Ultrasensitive and quantitative toxin measurement correlates with baseline severity, severe outcomes, and recurrence among hospitalized patients with Clostridioides difficile infection

2021 ◽  
Author(s):  
Carolyn D Alonso ◽  
Ciarán P Kelly ◽  
Kevin W Garey ◽  
Anne J Gonzales-Luna ◽  
David Williams ◽  
...  
Keyword(s):  
Single Molecule ◽  
Scoring Systems ◽  
Toxin A ◽  
Baseline Severity ◽  
Clostridioides Difficile ◽  
Positive Stool ◽  
Outcome Group ◽  
Clostridioides Difficile Infection ◽  
Group 2 ◽  
Group 1

Abstract Background Stool toxin concentrations may impact Clostridioides difficile infection (CDI) severity and outcomes. We correlated fecal C. difficile toxin concentrations, measured by an ultrasensitive and quantitative assay, with CDI baseline severity, attributable outcomes, and recurrence. Methods We enrolled 615 hospitalized adults (≥ 18y) with CDI (acute diarrhea, positive stool NAAT, and decision to treat). Baseline stool toxin A and B concentrations were measured by Single Molecule Array. Subjects were classified by baseline CDI severity (four scoring methods) and outcomes within 40 days (death, ICU stay, colectomy, and recurrence). Results Among 615 patients (median 68.0 years), in all scoring systems, subjects with severe baseline disease had higher stool toxin A+B concentrations than those without (P<0.01). Nineteen subjects (3.1%) had a severe outcome primarily-attributed to CDI (group 1). This group had higher median toxin A+B [14,303 pg/mL (IQR 416.0, 141,967)] than subjects in whom CDI only contributed to the outcome [group 2, 163.2 pg/mL(0.0, 8423.3)], subjects with severe outcome unrelated to CDI [group 3, 158.6 pg/mL (0.0, 1795.2)], or no severe outcome [group 4, 209.5 pg/mL (0.0, 8566.3)](P=0.003). Group 1 was more likely to have detectable toxin (94.7%) than groups 2-4 (60.5-66.1%)(P=0.02). Individuals with recurrence had higher toxin A+B [2266.8 pg/mL(188.8, 29411)] than those without [154.0 pg/mL(0.0, 5864.3)](P<0.001) and higher rates of detectable toxin (85.7% versus 64.0%, P=0.004). Conclusions In CDI patients, ultrasensitive stool toxin detection and concentration correlated with severe baseline disease, severe CDI-attributable outcomes, and recurrence, confirming the contribution of toxin quantity to disease presentation and clinical course.

Cerebral oxygenation, vascular reactivity, and neurochemistry following decompressive craniectomy for severe traumatic brain injury

2008 ◽  
Vol 108 (5) ◽  
pp. 943-949 ◽  
Author(s):  
Chi Long Ho ◽  
Chee Meng Wang ◽  
Kah Keow Lee ◽  
Ivan Ng ◽  
Beng Ti Ang
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Decompressive Craniectomy ◽  
Severe Traumatic Brain Injury ◽  
Reactivity Index ◽  
Outcome Group ◽  
The Mean ◽  
Group 2 ◽  
Biochemical Indices ◽  
Group 1

Object This study addresses the changes in brain oxygenation, cerebrovascular reactivity, and cerebral neurochemistry in patients following decompressive craniectomy for the control of elevated intracranial pressure (ICP) after severe traumatic brain injury (TBI). Methods Sixteen consecutive patients with isolated TBI and elevated ICP, who were refractory to maximal medical therapy, underwent decompressive craniectomy over a 1-year period. Thirteen patients were male and 3 were female. The mean age of the patients was 38 years and the median Glasgow Coma Scale score on admission was 5. Results Six months following TBI, 11 patients had a poor outcome (Group 1, Glasgow Outcome Scale [GOS] Score 1–3), whereas the remaining 5 patients had a favorable outcome (Group 2, GOS Score 4 or 5). Decompressive craniectomy resulted in a significant reduction (p < 0.001) in the mean ICP and cerebrovascular pressure reactivity index to autoregulatory values (< 0.3) in both groups of patients. There was a significant improvement in brain tissue oxygenation (PbtO2) in Group 2 patients from 3 to 17 mm Hg and an 85% reduction in episodes of cerebral ischemia. In addition, the durations of abnormal PbtO2 and biochemical indices were significantly reduced in Group 2 patients after decompressive craniectomy, but there was no improvement in the biochemical indices in Group 1 patients despite surgery. Conclusions Decompressive craniectomy, when used appropriately in protocol-driven intensive care regimens for the treatment of recalcitrant elevated ICP, is associated with a return of abnormal metabolic parameters to normal values in patients with eventually favorable outcomes.

Abstract 14551: Biomarkers Predicting the Treatment-Resistant Kawasaki Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yukako Yoshikane ◽  
Ryuji Fukazawa ◽  
Kyoko Imanaka-yoshida ◽  
Naho Kobayashi ◽  
Yasuhiro Katsube
Keyword(s):  
Treatment Group ◽  
Kawasaki Disease ◽  
Predictive Value ◽  
Scoring Systems ◽  
Line Treatment ◽  
Treatment Resistant ◽  
Cutoff Value ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Introduction: Kawasaki disease (KD), which is the most common multisystem vasculitis with unknown causes in childhood, causes coronary artery lesions (CALs). Treatment with a high dose of intravenous immunoglobulin (IVIG), plus steroids if needed, is the most effective therapy for the acute phase of KD. However, there are some very severe cases who need several times additional treatments and are at risk for CALs. In Japan, there are some scoring systems that initially predict IVIG-resistant patients. However, the problem is that these scoring systems fail in multiethnic populations. The aim of this study is to find universal biomarkers that predict treatment-resistant cases of KD. Methods: The subject was 276 KD patients, including Group 1 (n=214) who needed only 1 st line treatment, Group 2 (n=48) who needed 2 nd line treatment, Group 3 (n=14) who needed 3 rd line treatment or more. Tenascin C (TN-C), Pentraxin 3 (PTX3) and Procalcitonin (PCT) values, which were selected by systematic review, were measured before initial treatment in each group. Results: TN-C; 99.8±41.05 ng/ml in Group 1, 118.0±71.4 ng/ml in Group 2 and 183.0±25.0 ng/ml in Group 3. The TN-C level of Group 3 was significantly higher than that of all the others (p<0.01). The cutoff value for distinguishing Group 3 was 142.0 ng/ml (Area under the Curve (AUC)=0.81). PTX3; 16.2±9.0 ng/ml in Group 1, 31.4±19.7 ng/ml in Group 2 and 58.0±33.0 ng/ml in Group 3. The PTX3 level of Group 3 was significantly higher than that of all the others (p<0.01). The cutoff value for distinguishing Group 3 was 35.1 ng/ml (AUC=0.86). PCT; 0.79±0.77 ng/ml in Group 1, 2.55±3.01 ng/ml in Group 2 and 4.15±4.49 ng/ml in Group 3. The PCT level of Group 3 was significantly higher than that of all the others (p<0.01). The cutoff value for distinguishing Group 3 was 2.55 ng/ml (AUC=0.88). When those three biomarkers combined, Group 3 can be predicted with the sensitivity 79%, the specificity 96%, the positive predictive value 50% and the negative predictive value 99%. Conclusions: It may be possible to predict treatment-resistant KD cases with high sensitivity and specificity by combining the measurement from the universal biomarkers, TN-C, PTX3 and PCT, before initial treatment.

scholarly journals 2356. Increased Clinical Specificity with Ultrasensitive Detection of Clostridioides difficile Toxins: Reduction of Overdiagnosis Compared with Nucleic Acid Amplification Tests

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S811-S812 ◽  
Author(s):  
Johanna Sandlund ◽  
Joel Estis ◽  
Phoebe Katzenbach ◽  
Niamh Nolan ◽  
Kirstie Hinson ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Disease Severity ◽  
Single Molecule ◽  
Clinical Performance ◽  
Neutralization Assay ◽  
Nucleic Acid Amplification ◽  
Clostridioides Difficile ◽  
Percent Agreement ◽  
Clostridioides Difficile Infection ◽  
Healthcare Associated

Abstract Background Clostridioides difficile infection (CDI) is one of the most common healthcare-associated infections, resulting in significant morbidity, mortality, and economic burden. Diagnosis of CDI relies on the assessment of clinical presentation and laboratory tests. We have evaluated the clinical performance of ultrasensitive Single Molecule Counting technology for detection of C. difficile toxins A and B. Methods Stool specimens from 298 patients with suspected CDI were tested with nucleic acid amplification test (NAAT; BD MAX™ Cdiff assay or Xpert® C. difficile assay) and Singulex Clarity® C. difficile toxins A/B assay. Specimens with discordant results were tested with cell cytotoxicity neutralization assay (CCNA), and results were correlated with disease severity and outcome. Results There were 64 NAAT-positive and 234 NAAT-negative samples. Of the 32 NAAT+/Clarity− and 4 NAAT-/Clarity+ samples, there were 26 CCNA− and 4 CCNA- samples, respectively. CDI relapse or overall death was more common in NAAT+/toxin+ patients than in NAAT+/toxin− and NAAT−/toxin− patients, and NAAT+/toxin+ patients were 3.7 times more likely to experience relapse or death (Figure 1). The clinical specificity of Clarity and NAAT was 97.4% and 89.0%, respectively, and overdiagnosis was over three times more common in NAAT+/toxin− than in NAAT+/toxin+ patients (Figure 2). Negative percent agreement between NAAT and Clarity was 98.3%, and positive percent agreement increased from 50.0% to effective 84.2% and 94.1% after CCNA testing and clinical assessment. Conclusion The Clarity assay was superior to NAATs in diagnosis of CDI, by reducing overdiagnosis and thereby increasing clinical specificity, and presence of toxins was associated with disease severity and outcome. Disclosures All authors: No reported disclosures.

scholarly journals 1496. Bezlotoxumab Administered at the End of a Suppressive Drug Regimen for Patients with Multiply Recurrent Clostridioides difficile Infection

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S545-S545
Author(s):  
Xing Tan ◽  
Larry H Danziger ◽  
Dale N Gerding
Keyword(s):  
Treatment Regimen ◽  
Initial Response ◽  
Drug Regimen ◽  
Retrospective Case ◽  
Public Health Burden ◽  
Clostridioides Difficile ◽  
Positive Stool ◽  
Clostridioides Difficile Infection ◽  
Effective Therapeutic Strategy ◽  
Irritable Bowel

Abstract Background Recurrent Clostridioides difficile infection (CDI) remains a public health burden, affecting as many as 35% of patients with primary CDI. Bezlotoxumab, a monoclonal anti-toxin B antibody, was the first FDA-approved agent indicated for the prevention of recurrent CDI, but real-world experience is limited, particularly in patients with multiple CDI recurrences. Methods We conducted a retrospective case study of patients with multiple CDI recurrences who failed prior treatments with pulsed and tapered vancomycin and fidaxomicin regimens. Six patients in a single CDI specialty outpatient clinic received a single iv infusion of bezlotoxumab at the end of a suppressive vancomycin or fidaxomicin treatment regimen. The suppressive treatment was stopped immediately after the bezlotoxumab infusion and the patients were followed closely for recurrent symptoms and need for additional CDI treatment. Results Four of 6 patients who received bezlotoxumab at the end of a suppressive treatment regimen did not require subsequent CDI treatment and have been followed for 2 weeks to 1.5 years to date. These four patients experienced a single, self-limited episode of diarrhea within 2 weeks of the infusion, and did not require subsequent CDI treatment. Two patients had recurrent symptoms and positive stool C. difficile tests one month after infusion and were re-started on CDI treatment. One of the patients had longstanding underlying irritable bowel syndrome and variable initial response to re-starting vancomycin. The other patient responded to re-starting fidaxomicin. Conclusion Bezlotoxumab at the end of a prolonged suppressive treatment regimen may be an effective therapeutic strategy in preventing recurrent CDI in complicated, multiply recurrent CDI patients. Disclosures All authors: No reported disclosures.

scholarly journals The higher the better? Defining the optimal beta-lactam target for critically ill patients to reach infection resolution and improve outcome

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Christina Scharf ◽  
Uwe Liebchen ◽  
Michael Paal ◽  
Max Taubert ◽  
Michael Vogeser ◽  
...  
Keyword(s):  
Liver Function ◽  
Hospital Mortality ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Beta Lactam ◽  
Target Attainment ◽  
Outcome Group ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Objectives Beta-lactam antibiotics are often subject to therapeutic drug monitoring, but breakpoints of target attainment are mostly based on expert opinions. Studies that show a correlation between target attainment and infection resolution are missing. This analysis investigated whether there is a difference in infection resolution based on two breakpoints of target attainment. Methods An outcome group out of 1392 critically ill patients treated with meropenem or piperacillin-tazobactam was formed due to different selection criteria. Afterwards, three groups were created: group 1=free drug concentration (f) was < 100% of the time (T) above the minimal inhibitory concentration (MIC) (< 100% fT >MIC), group 2=100% fT >MIC<4xMIC, and group 3=100% fT >4xMIC. Parameters for infection control, renal and liver function, and estimated and observed in-hospital mortality were compared between those groups. Statistical analysis was performed with one-way analysis of variance, Tukey post hoc test, U test, and bivariate logistic regression. Results The outcome group consisted of 55 patients (groups 1–3, 17, 24, and 14 patients, respectively). Patients allocated to group 2 or 3 had a significantly faster reduction of the C-reactive protein in contrast to patients allocated to group 1 (p = 0.033 and p = 0.026). Patients allocated to group 3 had a worse renal function, a higher Acute Physiology and Chronic Health Evaluation (APACHE II) score, were older, and had a significantly higher in-hospital mortality compared to group 1 (p = 0.017) and group 2 (p = 0.001). The higher mortality was significantly influenced by worse liver function, higher APACHE II, and higher Sequential Organ Failure Assessment (SOFA) score and norepinephrine therapy. Conclusion Achieving the target 100% fT >MIC leads to faster infection resolution in the critically ill. However, there was no benefit for patients who reached the highest target of 100% fT >4xMIC, although the mortality rate was higher possibly due to confounding effects. In conclusion, we recommend the target 100% fT >MIC<4xMIC for critically ill patients. Trial registration NCT03985605

scholarly journals Potential for the current National Healthcare Safety Network (NHSN) >3 days after admission definition of laboratory-identified, healthcare-facility–onset, Clostridioides difficile infection (HO-CDI) to overestimate rates

2020 ◽  
Vol 41 (4) ◽  
pp. 467-468
Author(s):  
Shruti Puri ◽  
Heather Y. Hughes ◽  
Monica D. McCrackin ◽  
Robert Williford ◽  
Mulugeta Gebregziabher ◽  
...  
Keyword(s):  
Healthcare Facility ◽  
National Healthcare ◽  
Clostridioides Difficile ◽  
National Healthcare Safety Network ◽  
Positive Stool ◽  
Clostridioides Difficile Infection ◽  
Stool Samples ◽  
Definition Of

AbstractHealthcare-facility–onset C.difficile LabID events are defined as positive stool samples collected >3 days after hospitalization. Using a definition of >72 hours, we found that 84 of 1013 cases (8.3%) identified as C. difficile LabID events were collected between 48 and 72 hours after admission.

scholarly journals Characterization of a clinical Clostridioides difficile isolate with markedly reduced fidaxomicin susceptibility and a V1143D mutation in rpoB

2018 ◽  
Vol 74 (1) ◽  
pp. 6-10 ◽  
Author(s):  
Julian Schwanbeck ◽  
Thomas Riedel ◽  
Friederike Laukien ◽  
Isabel Schober ◽  
Ines Oehmig ◽  
...  
Keyword(s):  
Single Molecule ◽  
Sequence Data ◽  
Normal Growth ◽  
Amplicon Sequencing ◽  
Spore Formation ◽  
Compensatory Mechanisms ◽  
Toxin A ◽  
Clostridioides Difficile

Abstract Objectives The identification and characterization of clinical Clostridioides difficile isolates with reduced fidaxomicin susceptibility. Methods Agar dilution assays were used to determine fidaxomicin MICs. Genome sequence data were obtained by single-molecule real-time (SMRT) sequencing in addition to amplicon sequencing of rpoB and rpoC alleles. Allelic exchange was used to introduce the identified mutation into C. difficile 630Δerm. Replication rates, toxin A/B production and spore formation were determined from the strain with reduced fidaxomicin susceptibility. Results Out of 50 clinical C. difficile isolates, isolate Goe-91 revealed markedly reduced fidaxomicin susceptibility (MIC >64 mg/L). A V1143D mutation was identified in rpoB of Goe-91. When introduced into C. difficile 630Δerm, this mutation decreased fidaxomicin susceptibility (MIC >64 mg/L), but was also associated with a reduced replication rate, low toxin A/B production and markedly reduced spore formation. In contrast, Goe-91, although also reduced in toxin production, showed normal growth rates and only moderately reduced spore formation capacities. This indicates that the rpoBV1143D allele-associated fitness defect is less pronounced in the clinical isolate. Conclusions To the best of our knowledge, this is the first description of a pathogenic clinical C. difficile isolate with markedly reduced fidaxomicin susceptibility. The lower-than-expected fitness burden of the resistance-mediating rpoBV1143D allele might be an indication for compensatory mechanisms that take place during in vivo selection of mutants.

scholarly journals 2404. Molecular Epidemiology of Clostridioides difficile in the United States, 2017

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S830-S830 ◽  
Author(s):  
Ashley Paulick ◽  
Michelle Adamczyk ◽  
Lauren C Korhonen ◽  
Alice Guh ◽  
Amy Gargis ◽  
...  
Keyword(s):  
United States ◽  
Molecular Epidemiology ◽  
The United States ◽  
Emerging Infections ◽  
Convenience Sample ◽  
Clostridioides Difficile ◽  
Positive Stool ◽  
Control And Prevention ◽  
Clostridioides Difficile Infection ◽  
Healthcare Associated

Abstract Background In 2009, the Centers for Disease Control and Prevention (CDC) implemented Clostridioides difficile infection (CDI) surveillance through the Emerging Infections Program (EIP) to monitor the incidence and evolving epidemiology of CDI in the United States. Since 2012, ribotypes (RTs) 027, 106, 002, 014, and 020 have constituted the top five strain types among both US community- and healthcare-associated isolates. Here we describe the changes in molecular epidemiology of C. difficile isolates collected in the United States in 2017. Methods In 2017, CDI surveillance was conducted at 10 EIP sites (CA, CO, CT, GA, MD, MN, NM, NY, OR, and TN). A convenience sample of clinical laboratories across EIP sites submitted C. difficile-positive stool specimens to the MN Department of Health Public Health Laboratory and Hines VA Hospital (IL) for culture. Isolates were forwarded to CDC and characterized by capillary-based PCR-ribotyping and PCR detection of tcdA, tcdB, cdtA, cdtB, and deletions in tcdC. Results In 2017, 1,051 C. difficile isolates were submitted; the total number of isolates received from each site ranged from 11 to 286 with a median of 85.5. In total, 143 RTs were observed, with the majority of isolates harboring toxin genes tcdA and tcdB (95%) and a wild-type tcdC sequence (71%). Among 556 healthcare-associated isolates, RT 027 was the most prevalent and the top RT at 5 sites (CA, GA, MD, NM, TN). Ribotype 106 was the most prevalent among 495 community-associated CA isolates and the top RT at 6 sites (CO, CT, GA, MD, MN, TN). Ribotype 027 significantly decreased from 2012 to 2017 among both healthcare-associated (21% vs 15%; p = 0.02) and community-associated isolates (17% vs 6%; P < 0.0001). Among healthcare-associated isolates, RT 076, which was observed in 8 EIP sites, increased from 2% in 2016 to 5% in 2017 (p = 0.05) and replaced RT 020 as one of the top 5 healthcare-associated RTs in 2017. Conclusion Despite an overall decline since 2012, RT 027 remained the most prevalent RT among healthcare-associated isolates submitted in 2017. The increased frequency of RT 076 among healthcare-associated isolates submitted in 2017 highlights the evolving molecular epidemiology of C. difficile and the need for continued surveillance to monitor potential emerging strains. Disclosures All authors: No reported disclosures.

scholarly journals Host Immune Markers Distinguish Clostridioides difficile Infection From Asymptomatic Carriage and Non–C. difficile Diarrhea

2019 ◽  
Author(s):  
Ciaran P Kelly ◽  
Xinhua Chen ◽  
David Williams ◽  
Hua Xu ◽  
Christine A Cuddemi ◽  
...  
Keyword(s):  
Adaptive Immunity ◽  
Symptomatic Patient ◽  
Nucleic Acid Amplification ◽  
Toxin A ◽  
Toxin B ◽  
Innate And Adaptive Immunity ◽  
Clostridioides Difficile ◽  
Asymptomatic Carriage ◽  
Positive Stool ◽  
Tnf Α

Abstract Background Recent data indicate that Clostridioides difficile toxin concentrations in stool do not differentiate between C. difficile infection (CDI) and asymptomatic carriage. Thus, we lack a method to distinguish a symptomatic patient with CDI from a colonized patient with diarrhea from another cause. To address this, we evaluated markers of innate and adaptive immunity in adult inpatients with CDI (diagnosed per US guidelines), asymptomatic carriage, or non-CDI diarrhea. Methods CDI-NAAT patients had clinically significant diarrhea and positive nucleic acid amplification testing (NAAT) and received CDI treatment. Carrier-NAAT patients had positive stool NAAT but no diarrhea. NAAT-negative patients (with and without diarrhea) were also enrolled. A panel of cytokines and anti–toxin A and B immunoglobulin (Ig) were measured in serum; calprotectin and anti–toxin B Ig A/G were measured in stool. NAAT-positive stool samples were tested by an ultrasensitive toxin assay (clinical cutoff, 20 pg/mL). Results Median values for interleukin (IL)-4, IL-6, IL-8, IL-10, IL-15, granulocyte colony-stimulating factor (GCSF), MCP-1, tumor necrosis factor α (TNF-α), and IgG anti–toxin A in blood and IgA/G anti–toxin B in stool were significantly higher in CDI patients compared with all other groups (P < .05). Concentration distributions for IL-6, GCSF, TNF-α, and IgG anti–toxin A in blood, as well as IgA and IgG anti–toxin B in stool, separated CDI patients from all other groups. Conclusions Specific markers of innate and adaptive immunity distinguish CDI from all other groups, suggesting potential clinical utility for identifying which NAAT- and toxin-positive patients with diarrhea truly have CDI.

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