Toxigenic Clostridium difficile carriage in general practice: results of a laboratory-based cohort study

ObjectivesReported rates of community-acquired Clostridium difficile infections (CDIs) have been increasing. However, the true burden of the disease in general practice is unknown in France. Our objective was to determine the incidence of toxigenic C. difficile carriage and the percentage of stool samples prescribed by general practitioners (GPs) which contained free C. difficile toxins.MethodsDuring an 11-month period, all stool samples submitted for any enteric pathogen detection to 15 different private laboratories in Paris and the surrounding areas were tested for C. difficile, irrespective of the GPs' request. A clinical questionnaire was completed for each patient. Stool samples were screened using a rapid simultaneous glutamate dehydrogenase and toxins A/B detection test: any positive result (glutamate dehydrogenase or toxin) was further confirmed by the stool cytotoxicity assay (CTA) on MRC-5 cells and by toxigenic culture (TC) at a central laboratory. The C. difficile isolates were characterized by PCR ribotyping.ResultsA total of 2541 patients (1295 female, 1246 male) were included. The incidences of patients with a positive toxigenic culture and a positive CTA were 3.27% (95% CI 2.61%–4.03%) and 1.81% (95% CI 1.33%–2.41%), respectively. GPs requested C. difficile testing in only 12.93% of the stool samples, detecting 52.30% of all TC-positive patients. The 83 toxigenic C. difficile strains belonged to 36 different PCR ribotypes.ConclusionsToxigenic C. difficile carriage is frequent in general practice but remains under-recognized. It may affect young patients without previous antimicrobial therapy or hospitalization.     

The efficacy of fidaxomicin in the treatment of Clostridium difficile infection in a real-world clinical setting: a Spanish multi-centre retrospective cohort

The objective of this study was to evaluate the efficacy and safety of fidaxomicin in the real-life clinical setting. This was a retrospective cohort of patients with Clostridium difficile infection (CDI) treated with fidaxomicin in 20 Spanish hospitals between July 2013 and July 2014. Clinical cure, 30-day recurrence, 30-day mortality, sustained cure, and factors associated with the failure to achieve sustained cure were analyzed. Of the 72 patients in the cohort 41 (56.9 %) had a fatal underlying disease. There were 44 (61.1 %) recurrent episodes and 26 cases (36.1 %) with a history of multiple recurrences. Most episodes were severe (26, 36 %) or severe-complicated (14, 19.4 %). Clinical cure rate was 90.3 %, recurrence rate was 16.7 % and three patients (4.2 %) died during the follow-up period. Sustained cure was achieved in 52 cases (72.2 %). Adverse events were reported in five cases (6.9 %). Factors associated with the lack of sustained cure were cardiovascular comorbidity (OR 11.4; 95 %CI 1.9–67.8), acute kidney failure (OR 7.4; 95 %CI 1.3–43.1), concomitant systemic antibiotic treatment (OR 6.2; 95 %CI 1.1–36.8), and C-reactive protein value at diagnosis (OR 1.2 for each 1 mg/dl increase; 95 %CI 1.03–1.3). Fidaxomicin is an effective and well tolerable treatment for severe CDI and for cases with elevated recurrence risk.     

Clinical features of Clostridium difficile infection and molecular characterization of the isolated strains in a cohort of Danish hospitalized patients

The purpose of this study was to compare clinical features of Clostridium difficile infection (CDI) to toxin gene profiles of the strains isolated from Danish hospitalized patients. C. difficile isolates were characterized by PCR based molecular typing methods including toxin gene profiling and analysis of deletions and truncating mutations in the toxin regulating gene tcdC. Clinical features were obtained by questionnaire. Thirty percent of the CDI cases were classified as community-acquired. Infection by C. difficile with genes encoding both toxin A, toxin B and the binary toxin was significantly associated with hospital-acquired/healthcare-associated CDI compared to community-acquired CDI. Significantly higher leukocyte counts and more severe clinical manifestations were observed in patients infected by C. difficile containing genes also encoding the binary toxin together with toxin A and B compared to patients infected by C. difficile harbouring only toxin A and B. In conclusion, infection by C. difficile harbouring genes encoding both toxin A, toxin B and the binary toxin were associated with hospital acquisition, higher leukocyte counts and severe clinical disease.     

Severe Clostridium difficile infections in intensive care units: Diverse clinical presentations

BackgroundClostridium difficile infections (CDIs) cause significant mortality and morbidity. Critically ill patients are susceptible to CDIs and tend to have severe CDIs, and their clinical presentations are not merely diarrhea.Materials and methodsFrom September 2017 to March 2018, the adults with CDIs in the ICUs were included. Fecal specimens with positive results of glutamate dehydrogenase assay were cultured for C. difficile, and toxinotyping and ribotyping for available C. difficile isolates were done. The CDI cases were categorized into the diarrheal group and ileus group. Difficult-to-treat cases with the presentations of life-threatening complications (bowel perforation or bacteremia), toxic megacolon, and refractory diarrhea, were analyzed.ResultsTotally 23 cases, including 6 cases of ileus and 17 of diarrhea, were included. Overall, the incidence of CDI in the ICUs was 10.7 cases per 10,000 patient-days. The ileus group tended to have more severe presentation, shorter ICU stay, higher ICU mortality, and receive initial intravenous metronidazole therapy. Severe and fulminant CDIs accounted for 65.2% (15 cases). The ICU mortality rate was 39.1%, but only one death was directly related to CDI (4.3%). Of nine (39.1%) difficult-to-treat cases, there was only one isolate of RT611 with tcdC deletion and cdtA/cdtB from a case with toxic megacolon. No hypervirulent isolates of RT027 or 078 were detected.ConclusionSevere CDIs in the ICU were not rare. Clinicians should be aware of abdominal symptoms and signs other than diarrhea, such as ileus, to make timely diagnosis and management of CDI.     

Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections

Asymptomatic Clostridium difficile colonization is common in hospitalized patients. Existing C. difficile assay comparisons lack data on severity of diarrhea or patient outcomes, limiting the ability to interpret their results in regard to the diagnosis of C. difficile infection (CDI). The objective of this study was to measure how including patient presentation with the C. difficile assay result impacted assay performance to diagnose CDI. Stool specimens from 150 patients that met inclusion and exclusion criteria were selected. Nine methods to detect C. difficile in stool were evaluated. All patients were interviewed prospectively to assess diarrhea severity. We then assessed how different reference standards, with and without the inclusion of patient presentation, impact the sensitivity, specificity, and positive and negative predictive values of the assays to diagnose CDI. There were minimal changes in sensitivity; however, specificity was significantly lower for the assays Tox A/B II, C. diff Chek-60, BD GeneOhm Cdiff, Xpert C. difficile, and Illumigene C. difficile and for toxigenic culture (P was <0.01 for all except Tox A/B II from fresh stool, for which the P value was 0.016) when the reference standard was recovery of toxigenic C. difficile from stool plus the presence of clinically significant diarrhea compared to when the reference standard was having at least four assays positive while ignoring diarrhea severity. There were 15 patients whose assay result was reported as negative but subsequently found to be positive by at least four assays in the comparison. None suffered from any CDI-related adverse events. In conclusion, clinical presentation is important when interpreting C. difficile diagnostic assays.     

Hemoglobinopathies in a general and family practice setting

The incidence of sickle cell trait varies among blacks in North America. Although the average hemoglobin (Hb)-AS gene frequency is 8% in the United States, a value of 13.4% was recorded in South Carolina. Preliminary studies during a two-day community sponsored health fair in Selma, Alabama, revealed a sickle cell gene frequency of 15.96%. This study also found an intermediate frequency of 12.4% in a family practice center that is accredited for a residency program. Through a screening program, sickle cell trait was detected, a rigorous training program for resident physicians in family practice was implemented, and proper counseling to patients with hemoglobinopathies was provided. In the authors' judgment, laboratory screening for sickle cell trait is a first step toward genetic counseling and medical practice by family physicians and general practitioners.     

The role of tigecycline in the management of Clostridium difficile infection: a retrospective cohort study

ObjectiveWe aimed to compare the outcomes of patients with C.difficile infection (CDI) treated either with tigecycline associated with vancomycin, or with vancomycin alone.MethodsThis single-centre retrospective cohort study included all adults hospitalized from September 2014 through August 2015 for symptomatic, incident CDI confirmed by polymerase chain reaction for C. difficile toxin in stools. The primary outcome was the rate of favourable outcome, defined as a composite of clinical response (resolution of symptoms without need for additional CDI therapy) and achieving discharge without CDI-related surgery or intensive care; a secondary outcome was CDI recurrence. We constructed a non-parsimonious logistic regression model to calculate a propensity score (PS) for those receiving tigecycline.ResultsIn all, 266 patients were included: 62 patients received both vancomycin and tigecycline, and 204 patients received vancomycin alone. The patients from the two groups were similar regarding demographics and comorbidities but patients in the tigecycline group had a more severe CDI. A favourable outcome in the tigecycline group versus the vancomycin group was found in 50/62 (81%) versus 193/204 (95%). We matched patients receiving tigecycline or not according to the PS and 86 patients (43 pairs) could be matched. The OR for favourable outcome with tigecycline in the matched analysis was 0.92 (95% CI 0.60–1.44; p 0.74). The rate of CDI recurrences was 8/62 (13%) in the tigecycline group versus 39/204 (19%) in the vancomycin group (p 0.2).ConclusionAdding tigecycline to CDI standard therapy did not increase the clinical cure nor reduce the rate of CDI recurrences.     

Quantification of Clostridium difficile in antibiotic-associated-diarrhea patients

Comparing culture- and non-culture-based methods for quantifying Clostridium difficile in antibiotic-associated-diarrhea patients, we found that the real-time PCR method correlated well with quantitative culture and was more sensitive. A positive association between the population levels of C. difficile and the presence of its toxins was found.     

Correlation of immunoblot type, enterotoxin production, and cytotoxin production with clinical manifestations of Clostridium difficile infection in a cohort of hospitalized patients.

To determine whether strain-specific differences in immunoblot type, enterotoxin production, or cytotoxin production correlated with clinical presentation of Clostridium difficile infection, we evaluated isolates obtained from 428 prospectively studied hospitalized patients. Of 99 isolates available for immunoblot typing, 61 were recovered from asymptomatic carriers and 38 were from patients with C. difficile-associated diarrhea. Of 17 immunoblot types, the seven types comprising the majority of isolates (82 of 99; 83%) were variably associated with disease. Neither the presence of cytotoxin in the stool nor the production of cytotoxin or enterotoxin by isolates in vitro was significantly different for symptomatic versus asymptomatic patients. Selected host factors were more predictive of symptomatic disease than was the specific infecting C. difficile strain. These results suggest that variations in the clinical severity of C. difficile infection in different patients are not solely strain-specific phenomena related to immunoblot type or to the production of cytotoxin or enterotoxin.     

The incidence and management of female breast disease in a general practice

A retrospective study is reported of 180 women with breast symptoms consulting at a group practice during a 27-month period. The management policies of the general practitioners are discussed in the light of the observed short-term outcomes and of proposals to introduce screening clinics for breast cancer.     

Comparison of anticoagulant control among patients attending general practice and a hospital anticoagulant clinic.

Management of patients receiving oral anticoagulant therapy was assessed in general practice and a dedicated hospital anticoagulant clinic. The demographic characteristics of patients in both groups were similar, as were the indications for anticoagulation therapy and the duration of treatment. General practice patients were reviewed significantly more frequently, with a median interval of 16 days compared with 42 days for hospital patients (P < 0.001). Twenty four per cent of general practice visits and 26% of hospital attendances resulted in an alteration to the warfarin dosage. Overall, 52% of general practice thrombotest results lay within the ranges recommended by the British Society for Haematology, compared with 45% of hospital results (P < 0.001). There was no difference in the rate of complications in general practice and the hospital clinic. In this study, the anticoagulant control achieved in a general practice setting was superior to that in a dedicated hospital outpatient clinic, although control was far from ideal in either setting.     

Invitation to attend a health check in a general practice setting: the views of a cohort of non-attenders

Two hundred and fifty-nine men and women aged 20-45 years who did not respond to an offer from their general practitioner for a health check were interviewed at home to explore the reasons for non-response. There was no support for the view that the invitation aroused anxiety or that the administrative arrangements had been a barrier to acceptance. Many subjects were not really interested (44%) or just forgot to attend (24%). Crises at work or home (26%) and current attendance at a doctor (16%) were other reasons offered, while 11% felt screening to be in appropriate. There is little that can be done to change these rates except by a shift of public opinion to more consumer demand for health checks or by more opportunistic health checks when people attend their doctors for other reasons. The dangers of marketing health checks to increase consumer demand are discussed in the light of these findings and other work.     

Urinary tract infections in adult general practice patients.

Urinary tract infections (UTIs) are symptomatic infections of the urinary tract, mainly caused by the bacterium Escherichia coli. One in two women suffers from a UTI at least once in her life. The young and sexually active are particulaly affected, but it is also seen in elderly, postmenopausal women. The likelihood of recurrence is high. Diagnosis is made with regard to typical complaints and the presence of leucocytes and nitrites in the urine. A culture is unnecessary in most cases. Uncomplicated UTI should be distinguished from complicated UTI, which has a risk of severe illness. The treatment of choice--short-term therapy with trimethoprim or nitrofurantoin--is successful in over 80% of the cases. Co-trimoxazol fluoroquinolones or cephalsporins are not considered first-choice drugs. There are indications that general practitioners' (GPs') management of UTI is not always optimal, specifically concerning diagnostic tests, the application of second-choice antibiotics, and the length of prescribed treatment courses. Many points relevant to GPs requirefurther research, such as epidemiology and resistance of urinary pathogens in the community and natural history of UTI, as well as optimal management in elderly or complicated patients and men.     

Epidemiology and clinical characteristics of Clostridium difficile infection in a Korean tertiary hospital

In order to investigate the incidence, clinical and microbiologic characteristics of Clostridium difficile infection (CDI) in Korea, a prospective observational study was performed. From September 2008 through January 2010, all patients whose stool was tested for toxin assay A&B and/or C. difficile culture were studied for clinical characteristics. Toxin types of the isolates from stool were tested. The mean incidence of CDI per 100,000 patient-days was 71.6 by month (range, 52.5-114.0), and the ratio of CDI to antibiotic-associated diarrhea was 0.23. Among 200 CDI patients, 37.5% (75/200) was severe CDI based on severity score. Clinical outcome of 189 CDI was as followed; 25.9% (49/189) improved without treatment, 84.3% (118/140) achieved clinical cure and attributed mortality was 0.7% (1/140) with the treatment. Recurrence rate was 21.4% (30/140) and cure without recurrence was 66.4% (93/140). The most common type of toxin was toxin A-positive/toxin B-positive strain (77.5%), toxin A-negative/toxin B-positive strains or binary toxin-producing strains comprised 15.4% or 7.1%, respectively. In conclusion, the incidence of CDI in Korea is a little higher than other reports during the non-epidemic setting. We expect that the change of epidemiology and clinical severity in CDI can be evaluated based on these results.     

Epidemiology, risk factors and prevention of Clostridium difficile nosocomial infections

Clostridium difficile is responsible for 10-25% of cases of antibiotic-associated diarrhea (AAD) and for virtually all cases of antibiotic-associated pseudo-membranous colitis (PMC). This anaerobic spore-forming bacterium has been identified as the leading cause of nosocomial infectious diarrhea in adults. Pathogenesis relies on a disruption of the normal bacterial flora of the colon, a colonization by C. difficile and the release of toxins A and B that cause mucosal damage and inflammation. Incidence of C. difficile intestinal disorders usually varies from one to 40 per thousand patient admissions. Risk factors for C. difficile-associated diarrhea include antimicrobial therapy, older age (> 65 years), antineoplastic chemotherapy, and length of hospital stay. Nosocomial transmission of C. difficile via oro-fecal route occurs in 3-30% of total patient admissions but it remains asymptomatic in more than 66% of cases. Persistent environmental contamination and carrying of the organism on the hands of hospital staff are common. Measures that are effective in reducing cross-infection consist of an accurate and rapid diagnosis, an appropriate treatment, an implementation of enteric precautions for symptomatic patients, a reinforcement of hand-washing and a daily environmental disinfection. C. difficile is a common cause of infectious diarrhea and should be therefore systematically investigated in patients with nosocomial diarrhea.     

Lack of association between clinical outcome of Clostridium difficile infections, strain type, and virulence-associated phenotypes

Clostridium difficile strain NAP1/027 (North American pulsed-field gel electrophoresis [PFGE] type 1 and PCR ribotype 027 [R027]) has been associated with recent outbreaks in North America and Europe. It has been associated with more severe disease symptoms, higher mortality rates, and greater risk of relapse. This strain is thought to produce more toxins and sporulate to higher levels. However, recent studies suggest that this may not always be the case. The objective of our study was to assess, in a nonoutbreak situation, whether specific strains, such as NAP1/027, were associated with more severe disease symptoms, higher toxin production, and/or greater sporulation in vitro. We isolated and characterized C. difficile strains from 21 patients with mild to moderate, severe, or complicated symptoms of C. difficile infection (CDI). The isolates were characterized by different molecular typing methods, including PCR ribotyping, tandem repeat sequence typing (TRST), and sequencing of the tcdC gene. Fourteen isolates were of PCR ribotype 027 with deletions in tcdC, but no association with severity or clinical outcome was found. We show by immunodot blot detection of toxins with monoclonal antibodies that all R027 isolates produced more TcdA and TcdB than other strains. On the other hand, they consistently produced fewer spores than non-R027 isolates. Taken together, our data suggest that NAP1/027 isolates are not always associated with more severe disease, even though they may produce larger amounts of toxins. Our study also suggests that current assertions regarding the NAP1/027 may not apply to all isolates and that other factors may come into play.     

Evaluation of a loop-mediated isothermal amplification assay for diagnosis of Clostridium difficile infections

A new assay (illumigene C. difficile; Meridian Bioscience), based on the original loop-mediated isothermal amplification (LAMP) assay, was evaluated with 472 unformed stools from patients suspected of Clostridium difficile infection. Compared to the toxigenic culture, the sensitivity, specificity, and positive and negative predictive values were 91.8, 99.1, 91.8, and 99.1% for the illumigene C. difficile assay and 69.4, 100, 100, and 96.6% for the cytotoxicity assay, respectively.