Occurrence and trends of Clostridioides difficile infections in hospitalized patients: a prospective multi-centre cohort study in six German university hospitals, 2016-2020.

BACKGROUND: For Clostridioides difficile infections (CDIs) in Germany no longitudinal multi-centre studies with standardized protocols for diagnosing CDI are available. Recent evaluations of general surveillance databases in Germany indicate a downward trend in CDI rates. We aimed to describe the actual burden and trends of CDI in German university hospitals from 2016 to 2020. METHODS: Our study was a prospective multi-centre study covering six German university hospitals. We report the data in total, stratified by year, by medical specialty as well as by CDI severity. Multi-variable regression analyses were performed to assess risk factors for severe CDI. RESULTS: We registered 3780 CDI cases among 1,436,352 patients. The median length of stay (LOS) of CDI cases was 20 days (interquartile range 11-37) compared with a general LOS of 4.2 days. In-hospital all-cause mortality in CDI patients was 11.7% (N = 444/3780), while mortality attributed to CDI was 0.4% (N = 16/3761). CDI recurrence rate was comparatively low at 7.2%. The incidence density of severe healthcare-associated healthcare onset (HAHO)-CDI showed a significant decrease from 2.25/10,000 patient days (pd) in 2016 to 1.49/10,000 pd in 2020 (trend calculation P=0.032). CONCLUSIONS: Compared with a European point-prevalence study in 2013/2014, where overall CDI incidence density was 11.2 cases/10,000 pd in Germany (EUCLID), we see in our study halved overall CDI rates of 5.6 cases/10,000 pd in 2020. Our study shows current data on the distribution of CDI cases in German university hospitals and thus provides international comparative data on the key indicators of CDI.

PCR based detection of tcdCΔ117 in Clostridium difficile infection identifies patients at risk for recurrence - A hospital-based prospective observational study.

OBJECTIVES: Increasing incidence and severity of Clostridium difficile infection (CDI) in the last decades has been attributed to the emergence of hypervirulent C. difficile strain PCR-ribotype 027 (RT027). Commercial multiplex real-time PCR tests allow the presumptive identification of RT027 by detecting a single-base deletion at nt117 in the tcdC gene (tcdCΔ117). The clinical usefulness of the detection of tcdCΔ117 is unclear. Therefore, we evaluated test performance and clinical association of the detection of tcdCΔ117 in patients with CDI in a prospective observational study conducted in a tertiary care hospital in Germany. METHODS: From June to October 2015, stool from all patients with suspected CDI was tested for C. difficile according to ESCMID guidelines. C. difficile was cultured from positive samples and ribotyping was performed. Clinical data were collected prospectively from all C. difficile positive patients. RESULTS: From 1121 tested stool samples 107 patients with CDI were included in the study. TcdCΔ117 was detected in 18 (16.8%) of these patients. Multivariable logistic regression analysis revealed an independent association of detection of tcdCΔ117 with a further episode of CDI (OR 14.6; 95% CI 3.6-58.3; p < 0.001) and death within 30 days of the positive test (OR 5.1; 95% CI 1.0-25.7; p = 0.046). As follow up data are limited, it remains unclear, whether the further episode of CDI was due to tcdCΔ117 (recurrence) or another type. CONCLUSION: In our setting, PCR-based detection of tcdCΔ117 identified patients at risk for recurrent CDI and increased mortality and thus may guide therapeutic choices in CDI patients at the time of diagnosis.

Changes in Clostridium (Clostridioides) difficile PCR-Ribotype Distribution and Antimicrobial Resistance in a German Tertiary Care Hospital Over the Last 10 Years.

Clostridium (Clostridioides) difficile ribotype 027 (RT027) was detected in Germany for the first time in 2007 during an outbreak in the region of Trier, Rhineland-Palatinate and is today the most prevalent ribotype (RT) in Europe. We aimed to determine the changes in RT distribution and corresponding antimicrobial resistance in clinical C. difficile isolates between two time points (2007 and 2017) in one tertiary care hospital in Germany. C. difficile isolates recovered in 2007 and in 2017 (80 isolates per year, respectively) from patients at a Tertiary Care University Hospital in North-Rhine Westphalia were analyzed. Isolates were characterized by ribotyping and susceptibility testing using gradient tests (metronidazole, vancomycin) and the disk diffusion method (moxifloxacin). Between 2007 and 2017, a clear switch from RT001 [18.75% (n = 15) in 2007 versus 3.75% (n = 3) in 2017 P = 0.003] to RT027 [0% in 2007 versus 21.25% (n = 17) in 2017] was evident. While minimal inhibitory concentrations (MICs) of vancomycin were stable, a significant metronidazole MIC creep was determined (MIC50 = 0.047 in 2007 versus MIC50 = 0.094 in 2017, P < 0.0001 using the Man-Whitney test). We detected one metronidazole-resistant isolate (0.6%). Interestingly, in total we encountered more isolates resistant to moxifloxacin in 2007 (42 (52.25%) than in 2017 [(30 (37.5%), P = 0.06)]). We could demonstrate that RT027 replaced RT001 in the last 10 years in our hospital. Furthermore, our data show a metronidazole MIC creep in C. difficile isolates over the last 10 years and an unexpected decrease of isolates resistant to moxifloxacin.

Evaluation of the Use of Rectal Swabs for Laboratory Diagnosis of Clostridium difficile Infection.

For the diagnosis of Clostridium difficile infection (CDI), microbiological testing is almost always accomplished through the analysis of stool specimens. We evaluated the performances of rectal swabs with liquid transport medium (FS) and nylon flocked dry swabs for the detection of C. difficile Additionally, the impact on the diagnostic yield of storing swabs at -80°C for up to 3 months was evaluated. Sixty clinical stool samples positive for C. difficile by PCR were used for simulating rectal swabbing. FS and dry swabs were dipped into the stool and tested by PCR directly after swabbing at 1 and 3 months after storage at -80°C. Stool and the liquid medium of FS were additionally tested by a combination of glutamate dehydrogenase antigen (GDH) testing and toxin A/B enzyme immunoassay (EIA), as well as by toxigenic culture (TC). Using dry swabs, the PCR-based detection rate of C. difficile was equal to the rate using stool samples (30/30 [100%]), whereas the detection rate in FS was significantly lower (25/30 [83.2%]; P = 0.019). The sensitivities of FS for detecting C. difficile by PCR, TC, GDH testing, and toxin A/B EIA were 83.3%, 85.7%, 88%, and 68.9%, respectively. Storage of swabs at -80°C had no impact on the detection rate. FS cannot replace stool samples in the two-step laboratory diagnosis of CDI, as the sensitivities were too low, probably due to diluting effects of the fecal sample in the liquid medium. For simple PCR-based detection of C. difficile, dry swabs proved to be a suitable alternative to the use of stool samples.

Impact of choice, timing, sequence and combination of broad-spectrum antibiotics on the outcome of allogeneic haematopoietic stem cell transplantation.

Recent data link the incidence of intestinal GvHD (iGvHD) after allogeneic haematopoietic stem cell transplantation (aSCT) to exposure with piperacillin-tazobactam or imipenem-cilastatin. To assess relevance of timing, duration, sequence and combination of antibiotic treatment in this setting, we applied a time-dependent model to our aSCT cohort. Patients from the prospective Cologne Cohort of Neutropenic Patients (CoCoNut) undergoing aSCT from January 2007 to April 2013 were included into a time-dependent multivariate Cox proportional hazards regression model with backward-stepwise selection. In 399 eligible patients, cumulative antibiotic exposure (hazard ratio (HR) 2.46; 95% confidence interval (95% CI) 1.59-3.81; P<0.001) and exposure to sequential treatment with penicillin derivatives and carbapenems (HR 6.22, 95% CI 1.27-30.31), but not to the individual classes, were associated with iGvHD at day 100. Glycopeptides were assessed as a risk factor (HR 3.73, 95% CI 1.51-9.19), but not considered independent, since their use was dependent on previous exposure to penicillin derivatives and carbapenems. Patients with iGvHD presented with increased non-relapse mortality at day 365 (HR 3.51; 95% CI 2.10-5.89; P<0.001). We identified sequential exposure to penicillin derivatives and carbapenems as well as overall exposure to antibiotics as independent risk factors for iGVHD. Confirmation of these findings in larger, prospective cohorts is necessary.

Importance of pre-enrichment for detection of third-generation cephalosporin-resistant Enterobacteriaceae (3GCREB) from rectal swabs.

Screening for multidrug-resistant Enterobacteriaceae is performed in many institutions as part of infection control measures. However, the sensitivity of current standard diagnostics is modest. Furthermore, patients are usually screened by rectal swabs (mostly rayon based), which have been shown to be sub-optimal for the recovery of Enterobacteriaceae. Therefore, it is likely that many patients colonised with multidrug-resistant Enterobacteriaceae remain undetected. The present study aimed to analyse if the detection of multidrug-resistant Enterobacteriaceae can be improved when screening with rayon swabs is done in combination with an additional pre-enrichment step. The detection of third-generation cephalosporin-resistant Enterobacteriaceae (3GCREB) was assessed in 514 rectal samples by the standard diagnostic approach (direct plating of swabs on selective ESBL agar) and after pre-enrichment in 5 mL of a semi-selective MacConkey broth. The recovery rate of 3GCREB and extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E), patient characteristics and isolate characteristics were evaluated for both diagnostic approaches. Overall, by pre-enrichment, the detection of 3GCREB carriers increased by 22.8% (13/57, p = 0.004) and the detection of ESBL-E carriers by 21.4% (9/42, p = 0.01). This study demonstrates the low sensitivity of rectal screening by direct plating and the improvement by pre-enrichment. We believe that it is no longer acceptable to refrain from pre-enrichment as, with the standard approach, more than 20% of 3GCREB and ESBL-E carriers remain undetected.

Economic burden of Clostridium difficile associated diarrhoea: a cost-of-illness study from a German tertiary care hospital.

PURPOSE: Clostridium difficile associated diarrhoea (CDAD) is the most common cause of health-care-associated infectious diarrhoea. In the context of the German health-care system, direct and indirect costs of an initial episode of CDAD and of CDAD recurrence are currently unknown. METHODS: We defined CDAD as presence of diarrhoea (≥3 unformed stools/day) in association with detection of Clostridium difficile toxin in an unformed faecal sample. Patients treated with metronidazole (PO or IV) and/or vancomycin (PO) were included. Comprehensive data of patients were retrospectively documented into a database using the technology of the Cologne Cohort of Neutropenic Patients (CoCoNut). Patients with CDAD were matched to control patients in a 1:1 ratio. Analysis was split in three groups: incidence group (CDAD patients without recurrence), recurrence group (CDAD patients with ≥1 recurrence) and control group (matched non-CDAD patients). RESULTS: Between 02/2010 and 12/2011, 150 patients with CDAD (114 patients in the incidence and 36 (24 %) in the recurrence group) and 150 controls were analysed. Mean length of stay was: 32 (95 %CI: 30-37), 94 (95 %CI: 76-112) and 24 days (95 %CI: 22-27; P = <0.001), resulting in mean overall direct treatment costs per patient of €18,460 (95 %CI: €14,660-€22,270), €73,900 (95 %CI: €50,340-€97,460) and €14,530 (95 %CI: €11,730-€17,330; P = <0.001). In the incidence and recurrence group, the mean cumulative number of antibiotic CDAD treatment days was 11 (95 %CI: 10-12) and 36 (95 %CI: 27-45; P = <0.001). CONCLUSIONS: Especially CDAD recurrence was associated with excessive costs, which were mostly attributable to a significantly longer overall length of stay. Innovative treatment strategies are warranted to reduce treatment costs and prevent recurrence of CDAD.