Clostridium difficile infection in the community: a zoonotic disease?

Clostridium difficile infections (CDIs) are traditionally seen in elderly and hospitalized patients who have used antibiotic therapy. In the community, CDIs requiring a visit to a general practitioner are increasingly occurring among young and relatively healthy individuals without known predisposing factors. C. difficile is also found as a commensal or pathogen in the intestinal tracts of most mammals, and various birds and reptiles. In the environment, including soil and water, C. difficile may be ubiquitous; however, this is based on limited evidence. Food products such as (processed) meat, fish and vegetables can also contain C. difficile, but studies conducted in Europe report lower prevalence rates than in North America. Absolute counts of toxigenic C. difficile in the environment and food are low, however the exact infectious dose is unknown. To date, direct transmission of C. difficile from animals, food or the environment to humans has not been proven, although similar PCR ribotypes are found. We therefore believe that the overall epidemiology of human CDI is not driven by amplification in animals or other sources. As no outbreaks of CDI have been reported among humans in the community, host factors that increase vulnerability to CDI might be of more importance than increased exposure to C. difficile. Conversely, emerging C. difficile ribotype 078 is found in high numbers in piglets, calves, and their immediate environment. Although there is no direct evidence proving transmission to humans, circumstantial evidence points towards a zoonotic potential of this type. In future emerging PCR ribotypes, zoonotic potential needs to be considered.     

Diarrhoea in general practice: when should a Clostridium difficile infection be considered? Results of a nested case-control study

Clostridium difficile infections (CDIs) are frequent in hospitals, but also seem to increase in the community. Here, we aim to determine the incidence of CDI in general practice and to evaluate current testing algorithms for CDI. Three Dutch laboratories tested all unformed faeces (12 714) for C. difficile when diagnostic testing (for any enteric pathogen) was requested by a general practitioner (GP). Additionally, a nested case-control study was initiated, including 152 CDI patients and 304 age and sex-matched controls. Patients were compared using weighted multivariable logistic regression. One hundred and ninety-four samples (1.5%) were positive for C. difficile (incidence 0.67/10 000 patient years). This incidence was comparable to that of Salmonella spp. Compared with diarrhoeal controls, CDI was associated with more severe complaints, underlying diseases, antibiotic use and prior hospitalization. In our study, GPs requested a test for C. difficile in 7% of the stool samples, thereby detecting 40% of all CDIs. Dutch national recommendations advise testing for C. difficile when prior antibiotic use or hospitalization is present (18% of samples). If these recommendations were followed, 61% of all CDIs would have been detected. In conclusion, C. difficile is relatively frequent in general practice. Currently, testing for C. difficile is rare and only 40% of CDI in general practice is detected. Following recommendations that are based on traditional risk factors for CDI, would improve detection of CDI.     

Does a rapid diagnosis of Clostridium difficile infection impact on quality of patient management?

A rapid and accurate diagnosis of Clostridium difficile infection (CDI) is essential for patient management and implementation of infection control measures. During a prospective time-series study, we compared the impact of three different diagnostic strategies on patient care. Each strategy was tested during a 3-month period: P1 (diagnosis based on the stool cytotoxicity assay and the toxigenic culture), P2 (diagnosis based on PCR) and P3 (two-step algorithm based on glutamate dehydrogenase detection followed by nucleic acid amplification test). The following criteria were used to assess the quality of patient management: (i) time for result reporting, (ii) frequency of repeat testing within 7 days, (iii) time elapsed between stool collection and beginning of treatment for patients with CDI, and (iv) frequency of empirical treatment for patients without CDI. Of 1122 stool samples (P1 n = 359, P2 n = 374, P3 n = 389), 36 (10.0%), 47 (12.3%) and 48 (12.3%) were positive for C. difficile during P1, P2 and P3, respectively. The time for reporting of a positive or a negative result was significantly shorter and the frequency of redundant stool samples within 7 days was lower during P2 and P3 than during P1. Patients with CDI were specifically treated with vancomycin or metronidazole earlier during P2 and P3 than patients from P1 (0.5 ± 0.5 days and 1.0 ± 1.8 days vs. 2.0 ± 1.7 days). The empirical therapy among patients without CDI decreased from 13.6% during P1 to 6.4% during P2 and 5.6% during P3. A rapid CDI diagnosis impacts positively on patient care.     

Role of fecal Clostridium difficile load in discrepancies between toxin tests and PCR: is quantitation the next step in C. difficile testing?

Direct tests for Clostridium difficile are 30–50?% more sensitive than tests for C. difficile toxins but the reasons for this discrepancy are incompletely understood. In addition to toxin degradation and strain differences, we hypothesized that C. difficile concentration could be important in determining whether toxins are detected in fecal samples. We performed standard curves on an FDA-approved real-time PCR test for the C. difficile tcdB gene (Xpert C. difficile/Epi, Cepheid) during a prospective comparison of a toxin immunoassay (Meridian Premier), PCR and toxigenic culture. Immunoassay-negative, PCR-positive samples were retested with a cell cytotoxin assay (TechLab). Among 107 PCR-positive samples, 46 (43.0?%) had toxins detected by immunoassay and an additional 18 (16.8?%) had toxin detected by the cytotoxin assay yielding 64 (59.8?%) toxin-positive and 43 (40.2?%) toxin-negative samples. Overall, toxin-negative samples with C. difficile had 10¹–10⁴ fewer DNA copies than toxin-positive samples and most discrepancies between toxin tests and PCR were associated with a significant difference in C. difficile quantity. Of the toxin-positive samples, 95?% had ≥4.1 log₁₀ C. difficile tcdB DNA copies/mL; 52?% of immunoassay-negative samples and 70?% of immunoassay and cytotoxin negative samples had <4.1 log₁₀ C. difficile tcdB DNA copies/mL. These findings suggest that fecal C. difficile concentration is a major determinant of toxin detection and C. difficile quantitation may add to the diagnostic value of existing test methods. Future studies are needed to validate the utility of quantitation and determine the significance of low concentrations of C. difficile in the absence of detectable toxin.     

Bye-bye urinary gonadotrophins?: Risk of infection is not the main problem

The risk of infection from prion proteins in urinary preparationsof human gonadotrophins is uncertain—and is of lesserimportance than the risk of multiple pregnancies and issuesof cost.     

Reference assays for Clostridium difficile infection: one or two gold standards?

Accurate diagnosis of Clostridium difficile infection (CDI) is essential for optimal treatment, prevention and control. There are two reference assays for CDI diagnosis: the cell cytotoxicity assay (CCTA) and toxigenic culture (TC). Importantly, these tests actually detect different targets: CCTA detects the presence of C difficile toxins (primarily toxin B, but also toxin A), whereas TC detects the presence in the stool of C difficile with the potential to produce toxin. Not surprisingly studies comparing the results of these assays show imperfect agreement. Thus, a faecal sample may be CCTA negative but TC positive, and this raises the crucial question about the clinical significance of the presence of C difficile with the capacity to produce toxin but no actual detectable free toxin. A positive TC result indicates that a patient with diarrhoea is potentially infectious. TC also has the advantage that the cultured isolate is available for typing and for susceptibility testing. In general, however, CCTA has been shown to be a better test for the laboratory confirmation of CDI, although additional culture may be needed to optimise sensitivity. Crucially, when these reference assays are used to determine the accuracy of alternative diagnostic tests, care should be taken to compare methods with their appropriate standard (ie, compare tests that target equivalent end-points). Such issues have contributed to the variable and often suboptimal performance of rapid diagnostic tests for CDI. Further research is urgently needed to improve knowledge of the utility of routine diagnostic tests in CDI and the factors that influence their performance.     

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.     

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.

The cerebellum in the spatial problem solving: a co-star or a guest star?

The experimental findings reviewed here indicate that the cerebellum has to be added to the regions known to be involved in the spatial learning. Cerebellar function is specifically linked to `how to find an object' rather than `where the object is in the space'. In the Morris water maze (MWM) hemicerebellectomized (HCbed) rats displayed a severe impairment in coping with spatial information, displaying only peripheral circling. And yet, when the MWM cue phase was prolonged, HCbed rats succeeded in acquiring some abilities to learn platform position, even in a pure place paradigm, such as finding a hidden platform with the starting points sequentially changed. Conversely, whether the searching strategy was acquired preoperatively, no exploration deficit appeared. Thus, cerebellar lesions appear to affect the procedural components of spatial function, sparing the declarative ones. When intact animals were non-spatially pre-trained and then HCbed, they exhibited an expanded scanning strategy, underlining the cerebellar involvement in procedural component acquisition. By testing HCbed rats in an active avoidance task, first without and then with a request for right/left discrimination, lesioned rats displayed severe deficits. Thus, besides a marked impairment in facing procedural components of spatial processing, cerebellar lesion provokes deficits also in right/left discrimination task. In conclusion, it is possible to propose the cerebellum as one part of a large system that includes frontal, posterior parietal, inferior temporal cortices, hippocampus and basal ganglia. These structures form an allocentric spatial system and an egocentric control system, that interlock to process the information involved in representing an object in the space.     

Atopic disorders: a default pathway in the absence of infection?

Atopic disorders, such as asthma, are increasingly prevalent in the developed world. Recent epidemiological and experimental data suggest that some infectious diseases prevalent in the developing nations can inhibit the development of allergic disorders. Here, Klaus Erb reviews the data and presents a model showing how a steady decline of infectious diseases could account for an increase in atopic disorders.     

What Is the Current Role of Algorithmic Approaches for Diagnosis of Clostridium difficile Infection?

With the recognition of several serious outbreaks of Clostridium difficile infection in the industrialized world coupled with the development of new testing technologies for detection of this organism, there has been renewed interest in the laboratory diagnosis of C. difficile infection. Two factors seem to have driven much of this interest. First, the recognition that immunoassays for detection of C. difficile toxins A and B, for many years the most widely used tests for C. difficile infection diagnosis, were perhaps not as sensitive as previously believed at a time when attributed deaths to C. difficile infections were showing a remarkable rise. Second, the availability of FDA-approved commercial and laboratory-developed PCR assays which could detect toxigenic strains of C. difficile provided a novel and promising testing approach for diagnosing this infection. In this point-counterpoint on the laboratory diagnosis of C. difficile infection, we have asked two experts in C. difficile infection diagnosis, Ferric Fang, who has recently published two articles in the Journal of Clinical Microbiology advocating the use of PCR as a standalone test (see this author''s references 12 and 28), and Mark Wilcox, who played a key role in developing the IDSA/SHEA guidelines on Clostridium difficile infection (see Wilcox and Planche''s reference 1), along with his colleague, Tim Planche, to address the following question: what is the current role of algorithmic approaches to the diagnosis of C. difficile infection?     

Mediterranean spotted fever in north Dalmatia: is there a problem?

We analyzed clinical and therapeutic characteristics of Mediterranean spotted fever (MSF) in north Dalmatia. Analysis was conducted in 93 patients hospitalized with MSF at Zadar General Hospital during the 1988-2000 period. The most frequently found signs of the disease were high fever (91; 97.8%), maculopapular rash (89; 95.7%), headaches (84; 90.3%), arthralgia (75; 80.6%), exhaustion (75; 80.6%) and nausea (65; 69.9%). Tache noire, as a pathognomonic sign of MSF, was found in 22 (23.7%) patients. The most frequently indicated diagnoses were febris cum exanthemate (43; 46.2), rickettsiosis suspecta (21; 22.6%) and exanthema maculopapulosum (15; 16.1%). Early therapeutic efficiency was achieved by doxycycline in 34/43 (79.1%), and by ciprofloxacin in 10/14 (71.4%) treated adult patients, and by azithromycin in 7/9 (77.8%) children. The identification of MSF endemic rickettsiosis in north Dalmatia, serious clinical forms of the disease and the success of early and adequate anti-rickettsial antibiotic therapy are a clear warning that our physicians must be very familiar with this disease and include this rickettsial disease in differential diagnosis of acute febrile diseases accompanied by rash.     

Empirically supported treatments in pediatric psychology: where is the diversity?

OBJECTIVE: To examine the extent to which studies used to support empirically supported treatments for asthma, cancer, diabetes, and obesity address issues of cultural diversity. METHOD: We chose original articles (71) of treatments used to support empirically supported treatments (ESTs) published as part of a special series on ESTs in the Journal of Pediatric Psychology. Trained coders reviewed each study to determine if the following were reported: race/ethnicity and socioeconomic status (SES) of the sample, moderating cultural variables, cultural assumptions or biases of the treatment, larger cultural issues, and measurement or procedure bias. RESULTS: Results revealed that few studies addressed cultural variables in any way. Only 27% of the studies reported the race or ethnicity and 18% reported the SES of research participants. Additionally, 6% discussed potential moderating cultural variables. The remaining variables were addressed in 7% or less of the studies. CONCLUSIONS: These data support the criticism that ESTs fail to address important issues of culture and call into question the external validity of ESTs to diverse populations. Future research should explicitly address cultural issues according to the nine recommendations described here.     

The dysregulation of the endocannabinoid system in diabesity—a tricky problem

Endocannabinoids (ECs) are small lipid mediators that play a critical role in energy metabolism. Human studies have shown that the EC tone in peripheral tissues positively correlates with increased adiposity. Furthermore, pharmacological inhibition of EC signaling results in weight loss in humans. However, the mechanisms that cause the dysregulation of the EC system in obesity are not well-understood. Since the clinical utility of currently available EC blockers is severely limited due to their side effects like depression and suicidal ideation that are caused by central effects, it is important to delineate the role of central and peripheral effects of EC signaling in regulating glucose and lipid metabolism.