [Indexed: 08/29/2023] Open
Abstract
Clostridioides difficile infection (CDI) is the leading cause of healthcare-associated diarrhea. This infection can particularly affect older adults, the most susceptible to CDI. Currently, the standard therapeutic measure is antibiotic therapy, which in turn increases the risk of recurrence of the infection by its collateral damage to the patient's microbiota. Probiotics are live microorganisms capable of maintaining balance in the intestinal microbiota. This study aims to perform an integrative review of the protective benefit of probiotics in CDI and diarrhea associated with C. difficile. The PubMed, Scopus, and Web of Science databases, the 10-year time cutoff, and the Prism Flow diagram were used for data collection. We observed no consensus among the studies; however, three of the seven evaluated studies demonstrated that the use of probiotics in older adults could contribute to reducing the incidence of hospital-onset CDI. We also found that the studies evaluated a wide variety of microorganisms, particularly Saccharomyces boulardii, associated with beneficial effects. More research is needed to understand the successful use of probiotics in the prevention of CDI in hospitalized older adults receiving antibiotics.
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Affiliation(s)
| | | | | | | | - Gerly Anne de Castro Brito
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
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17
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Miller AC, Arakkal AT, Sewell DK, Segre AM, Tholany J, Polgreen PM. Comparison of Different Antibiotics and the Risk for Community-Associated Clostridioides difficile Infection: A Case-Control Study. Open Forum Infect Dis 2023; 10:ofad413. [PMID: 37622034 PMCID: PMC10444966 DOI: 10.1093/ofid/ofad413] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
Background Antibiotics are the greatest risk factor for Clostridioides difficile infection (CDI). Risk for CDI varies across antibiotic types and classes. Optimal prescribing and stewardship recommendations require comparisons of risk across antibiotics. However, many prior studies rely on aggregated antibiotic categories or are underpowered to detect significant differences across antibiotic types. Using a large database of real-world data, we evaluate community-associated CDI risk across individual antibiotic types. Methods We conducted a matched case-control study using a large database of insurance claims capturing longitudinal health care encounters and medications. Case patients with community-associated CDI were matched to 5 control patients by age, sex, and enrollment period. Antibiotics prescribed within 30 days before the CDI diagnosis along with other risk factors, including comorbidities, health care exposures, and gastric acid suppression were considered. Conditional logistic regression and a Bayesian analysis were used to compare risk across individual antibiotics. A sensitivity analysis of antibiotic exposure windows between 30 and 180 days was conducted. Results We identified 159 404 cases and 797 020 controls. Antibiotics with the greatest risk for CDI included clindamycin and later-generation cephalosporins, and those with the lowest risk included minocycline and doxycycline. We were able to differentiate and order individual antibiotics in terms of their relative level of associated risk for CDI. Risk estimates varied considerably with different exposure windows considered. Conclusions We found wide variation in CDI risk within and between classes of antibiotics. These findings ordering the level of associated risk across antibiotics can help inform tradeoffs in antibiotic prescribing decisions and stewardship efforts.
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Affiliation(s)
- Aaron C Miller
- University of Iowa, Carver College of Medicine, Iowa City, Iowa, USA
| | - Alan T Arakkal
- University of Iowa, College of Public Health, Iowa City, Iowa, USA
| | - Daniel K Sewell
- University of Iowa, College of Public Health, Iowa City, Iowa, USA
| | - Alberto M Segre
- Department of Computer Science, University of Iowa, Iowa City, Iowa, USA
| | - Joseph Tholany
- University of Iowa, Carver College of Medicine, Iowa City, Iowa, USA
| | - Philip M Polgreen
- University of Iowa, Carver College of Medicine, Iowa City, Iowa, USA
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Harrison MA, Farthing RJ, Allen N, Ahern LM, Birchall K, Bond M, Kaur H, Wren BW, Bergeron JRC, Dawson LF. Identification of novel p-cresol inhibitors that reduce Clostridioides difficile's ability to compete with species of the gut microbiome. Sci Rep 2023; 13:9492. [PMID: 37303029 PMCID: PMC10258198 DOI: 10.1038/s41598-023-32656-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 03/30/2023] [Indexed: 06/13/2023] Open
Abstract
Treatment of Clostridioides difficile infection (CDI) is expensive and complex, with a high proportion of patients suffering infection relapse (20-35%), and some having multiple relapses. A healthy, unperturbed gut microbiome provides colonisation resistance against CDI through competition for nutrients and space. However, antibiotic consumption can disturb the gut microbiota (dysbiosis) resulting in the loss of colonisation resistance allowing C. difficile to colonise and establish infection. A unique feature of C. difficile is the production of high concentrations of the antimicrobial compound para-cresol, which provides the bacterium with a competitive advantage over other bacteria found in the gut. p-cresol is produced by the conversion of para-Hydroxyphenylacetic acid (p-HPA) by the HpdBCA enzyme complex. In this study, we have identified several promising inhibitors of HpdBCA decarboxylase, which reduce p-cresol production and render C. difficile less able to compete with a gut dwelling Escherichia coli strain. We demonstrate that the lead compound, 4-Hydroxyphenylacetonitrile, reduced p-cresol production by 99.0 ± 0.4%, whereas 4-Hydroxyphenylacetamide, a previously identified inhibitor of HpdBCA decarboxylase, only reduced p-cresol production by 54.9 ± 13.5%. To interpret efficacy of these first-generation inhibitors, we undertook molecular docking studies that predict the binding mode for these compounds. Notably, the predicted binding energy correlated well with the experimentally determined level of inhibition, providing a molecular basis for the differences in efficacy between the compounds. This study has identified promising p-cresol production inhibitors whose development could lead to beneficial therapeutics that help to restore colonisation resistance and therefore reduce the likelihood of CDI relapse.
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Affiliation(s)
- Mark A Harrison
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | - Rebecca J Farthing
- Randall Centre for Cell and Molecular Biophysics, King's College London, London, WC2R 2LS, UK
| | - Nyasha Allen
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | - Lucy M Ahern
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | | | - Michael Bond
- LifeArc, Lynton House, 7-12 Tavistock Square, London, WC1H 9LT, UK
| | - Harparkash Kaur
- Department of Clinical Research, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | - Brendan W Wren
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | - Julien R C Bergeron
- Randall Centre for Cell and Molecular Biophysics, King's College London, London, WC2R 2LS, UK
| | - Lisa F Dawson
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
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19
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Gawey BJ, Khanna S. Clostridioides difficile Infection: Landscape and Microbiome Therapeutics. Gastroenterol Hepatol (N Y) 2023; 19:319-328. [PMID: 37706187 PMCID: PMC10496268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023]
Abstract
Clostridioides difficile infection (CDI) is the leading cause of hospital-acquired diarrhea and is common in the community. Both younger individuals who may be healthy otherwise and older individuals with comorbid conditions are at risk for developing CDI, with the predominant risk factor being antibiotic use. Unlike other gastrointestinal infections, CDI is not self-limited, requires antimicrobial therapy, and tends to recur at high rates even without additional risk factor exposure. The goals of CDI management include controlling active symptoms and using a recurrence prevention strategy such as a narrow-spectrum antibiotic, tapered and pulsed regimens, antibody- based therapies (directed against toxin B), or microbiome restoration. In recent years, fecal microbiota transplantation (FMT) has been the most used modality to prevent recurrent CDI with high cure rates. Heterogeneity, lack of scalability, and serious adverse events from FMT have led to development of standardized microbiota restoration therapies (MRTs). The US Food and Drug Administration has approved 2 stool-derived MRTs for prevention of recurrent CDI: fecal microbiota, live-jslm, an enema-based therapy; and fecal microbiota spores, live-brpk, an oral therapy. A phase 3 trial for a synthetic oral MRT is underway. This article outlines the pathophysiology and treatment of CDI, focusing primarily on the gut microbiome and standardized MRTs.
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Affiliation(s)
- Brent J. Gawey
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Sahil Khanna
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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20
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Madden GR, Rigo I, Boone R, Abhyankar MM, Young MK, Basener W, Petri WA. Novel Biomarkers, Including tcdB PCR Cycle Threshold, for Predicting Recurrent Clostridioides difficile Infection. Infect Immun 2023; 91:e0009223. [PMID: 36975808 PMCID: PMC10112139 DOI: 10.1128/iai.00092-23] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/29/2023] Open
Abstract
Traditional clinical models for predicting recurrent Clostridioides difficile infection do not perform well, likely owing to the complex host-pathogen interactions involved. Accurate risk stratification using novel biomarkers could help prevent recurrence by improving underutilization of effective therapies (i.e., fecal transplant, fidaxomicin, bezlotoxumab). We used a biorepository of 257 hospitalized patients with 24 features collected at diagnosis, including 17 plasma cytokines, total/neutralizing anti-toxin B IgG, stool toxins, and PCR cycle threshold (CT) (a proxy for stool organism burden). The best set of predictors for recurrent infection was selected by Bayesian model averaging for inclusion in a final Bayesian logistic regression model. We then used a large PCR-only data set to confirm the finding that PCR CT predicts recurrence-free survival using Cox proportional hazards regression. The top model-averaged features were (probabilities of >0.05, greatest to least): interleukin 6 (IL-6), PCR CT, endothelial growth factor, IL-8, eotaxin, IL-10, hepatocyte growth factor, and IL-4. The accuracy of the final model was 0.88. Among 1,660 cases with PCR-only data, cycle threshold was significantly associated with recurrence-free survival (hazard ratio, 0.95; P < 0.005). Certain biomarkers associated with C. difficile infection severity were especially important for predicting recurrence; PCR CT and markers of type 2 immunity (endothelial growth factor [EGF], eotaxin) emerged as positive predictors of recurrence, while type 17 immune markers (IL-6, IL-8) were negative predictors. In addition to novel serum biomarkers (particularly, IL-6, EGF, and IL-8), the readily available PCR CT may be critical to augment underperforming clinical models for C. difficile recurrence.
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Affiliation(s)
- Gregory R. Madden
- Division of Infectious Diseases & International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Isaura Rigo
- Division of Infectious Diseases & International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Rachel Boone
- Division of Infectious Diseases & International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Mayuresh M. Abhyankar
- Division of Infectious Diseases & International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Mary K. Young
- Division of Infectious Diseases & International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - William Basener
- School of Data Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - William A. Petri
- Division of Infectious Diseases & International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA
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21
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Liu J, Liu H, Teng Y, Qin N, Ren X, Xia X. A high-sucrose diet causes microbiota composition shift and promotes the susceptibility of mice to Salmonella Typhimurium infection. Food Funct 2023; 14:2836-2846. [PMID: 36880221 DOI: 10.1039/d2fo03467k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Abstract
A westernized diet characterized by high fat and sugar is tightly associated with the development of metabolic diseases and inflammatory bowel disease. Although a high-fat diet has been extensively studied for its involvement in various diseases, fewer studies have examined the impact of a high-sugar diet on the development of certain diseases, particularly enteric infections. This study aimed to explore the effect of a high sucrose diet on Salmonella Typhimurium-induced infection. C57BL/6 mice received a normal diet (Control) or a high sucrose diet (HSD) for eight weeks and then were infected by Salmonella Typhimurium. The high-sugar diet profoundly altered the relative abundance of certain microbial taxa. Bacteroidetes and Verrucomicrobiota were more abundant in normal diet-fed mice than in HSD-fed mice. Moreover, short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs) were significantly higher in mice from the control group than the HSD group. More S. Typhimurium counts in feces and other tissues were observed in HSD-fed mice after infection. Tight junction proteins and antimicrobial peptides were significantly decreased in HSD-fed mice. Fecal microbiota transplantation (FMT) demonstrated that mice that received normal fecal microbiota had lower Salmonella Typhimurium burdens compared with mice that received HSD fecal microbiota, indicating that the altered microbial communities are associated with the severity of infection. Together, these findings suggest that the excessive intake of sucrose disturbs intestinal homeostasis and predisposes mice to Salmonella-induced infection.
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Affiliation(s)
| | | | - Yue Teng
- Dalian Polytechnic University, China.
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22
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Claeys KC, Johnson MD. Leveraging diagnostic stewardship within antimicrobial stewardship programmes. Drugs Context 2023; 12:dic-2022-9-5. [PMID: 36843619 PMCID: PMC9949764 DOI: 10.7573/dic.2022-9-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/16/2022] [Indexed: 02/17/2023] Open
Abstract
Novel diagnostic stewardship in infectious disease consists of interventions that modify ordering, processing, and reporting of diagnostic tests to provide the right test for the right patient, prompting the right action. The interventions work upstream and synergistically with traditional antimicrobial stewardship efforts. As diagnostic stewardship continues to gain public attention, it is critical that antimicrobial stewardship programmes not only learn how to effectively leverage diagnostic testing to improve antimicrobial use but also ensure that they are stakeholders and leaders in developing new diagnostic stewardship interventions within their institutions. This review will discuss the need for diagnostic and antimicrobial stewardship, the interplay of diagnostic and antimicrobial stewardship, evidence of benefit to antimicrobial stewardship programmes, and considerations for successfully engaging in diagnostic stewardship interventions. This article is part of the Antibiotic stewardship Special Issue: https://www.drugsincontext.com/special_issues/antimicrobial-stewardship-a-focus-on-the-need-for-moderation.
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Affiliation(s)
- Kimberly C Claeys
- University of Maryland School of Pharmacy, Department of Practice Science and Health Outcomes Research, Baltimore, MD, USA
| | - Melissa D Johnson
- Division of Infectious Diseases & International Health, Duke University School of Medicine, Durham, NC, USA,Duke Antimicrobial Stewardship Outreach Network (DASON), Duke University Medical Center Durham, NC, USA
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23
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Epidemiology and Economic Burden of Acute Infectious Gastroenteritis Among Adults Treated in Outpatient Settings in US Health Systems. Am J Gastroenterol 2023:00000434-990000000-00647. [PMID: 36728224 DOI: 10.14309/ajg.0000000000002186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 01/06/2023] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Acute infectious gastroenteritis (AGE) is a common reason for outpatient visits and hospitalizations in the United States. This study aimed to understand the demographic and clinical characteristics, common pathogens detected, health care resource utilization (HRU), and cost among adult outpatients with AGE visiting US health systems. METHODS A retrospective cohort study was conducted using one of the largest hospital discharge databases (PINC AI Healthcare Database) in the United States. Adult patients (aged ≥18 years) with a principal diagnosis of AGE during an outpatient visit between January 1, 2016, and June 30, 2021, were included. Pathogen detection analysis was performed in those with microbiology data available. RESULTS Among 248,896 patients, the mean age was 44.3 years (range 18-89+ years), 62.9% were female, and 68.5% were White. More than half (62.0%) of the patients did not have any preexisting comorbidity, and only 18.3% underwent stool workup at the hospital. Most patients (84.7%) were seen in the emergency department, and most (96.4%) were discharged home. Within 30 days of discharge, 1.0% were hospitalized, and 2.8% had another outpatient visit due to AGE. The mean cost of the index visit plus 30-day AGE-related follow-up was $1,338 per patient, amounting to $333,060,182 for the total study population. Among patients with microbiology data available (n = 12,469), common pathogens detected were Clostridioides difficile (32.2%), norovirus (6.3%), and Campylobacter spp. (4.0%). DISCUSSION AGE is a common and costly disease affecting adults of all ages and more females than males, including individuals with or without baseline conditions in a hospital-based outpatient setting. C. difficile was the most common pathogen detected.
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24
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Garey KW, Rose W, Gunter K, Serio AW, Wilcox MH. Omadacycline and Clostridioides difficile: A Systematic Review of Preclinical and Clinical Evidence. Ann Pharmacother 2023; 57:184-192. [PMID: 35656828 PMCID: PMC9874691 DOI: 10.1177/10600280221089007] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE The objective of this systematic review is to summarize in vitro, preclinical, and human data related to omadacycline and Clostridioides difficile infection (CDI). DATA SOURCES PubMed and Google Scholar were searched for "omadacycline" AND ("Clostridium difficile" OR "C difficile" OR "Clostridioides difficile") for any studies published before February 15, 2022. The US Food and Drug Administration (FDA) Adverse Events Reporting System (AERS) was searched for omadacycline (for reports including "C. difficile" or "CDI" or "gastrointestinal infection"). The publications list publicly available at Paratek Pharmaceuticals, Inc. Web site was reviewed. STUDY SELECTION AND DATA EXTRACTION Publications presenting primary data on omadacycline and C. difficile published in English were included. DATA SYNTHESIS Preclinical and clinical evidence was extracted from 14 studies. No case reports in indexed literature and no reports on FDA AERS were found. Omadacycline has potent in vitro activity against many C. difficile clinical strains and diverse ribotypes. In phase 3 studies, there were no reports of CDI in patients who received omadacycline for either community-acquired bacterial pneumonia or acute bacterial skin and skin structure infection. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Omadacycline should be considered a low-risk antibiotic regarding its propensity to cause CDI. CONCLUSIONS Reducing the burden of CDI on patients and the health care system should be a priority. Patients with appropriate indications who are at heightened risk of CDI may be suitable candidates for omadacycline therapy. In these patients, omadacycline may be preferable to antibiotics with a high CDI risk.
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Affiliation(s)
- Kevin W. Garey
- University of Houston College of
Pharmacy, Houston, TX, USA
| | - Warren Rose
- School of Pharmacy, University of
Wisconsin–Madison, Madison, WI, USA
| | - Kyle Gunter
- Paratek Pharmaceuticals, Inc., King of
Prussia, PA, USA,Kyle Gunter, Director of Medical Science,
Paratek Pharmaceuticals, Inc., 1000 First Avenue, Suite 200, King of Prussia, PA
19406, USA.
| | | | - Mark H. Wilcox
- University of Leeds & Leeds
Teaching Hospitals, Leeds, UK
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25
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Chopra T, Hecht G, Tillotson G. Gut microbiota and microbiota-based therapies for Clostridioides difficile infection. Front Med (Lausanne) 2023; 9:1093329. [PMID: 36698844 PMCID: PMC9868170 DOI: 10.3389/fmed.2022.1093329] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/15/2022] [Indexed: 01/10/2023] Open
Abstract
Clostridioides difficile infection poses significant clinical challenges due to its recurrent nature. Current antibiotic management does not address the underlying issue, that of a disturbed gastrointestinal microbiome, called dysbiosis. This provides a supportive environment for the germination of C. difficile spores which lead to infection and toxin production as well as an array of other health conditions. The use of microbiome restoration therapies such as live biotherapeutics can reverse dysbiosis and lead to good clinical outcomes. Several such therapies are under clinical investigation.
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Affiliation(s)
- Teena Chopra
- Division of Infectious Diseases, Wayne State University, Detroit, MI, United States,*Correspondence: Teena Chopra,
| | - Gail Hecht
- Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States
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26
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Patel D, Senecal J, Spellberg B, Morris AM, Saxinger L, Footer BW, McDonald EG, Lee TC. Fidaxomicin to prevent recurrent Clostridioides difficile: what will it cost in the USA and Canada? JAC Antimicrob Resist 2023; 5:dlac138. [PMID: 36632358 PMCID: PMC9825808 DOI: 10.1093/jacamr/dlac138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 12/13/2022] [Indexed: 01/09/2023] Open
Abstract
Importance Recent changes in guidelines for managing Clostridioides difficile infections (CDI) have placed fidaxomicin as a first-line treatment. Objective To estimate the net cost of first-line fidaxomicin compared to vancomycin in the American and Canadian healthcare systems and to estimate the price points at which fidaxomicin would become cost saving for the prevention of recurrence. Data sources and study selection We identified randomized, placebo-controlled trials directly comparing fidaxomicin with vancomycin that reported on recurrence. Medication costs were obtained from the Veterans Affairs Federal Supply Schedule (US) and the Quebec drug formulary (Canada). The average cost of a CDI recurrence was established through a systematic review for each country. Data extraction synthesis and outcome measures For efficacy, data on CDI recurrence at day 40 were pooled using a restricted maximal likelihood random effects model. For the cost review, the mean cost across identified studies was adjusted to reflect May 2022 dollars. These were used to estimate the net cost per recurrence prevented with fidaxomicin and the price point below which fidaxomicin would be cost saving. Results The estimated mean system costs of a CDI recurrence were $15 147USD and $8806CAD, respectively. Preventing one recurrence by using first-line fidaxomicin over vancomycin would cost $38 222USD (95%CI $30 577-$57 332) and $13 760CAD (95%CI $11 008-$20 640), respectively. The probability that fidaxomicin was cost saving exceeded 95% if priced below $1140USD or $860CAD, respectively. Conclusions and Relevance An increased drug expenditure on fidaxomicin may not be offset through recurrence prevention unless the fidaxomicin price is negotiated.
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Affiliation(s)
- Devangi Patel
- Faculty of Medicine and Health Sciences, McGill University, Montréal, Canada
| | - Julien Senecal
- Faculty of Medicine and Health Sciences, McGill University, Montréal, Canada
| | - Brad Spellberg
- Los Angeles County and University of Southern California Medical Center, Los Angeles, CA, USA
| | - Andrew M Morris
- Division of Infectious Diseases, Department of Medicine, Sinai Health, University Health Network, and University of Toronto, Toronto, Canada
| | - Lynora Saxinger
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada
| | | | - Emily G McDonald
- Division of General Internal Medicine, Department of Medicine, McGill University Health Centre, Montréal, Canada,Clinical Practice Assessment Unit, Department of Medicine, McGill University Health Centre, Montréal, Canada
| | - Todd C Lee
- Corresponding author. E-mail: @DrToddLee, @ASPphysician, @DrEmilyMcD, @BrentFooter, @AntibioticDoc, @BradSpellberg
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27
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Tillotson G, Archbald-Pannone L, Johnson S, Ng S, Ando M, Harvey A, Bancke L, Feuerstadt P. Microbiota-Based Live Biotherapeutic RBX2660 for the Reduction of Recurrent Clostridioides difficile Infection in Older Adults With Underlying Comorbidities. Open Forum Infect Dis 2023; 10:ofac703. [PMID: 36686631 PMCID: PMC9846189 DOI: 10.1093/ofid/ofac703] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 12/29/2022] [Indexed: 12/31/2022] Open
Abstract
Background Advanced age and underlying comorbidities are associated with greater rates of recurrence in patients with Clostridioides difficile infection (CDI). Reducing the likelihood of recurrence through treatment with an antimicrobial followed by a microbiota replacement therapy can decrease the burden of this infection and improve patient outcomes. We report the efficacy and safety of RBX2660, a microbiota-based live biotherapeutic, in older adults with recurrent CDI, grouped by comorbidities. Methods In this post hoc subgroup analysis of the PUNCH CD3 trial, we assessed outcomes in older adults (age ≥65 years) grouped by Charlson Comorbidity Index severity scores at screening (moderate [3-4] and severe [≥5]) and by the presence of underlying cardiac, renal, or gastrointestinal disorders. Results RBX2660 treatment success rates in older adults with comorbidities were consistent across subgroups and similar to those in the total RBX2660-treated population. A greater percentage of RBX2660-treated older adults remained free of CDI recurrence through 8 weeks following treatment compared with placebo-treated participants in all but 2 subgroups assessed. Across all subgroups, most treatment-emergent adverse events (TEAEs) were mild or moderate in severity and related to a preexisting condition. None of the serious or life-threatening TEAEs that occurred were related to RBX2660 or its administration. Occurrence of TEAEs did not cluster in any subgroup. Conclusions RBX2660 is efficacious and safe in older adults with recurrent CDI and underlying comorbidities.
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Affiliation(s)
- Glenn Tillotson
- Correspondence: Glenn Tillotson, PhD, GST Micro, 327 Plantation Road, North, VA 23128, USA ()
| | - Laurie Archbald-Pannone
- Department of Internal Medicine and Infectious Diseases, University of Virginia Hospital, Charlottesville, Virginia, USA
| | - Stuart Johnson
- Department of Infectious Diseases, Edward Hines Jr Veterans Affairs Hospital, Hines, Illinois, USA
- Loyola University Medical Center, Maywood, Illinois, USA
| | - Samson Ng
- Medical Affairs, Ferring Pharmaceuticals, Parsippany, New Jersey, USA
| | | | - Adam Harvey
- Clinical Research Department, Rebiotix Inc, a Ferring Company, Roseville, Minnesota, USA
| | - Lindy Bancke
- Clinical Research Department, Rebiotix Inc, a Ferring Company, Roseville, Minnesota, USA
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28
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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. [PMID: 36425405 PMCID: PMC9679343 DOI: 10.1177/17562848221134396] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 10/04/2022] [Indexed: 11/21/2022] Open
Abstract
The species composition of the human gut microbiota is related to overall health, and a healthy gut microbiome is crucial in maintaining colonization resistance against pathogens. Disruption of gut microbiome composition and functionality reduces colonization resistance and has been associated with several gastrointestinal and non-gastrointestinal diseases. One prime example is Clostridioides difficile infection (CDI) and subsequent recurrent infections that occur after the development of systemic antibiotic-related dysbiosis. Standard-of-care antibiotics used for both acute and recurrent infections do not address dysbiosis and often worsen the condition. Moreover, monoclonal antibodies, recommended in conjunction with standard-of-care antibiotics for the prevention of recurrent CDI in patients at high risk of recurrence, reduce recurrences but do not address the underlying dysbiosis. Fecal microbiota transplantation (FMT) is an evolving therapeutic strategy in which microbes are harvested from healthy donor stool and transplanted into the gut of a recipient to restore the gut microbiome. Although effective in the prevention of recurrent CDI, some existing challenges include screening and the standardization of stool acquisition and processing. Recent safety alerts by the US Food and Drug Administration raised concern about the possibility of transmission of multidrug-resistant organisms or severe acute respiratory syndrome coronavirus 2 via FMT. Increased knowledge that microbes are beneficial in restoring the gut microbiome has led to the clinical development of several newer biotherapeutic formulations that are more regulated than FMT, which may allow for improved restoration of the gut microbiome and prevention of CDI recurrence. This review focuses on mechanisms by which gut microbiome restoration could influence colonization resistance against the pathogen C. difficile. Plain language summary The Role of the Gut Microbiome in Clostridioides difficile Infection Introduction: A rich and diverse gut microbiome is key to immune system regulation and colonization resistance against pathogens.A disruption in the gut microbiome composition can make the gut more vulnerable to diseases such as Clostridioides difficile infection (CDI), caused by the bacterium C. difficile.CDI management presents a therapeutic dilemma, as it is usually treated with antibiotics that can treat the infection but also can damage the microbiome.Treatment of CDI using antibiotics can further reduce microbial diversity and deplete beneficial bacteria from the gut leading to a condition called dysbiosis.Antibiotic treatment can be followed by therapies that restore the gut microbiota, boost colonization resistance, and prevent the development of antimicrobial resistance.It is important to evaluate treatment options to determine their safety and effectiveness. Methods: The researchers provided an overview of the mechanisms that the gut microbiome uses to prevent colonization of the gut by pathogens.They subsequently reviewed the efficacy and shortcomings of the following treatments for CDI: - Antibiotics- Monoclonal antibodies- Fecal microbiota transplantation (FMT) Results: Commensal intestinal bacteria prevent colonization of the gut by pathogens using mechanisms such as: - Competition for key nutrients- Production of inhibitory bile acids- Short-chain fatty acid production- Lowering the luminal pH- Production of bacteriocinsAntibiotic therapy is recommended as a standard treatment for CDI. However, patients are vulnerable to recurrent CDI after discontinuation of the therapy.Monoclonal antibodies that inactivate C. difficile toxins may be recommended along with antibiotics to prevent recurrent CDI. However, this approach does not restore the microbiome.FMT is one method of microbial restoration, where stool is harvested from a healthy donor and transplanted into a patient's colon.Although FMT has shown some efficacy in the treatment of recurrent CDI, the procedure is not standardized.Safety concerns have been raised about the possibility of transmission of multidrug-resistant pathogens via FMT. Conclusion: Treatment methods that can efficiently restore the diversity of the gut microbiome are crucial in preventing recurrence of CDI.
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Affiliation(s)
| | - Nasia Safdar
- University of Wisconsin, Madison, WI, USA
- William S. Middleton Memorial VA Hospital, Madison, WI, USA
| | - Sahil Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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29
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Herrera G, Arboleda JC, Pérez-Jaramillo JE, Patarroyo MA, Ramírez JD, Muñoz M. Microbial Interdomain Interactions Delineate the Disruptive Intestinal Homeostasis in Clostridioides difficile Infection. Microbiol Spectr 2022; 10:e0050222. [PMID: 36154277 PMCID: PMC9602525 DOI: 10.1128/spectrum.00502-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 09/06/2022] [Indexed: 11/20/2022] Open
Abstract
Clostridioides difficile infection (CDI) creates an imbalance in the intestinal microbiota due to the interaction of the components making up this ecosystem, but little is known about the impact of this disease on other microbial members. This work has thus been aimed at evaluating the taxonomic composition, potential gene-associated functions, virulence factors, and antimicrobial resistance profiles of gut microbiomes. A total of 48 DNA samples obtained from patients with health care facility-acquired (HCFO) and community-onset (CO) diarrhea were distributed in the following four groups according to CDI status: HCFO/+ (n = 13), HCFO/- (n = 8), CO/+ (n = 13), and CO/- (n = 14). These samples were subjected to shotgun metagenomics sequencing. Although the CDI groups' microbiota had microbiome alterations, the greatest imbalance was observed in the in the HCFO+/- groups, with an increase in common pathogens and phage populations, as well as a decrease in beneficial microorganisms that leads to a negative impact on some intestinal homeostasis-related metabolic processes. A reduction in the relative abundance of butyrate metabolism-associated genes was also detected in the HCFO groups (P < 0.01), with an increase in some virulence factors and antibiotic-resistance markers. A set of 51 differentially abundant species in the groups with potential association to CDI enabled its characterization, leading to their spatial separation by onset. Strong correlations between phages and some archaeal and bacterial phyla were identified. This highlighted the need to study the microbiota's various components since their imbalance is multifactorial, with some pathogens contributing to a greater or lesser extent because of their interaction with the ecosystem they inhabit. IMPORTANCE Clostridioides difficile infection represents a serious public health problem in different countries due to its high morbi-mortality and the high costs it represents for health care systems. Studies have shown the impact of this infection on intestinal microbiome homeostasis, mainly on bacterial populations. Our research provides evidence of the impact of CDI at both the compositional (bacteria, archaea, and viruses), and functional levels, allowing us to understand that the alterations of the microbiota occur systemically and are caused by multiple perturbations generated by different members of the microbiota as well as by some pathogens that take advantage of the imbalance to proliferate. Likewise, the 51 differentially abundant species in the study groups with potential association to CDI found in this study could help us envisage future treatments against this and other inflammatory diseases, improving future therapeutic options for patients.
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Affiliation(s)
- Giovanny Herrera
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
| | - Juan Camilo Arboleda
- Unidad de Bioprospección and Estudio de Microbiomas, Programa de Estudio y Control de Enfermedades Tropicales (PECET), Sede de Investigación Universitaria, Universidad de Antioquia, Medellín, Colombia
- Semillero de Investigación en Bioinformática-GenomeSeq, Seccional Oriente, Universidad de Antioquia, Medellín, Colombia
- Grupo de Fundamentos y Enseñanza de la Física y los Sistemas Dinámicos, Instituto de Biología, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, Colombia
| | - Juan E. Pérez-Jaramillo
- Semillero de Investigación en Bioinformática-GenomeSeq, Seccional Oriente, Universidad de Antioquia, Medellín, Colombia
- Grupo de Fundamentos y Enseñanza de la Física y los Sistemas Dinámicos, Instituto de Biología, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, Colombia
| | - Manuel Alfonso Patarroyo
- Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Bogotá, Colombia
- Microbiology Department, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
- Health Sciences Division, Universidad Santo Tomás, Bogotá, Colombia
| | - Juan David Ramírez
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
- Molecular Microbiology Laboratory, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Marina Muñoz
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
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Bhute SS, Mefferd CC, Phan JR, Ahmed M, Fox-King AE, Alarcia S, Villarama JV, Abel-Santos E, Hedlund BP. A High-Carbohydrate Diet Prolongs Dysbiosis and Clostridioides difficile Carriage and Increases Delayed Mortality in a Hamster Model of Infection. Microbiol Spectr 2022; 10:e0180421. [PMID: 35708337 PMCID: PMC9431659 DOI: 10.1128/spectrum.01804-21] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 05/21/2022] [Indexed: 12/20/2022] Open
Abstract
Studies using mouse models of Clostridioides difficile infection (CDI) have demonstrated a variety of relationships between dietary macronutrients on antibiotic-associated CDI; however, few of these effects have been examined in more susceptible hamster models of CDI. In this study, we investigated the effect of a high-carbohydrate diet previously shown to protect mice from CDI on the progression and resolution of CDI in a hamster disease model, with 10 animals per group. Hamsters fed the high-carbohydrate diet developed distinct diet-specific microbiomes during antibiotic treatment and CDI, with lower diversity, persistent C. difficile carriage, and delayed microbiome restoration. In contrast to CDI protection in mice, most hamsters fed a high-carbohydrate diet developed fulminant CDI including several cases of late-onset CDI, that were not observed in hamsters fed a standard lab diet. We speculate that prolonged high-carbohydrate diet-specific dysbiosis in these animals allowed C. difficile to persist in the gut of the animals where they could proliferate postvancomycin treatment, leading to delayed CDI onset. This study, along with similar studies in mouse models of CDI, suggests some high-carbohydrate diets may promote antibiotic-associated dysbiosis and long-term C. difficile carriage, which may later convert to symptomatic CDI. IMPORTANCE The effects of diet on CDI are not completely known. Here, we used a high-carbohydrate diet previously shown to protect mice against CDI to assess its effect on a hamster model of CDI and paradoxically found that it promoted dysbiosis, C. difficile carriage, and higher mortality. A common thread in both mouse and hamster experimental models was that the high-carbohydrate diet promoted dysbiosis and long-term carriage of C. difficile, which may have converted to fulminant CDI only in the highly susceptible hamster model system. If diets high in carbohydrates also promote dysbiosis and C. difficile carriage in humans, then these diets might paradoxically increase chances of CDI relapse despite their protective effects against primary CDI.
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Affiliation(s)
- Shrikant S. Bhute
- School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
| | - Chrisabelle C. Mefferd
- School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
- School of Public Health, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
| | - Jacqueline R. Phan
- Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
| | - Muneeba Ahmed
- School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
- College of Osteopathic Medicine, Touro University, Nevada, Henderson, Nevada, USA
| | - Amelia E. Fox-King
- School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
- College of Osteopathic Medicine, Touro University, Nevada, Henderson, Nevada, USA
| | - Stephanie Alarcia
- School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
| | - Jacob V. Villarama
- School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
- Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
| | - Ernesto Abel-Santos
- Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
- Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
| | - Brian P. Hedlund
- School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
- Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
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Schnizlein MK, Young VB. Capturing the environment of the Clostridioides difficile infection cycle. Nat Rev Gastroenterol Hepatol 2022; 19:508-520. [PMID: 35468953 DOI: 10.1038/s41575-022-00610-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/21/2022] [Indexed: 12/11/2022]
Abstract
Clostridioides difficile (formerly Clostridium difficile) infection is a substantial health and economic burden worldwide. Great strides have been made over the past several years in characterizing the physiology of C. difficile infection, particularly regarding how gut microorganisms and their host work together to provide colonization resistance. As mammalian hosts and their indigenous gut microbiota have co-evolved, they have formed a complex yet stable relationship that prevents invading microorganisms from establishing themselves. In this Review, we discuss the latest advances in our understanding of C. difficile physiology that have contributed to its success as a pathogen, including its versatile survival factors and ability to adapt to unique niches. Using discoveries regarding microorganism-host and microorganism-microorganism interactions that constitute colonization resistance, we place C. difficile within the fiercely competitive gut environment. A comprehensive understanding of these relationships is required to continue the development of precision medicine-based treatments for C. difficile infection.
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Affiliation(s)
- Matthew K Schnizlein
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Vincent B Young
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA.
- Department of Internal Medicine/Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
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32
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Liu MY, Challa M, McCoul ED, Chen PG. Economic Viability of Penicillin Allergy Testing to Avoid Improper Clindamycin Surgical Prophylaxis. Laryngoscope 2022; 133:1086-1091. [PMID: 35904127 DOI: 10.1002/lary.30329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 07/07/2022] [Accepted: 07/21/2022] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Patients mislabeled with a penicillin allergy are often unnecessarily given prophylactic clindamycin. Thus, otolaryngologists may cause harm due to clindamycin's associated risk of Clostridioides difficile infections (CDI) and surgical site infections (SSI). The objective of this study was to determine the economic feasibility of penicillin allergy testing in preventing unnecessary clindamycin use among patients with an unconfirmed penicillin allergy prior to otolaryngologic surgery. METHODS A break-even analysis was performed using the average cost of penicillin allergy testing and a CDI/SSI to calculate the absolute risk reduction (ARR) in baseline CDI/SSI rate due to clindamycin required for penicillin testing to be economically sustainable. The binomial distribution was used to calculate the probability that current penicillin testing can achieve this study's ARR. RESULTS Preoperative penicillin testing was found to be economically sustainable if it could decrease the baseline CDI rate by an ARR of 1.06% or decrease the baseline SSI rate by an ARR of 1.34%. The probability of penicillin testing achieving these ARRs depended on the baseline CDI and SSI rates. When the CDI rate was at least 5% or the SSI rate was at least 7%, penicillin allergy testing was guaranteed to achieve economic sustainability. CONCLUSION In patients mislabeled with a penicillin allergy, preoperative penicillin allergy testing may be an economically sustainable option to prevent the unnecessary use of prophylactic clindamycin during otolaryngologic surgery. Current practice guidelines should be modified to recommend penicillin allergy testing in patients with an unconfirmed allergy prior to surgery. LEVEL OF EVIDENCE N/A Laryngoscope, 2022.
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Affiliation(s)
- Matthew Y Liu
- Dell Medical School, The University of Texas at Austin, Austin, Texas, USA.,Department of Otolaryngology - Head and Neck Surgery, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Megana Challa
- Department of Otolaryngology - Head and Neck Surgery, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Edward D McCoul
- Department of Otorhinolaryngology, Ochsner Health System, New Orleans, Louisiana, USA.,Department of Otolaryngology - Head and Neck Surgery, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Philip G Chen
- Department of Otolaryngology - Head and Neck Surgery, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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Ragan MV, Wala SJ, Goodman SD, Bailey MT, Besner GE. Next-Generation Probiotic Therapy to Protect the Intestines From Injury. Front Cell Infect Microbiol 2022; 12:863949. [PMID: 35837474 PMCID: PMC9273849 DOI: 10.3389/fcimb.2022.863949] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 05/25/2022] [Indexed: 12/20/2022] Open
Abstract
Probiotics are live microorganisms that, when administered in adequate amounts, provide health benefits to the host. Some strains of the probiotic Lactobacillus reuteri (L. reuteri) have both antimicrobial and anti-inflammatory properties that may be exploited for the treatment and prevention of different gastrointestinal diseases, including necrotizing enterocolitis (NEC) and Clostridioides difficile (C. difficile) infection. Our laboratory has developed a new delivery system for L. reuteri in which the probiotic is incubated with biocompatible, semipermeable, porous dextranomer microspheres (DM) that can be loaded with beneficial and diffusible cargo. L. reuteri can be induced to form a biofilm by incubating the bacteria on the surface of these microspheres, which enhances the efficacy of the probiotic. Loading the DM with sucrose or maltose induces L. reuteri to produce more biofilm, further increasing the efficacy of the probiotic. Using a rat model of NEC, L. reuteri administered in its biofilm state significantly increases animal survival, reduces the incidence of NEC, preserves gut barrier function, and decreases intestinal inflammation. In a murine model of Clostridiodes difficile infection, L. reuteri administered in its biofilm state decreases colitis when administered either before or after C. difficile induction, demonstrating both prophylactic and therapeutic efficacy. There are currently no FDA-approved probiotic preparations for human use. An FDA-approved phase I clinical trial of L. reuteri in its biofilm state in healthy adults is currently underway. The results of this trial will be used to support a phase 1 clinical trial in neonates, with the goal of utilizing L. reuteri in its biofilm state to prevent NEC in premature neonates in the future.
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Affiliation(s)
- Mecklin V. Ragan
- Center for Perinatal Research, Department of Pediatric Surgery, Columbus, OH, United States
| | - Samantha J. Wala
- Center for Perinatal Research, Department of Pediatric Surgery, Columbus, OH, United States
| | - Steven D. Goodman
- Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, United States
| | - Michael T. Bailey
- Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, United States
| | - Gail E. Besner
- Center for Perinatal Research, Department of Pediatric Surgery, Columbus, OH, United States
- *Correspondence: Gail E. Besner,
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Adamson H, Ajayi MO, Gilroy KE, McPherson MJ, Tomlinson DC, Jeuken LJC. Rapid Quantification of C. difficile Glutamate Dehydrogenase and Toxin B (TcdB) with a NanoBiT Split-Luciferase Assay. Anal Chem 2022; 94:8156-8163. [PMID: 35634999 PMCID: PMC9201815 DOI: 10.1021/acs.analchem.1c05206] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
![]()
C. difficile infection (CDI) is a leading healthcare-associated
infection with a high morbidity and mortality and is a financial burden.
No current standalone point-of-care test (POCT) is sufficient for
the identification of true CDI over a disease-free carriage of C. difficile, so one is urgently required to ensure timely,
appropriate treatment. Here, two types of binding proteins, Affimers
and nanobodies, targeting two C. difficile biomarkers,
glutamate dehydrogenase (GDH) and toxin B (TcdB), are combined in
NanoBiT (NanoLuc Binary Technology) split-luciferase assays. The assays
were optimized and their performance controlling parameters were examined.
The 44 fM limit of detection (LoD), 4–5 log range and 1300-fold
signal gain of the TcdB assay in buffer is the best observed for a
NanoBiT assay to date. In the stool sample matrix, the GDH and TcdB
assay sensitivity (LoD = 4.5 and 2 pM, respectively) and time to result
(32 min) are similar to a current, commercial lateral flow POCT, but
the NanoBit assay has no wash steps, detects clinically relevant TcdB
over TcdA, and is quantitative. Development of the assay into a POCT
may drive sensitivity further and offer an urgently needed ultrasensitive
TcdB test for the rapid diagnosis of true CDI. The NanoBiTBiP (NanoBiT
with Binding Proteins) system offers advantages over NanoBiT assays
with antibodies as binding elements in terms of ease of production
and assay performance. We expect this methodology and approach to
be generally applicable to other biomarkers.
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Affiliation(s)
- Hope Adamson
- School of Biomedical Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - Modupe O. Ajayi
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - Kate E. Gilroy
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - Michael J. McPherson
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - Darren C. Tomlinson
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - Lars J. C. Jeuken
- School of Biomedical Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
- Leiden Institute of Chemistry, Leiden University, PC Box 9502, 2300 RA, Leiden, The Netherlands
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Hengel RL, Schroeder CP, Jo J, Ritter TE, Nathan RV, Gonzales-Luna AJ, Obi EN, Dillon RJ, Van Anglen LJ, Garey KW. Recurrent Clostridioides difficile infection worsens anxiety-related patient-reported quality of life. J Patient Rep Outcomes 2022; 6:49. [PMID: 35567724 PMCID: PMC9107550 DOI: 10.1186/s41687-022-00456-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 04/29/2022] [Indexed: 12/03/2022] Open
Abstract
Background Clostridioides difficile infection (CDI) is associated with high recurrence rates impacting health-related quality of life (HrQOL). However, patient-reported data are lacking particularly in the outpatient setting. We assessed changes in HrQOL over time in patients treated with bezlotoxumab at US infusion centers and determined clinical factors associated with HrQOL changes. Methods The HrQOL survey was conducted in adult patients with CDI, who received bezlotoxumab in 25 US outpatient infusion centers. The survey was adapted from the Cdiff32 instrument to assess anxiety-related changes to HrQOL and completed on the day of infusion (baseline) and at 90 days post bezlotoxumab (follow-up). Demographics, disease history, CDI risk factors, and recurrence of CDI (rCDI) at 90-day follow-up were collected. Changes in HrQOL scores were calculated and outcomes assessed using a multivariable linear regression model with P < 0.05 defined as statistically significant. Results A total of 144 patients (mean age: 68 ± 15 years, 63% female, median Charlson index: 4, 15.9% rCDI) were included. The overall mean baseline and follow-up HrQOL scores were 26.4 ± 11.5 and 56.4 ± 25.0, respectively. At follow-up, this score was significantly higher for patients who had primary CDI (34.5 ± 21.7) compared to those with multiple rCDI (24.7 ± 21.0; P = 0.039). The mean HrQOL change at follow-up was significantly higher for patients without rCDI (34.1 ± 28.8 increase) compared to patients with rCDI (6.7 ± 19.5 increase; P < 0.001), indicating improvement in anxiety. Conclusions Using the Cdiff32 instrument, we demonstrated that HrQOL worsened significantly in patients with further rCDI. These findings support the use of Cdiff32 in assessing CDI-related humanistic outcomes.
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Affiliation(s)
- Richard L Hengel
- Atlanta ID Group, 275 Collier Rd, Suite 450, Atlanta, GA, 30309, USA.
| | - Claudia P Schroeder
- Healix Infusion Therapy, LLC, 14140 Southwest Freeway, Suite 400, Sugar Land, TX, 77478, USA
| | - Jinhee Jo
- University of Houston College of Pharmacy, 4800 Calhoun Rd, Houston, TX, 77004, USA
| | | | - Ramesh V Nathan
- Los Robles Health System, 215 W Janss Rd, Thousand Oaks, CA, 91360, USA
| | - Anne J Gonzales-Luna
- University of Houston College of Pharmacy, 4800 Calhoun Rd, Houston, TX, 77004, USA
| | - Engels N Obi
- Merck & Co., Inc, 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA
| | - Ryan J Dillon
- Merck & Co., Inc, 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA
| | - Lucinda J Van Anglen
- Healix Infusion Therapy, LLC, 14140 Southwest Freeway, Suite 400, Sugar Land, TX, 77478, USA
| | - Kevin W Garey
- University of Houston College of Pharmacy, 4800 Calhoun Rd, Houston, TX, 77004, USA
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Kullin B, Abratt VR, Reid SJ, Riley TV. Clostridioides difficile infection in Africa: A narrative review. Anaerobe 2022; 74:102549. [PMID: 35337974 DOI: 10.1016/j.anaerobe.2022.102549] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 03/13/2022] [Accepted: 03/17/2022] [Indexed: 12/12/2022]
Abstract
Clostridioides (Clostridium) difficile infection (CDI) places a burden on healthcare facilities worldwide. Most research studies have been concentrated in high-income countries in North America, Europe, Asia and Australia, where C. difficile is the leading cause of diarrhoea associated with antimicrobial use. This narrative review summarises African CDI studies, focussing on reports published in the last 20 years. Although relatively sparse, the data suggest that CDI is an important cause of diarrhoea on the continent. African CDI patient populations are often younger than in European and North American settings, probably due to the high prevalence of co-morbid conditions such as tuberculosis, particularly in sub-Saharan Africa. Strain typing data are rare and where reported generally limited to single sites and institutions. Despite challenges, including a lack of facilities and awareness, there is a need for further investigation to more accurately determine the true burden of disease caused by C. difficile in Africa.
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Affiliation(s)
- Brian Kullin
- Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa
| | - Valerie R Abratt
- Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa
| | - Sharon J Reid
- Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa
| | - Thomas V Riley
- Medical, Molecular and Forensic Sciences, Murdoch University, Murdoch, Western Australia WA, Australia; School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia; Department of Microbiology, PathWest Laboratory Medicine, Nedlands, WA, Australia; School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia.
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Antibiotic Stewardship and Inpatient Clostridioides difficile Testing in Solid Organ Transplant Recipients: The Need for Multilevel Checks and Balances. Transplant Proc 2022; 54:605-609. [DOI: 10.1016/j.transproceed.2021.10.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 09/29/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022]
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Flock G, Yin HB, Chen CH, Pellissery AJ, Venkitanarayanan K. Survivability of Clostridioides difficile spores in fermented pork summer sausage during refrigerated storage. Vet World 2022; 15:162-167. [PMID: 35369600 PMCID: PMC8924379 DOI: 10.14202/vetworld.2022.162-167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/23/2021] [Indexed: 01/05/2023] Open
Abstract
Background and Aim: Clostridioides difficile is a spore-forming pathogen that causes serious enteric disease in humans. Strains have been isolated from food animals and meat, including pork, which suggest a potential for foodborne transmission. Pork summer sausage is a popular fermented meat product, which is consumed cooked or cooked to a lower internal temperature due to acidification of the product. The effect of acidity and cooking on the viability of C. difficile spores in a fermented meat product has not been determined. Therefore, the aim was to study the survivability of C. difficile spores in fermented pork summer sausage. Materials and Methods: Fermented pork sausages were prepared according to a commercial recipe with or without starter culture and C. difficile spores followed by fermentation at 37°C for ~12 h under 85% relative humidity until pH 5.0 was reached and further processed as cooked (>57°C) or uncooked (≤57°C) and stored at 4°C. C. difficile spores in sausages were enumerated at 1 h following inoculation and on days 0, 1, 7, 14, 21, 30, 60, and 90 of storage. Results: It was observed that C. difficile spore viability in control unfermented treatment was significantly different on day 0 from the fermented, fermented cooked, and control unfermented cooked treatments (p<0.05); however, there was no significant difference among the latter three treatment groups throughout 90 days of storage (p>0.05). On day 90 of storage, the unfermented control sausages yielded ~4.0 log colony-forming unit (CFU)/g of C. difficile spores compared to ~3.5 log CFU/g recovered from fermented samples and the unfermented cooked control samples identifying spore viability in all treatment groups. Conclusion: C. difficile spores were found to survive the acidity and cooking of fermented pork summer sausage and storage at 4°C for 3 months, thereby highlighting the need for effective intervention strategies to reduce the risk of C. difficile contamination in pork products.
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Affiliation(s)
- Genevieve Flock
- Combat Capabilities Development Command Soldier Center, Soldier Sustainment Directorate, Combat Feeding Division, Natick 01760, Massachusetts, United States
| | - Hsin-Bai Yin
- Department of Agriculture, USDA Agricultural Research Service, Beltsville, Maryland 20705, United States
| | - Chi-Hung Chen
- Department of Agriculture, USDA Agricultural Research Service, Beltsville, Maryland 20705, United States
| | - Abraham Joseph Pellissery
- Department of Animal Science, University of Connecticut, College of Agriculture Health and Natural Resources, Mansfield 06269, Connecticut, United States
| | - Kumar Venkitanarayanan
- Department of Animal Science, University of Connecticut, College of Agriculture Health and Natural Resources, Mansfield 06269, Connecticut, United States
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Rao K, Dubberke ER. Can prediction scores be used to identify patients at risk of Clostridioides difficile infection? Curr Opin Gastroenterol 2022; 38:7-14. [PMID: 34628418 DOI: 10.1097/mog.0000000000000793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
PURPOSE OF REVIEW To describe the current state of literature on modeling risk of incident and recurrent Clostridioides difficile infection (iCDI and rCDI), to underscore limitations, and to propose a path forward for future research. RECENT FINDINGS There are many published risk factors and models for both iCDI and rCDI. The approaches include scores with a limited list of variables designed to be used at the bedside, but more recently have also included automated tools that take advantage of the entire electronic health record. Recent attempts to externally validate scores have met with mixed success. SUMMARY For iCDI, the performance largely hinges on the incidence, which even for hospitalized patients can be low (often <1%). Most scores fail to achieve high accuracy and/or are not externally validated. A challenge in predicting rCDI is the significant overlap with risk factors for iCDI, reducing the discriminatory ability of models. Automated electronic health record-based tools show promise but portability to other centers is challenging. Future studies should include external validation and consider biomarkers to augment performance.
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Affiliation(s)
- Krishna Rao
- Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Erik R Dubberke
- Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
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Amin A, Nelson WW, Dreyfus J, Wong AC, Mohammadi I, Teigland C, Dahdal DN, Feuerstadt P. Mortality, healthcare resource utilization, and cost among Medicare beneficiaries with Clostridioides difficile infection with and without sepsis. Ther Adv Infect Dis 2022; 9:20499361221095679. [PMID: 35510091 PMCID: PMC9058456 DOI: 10.1177/20499361221095679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/30/2022] [Indexed: 12/02/2022] Open
Abstract
Objective To describe mortality, healthcare resource utilization (HRU), and costs among Medicare beneficiaries with primary Clostridioides difficile infection (pCDI) or recurrent CDI (rCDI), with and without sepsis. Methods We conducted a retrospective observational study of 100% Medicare Fee-for-Service claims from adults aged ⩾ 65 years with ⩾1 CDI episode between 1 January 2009 and 31 December 2017. Patients were continuously enrolled in Medicare Parts A/B/D 12 months before and up to 12 months after pCDI. ICD-9/10 codes defined CDI using ⩾1 inpatient claim, or ⩾1 outpatient claim plus ⩾1 claim for CDI treatment. The pCDI episode ended after 14 days without a CDI claim. rCDI episodes started within 8 weeks from the end of a previous CDI episode. ICD-9/10 codes identified all-cause sepsis over 12 month follow-up. Results Of 497,489 CDI patients, 41.0% (N = 203,888) had sepsis; 57.7% with sepsis died versus 32.4% without sepsis. Among patients with pCDI only (N = 345,893) or ⩾1 rCDI (N = 151,596), 39.2% and 45.1% suffered sepsis, respectively. All-cause hospitalizations were frequent for all cohorts (range: 81-99%). Among patients who died, those with sepsis versus without had more-frequent intensive care unit (ICU) use (pCDI: 29% versus 15%; rCDI: 65% versus 34%), longer hospital stays (pCDI: 12 versus 10 days; rCDI: 12 versus 9 days), and higher per-patient-per-month costs (pCDI: $34,841 versus $22,753; rCDI: $42,269 versus $25,047). In both cohorts, sepsis patients who survived had higher total costs and all-cause HRU than those without sepsis. All p < 0.001 above. Conclusions Sepsis was common among Medicare beneficiaries with CDI. CDI patients with sepsis, especially after an rCDI, experienced higher mortality, HRU, and costs compared with those without sepsis.
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Affiliation(s)
- Alpesh Amin
- UCI Medical Center, 101 The City Drive, City Tower, Suite 500, Orange, CA 92868, USA
| | | | | | | | | | | | | | - Paul Feuerstadt
- PACT Gastroenterology Center, Hamden, CT, USA
- Yale School of Medicine, Yale University, New Haven, CT, USA
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Harrison MA, Strahl H, Dawson LF. Regulation of para-cresol production in Clostridioides difficile. Curr Opin Microbiol 2021; 65:131-137. [PMID: 34856509 DOI: 10.1016/j.mib.2021.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 11/03/2022]
Abstract
The human pathogen Clostridioides difficile colonises the gastrointestinal tract following antibiotic exposure, which causes perturbations in the beneficial microbiome. An unusual feature of C. difficile among the gut microbiota is its ability to produce high concentrations of the antimicrobial compound para-cresol, which selectively targets Gram-negative bacteria. Production of p-cresol occurs either by: (a) tyrosine fermentation via the intermediate para-hydroxyphenylacetate (p-HPA), or (b) direct turnover of exogenous p-HPA in the human gut. p-HPA is decarboxylated to produce p-cresol, by the action of HpdBCA decarboxylase encoded by the hpdBCA operon. HpdBCA decarboxylase production is induced at the transcriptional level by elevated p-HPA, which causes elevated p-cresol production, that significantly reduces microbiome diversity and richness. This deleterious effect of p-cresol on the beneficial gut microbiome is advantageous for C. difficile pathogenesis and infection relapse. Inhibiting this pathway would provide a highly specific therapeutic.
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Affiliation(s)
- Mark A Harrison
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | - Henrik Strahl
- Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, Baddiley-Clark Building, Richardson Road, Newcastle upon Tyne, NE2 4AX, UK
| | - Lisa F Dawson
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
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Krishna A, Chopra T. Prevention of Infection due to Clostridium (Clostridioides) difficile. Infect Dis Clin North Am 2021; 35:995-1011. [PMID: 34752229 DOI: 10.1016/j.idc.2021.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Clostridium (Clostridioides) difficile infection (CDI) causes significant morbidity and mortality in the United States every year. Prevention of CDI is difficult because of spore durability and requires implementation of multipronged strategies. Two categories of prevention strategies are infection control and prevention and risk factor reduction. Hand hygiene, contact precautions, patient isolation, and environmental decontamination are cornerstones of infection control and prevention. Risk factor reduction should focus on antibiotic stewardship to reduce unnecessary antibiotic use. If CDI incidence remains higher than the institution's goal despite these measures, then special measures should be considered.
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Affiliation(s)
- Amar Krishna
- Internal Medicine, Norther Light AR Gould Hospital, 140 Academy Street, Presque Isle, ME 04769, USA.
| | - Teena Chopra
- Infectious Diseases, Wayne State University/Detroit Medical Center, UHC-2B, 4201 St Antoine, Detroit, MI 48201, USA
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Aguirre AM, Yalcinkaya N, Wu Q, Swennes A, Tessier ME, Roberts P, Miyajima F, Savidge T, Sorg JA. Bile acid-independent protection against Clostridioides difficile infection. PLoS Pathog 2021; 17:e1010015. [PMID: 34665847 PMCID: PMC8555850 DOI: 10.1371/journal.ppat.1010015] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/29/2021] [Accepted: 10/07/2021] [Indexed: 12/21/2022] Open
Abstract
Clostridioides difficile infections occur upon ecological / metabolic disruptions to the normal colonic microbiota, commonly due to broad-spectrum antibiotic use. Metabolism of bile acids through a 7α-dehydroxylation pathway found in select members of the healthy microbiota is regarded to be the protective mechanism by which C. difficile is excluded. These 7α-dehydroxylated secondary bile acids are highly toxic to C. difficile vegetative growth, and antibiotic treatment abolishes the bacteria that perform this metabolism. However, the data that supports the hypothesis that secondary bile acids protect against C. difficile infection is supported only by in vitro data and correlative studies. Here we show that bacteria that 7α-dehydroxylate primary bile acids protect against C. difficile infection in a bile acid-independent manner. We monoassociated germ-free, wildtype or Cyp8b1-/- (cholic acid-deficient) mutant mice and infected them with C. difficile spores. We show that 7α-dehydroxylation (i.e., secondary bile acid generation) is dispensable for protection against C. difficile infection and provide evidence that Stickland metabolism by these organisms consumes nutrients essential for C. difficile growth. Our findings indicate secondary bile acid production by the microbiome is a useful biomarker for a C. difficile-resistant environment but the microbiome protects against C. difficile infection in bile acid-independent mechanisms. Secondary bile acid production by the colonic microbiome strongly correlates with an environment that is resistant to C. difficile invasion. However, it remained unclear if these bile acids provided in vivo protection. Here, we show that members of the microbiome that generate secondary bile acids (e.g., C. scindens) protect against C. difficile disease independently of secondary bile acid generation. These results are important because efforts to restore colonization resistance (e.g., FMT or precision bacterial therapy) focus on restoring secondary bile acid generation. Instead, restoring the organisms that produce 5-aminovalerate or consume proline / glycine are more important.
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Affiliation(s)
- Andrea Martinez Aguirre
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
| | - Nazli Yalcinkaya
- Baylor College of Medicine & Texas Children’s Hospital, Houston, Texas, United States of America
| | - Qinglong Wu
- Baylor College of Medicine & Texas Children’s Hospital, Houston, Texas, United States of America
| | - Alton Swennes
- Baylor College of Medicine & Texas Children’s Hospital, Houston, Texas, United States of America
| | - Mary Elizabeth Tessier
- Baylor College of Medicine & Texas Children’s Hospital, Houston, Texas, United States of America
| | - Paul Roberts
- Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom
| | - Fabio Miyajima
- Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom
- Oswaldo Cruz Foundation, Ceara branch, Fortaleza, Brazil
| | - Tor Savidge
- Baylor College of Medicine & Texas Children’s Hospital, Houston, Texas, United States of America
| | - Joseph A. Sorg
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
- * E-mail:
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Episcopia B, Gupta A, Fornek M, Kaminski M, Malik S, Sunny S, Landman D, Xavier G, Quale J. Trends in Healthcare Facility-Onset Clostridioides difficile Infection and the Impact of Testing Schemes in an Acute Care Hospital System in New York City, 2016-2019. Am J Infect Control 2021; 49:1262-1266. [PMID: 33716096 DOI: 10.1016/j.ajic.2021.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 03/05/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Healthcare facility-onset Clostridioides difficile infection is associated with adverse clinical outcomes and hospital reimbursement. A four-year review involving eleven hospitals of the NYC Health + Hospital system was undertaken. METHODS From 2016-2019, infection rates and standardized infection ratios (SIRs) were gathered from National Healthcare Safety Network. The C. difficile testing scheme at each facility was recorded. RESULTS For the eleven hospitals, declines in rates of C. difficile infection and SIRs were documented. However, this decline was driven by two hospitals that had high rates of infection in 2016; for the remaining nine hospitals, rates of infection and SIRs were at a plateau. Most hospitals used a testing scheme that fell into the nucleic acid amplification test (NAAT) category for SIR risk adjustment. Hospitals that used the algorithm glutamate dehydrogenase (GDH) and toxin A/B immunoassay (EIA) followed by NAAT for discrepant results had significantly lower rates of C. difficile infection but similar SIRs. CONCLUSIONS For most hospitals in this system, rates of C. difficile remained level. Within the NAAT test categories, SIRs may not correlate with infection rates. Given the controversies regarding testing and calculation of SIRs, alternatives to C. difficile infection should be sought as a hospital quality measurement.
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Potential Cost Savings Associated with Targeted Substitution of Current Guideline-Concordant Inpatient Agents with Omadacycline for the Treatment of Adult Hospitalized Patients with Community-Acquired Bacterial Pneumonia at High Risk for Clostridioides difficile Infections: Results of Healthcare-Decision Analytic Model from the United States Hospital Perspective. Antibiotics (Basel) 2021; 10:antibiotics10101195. [PMID: 34680776 PMCID: PMC8532985 DOI: 10.3390/antibiotics10101195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 12/20/2022] Open
Abstract
Introduction: Approximately 3% of hospitalized patients with community-acquired bacterial pneumonia (CABP) develop healthcare-associated Clostridioides difficile infection (HCA-CDI). The validated Davis risk score (DRS) indicates that patients with a DRS ≥ 6 are at an increased risk of 30-day HCA-CDI. In the phase 3 OPTIC CABP study, 14% of CABP patients with DRS ≥ 6 who received moxifloxacin developed CDI vs. 0% for omadacycline. This study assessed the potential economic impact of substituting current guideline-concordant CABP inpatient treatments with omadacycline in hospitalized CABP patients with a DRS ≥ 6 across US hospitals. Methods: A deterministic healthcare-decision analytic model was developed. The model population was hospitalized adult CABP patients with a DRS ≥ 6 across US hospitals (100,000 patients). In the guideline-concordant arm, 14% of CABP patients with DRS ≥ 6 were assumed to develop an HCA-CDI, each costing USD 20,100. In the omadacycline arm, 5 days of therapy was calculated for the entire model population. Results: The use of omadacycline in place of guideline-concordant CABP inpatient treatments for CABP patients with DRS ≥ 6 was estimated to result in cost savings of USD 55.4 million annually across US hospitals. Conclusion: The findings of this simulated model suggest that prioritizing the use of omadacycline over current CABP treatments in hospitalized CABP with a DRS ≥ 6 may potentially reduce attributable HCA-CDI costs. The findings are not unique to omadacycline and could be applied to any antibiotic that confers a lower risk of HCA-CDI relative to current CABP inpatient treatments.
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Sahra S, Abureesh M, Amarnath S, Alkhayyat M, Badran R, Jahangir A, Gumaste V. Clostridioides difficile infection in liver cirrhosis patients: A population-based study in United States. World J Hepatol 2021; 13:926-938. [PMID: 34552699 PMCID: PMC8422922 DOI: 10.4254/wjh.v13.i8.926] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/11/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Clostridioides (formerly Clostridium) difficile infection (CDI) is an increasingly frequent cause of morbidity and mortality in hospitalized patients. Multiple risk factors are documented in the literature that includes, but are not limited to, antibiotics use, advanced age, and gastric acid suppression. Several epidemiological studies have reported an increased incidence of CDI in advanced liver disease patients. Some have also demonstrated a higher prevalence of nosocomial infections in cirrhotic patients.
AIM To use a large nationwide database, we sought to determine CDI’s risk among liver cirrhosis patients in the United States.
METHODS We queried a commercial database (Explorys IncTM, Cleveland, OH, United States), and obtained an aggregate of electronic health record data from 26 major integrated United States healthcare systems comprising 360 hospitals in the United States from 2018 to 2021. Diagnoses were organized into the Systematized Nomenclature of Medicine Clinical Terms (SNOMED–CT) hierarchy. Statistical analysis for the multivariable model was performed using Statistical Package for Social Sciences (SPSS version 25, IBM CorpTM). For all analyses, a two-sided P value of < 0.05 was considered statistically significant.
RESULTS There were a total of 19387760 patients in the database who were above 20 years of age between the years 2018-2021. Of those, 133400 were diagnosed with liver cirrhosis. The prevalence of CDI amongst the liver cirrhosis population was 134.93 per 100.000 vs 19.06 per 100.000 in non-cirrhotic patients (P < 0.0001). The multivariate analysis model uncovered that cirrhotic patients were more likely to develop CDI (OR: 1.857; 95%CI: 1.665-2.113, P < 0.0001) compared to those without any prior history of liver cirrhosis.
CONCLUSION In this large database study, we uncovered that cirrhotic patients have a significantly higher CDI prevalence than those without cirrhosis. Liver cirrhosis may be an independent risk factor for CDI. Further prospective studies are needed to clarify this possible risk association that may lead to the implementation of screening methods in this high-risk population.
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Affiliation(s)
- Syeda Sahra
- Department of Internal Medicine, Staten Island University Hospital, Staten Island, NY 10305, United States
| | - Mohammad Abureesh
- Department of Internal Medicine, Staten Island University Hospital, Staten Island, NY 10305, United States
| | - Shivantha Amarnath
- Department of Internal Medicine, Staten Island University Hospital, Staten Island, NY 10305, United States
| | - Motasem Alkhayyat
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, United States
| | - Rawan Badran
- Department of Internal Medicine, Staten Island University Hospital, Staten Island, NY 10305, United States
| | - Abdullah Jahangir
- Department of Internal Medicine, Staten Island University Hospital, Staten Island, NY 10305, United States
| | - Vivek Gumaste
- Department of Gastroenterology, Staten Island University Hospital, Staten Island, NY 10305, United States
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Haddad NS, Nozick S, Kim G, Ohanian S, Kraft C, Rebolledo PA, Wang Y, Wu H, Bressler A, Le SNT, Kuruvilla M, Cannon LE, Lee FEH, Daiss JL. Novel immunoassay for diagnosis of ongoing Clostridioides difficile infections using serum and medium enriched for newly synthesized antibodies (MENSA). J Immunol Methods 2021; 492:112932. [PMID: 33221459 DOI: 10.1016/j.jim.2020.112932] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND Clostridioides difficile infections (CDI) have been a challenging and increasingly serious concern in recent years. While early and accurate diagnosis is crucial, available assays have frustrating limitations. OBJECTIVE Develop a simple, blood-based immunoassay to accurately diagnose patients suffering from active CDI. MATERIALS AND METHODS Uninfected controls (N = 95) and CDI patients (N = 167) were recruited from Atlanta area hospitals. Blood samples were collected from patients within twelve days of a positive CDI test and processed to yield serum and PBMCs cultured to yield medium enriched for newly synthesized antibodies (MENSA). Multiplex immunoassays measured Ig responses to ten recombinant C. difficile antigens. RESULTS Sixty-six percent of CDI patients produced measurable responses to C. difficile antigens in their serum or MENSA within twelve days of a positive CDI test. Fifty-two of the 167 CDI patients (31%) were detectable in both serum and MENSA, but 32/167 (19%) were detectable only in MENSA, and 27/167 (16%) were detectable only in serum. DISCUSSION We describe the results of a multiplex immunoassay for the diagnosis of ongoing CDI in hospitalized patients. Our assay resolved patients into four categories: MENSA-positive only, serum-positive only, MENSA- and serum-positive, and MENSA- and serum-negative. The 30% of patients who were MENSA-positive only may be accounted for by nascent antibody secretion prior to seroconversion. Conversely, the serum-positive only subset may have been more advanced in their disease course. Immunocompromise and misdiagnosis may have contributed to the 34% of CDI patients who were not identified using MENSA or serum immunoassays. IMPORTANCE While there was considerable overlap between patients identified through MENSA and serum, each method detected a distinctive patient group. The combined use of both MENSA and serum to detect CDI patients resulted in the greatest identification of CDI patients. Together, longitudinal analysis of MENSA and serum will provide a more accurate evaluation of successful host humoral immune responses in CDI patients.
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Affiliation(s)
| | | | | | | | - Colleen Kraft
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Paulina A Rebolledo
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA; Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA
| | - Yun Wang
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Department of Pathology and Laboratory Medicine, Grady Memorial Hospital, Atlanta, GA, USA
| | - Hao Wu
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Adam Bressler
- Infectious Disease Specialists of Atlanta, Decatur, GA, USA
| | - Sang Nguyet Thi Le
- Pulmonary, Allergy, Critical Care & Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Merin Kuruvilla
- Pulmonary, Allergy, Critical Care & Sleep Medicine, Emory University, Atlanta, GA, USA
| | | | - F Eun-Hyung Lee
- MicroB-plex, Inc., Atlanta, GA, USA; Pulmonary, Allergy, Critical Care & Sleep Medicine, Emory University, Atlanta, GA, USA
| | - John L Daiss
- MicroB-plex, Inc., Atlanta, GA, USA; Department of Orthopedics, University of Rochester Medical Center, Rochester, NY, USA.
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Environmental Cleaning and Decontamination to Prevent Clostridioides difficile Infection in Health Care Settings: A Systematic Review. J Patient Saf 2021; 16:S12-S15. [PMID: 32809996 PMCID: PMC7447170 DOI: 10.1097/pts.0000000000000749] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Objective The aim of this systematic review was to examine the most effective and feasible methods for environmental cleaning and decontamination to prevent Clostridioides difficile infection (CDI) in health care settings. Methods A systematic search of the databases CINAHL and MEDLINE was conducted from 2008 to 2018 for English language articles with search terms including “Clostridium difficile,” and related medical subject headings, in combination with terms like “disinfection,” “decontamination,” and “no-touch decontamination.” Results Twelve studies and 2 systematic reviews were selected for inclusion in this review. The studies were primarily in hospitals (10/12) and used a before-after approach. The studied interventions included cleaning and decontamination with a chlorine-based agent (i.e., bleach; 2 studies), standard cleaning plus the use of hydrogen peroxide decontamination (3 studies), and standard bleach cleaning plus the use of ultraviolet light decontamination (6 studies), and there was 1 study about launderable bed covers. The interventions ranged in frequency, duration, and the area selected for cleaning and decontamination (e.g., all patient rooms versus only CDI patients’ rooms). Studies showed significant reductions in CDI associated with use of bleach (versus quaternary ammonium compound) and hydrogen peroxide decontamination after standard bleach cleaning (versus bleach cleaning alone). Four of 6 studies found significant reductions in CDI after the implementation of ultraviolet light decontamination after standard bleach cleaning. Conclusions The studied practices for environmental cleaning and decontamination were associated with significant decreases in facility-level CDI rates in most of the reviewed studies; however, study quality was low. Implementation challenges are worthy of further examination.
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Karyal C, Hughes J, Kelly ML, Luckett JC, Kaye PV, Cockayne A, Minton NP, Griffin R. Colonisation Factor CD0873, an Attractive Oral Vaccine Candidate against Clostridioides difficile. Microorganisms 2021; 9:microorganisms9020306. [PMID: 33540694 PMCID: PMC7913071 DOI: 10.3390/microorganisms9020306] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/18/2021] [Accepted: 01/29/2021] [Indexed: 12/12/2022] Open
Abstract
Clostridioides difficile is the main cause of health-care-associated infectious diarrhoea. Toxins, TcdA and TcdB, secreted by this bacterium damage colonic epithelial cells and in severe cases this culminates in pseudomembranous colitis, toxic megacolon and death. Vaccines in human trials have focused exclusively on the parenteral administration of toxin-based formulations. These vaccines promote toxin-neutralising serum antibodies but fail to confer protection from infection in the gut. An effective route to immunise against gut pathogens and stimulate a protective mucosal antibody response (secretory immunoglobulin A, IgA) at the infection site is the oral route. Additionally, oral immunisation generates systemic antibodies (IgG). Using this route, two different antigens were tested in the hamster model: The colonisation factor CD0873 and a TcdB fragment. Animals immunised with CD0873 generated a significantly higher titre of sIgA in intestinal fluid and IgG in serum compared to naive animals, which significantly inhibited the adherence of C. difficile to Caco-2 cells. Following challenge with a hypervirulent isolate, the CD0873-immunised group showed a mean increase of 80% in time to experimental endpoint compared to naïve animals. Survival and body condition correlated with bacterial clearance and reduced pathology in the cecum. Our findings advocate CD0873 as a promising oral vaccine candidate against C. difficile.
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Affiliation(s)
- Cansu Karyal
- Synthetic Biology Research Centre, The University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK; (C.K.); (J.H.); (M.L.K.); (A.C.); (N.P.M.)
| | - Jaime Hughes
- Synthetic Biology Research Centre, The University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK; (C.K.); (J.H.); (M.L.K.); (A.C.); (N.P.M.)
| | - Michelle L. Kelly
- Synthetic Biology Research Centre, The University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK; (C.K.); (J.H.); (M.L.K.); (A.C.); (N.P.M.)
| | - Jeni C. Luckett
- The University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK;
| | - Philip V. Kaye
- Department of Histopathology, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK;
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre (BRC), Nottingham NG7 2UH, UK
| | - Alan Cockayne
- Synthetic Biology Research Centre, The University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK; (C.K.); (J.H.); (M.L.K.); (A.C.); (N.P.M.)
| | - Nigel P. Minton
- Synthetic Biology Research Centre, The University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK; (C.K.); (J.H.); (M.L.K.); (A.C.); (N.P.M.)
| | - Ruth Griffin
- Synthetic Biology Research Centre, The University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK; (C.K.); (J.H.); (M.L.K.); (A.C.); (N.P.M.)
- Correspondence: ; Tel.: +44-0115-7486120
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Zhang RF, Man YX, Bai YY, Shao CH, Liu CM, Wang CH, Lei YX, Wang Y, Jin Y. Molecular characterization of Clostridioides difficile ribotype 027 in a major Chinese hospital. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2021; 54:1179-1183. [PMID: 33563561 DOI: 10.1016/j.jmii.2021.01.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 01/04/2021] [Accepted: 01/08/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND The rapid spread of C. difficile 027 has become one of the leading threats of healthcare-associated infections wordwild. However, C. difficile 027 infections have rarely been reported in China. The objective of this study was to strengthen the understanding of the molecular characterizations of C. difficile 027 in China. METHODS In this study, stool specimens from 176 suspected CDI cases were collected from 1 Jan 2018 to 30 Jun 2019. These specimens were measured by GeneXpert test and C.difficile colonies were identified and analyzed. RESULTS There were five samples positive for tcdA, tcdB, binary toxin genes and had deletions in tcdC gene. These five Clostridioides difficile isolates belonged to ST1 and confirmed as Clostridioides difficile 027 strains by PCR ribotyping. Through using whole genome sequencing, , we found that these five strains were closely clustered into the same predominant evolutionary branch and were highly similar to C. difficile 027 strain R20291. Antimicrobial susceptibility testing result showed they were highly resistant to fluoroquinolones. CONCLUSIONS In Our study, five C. difficile 027 isolates were identified and characterized using MLST, PCR ribotyping and whole genome sequencing. We proposed that C. difficile 027 infections are probably neglected in China. Further epidemiological studies across the country together with the introduction of routine diagnostic testing and multi-center or national level surveillance are needed to ascertain the size of this potentially significant problem.
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Affiliation(s)
- Ren-Feng Zhang
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yu-Xia Man
- LiaochengDongchangfu People's Hospital, Liaocheng, China
| | - Yuan-Yuan Bai
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chun-Hong Shao
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chun-Mei Liu
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Cong-Hui Wang
- Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou, China
| | - Yong-Xing Lei
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China; Shanghai ZJ Bio-Tech Co.,Ltd., China.
| | - Yong Wang
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Yan Jin
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
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