Clostridium difficile as a cause of healthcare-associated diarrhoea among children in Auckland,New Zealand: clinical and molecular epidemiology

We aimed to determine the incidence of Clostridium difficile infection (CDI), the molecular epidemiology of circulating C. difficile strains and risk factors for CDI among hospitalised children in the Auckland region. A cross-sectional study was undertaken of hospitalised children <15 years of age in two hospitals investigated for healthcare-associated diarrhoea between November 2011 and June 2012. Stool specimens were analysed for the presence of C. difficile using a two-step testing algorithm including polymerase chain reaction (PCR). C. difficile was cultured and PCR ribotyping performed. Demographic data, illness characteristics and risk factors were compared between children with and without CDI. Non-duplicate stool specimens were collected from 320 children with a median age of 1.2 years (range 3 days to 15 years). Forty-six patients (14 %) tested met the definition for CDI. The overall incidence of CDI was 2.0 per 10,000 bed days. The percentage of positive tests among neonates was only 2.6 %. PCR ribotyping showed a range of strains, with ribotype 014 being the most common. Significant risk factors for CDI were treatment with proton pump inhibitors [risk ratio (RR) 1.74, 95 % confidence interval (CI) 1.09–5.59; p?=?0.002], presence of underlying malignancy (RR 2.71, 95 % CI 1.65–4.62; p?=?0.001), receiving chemotherapy (RR 2.70, 95 % CI 1.41–4.83; p?=?0.003) and exposure to antibiotics (RR 1.17, 95 % CI 0.99–1.17; p?=?0.03). C. difficile is an important cause of healthcare-associated diarrhoea in this paediatric population. The notion that neonatal populations will always have high rates of colonisation with C. difficile may not be correct. Several risk factors associated with CDI among adults were also found to be significant.     

Binary toxin and its clinical importance in <Emphasis Type="Italic">Clostridium difficile</Emphasis> infection,Belgium

Binary toxin-producing Clostridium difficile strains such as ribotypes 027 and 078 have been associated with increased Clostridium difficile infection (CDI) severity. Our objective was to investigate the association between presence of the binary toxin gene and CDI severity and recurrence. We performed a laboratory-based retrospective study including patients between January 2013 and March 2015 whose fecal samples were analyzed by polymerase chain reaction (PCR) for the presence of the genes for toxin B and binary toxin and a deletion in the tcdC gene, specific for ribotype 027. Clinical and epidemiological characteristics were compared between 33 binary toxin-positive CDI patients and 33 binary toxin-negative CDI patients. Subsequently, the characteristics of 66 CDI patients were compared to those of 66 diarrhea patients who were carriers of non-toxigenic C. difficile strains. Fifty-nine of 1034 (5.7 %) fecal samples analyzed by PCR were binary toxin-positive, belonging to 33 different patients. No samples were positive for ribotype 027. Binary toxin-positive CDI patients did not differ from binary toxin-negative CDI patients in terms of disease recurrence, morbidity, or mortality, except for a higher peripheral leukocytosis in the binary toxin-positive group (16.30?×?10⁹/L vs. 11.65?×?10⁹/L; p?=?0.02). The second part of our study showed that CDI patients had more severe disease, but not a higher 30-day mortality rate than diarrhea patients with a non-toxicogenic C. difficile strain. In our setting with a low prevalence of ribotype 027, the presence of the binary toxin gene is not associated with poor outcome.     

Clostridium difficile infection in children hospitalized due to diarrhea

The frequency of Clostridium difficile infection (CDI)-related hospitalizations is increasing. The aim of this study was to determine the extent of CDI among children hospitalized with diarrhea, risk factors or predictors for severe CDI, the prevalence of NAP1, and to compare the course of CDI depending on bacteria toxicity profile. A retrospective analysis of case records of 64 children (age range 3 months–16 years, median age 2.12 years) with CDI as defined by diarrheal disease and positive polymerase chain reaction (PCR) test (Xpert C. difficile) was conducted. Modified national adult guidelines were used to assess the severity of CDI. CDIs represented 2.7 % of patients with diarrhea (13.5 cases per 1,000 admissions). Thirty-three CDIs (52 %) were community-associated. Antibacterial use preceded CDI in 61 patients (95 %). Seventeen cases (27 %) were binary toxin-positive (CDT+), 13 of which were NAP1 (20.5 %). Over 75 % of CDIs with NAP1 was hospital-acquired, and more often proceeded with generalized infection (p?<?0.05). Risk factors for severe CDI (34 %) included NAP1 [odds ratio (OR), 4.85; 95 % confidence interval (Cl), 1.23, 21.86) and co-morbidities (OR, 4.25; 95 % Cl, 1.34, 14.38). Diarrhea ≥10 stools daily was associated with severe CDI (p?=?0.01). Recurrence occurred in three patients (4.5 %). There was no mortality. C. difficile is an important factor of antibiotic-associated diarrhea in children. Co-morbidities and NAP1 predispose to severe CDI.     

Clostridium difficile infection diagnosis in a paediatric population: comparison of methodologies

The increasing incidence of Clostridium difficile infection (CDI) in paediatric hospitalised populations, combined with the emergence of hypervirulent strains, community-acquired CDI and the need for prompt treatment and infection control, makes the rapid, accurate diagnosis of CDI crucial. We validated commonly used C. difficile diagnostic tests in a paediatric hospital population. From October 2011 to January 2012, 150 consecutive stools were collected from 75 patients at a tertiary paediatric hospital in Perth, Western Australia. Stools were tested using: C. Diff Quik Chek Complete, Illumigene C. difficile, GeneOhm Cdiff, cycloserine cefoxitin fructose agar (CCFA) culture, and cell culture cytotoxin neutralisation assay (CCNA). The reference standard was growth on CCFA or Cdiff Chromagar and PCR on isolates to detect tcdA, tcdB, cdtA, and cdtB. Isolates were PCR ribotyped. The prevalence of CDI was high (43 % of patients). Quik Chek Complete glutamate dehydrogenase (GDH) demonstrated a low negative predictive value (NPV) (93 %). Both CCNA and Quik Chek Complete toxin A/B had poor sensitivity (33 % and 29 % respectively). Molecular methods both had 89 % sensitivity. Algorithms using GDH + Illumigene or GeneOhm reduced the sensitivity to 85 % and 83 % respectively. Ribotype UK014/20 predominated. GDH NPV and GeneOhm and Illumigene sensitivities were reduced compared with adult studies. Quik Chek Complete and CCNA cannot reliably detect toxigenic CDI. A GDH first algorithm showed reduced sensitivity. In a high prevalence paediatric population, molecular methods alone are recommended over the use of GDH algorithm or culture and CCNA, as they demonstrate the best test performance characteristics.     

Risk factors for recurrence in patients with Clostridium difficile infection due to 027 and non-027 ribotypes

Objectives

Our objective was to evaluate factors associated with recurrence in patients with 027+ and 027– Clostridium difficile infection (CDI).

The incidence and clinical symptomatology of Clostridium difficile infections in a community setting in a cohort of Danish patients attending general practice

Clostridium difficile infection (CDI) is gradually being recognised as a cause of morbidity in the community. We investigated the incidence and clinical characteristics of CDI in a community setting and characterised the C. difficile strains by toxin gene profiling and polymerase chain reaction (PCR) ribotyping. Patients included in the study had attended general practice, primarily because of diarrhoea; CDI patients (259 patients; 121 <2 years of age) had positive cultures for toxigenic C. difficile and non-CDI patients (455 patients) were culture-negative. Outcome variables included the frequency and duration of diarrhoea, vomiting, stomach ache, fever >38 °C, weight loss and sick leave. Data were analysed by logistic regression. CDI patients <2 and ≥2 years of age with C. difficile as the only enteropathogen in the faecal sample reported slimy stools (65 % vs. 62 %), stomach ache (60 % vs. 75 %), weight loss (50 % vs. 76 %) and duration of diarrhoea >15 days (59 % vs. 73 %) as the predominant symptoms. CDI patients ≥2 years old reported duration of diarrhoea >15 days more often compared to non-CDI patients (73 % vs. 27 %, p?<?0.0001). The annual incidence of CDI was 518 and 23/100,000 for patients <2 and ≥2 years of age, respectively, and 46/100,000 in the subgroup of patients ≥60 years of age. CDI was characterised by stomach ache and persistent diarrhoea, often leading to weight loss. This emphasises the importance of diagnosing CDI not only in hospitalised patients, but also in individuals ≥2 years of age attending general practice because of gastrointestinal symptoms, especially in the elderly, where the incidence of CDI is high.     

Impact of ribotype 027 on Clostridium difficile infection in a geriatric department

The purposes of this study were to describe the epidemiology (2001–2009) of Clostridium difficile infections (CDI) in a geriatric department and to compare the clinical data of patients infected with a 027 or non-027 strain. We retrospectively identified all geriatric patients with CDI and analysed the clinical and microbiological data of 133 patients for whom a ribotype was available between March 2003 and December 2009. The incidence of CDI in our geriatric department increased from 0.2 per 100 admissions in 2001 to 8.1 in 2004 and decreased to 1.3 in 2008 before a new rise to 2.1 in 2009. The percentage of ribotype 027 decreased from 2007 but it remained the most prevalent ribotype during the years 2007–2009, with a greater dispersion of ribotypes. The mean age of the patients was 84 years and the median Charlson index was 6.0. Previous use of fluoroquinolones was a significant risk factor for developing a CDI with an 027 strain (p?=?0.001). Cure was significantly lower in the 027 group (p?=?0.003). The total attributable mortality was 24.1 %. A multiparametric model showed that attributable mortality was influenced by the ribotype 027 (p?=?0.037), the severity of clinical symptoms (p?=?0.001) and the type of treatment (p?=?0.002). Oral vancomycin had a protective effect against mortality. Attention should be paid to elderly patients developing a CDI, especially after the administration of fluoroquinolones. Oral vancomycin could be recommended as the first-line agent not only to protect against recurrence or severe CDI, but to diminish the attributable mortality risk.     

Impact of malignancy on <Emphasis Type="Italic">Clostridium difficile</Emphasis> infection

Purpose

The purpose of this study was to investigate the impact of malignancy and chemotherapy on the clinical and microbiological characteristics of Clostridium difficile infections (CDI).

Methods

CDI patients with a history of malignancy within 5 years were defined as the cancer group. The characteristics of the patients were compared according to the presence of malignancy.

Results

Of 580 patients with CDI, 159 (27.4 %) belonged to the cancer group and 421 (72.6 %) to the non-cancer group. More of the patients in the cancer group than those in the non-cancer group had been hospitalized within the prior 2 months (P?<?0.001). Leukocytosis was more common in the non-cancer group (P?=?0.034), while infection by PCR ribotype 017 strains was more common in the cancer group, with marginal significance (P?=?0.07). Recurrence was more frequent in the cancer group (20.4 % vs. 9.5 %, P =0.005) and cancer was an independent risk factor for recurrence of CDI (OR?=?2.66, 95 % CI 1.34-5.29, P =0.005). Age also contributed to the recurrence of CDI (OR?=?1.03, 95 % CI 1.00-1.06, P =0.026).

Conclusions

Malignancy and age are independent risk factors for recurrence of CDI. Cancer patients require careful observation for recurrence after treatment of CDI.

     

The undiagnosed cases of Clostridium difficile infection in a whole nation: where is the problem?

Underdiagnosis of Clostridium difficile infection (CDI) because of lack of clinical suspicion or the use of non-sensitive diagnostic techniques is a known problem whose real magnitude has not yet been quantified. In order to estimate the extent of this underdiagnosis, we performed C. difficile cultures on all unformed stool specimens sent—irrespective of the type of request—to a series of laboratories in Spain on a single day. The specimens were cultured, and isolates were characterized at a central reference laboratory. A total of 807 specimens from 730 patients aged ≥2 years were selected from 118 laboratories covering 75.4% of the Spanish population. The estimated rate of hospital-acquired CDI was 2.4 episodes per 1000 admissions or 3.8 episodes per 10 000 patient-days. Only half of the episodes occurred in patients hospitalized for >2 days. Two of every three episodes went undiagnosed or were misdiagnosed, owing to non-sensitive diagnostic tests (19.0%) or lack of clinical suspicion and request (47.6%; mostly young people or non-hospitalized patients). The main ribotypes were 014/020 (20.5%), 001 (18.2%), and 126/078 (18.2%). No ribotype 027 strains were detected. Strains were fully susceptible to metronidazole and vancomycin. CDI was underdiagnosed in diarrhoeic stools in a high proportion of episodes, owing to the use of non-sensitive techniques or lack of clinical suspicion, particularly in people aged <65 years or patients with community-acquired diarrhoea. C. difficile toxins should be routinely sought in unformed stools of any origin sent for microbiological diagnosis. The ribotype 027 clone has not yet disseminated in Spain.     

Host factors are more important in predicting recurrent Clostridium difficile infection than ribotype and use of antibiotics

ObjectiveA frequent complication of Clostridium difficile infection (CDI) is recurrent disease. The aim of this study was to determine whether early recurrence risk was higher after infection with ribotype 027 (outbreak strain) compared with infection with endemic strain types of C. difficile.MethodsConsecutive patients diagnosed with CDI between May 2013 and March 2014 were included (outbreak strain, and non-outbreak strains). Patients who developed recurrent CDI within 30 days after completion of CDI treatment, were compared with patients without a recurrence. Medical charts were reviewed for demographic and clinical characteristics. General practitioners were contacted to complete data about the occurrence of recurrent CDI, and the use of medication after hospital discharge.ResultsIn total, 135 patients were at risk for the development of recurrent CDI; 74 patients were infected by ribotype 027, and 61 patients by other ribotypes. Thirty-nine patients (29%) developed recurrent CDI within 30 days after completion of CDI treatment. In multivariable analysis, age ≥70 years (HR 3.05, 95% CI 1.54–6.03), and a duration of CDI treatment ≥11 days (HR 1.92, 95% CI 1.00–3.69) were clearly associated with recurrence; infection with ribotype 027 showed a HR of 1.72 (95% CI 0.88–3.33).ConclusionDuring this outbreak of C. difficile in a tertiary care centre, age and a prolonged duration of CDI therapy (which is most likely a marker of underlying disease severity) were the main risk factors for recurrent CDI. This points to host factors as more important predictors for recurrent CDI than strain type or antibiotic use.     

Risk factors for recurrent <Emphasis Type="Italic">Clostridium difficile</Emphasis> infection in a tertiary hospital in Israel

To estimate the rate and identified risk factors for recurrent Clostridium difficile infection (rCDI) in Israel. We conducted a retro-prospective case-control study of all adult (age?≥?18 years) patients with an initial episode of CDI (iCDI) at Tel Aviv Sourasky Medical Center from January 1, 2012 to December 31, 2014. We collected demographic, clinical, and epidemiological information for patients who were classified as recurrent (cases) and non-recurrent (control) groups. In total, 648 patients with iCDI were identified in the study. During the 36-month study period, 82 (12.7%) patients had at least one rCDI identified. We identified several factors as independent variables significantly associated with recurrent CDI: functional disability, severity of the initial infection, continuous non-Clostridium difficile antibiotic treatment with third-generation cephalosporins or clindamycin, and iCDI treatment with metronidazole and vancomycin; however, neutropenia had high measure of effect as a predictor for rCDI (adjusted odds ratio, 7.9; 95% confidence interval, 1.27–49.58; p?=?0.026). The identification of the main modifiable risk factors for recurrent CDI, continuous non-Clostridium difficile antibiotics after diagnosis of the initial infection, and antibiotic treatment with third-generation cephalosporins or clindamycin are critical in reducing the spread of recurrent infection with Clostridium difficile in hospital.     

The ClosER study: results from a three-year pan-European longitudinal surveillance of antibiotic resistance among prevalent Clostridium difficile ribotypes, 2011–2014

ObjectivesUntil the introduction of fidaxomicin, antimicrobial treatment for Clostridium difficile infection (CDI) was limited to metronidazole and vancomycin. The changing epidemiology of CDI and the emergence of epidemic C. difficile PCR ribotype 027 necessitate continued surveillance to identify shifts in antibiotic susceptibility. ClosER, currently the largest pan-European epidemiological study of C. difficile ribotype distribution and antibiotic susceptibility, aimed to undertake antimicrobial resistance surveillance pre- and post-introduction of fidaxomicin.MethodsBetween July 2011 and July 2014, 39 sites across 22 European countries submitted 2830 C. difficile isolates for ribotyping, toxin testing and susceptibility testing to metronidazole, vancomycin, fidaxomicin, rifampicin, moxifloxacin, clindamycin, imipenem, chloramphenicol and tigecycline.ResultsRibotypes 027, 014, 001, 078, 020, 002, 126, 015 and 005 were most frequently isolated, and emergent ribotypes 198 and 356 were identified in Hungary and Italy, respectively. All isolates were susceptible to fidaxomicin, with scarce resistance to metronidazole (0.2%, 6/2694), vancomycin (0.1%, 2/2694) and tigecycline (0%). Rifampicin, moxifloxacin and clindamycin resistance was evident in multiple ribotypes. Lack of ribotype diversity correlated with greater antimicrobial resistance. Epidemic ribotypes (027/001) were associated with multiple antimicrobial resistance, and ribotypes 017, 018 and 356 with high-level resistance. Additional factors may also influence local ribotype prevalence.ConclusionsFidaxomicin susceptibility was retained post-introduction, and resistance to metronidazole and vancomycin was rare. Continued surveillance is needed, with more accurate classification and clarification of ribotype subtypes to further understand their role in the spread of resistance. Other factors may also influence changes in prevalence of C. difficile ribotypes with reduced antibiotic susceptibility.     

Community-onset Clostridium difficile infection at a tertiary medical center in southern Taiwan, 2007–2015

Background

Clostridium difficile infection (CDI) is well-known as the major cause of infectious diarrhea in hospitalized patients. Community-onset CDI (CO-CDI) is an emerging threat. However, clinical information of CO-CDI in Taiwan remains scarce.

Comparison of resistance against erythromycin and moxifloxacin, presence of binary toxin gene and PCR ribotypes in Clostridium difficile isolates from 1990 and 2008

Worldwide increasing rates of Clostridium difficile infections (CDI) with severe courses and outbreaks have been reported. This change in CDI epidemiology has on one hand been related to the spread of specific PCR ribotypes (e.g. 027) and on the other hand to increased prevalence of resistant C. difficile strains. This single-centre retrospective analysis characterized resistance against erythromycin and moxifloxacin, presence of binary toxin gene and ribotypes in 73 C. difficile isolates from 2008 in comparison with 23 isolates from 1990. In 1990, five different PCR ribotypes including 027 were identified. Resistance against erythromycin was detected in 3 of 23 (13%), while 20 of 23 (87%) from all isolates were susceptible to both erythromycin and moxifloxacin. In contrast, in 2008 a significantly increased prevalence of resistant C. difficile strains was observed, with 40 of 73 (54.8%) isolates being resistant against both antibiotics. Resistant C. difficile strains were mainly assigned to PCR ribotype 001. No isolates belonging to PCR ribotype 027 were identified. Our data provide evidence that the increase of resistant C. difficile strains belonging to PCR ribotype 001 rather than the spread of C. difficile PCR ribotype 027 contribute to the changing epidemiology of CDI.     

Molecular Epidemiology of Clostridium difficile Infection in a Major Chinese Hospital: an Underrecognized Problem in Asia?

Clostridium difficile infection is almost unrecognized in mainland China. We have undertaken a study in a large Chinese teaching hospital in Changsha, Hunan, China, to identify cases of C. difficile, record patient characteristics, and define the molecular epidemiology with respect to ribotype distribution and cross-infection. Between April 2009 and February 2010, we examined fecal samples from 70 hospitalized patients with diarrhea who were receiving or had received antibiotics within the previous 6 weeks. Clinical information was collected and the samples were cultured for C. difficile retrospectively. Isolates were ribotyped, and multiple-locus variable-number tandem-repeat assay (MLVA) subtyping was performed on clusters of the same ribotype. The mean age of patients from whom C. difficile was cultured was 58 years, with only 4/21 patients aged >65 years. All patients, with a single exception, had received a third-generation cephalosporin and/or a quinolone antibiotic. Twenty-one isolates of C. difficile were recovered, and seven different ribotypes were identified, the dominant types being 017 (48%), 046 (14%), and 012 (14%). We identified two clusters of cross-infection with indistinguishable isolates of ribotype 017, with evidence of spread both within and between wards. We have identified C. difficile as a possibly significant problem, with cross-infection and a distinct ribotype distribution, in a large Chinese hospital. C. difficile may be underrecognized in China, and further epidemiological studies across the country together with the introduction of routine diagnostic testing are needed to ascertain the size of this potentially significant problem.     

Ribotype 027 Clostridium difficile infections with measurable stool toxin have increased lactoferrin and are associated with a higher mortality

We evaluated clinical and diagnostic indicators of severe C. difficile infection (CDI) and their association with poor clinical outcome. A total of 210 patients positive according to PCR (toxin B: tcdB) were included, with patients having a median age of 62 years and a Charlson co-morbidity index (CI) score of 5. Ninety-one percent (n?=?191) were positive by toxigenic culture and 61 % (n?=?129) had stool toxin. Toxin-positive patients had significantly higher fecal lactoferrin (mean 316 μg/g versus 106 μg/g stool; p?<?0.0001). Forty percent of patients (n?=?85) were infected with ribotype 027 and significantly more of these patients had measurable stool toxin (79 % vs. 50 %; p?<?0.0001). The mean fecal lactoferrin was significantly higher for toxin-positive 027 CDI compared with the 027 toxin-negative group (317 vs 60 μg/g; p?=?0.0014). Ribotype 027 CDI with stool toxin showed a higher all-cause, 100-day mortality compared with non-027 with stool toxin (36 % vs 18 %; p?=?0.017). Logistic regression univariate analysis for odds ratio (OR) and p values revealed that age (OR?=?1.1), intensive care unit treatment (OR?=?2.7), CI (OR?=?1.2), 027 CDI (OR?=?2.1), white blood cell count (OR?=?1.0), albumin level (OR?=?0.1), and stool toxin-positive 027 CDI (OR?=?2.5) were significantly associated with 100-day mortality (p?<?0.05). In conclusion, CDI PCR-positive patients with 027 infection and stool toxin have increased lactoferrin and are at an increased risk of death.     

Elevated lactoferrin is associated with moderate to severe Clostridium difficile disease, stool toxin, and 027 infection

We evaluated blood and fecal biomarkers as indicators of severity in symptomatic patients with confirmed Clostridium difficile infection (CDI). Recruitment included patients with CDI based on clinical symptoms and supporting laboratory findings. Disease severity was defined by physician’s assessment and blood and fecal biomarkers were measured. Toxigenic culture done using spore enrichment and toxin B detected by tissue culture were done as confirmatory tests. Polymerase chain reaction (PCR) ribotyping was performed on each isolate. There were 98 patients recruited, with 85 (87 %) confirmed cases of toxigenic CDI (21 severe, 57 moderate, and seven mild), of which 68 (80 %) were also stool toxin-positive. Elevated lactoferrin (p?=?0.01), increased white blood cell (WBC) count (p?=?0.08), and low serum albumin (p?=?0.03) were all associated with the more severe cases of CDI. Ribotype 027 infection accounted for 71 % of severe cases (p?<?0.01) and patients with stool toxin had significantly higher lactoferrin levels and WBC counts (p?<?0.05). Our findings show that elevated fecal lactoferrin, along with increased WBC count and low serum albumin, were associated with more severe CDI. In addition, patients infected with ribotype 027 and those with stool toxin had significantly higher fecal lactoferrin and WBC counts.     

Emergence of Clostridium difficile infection in tuberculosis patients due to a highly rifampicin-resistant PCR ribotype 046 clone in Poland

Clostridium difficile infection (CDI) is a major cause of nosocomial diarrhea. CDI is known to develop after antibiotic administration, but anti-tuberculosis agents have rarely been implicated. We documented an outbreak caused by a highly rifampicin-resistant C. difficile strain of polymerase chain reaction (PCR) ribotype 046 in patients with active tuberculosis.