Symptomatic Clostridium Difficile Infection Research Articles

Inflammatory bowel disease and Clostridium difficile infection: clinical presentation, diagnosis, and management.

As a frequent complication of inflammatory bowel disease (IBD), Clostridium difficile infection (CDI) was confirmed to not only aggravate the symptoms of IBD but also result in unexpected outcomes, including death. With the increasing prevalence rate of IBD and the updating of CDI diagnosis, the incidence of CDI in IBD patients is also seen rising. Although a detection method consisting of glutamate dehydrogenase immunoassay or nucleic acid amplification test and then toxin A/B enzyme immunoassay was recommended and widely adopted, the diagnosis of CDI in IBD is still a challenge because of the overlap between the symptoms of CDI in IBD and CDI itself. Vancomycin and fidaxomicin are the first-line therapy for CDI in IBD; however, the treatment has different effects due to the complexity of IBD patients' conditions and the choice of different treatment schemes. Although the use of fecal microbial transplantation is now in the ascendant for IBD management, the prospects are still uncertain and the prevention and treatment of the recurrence of CDI in IBD remain a clinical challenge. In this paper, the epidemiology, pathophysiology, clinical manifestation, prevention, and therapy of CDI in IBD were summarized and presented.

P32 Therapeutic dilemma due to gut complications with spondyloarthritis

Introduction/BackgroundTumor necrosis factor (TNF) inhibitor therapy is one of the primary modalities of treating spondyloarthritis. However, infections secondary to biologic use is a common complication. Clostridium difficile is a gut colonizer which may become pathogenic in the presence of dysbiosis and antibiotic use. Symptomatic clostridium difficile infection(CDI) due to adalimumab(ADA) use causing lymphocytic colitis(LC) is rarely reported. We present a case of axial plus peripheral spondyloarthritis on adalimumab who developed CDI and presented a therapy related dilemma.Description/MethodWe present a case of a 52-year-old lady who was diagnosed as HLAB27 positive axial spondyloarthritis with bilateral sacroiliitis on MRI bilateral sacroiliac joint in 2016. She failed two non-steroidal antinflammatory drugs (NSAID) with high disease activity scores(BASDAI 8.6, BASFI 6.2, Spinal VAS 9). She was eventually initiated on injection adalimumab in 2017. There was clinical improvement after 6 months of initiating ADA. Repeat MRI spine and SI joint showed resolution of inflammatory changes with adalimumab. Sulfasalazine was added in the treatment protocol due to peripheral arthralgia, however she developed a drug rash to it and it was stopped. In September 2021, she developed recurrent non-bloody watery diarrhoeal episodes. Adalimumab was stopped and she tested positive for Clostridium difficile on three occasions. She received multiple courses of vancomycin, fidoxamycin and metronidazole with partial resolution of diarrhoea. Adalimumab was rechallended in January 2022 since her disease activity was worsening in the absence of NSAID and biologic use. However, it was paused again due to worsening of diarrhoea. Gastroenterology conducted a Colonoscopy and biopsy of colonic polyps which showed increased number of intraepithelial lymphocytes with no thickening of subepithelial collagen plate suggestive of lymphocytic colitis (LC). It was postulated that CDI may have been the trigger for her LC. She has been started on local corticosteroid therapy(budesonide) for her LC. At this junction, we were faced with the decision of restarting adalimumab for her which may have been the original cause of her CDI.Discussion/ResultsWe present this case in view of a dilemma regarding which problem occurred first Did immunosuppression due to adalimumab lead to CDI? Literature is not suggestive of increased risk of CDI with adalimumab, especially in a non-inflammatory bowel disease (IBD) background. Was the lymphocytic colitis triggered by the CDI or was clostridium difficile just incidentally detected on a background of LC? There is a well documented associated of LC with autoimmune conditions and use of NSAIDs along with proton pump inhibitor is another trigger for it. TNF alpha inhibitor is one of the treatment modalities of refractory LC. Would it be appropriate to restart ADA for her since she responded well despite there being a risk of recurrence of a CDI? Finally, what is the role of gut dysbiosis in the role of CDI and LC in this situation. Presently, she is planned to be treated with local steroid therapy for her LC. ADA will be rechallenged once her gut has responded to the steroid course. In the event of her gut worsening on a rechallenge, she will be given a trial of Infliximab.Key learning points/ConclusionThe case highlights the crucial point of thinking of causes of diarrhea apart from well documented conditions of ulcerative colitis/Crohn’s disease in an immunosuppressed spondyloarthritis patient. A detailed stool examination including bacterial and parasitic examination is crucial in recurrent diarrhea. The threshold for colonoscopy should be low when episodes are refractory to treatment. The case-based conference gives us an opportunity to receive feedback regarding further management approaches in this case.

Isobavachalcone From Cullen corylifolium Presents Significant Antibacterial Activity Against Clostridium difficile Through Disruption of the Cell Membrane.

Background: Clostridium difficile infection (CDI) has been widely reported in human and animals around the world over the past few decades. The high relapse rate and increasing drug resistance of CDI make the discovery of new agents against C. difficile fairly urgent. This study aims to investigate the antibacterial activity against C. difficile from traditional Chinese herb medicine Cullen corylifolium and confirm its active components. Methods: Phenolic extract from the seeds of C. corylifolium was prepared routinely and the contents of relative flavonoids were determined by High Performance Liquid Chromatography (HPLC). In vitro antibacterial activities of the phenolic extract and its major components were tested. The influence of the major components on cell membrane was investigated with membrane integrity by SEM and propidium iodid uptake assay. Cytotoxicity of the extract and its active compounds on Caco-2 cell line was assessed by CCK-8 kit. The in vivo therapeutic efficacy of IBCL was evaluated on the mice model. Results: Phenolic extract was found to be active against C. difficile with minimum inhibitory concentrations (MIC) of 8 μg/mL. As the major component of the extract, IBCL was the most active compound against C. difficile. The MIC of IBCL and 4MBCL were 4 μg/ml and 4 μg/ml, respectively. Meanwhile, PFPE, IBCL, and 4MBCL showed rapid bactericidal effect against C. difficile in 1 h, which was significant compared to antibiotic vancomycin. Mechanism studies revealed that IBCL can disrupt the integrity of the cell membrane, which may lead to the death of bacteria. PFPE was low cytotoxic against Caco-2 cells, and the cytotoxicity of IBCL and 4MBCL were moderate. Symptoms of CDI were effectively alleviated by IBCL on the mice model and weight loss was reduced. From death rates, IBCL showed better efficacy compared to vancomycin at 50 mg/kg dosage. Conclusion: As the major component of phenolic extract of C. corylifolium seeds, IBCL showed significant antibacterial activity against C. difficile in vitro and rapidly killed the bacteria by disrupting the integrity of the cell membrane. IBCL can significantly prevent weight loss and reduce death caused by CDI on the mice model. Therefore, IBCL may be a promising lead compound or drug candidate for CDI.

Rifaximin Therapy for Patients With Metronidazole-Unresponsive Clostridium difficile Infection.

BackgroundClostridium difficile infection (CDI) is a leading cause of hospital-acquired diarrhea. Rifaximin is an antibiotic that offers marginal resistance to C. difficile bacteria. This study was conducted to evaluate the efficacy of rifaximin in metronidazole non-responsive CDI patients.MethodsA cross-sectional study was performed from August 2019 to May 2020 at the Lahore General Hospital, Lahore, Pakistan. A total of 200 cases were included. Patients who developed diarrhea after receiving antibiotics for seven days and a positive C. difficile toxin stool test as detected by the enzyme immunoassay (BioCheck, Inc., CA) were diagnosed with CDI. Only patients who were unresponsive to metronidazole therapy were enrolled in our analysis. Two groups were formed. The intervention group was administered 200 mg tablets of rifaximin three times a day for 10 days. For patients in the control group, no new treatment was started. The efficacy of rifaximin was defined in terms of the resolution of diarrhea after two weeks of therapy and a negative stool test. All data were recorded in a predefined pro forma.ResultsThe mean age of 45.41 ± 8.54 years was found in the intervention group. The majority of the patients were aged 35-50 years. The majority of the patients had watery diarrhea, abdominal cramping, and loss of appetite on presentation. Rifaximin was found to be significantly effective in the resolution of symptoms of CDI, which was previously unresponsive to metronidazole (p<0.00001). it was found that the duration of diarrhea of more than three weeks was significantly associated with failure of therapy (p=0.03).ConclusionWe concluded that rifaximin therapy is effective for patients of CDI non-responsive to metronidazole in more than 65% of the cases. Even though several new developments are made to address the concerned subject, such as microbiota transplantation, antibiotics, and immunotherapy, rifaximin can be considered for patients with metronidazole non-responsive CDI.

Effectiveness and cost-effectiveness of a Clostridium difficile vaccine candidate in a hospital setting

Toxoid vaccines against Clostridium difficile infections (CDI) appear promising in reducing the risk of developing toxin-mediated symptoms. We sought to evaluate the effectiveness and cost-effectiveness of a vaccine candidate in a hospital setting. We developed an agent-based simulation model of nosocomial CDI in a 300-bed hospital. Targeting high-risk patients for vaccination, we estimated the reduction of symptomatic CDI. Using the net reduction of CDI-associated isolation days, we evaluated the vaccine’s cost-effectiveness from a healthcare provider perspective over a 2-year period with an average monthly incidence of 5 cases per 10,000 patient-days pre-vaccination.Assuming a vaccine efficacy in the range 60–90%, vaccinating 40% of high-risk patients pre-admission reduced symptomatic CDI by 16.6% (95% CI: 15.2, 17.9). When the vaccine coverage increased to 80%, the reduction of symptomatic CDI was 34.6% (95% CI: 33.7, 35.9). For a willingness to pay (WTP) of CDN$1000 (corresponding to the average costs of case isolation per day), vaccine was cost-effective for vaccination costs per individual (VCPI) up to CDN$111 in the scenario of 40% vaccine coverage. With the same WTP, vaccine was cost-effective for VCPI up to CDN$121 when the vaccine coverage increased to 80%. A significant portion (~80%) of hospital colonization is caused by environmental transmission of C. difficile, which markedly reduced the effectiveness of vaccine below its assumed efficacy. However, due to the number of CDI-associated isolation days averted, vaccination of high-risk patients can be cost-effective depending on the WTP and the VCPI.

Clinical practice guidelines for Clostridioides (Clostridium) difficile infection and fecal microbiota transplant protocol - recommendations of the Polish Society od Epidemiology and Infectious Diseases.

Symptomatic Clostridium difficile infection (CDI) is an acute inflammatory disease of the gastrointestinal tract, manifesting in at least 3 unformed stools within 24 hours. Predicting factors for CDI include contact with medical care (mainly hospitalization), antibiotic therapy in the last 12 weeks, use of proton pump inhibitors (PPI), H2 blockers, cancer chemotherapy, especially in the neutropenia stage, gastrointestinal surgery, advanced age and concomitant chronic diseases (renal failure, liver failure, chronic inflammatory bowel disease - especially ulcerative bowel disease, cancer, HIV infection, cachexia and hypoalbuminaemia) and vitamin D deficiency. Clinical classification distinguishes three types of CDI - mild / moderate, severe, and fulminant. The principles of treatment of the first and subsequent CDI incidents depending on the clinical course are based on oral vancomycin. CDI is recurrent. The basis for treating CDI relapses is vancomycin administered orally at a dose of 4x125 mg for 10 days followed by concomitant vancomycin dose reduction therapy. The use of fecal microbiota transfer (FMT) in the treatment of CDI relapses is considered to be the most effective therapy for recurrent CDI. An indication for FMT is antibiotic-resistant C. difficile infection, regardless of the number of incidents CDI. The panel of tests recommended for a bacterial flora donor is presented in the recommendations.

Clostridium difficile infection in fever patients with gynecological malignancies.

Although Clostridium difficile infection (CDI) often results in severe manifestations due to toxin-producing clostridium, the correlation between CDI and having a fever in gynecological malignancies is not completely understood. The incidence, and clinical features, and clinical management of CDI in patients with gynecological malignancies who have fevers were investigated, and the clinical managements of this complication are discussed. We retrospectively reviewed 485 patients newly diagnosed with invasive gynecological cancers who underwent anticancer treatment between July 2012 and December 2016. The diagnosis of CDI was performed using enzyme immunoassays for Cdifficile glutamate dehydrogenase and toxin A/B enzyme immunoassay. The cumulative risk of CDI was 9.5% (six of 63) in overall fever patients and 6.3% (six of 95) in patients with fever episodes. Two CDI patients (33.3%) did not show diarrheal symptoms, with the fever of unknown origin criteria prompting their CDI testing and diagnosis. CDI patients were treated using vancomycin or metronidazole without suffering from fatal clinical course. Overall, eight patients with gynecological malignancies were diagnosed with CDI, including two patients with fever lower than 38.5°C. The cumulative risk of CDI was 0.48% (eight of 1652) for all admitted patients and 1.6% (eight of 485) in those with gynecological malignancies. Of all the patients with confirmed CDI, only one had a history of administration of antibiotics prior to onset of CDI symptoms. CDI does not always present with typical manifestations in malignancy patients. Investigation of CDI, regardless of gastrointestinal symptoms or history of antibiotic use, is warranted in cases of fever of unknown origin in gynecological malignancy.

Clostridium difficile intervention timelines for diagnosis, isolation, and treatment

Developing timelines of nosocomial Clostridium difficile infection (CDI) is critical to improving control and preventive measures. The objective of this study was to provide data-driven estimates of CDI timelines of diagnosis, isolation, and treatment in a hospital setting. We obtained data for all CDI inpatients with symptoms onset occurring between January 1, 2013, and December 30, 2017, from St Joseph's Healthcare in Hamilton, Canada. We analyzed full empirical distributions of timelines associated with the diagnosis, isolation, and treatment of CDI. A total of 683 inpatients with CDI symptoms were recorded, of which 243 cases were identified as health care-associated infection (HAI). The mean time intervals between the onset of CDI symptoms after admission and the release of laboratory results were 1.2 days and 1.9 days for the HAI and community-associated infection (CAI) patient groups, respectively. The mean time intervals from symptoms onset to the start of isolation were 1.5 days and 2.6 days for the corresponding patient groups. The initiation of treatment within 2 days of symptoms onset reduced the duration of first isolation (P value < .0001); however, the type of initial antibiotic used for CDI treatment was not associated with the duration of isolation. Estimated timelines did not differ (P values > .6) between HAI and CAI patient groups with symptoms onset after admission. These estimates are useful for evaluating the effectiveness of CDI interventions.

Clostridium difficile Infection\u2013Daily Symptoms (CDI-DaySyms\u2122) questionnaire: psychometric characteristics and responder thresholds

BackgroundThe purpose of the current study was to determine the final content validation, psychometric characteristics, clinically meaningful improvement, and responder thresholds of the Clostridium difficile infection (CDI)–Daily Symptoms (CDI-DaySyms™) patient-reported outcome (PRO) questionnaire.MethodsThis validation study was part of two phase III studies (NCT01987895 and NCT01983683) conducted in patients with mild-to-moderate or severe CDI who completed the CDI-DaySyms™ daily throughout the treatment period. The questionnaire was evaluated in three stages: final PRO item content validation (Stage I); psychometric evaluation of reliability and construct validity (Stage II); and determination of clinically meaningful improvement and responder thresholds using distribution-based methods (Stage III).ResultsThe analysis included 168 patients. Most patients were female and Caucasian with mild-to-moderate CDI. The mean age was 57.1 years. Initial item analysis supported by confirmatory factor analysis demonstrated the relevance of 10 items grouped into three distinct domains (Diarrhea Symptoms, Abdominal Symptoms, and Systemic/Other Symptoms). Domain scores demonstrated acceptable internal consistency and test-retest reliability, were sensitive to change, and correlated in expected directions with other relevant symptom and disease-severity measures. Responder thresholds were defined as score changes of − 1.00, − 0.80, and − 0.70 in the Diarrhea Symptoms, Abdominal Symptoms, and Systemic/Other Symptoms domains, respectively.ConclusionsThe CDI-DaySyms™ is a valid measure of patient-reported CDI symptoms, with good measurement properties, which supports its utility as an endpoint in clinical studies. Further studies confirming responder thresholds based on anchor-based methods are required.Trial registrationNCT01987895, registered November 20, 2013; NCT01983683, registered November 14, 2013.

1344. Ridinilazole (RDZ) for Clostridium difficile Infection (CDI): Impact of Diagnostic Method on Outcomes From a Phase 2 Clinical Trial

BackgroundDiagnosis of CDI includes fecal detection of a C. difficile toxigenic strain (TS) or free toxins (FT). TS detection does not distinguish infection from colonization. Guidelines recommend an FT test be part of diagnostic algorithms. Here we report outcome differences, based on diagnostic method at enrollment, from a Phase 2 clinical trial of RDZ, a novel CDI antibiotic designed to treat CDI and reduce recurrence of CDI (rCDI).MethodsThis double-blind study randomized 100 patients 1:1 to 10 days RDZ 200 mg BID or vancomycin (VAN) 125 mg QID treatment. Subjects were enrolled with CDI symptoms and a positive diagnostic result (FT or TS). Baseline (BL) stool samples were assessed for the presence of FT. All subjects entered the intent to treat (ITT) population; those subjects positive for FT entered a modified ITT (mITT), the primary analysis population. Primary endpoint was sustained clinical response (SCR) defined as cure at end of therapy and no rCDI for the next 30 days. rCDI was defined as CDI symptoms, a positive diagnostic test and need for therapy; a sensitivity analysis considered positive FT rCDI cases. BL fecal concentrations of lactoferrin and calprotectin were determined by enzyme immunoassay.ResultsOf 100 subjects enrolled, 69 (36 RDZ: 33 VAN) were FT positive at BL. RDZ compared with VAN recipients had improved SCR rates via reduced rCDI. Absolute differences in SCR between RDZ and VAN (prespecified 90% CI) for MITT (FT positive) and ITT subjects were 24.3% (3.1, 39.1) and 14.0% (−1.8, 28.8), respectively. Absolute SCR differences between the MITT and ITT subjects from the sensitivity analysis were 26.2% (4.6, 40.6) and 14.3% (−1.7, 29.1). Median BL calprotectin and lactoferrin levels (µg/mL) were significantly higher for FT positive subjects at 1,002 and 87, than for FT negative subjects at 53 and 4, respectively.ConclusionRDZ showed improved SCR in comparison with VAN. Treatment differences were greater in MITT subjects. Lower SCR improvement in RDZ ITT subjects is likely due to enrollment of some colonized rather than infected subjects; this explanation is supported by higher calprotectin and lactoferrin levels in FT-positive samples. These data demonstrate the importance of FT testing in-line with CDI guideline recommendations.Disclosures R. Vickers, Summit Therapeutics: Employee, Salary and Stock options. S. Chowdhury, Summit Therapeutics: Employee, Salary and Stock options. M. Wilcox, Summit Therapeutics: Consultant, Research Contractor and Scientific. Advisor, Consulting fee, Research grant and Research support.

518. Modeling the Potential Impact of Administering Vaccines Against Clostridium difficile Infection to Individuals in Healthcare Facilities

BackgroundVaccines against Clostridium difficile infection (CDI) are in development, with potential to directly protect those vaccinated and to mitigate transmission by reducing environmental contamination caused by prevented symptoms. For a vaccine that may or may not alter susceptibility to acquiring colonization, its projected transmission-reduction effect may depend on the contribution of symptomatic CDI to overall transmission, which remains uncertain. Mathematical models can help project population effects of vaccine administration under assumptions consistent with existing data.MethodsWe designed a simulation model of CDI among patients in a network of 10 short- and long-term acute care hospitals and nursing homes. Model calibration relied on published infection and carriage data and whole genome sequencing studies that estimated the fraction of CDI attributable to transmission from other CDI patients in healthcare settings. The modeled vaccine effectiveness for reducing the rate of progression to CDI among carriers was set at 75%, achieved after completing a vaccine course. We then simulated initiation of this vaccine course to a random subset of patients at transfer or live discharge and tallied direct and indirect CDI-reduction effects per vaccinated patient over 5 years.ResultsModel calibration found that data are consistent with higher infectivity of CDI patients over other carriers by a factor of 30–85, depending on assumed rates of initial carriage importation. Vaccine simulations produced an average reduction of 36 CDI cases per 1,000 vaccinated patients, with 25 of those cases prevented among those vaccinated and 11 prevented among unvaccinated patients. These results were robust across transmission and carriage rates supported by data.ConclusionOur findings demonstrate potential for a vaccine against CDI to reduce transmissions in healthcare facilities, even if it does not decrease acquisition of carriage per exposure among those receiving it. The finding is robust to the remaining uncertainty around the relative prevalence and infectivity of CDI patients among all carriers. The vaccine will have maximal impact if received by individuals likely to experience future infections in settings where environmental contamination poses risk to others.Disclosures D. Toth, Pfizer, Inc.: Research Contractor, Research support. M. Samore, Pfizer, Inc.: Research Contractor, Research support. H. Yu, Pfizer, Inc: Employee and Shareholder, Salary. A. Quintana, Pfizer, Inc.: Employee and Shareholder, Salary. D. L. Swerdlow, Pfizer Inc.: Employee and Shareholder, Salary.

Oral Immunization with Nontoxigenic Clostridium difficile Strains Expressing Chimeric Fragments of TcdA and TcdB Elicits Protective Immunity against C. difficile Infection in Both Mice and Hamsters.

The symptoms of Clostridium difficile infection (CDI) are attributed largely to two C. difficile toxins, TcdA and TcdB. Significant efforts have been devoted to developing vaccines targeting both toxins through parenteral immunization routes. However, C. difficile is an enteric pathogen, and mucosal/oral immunization would be particularly useful to protect the host against CDI, considering that the gut is the main site of disease onset and progression. Moreover, vaccines directed only against toxins do not target the cells and spores that transmit the disease. Previously, we constructed a chimeric vaccine candidate, mTcd138, comprised of the glucosyltransferase and cysteine proteinase domains of TcdB and the receptor binding domain of TcdA. In this study, to develop an oral vaccine that can target both C. difficile toxins and colonization/adhesion factors, we expressed mTcd138 in a nontoxigenic C. difficile (NTCD) strain, resulting in strain NTCD_mTcd138. Oral immunization with spores of NTCD_mTcd138 provided mice full protection against infection with a hypervirulent C. difficile strain, UK6 (ribotype 027). The protective strength and efficacy of NTCD_mTcd138 were further evaluated in the acute CDI hamster model. Oral immunization with spores of NTCD_mTcd138 also provided hamsters significant protection against infection with 2 × 104 UK6 spores, a dose 200-fold higher than the lethal dose of UK6 in hamsters. These results imply that the genetically modified, nontoxigenic C. difficile strain expressing mTcd138 may represent a novel mucosal vaccine candidate against CDI.

Management of Clostridium difficile Infection Following Fecal Microbiota Transplant in the Immunocompromised Patient: A Case Series

Clostridium difficile infection (CDI) is a known healthcare burden and major cause of patient morbidity and mortality. It is estimated to result in billions of dollars in annual healthcare costs. Recurrent CDI after fecal microbiota transplant (FMT) is a clinically challenging scenario especially in elderly or immunocompromised patients who are unable or unwilling to undergo repeat FMT. Here we describe two cases that required a patient specific approach to treating refractory CDI. A 79 year-old lady with a history of non-Hodgkin lymphoma presented with complaints of diarrhea for three days prior to admission and one week after being treated with antibiotics for a UTI. Two months earlier, she had undergone successful treatment for CDI with a vancomycin-pulsed taper and a course of fidaxomicin. On this admission, her C.difficile toxin by PCR was positive and she underwent treatment with endoscopic FMT. Less than a week later, she was diagnosed with pneumonia and started on Cefepime. She continued to have multiple bowel movements and had not seen improvement in her CDI symptoms. She was unwilling to repeat FMT and the decision was made to start prophylactic oral vancomycin as she was on antibiotic treatment for her pneumonia and it was still too early to determine FMT success. Following initiation of oral vancomycin, her blood labs normalized and the frequency of bowel movements decreased. Similarly, a 70 year-old gentleman with a history of heart transplant presented with complaints of multiple bowel movements, up to 15 times daily. Three months earlier, he had undergone FMT for CDI. On this admission, CDI toxin by PCR was positive despite having had a negative result a month following FMT. He was offered repeat FMT but declined and was started on fidaxomicin with subsequent clinical improvement. FMT is the most effective alternative treatment for cure of recurrent CDI when antibiotics are unsuccessful. Up to a quarter of patients treated with a single FMT can failt reatment. Risk factors for failed FMT include inpatient status, immunocompromised state and previous hospitalization for CDI. Recurrent or persistent CDI following an initial FMT can often be addressed with repeat FMT sessions; however, in the elderly or immunocompromised patient, alternatives such as treatment with oral vancomycin or fidaxomicin can also be implemented with anticipated clinical success as described in our patient cases.

Lyophilised Full Spectrum Microbiota Capsules for Treatment of Severe Clostridium difficile Infection in 2 Patients in ICU: A Case Study

Clostridium difficile infection (CDI) is the most common cause of pseudomembranous colitis and in extreme cases may also result in death. CDI symptoms range in severity from loose stools to severe bloody diarrhoea in conjunction with colonic ulceration and life threatening peritonitis. Encapsulated Lyophilized Fecal Microbiota Transplantation (LFMT) for the treatment of severe CDI has not been used before and we report two such cases admitted to Australian Intensive Care Units (ICU). Patient A: Male patient, age 79 years, diagnosed with CDI Colitis in December 2017 with elevated inflammatory markers, white cell count (WCC) 60, C-reactive protein (CRP) 380. The patient was treated with metronidazole and oral vancomycin. In January 2018, he experienced severe diarrhoea with associated left side abdominal pain and was admitted to ICU for septic shock with presumed pseudomembranous colitis. He was administered 80 LFMT capsules over 7 days. The patient's inflammatory markers were reduced (WCC 14, CRP 105), however abdominal pain and distension continued. Bowel motions improved to formed stool. Stool test for culture and polymerase chain reaction (PCR) for C. difficile toxin was negative. The Patient was able to leave ICU. He later died of unrelated respiratory disease. Patient B: Male patient, age 68 years, was admitted into ICU for non-gastrointestinal related symptoms and developed abdominal distension, bowel dilatation and thickening. He also experienced left sided abdominal tenderness, pain and loose bowel motions. The patient was diagnosed with pseudo-obstruction and CDI colitis. Inflammatory markers were high (WCC 20, CRP 65). He commenced on oral metronidazole and vancomycin followed by 36 LFMT capsules administered over 3 days via nasogastric tube. His bowel motions and abdominal tenderness improved and WCC was reduced to 9. Stool test for culture and PCR for C. difficile toxin was negative. The patient was able to leave ICU but died later due to respiratory illness. Treatment with encapsulated LFMT can eradicate CDI and improve symptoms in patients suffering from severe CDI colitis. More studies are required to examine the efficacy and route of delivery in ICU of FMT for severe CDI.

Oral probiotic combination of Lactobacillus and Bifidobacterium alters the gastrointestinal microbiota during antibiotic treatment for Clostridium difficile infection.

Perturbations in the gastrointestinal microbiome caused by antibiotics are a major risk factor for Clostridium difficile infection (CDI). Probiotics are often recommended to mitigate CDI symptoms; however, there exists only limited evidence showing probiotic efficacy for CDI. Here, we examined changes to the GI microbiota in a study population where probiotic treatment was associated with significantly reduced duration of CDI diarrhea. Subjects being treated with standard of care antibiotics for a primary episode of CDI were randomized to probiotic treatment or placebo for 4 weeks. Probiotic treatment consisted of a daily multi-strain capsule (Lactobacillus acidophilus NCFM, ATCC 700396; Lactobacillus paracasei Lpc-37, ATCC SD5275; Bifidobacterium lactis Bi-07, ATCC SC5220; Bifidobacterium lactis B1-04, ATCC SD5219) containing 1.7 x 1010 CFUs. Stool was collected and analyzed using 16S rRNA sequencing. Microbiome analysis revealed apparent taxonomic differences between treatments and timepoints. Subjects administered probiotics had reduced Verrucomicrobiaceae at week 8 compared to controls. Bacteroides were significantly reduced between weeks 0 to 4 in probiotic treated subjects. Ruminococcus (family Lachnospiraceae), tended to be more abundant at week 8 than week 4 within the placebo group and at week 8 than week 0 within the probiotic group. Similar to these results, previous studies have associated these taxa with probiotic use and with mitigation of CDI symptoms. Compositional prediction of microbial community function revealed that subjects in the placebo group had microbiomes enriched with the iron complex transport system, while probiotic treated subjects had microbiomes enriched with the antibiotic transport system. Results indicate that probiotic use may impact the microbiome function in the face of a CDI; yet, more sensitive methods with higher resolution are warranted to better elucidate the roles associated with these changes. Continuing studies are needed to better understand probiotic effects on microbiome structure and function and the resulting impacts on CDI.

A Prospective Program to Reduce the Clinical Incidence of Clostridium Difficile Colitis Infection after Cystectomy

PurposeThe development of Clostridium difficile infection after cystectomy is associated with significant morbidity and mortality. We implemented a prospective screening program to identify asymptomatic carriers of Clostridium difficile and assessed its impact on clinical Clostridium difficile infection rates compared to historical matched controls. Materials and MethodsProspective Clostridium Difficile screening prior to cystectomy began in March 2015. The 380 consecutive patients undergoing cystectomy prior to initiation of screening (control cohort) were matched based on 5 clinical factors with the 386 patients who underwent cystectomy from March 2015 to December 2017 (trial cohort). Screened positive patients were placed in contact isolation and treated prophylactically with Metronidazole. Multivariable models were built on an intention-to-screen and an effectiveness of screening basis to determine if screening reduced the rates of symptomatic Clostridium Difficile infections postoperatively. ResultsWith the implementation of the screening protocol, Clostridium difficile infections rates declined from 9.4 to 5.5% (OR 0.52, p=0.0268) on an intention-to-screen protocol and from 9.2 to 4.9% on an effectiveness of screening protocol (OR 0.46, p=0.0174). ConclusionsClostridium difficile screening prior to cystectomy is associated with a significant decrease in rates of clinically symptomatic infections postoperatively. These results should be confirmed in a randomized controlled trial.

Molecular-based diagnosis of Clostridium difficile infection is associated with reduced mortality

Polymerase chain reaction (PCR) for the diagnosis of Clostridium difficile infection (CDI) might result in overdiagnosis. The clinical outcomes of symptomatic CDI patients diagnosed by PCR remain uncertain. We aimed to determine whether patients whose diagnosis of CDI was based on PCR had different characteristics and clinical outcomes than those diagnosed by toxin immunoassay. Consecutive CDI patients, hospitalized at Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel, between January 2013 and January 2016, were identified retrospectively and included in the study. Diagnosis of CDI was based on PCR or diagnosis by immunoassay for C. difficile toxin. The main outcome was 30- and 90-day all-cause mortality. The PCR group included 165 patients and the immunoassay group included 157 patients. In comparison to the immunoassay group, patients in the PCR group were more likely to be younger, to be independent, to undergo previous abdominal surgery, and to use laxatives. The 30-day mortality rate in the PCR group was significantly lower than that in the immunoassay group, 29/165 (18%) vs 49/157 (31%), respectively; p = 0.028. On multivariate analysis, PCR diagnosis was associated with reduced mortality, OR 0.48 (95% CI 0.26-0.88). PCR-based diagnosis of CDI is associated with reduced all-cause mortality rates. Further studies are needed to determine the management of patients with discrepant immunoassay and PCR diagnosis of CDI.

Fecal microbiota transplantation for recurrent Clostridium difficile infection in a patient with ulcerative colitis.

Fecal microbiota transplantation (FMT) has been reported as a safe and effective therapy in patients with refractory and recurrent Clostridium difficile infection (CDI). FMT has also been reported as a promising therapy in patients with ulcerative colitis (UC). Both, CDI and UC, are believed to be caused by dysbiosis, such as altered compositions or decreased diversity of the intestinal microbiota. This report describes a patient with UC in remission with a second recurrent episode of CDI, who was treated with FMT. A single FMT performed via colonoscopy completely resolved the patient's diarrhea and eradicated C. difficile bacteriologically without any severe complications. Molecular biological analysis of the patient's fecal microbiota showed that FMT could dramatically change the altered composition of intestinal microbiota and restore its diversity. Despite the restoration of the intestinal microbiota, FMT could not prevent a relapse of UC in this patient. However, it improved the intestinal symptoms of CDI and could prevent further recurrences of CDI.

The CDI-DaySyms: Content Development of a New Patient-Reported Outcome Questionnaire for Symptoms of Clostridium difficile Infection

ObjectivesTo develop a patient-reported outcome (PRO) questionnaire for symptoms of Clostridium difficile infection (CDI) following the US Food and Drug Administration PRO guidelines. MethodsPatients’ experiences of CDI symptoms were elicited in open-ended discussions with patients and nurses at five US sites (stage 1). A draft PRO measure was developed after demonstration of concept saturation. Two rounds of cognitive interviews were conducted with patients at three US sites (stage 2), with revision of the draft measure after each round. All patients were 18 years or older, with confirmed CDI. The study was conducted with input from a panel of five CDI experts in Europe and North America. ResultsStage 1 included interviews with 18 patients and supplementary interviews with 6 nurses; 16 additional patients were interviewed in stage 2. Patients were representative of the general CDI population and were diverse in age, sex, and disease severity. Concept saturation was reached in stage 1. Items were organized in a draft conceptual framework with five hypothesized domains: diarrhea, abdominal discomfort, tiredness, lightheadedness, and other symptoms. Stage 2 demonstrated initial content validity of the 13-item draft daily diary (CDI-DaySyms). Participants reported that the questions were clear, relevant, and comprehensive. They were able to use the instructions to complete the diary correctly and considered the 24-hour recall period appropriate. ConclusionsThe CDI-DaySyms captures symptoms relevant to patients undergoing CDI, demonstrating initial content validity. Final content and psychometric validity are being evaluated in a substudy comprising patients from two ongoing international clinical trials (ClinicalTrials.gov identifiers NCT01987895 and NCT01983683).

The Clostridium difficile Infection – Daily Symptoms (CDI-DaySyms™) Patient-Reported Outcome (PRO) Questionnaire: Final Validation and Responder Thresholds

BackgroundPatient perspectives on their disease are undoubtedly important in clinical trials and in practice. To date, no patient-reported outcome (PRO) questionnaire assessing symptoms of Clostridium difficile infection (CDI) has been developed following FDA guidance. The CDI-DaySyms™ is a new comprehensive measure of a broad range of local and systemic CDI symptoms (not only diarrhea) that patients report as meaningful. Objectives were to: finalize the CDI-DaySyms™ items (questions); assign them to domains (concepts); evaluate the questionnaire’s measurement properties; and define responder thresholds.MethodsBlinded data from a sub-study of two Phase III trials (NCT01987895 and NCT01983683) in CDI patients were analyzed following FDA guidance for validating PRO questionnaires. Patients completed the CDI-DaySyms™ daily from Day 1 until end of treatment. Items were selected for inclusion in the final questionnaire based on a range of validation analyses, input from expert clinicians, and findings from prior qualitative patient research. Responder-threshold analyses used Day-3 data to align with the rapid symptom improvement generally seen in response to CDI therapy.ResultsData were analyzed for 168 CDI patients (median age 60 years; 67.9% female; 81.5% mild/moderate, 11.3% severe, 7.1% unknown disease severity; 80.4% first CDI occurrence, 19.6% first recurrence). Three of the 13 items in the draft CDI-DaySyms™ were deleted; the remaining 10 were statistically assigned to three domains measuring different symptom concepts (Figure). Individual items in each domain correlated strongly with one another and their domain. Domain scores demonstrated acceptable consistency over time in stable patients, were sensitive to change, and correlated in expected directions with scores of other relevant symptom and disease-severity measures. Responder thresholds were defined as score changes of -1.00, -0.80, and -0.70 for Diarrhea, Abdominal, and Systemic/Other Symptoms domain scores, respectively.ConclusionThe CDI-DaySyms™ is a valid measure of diarrhea and other CDI symptoms useful in assessing response to therapy. It has good measurement properties, and with only 10 items can be easily administered in clinical trials and in practice.Disclosures G. H. Talbot, Actelion: Board Member, Consultant and Scientific Advisor, Consulting fee; L. Kleinman, Actelion: Consultant, Research support; E. W. Davies, Actelion: Employee, Salary; E. Hunsche, Actelion: Employee and Shareholder, Salary; L. Roberts, Actelion: Consultant, Research support; C. E. Nord, Actelion: Scientific Advisor, Consulting fee