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Clostridioides difficile (formerly Clostridium difficile) is a Gram-positive, spore-forming anaerobic bacterium that is widely distributed in the intestine of humans and animals and in the environment (Nyc et al. 2015; Janezic et al. 2016; Lawson et al. 2016). Its spores are usually found in the human or animal intestine as part of the microbiome (Czepiel et al. 2019), but some strains of C. difficile are capable of producing toxins (toxin A, toxin B, and binary toxin) that damage the intestinal mucosa and cause diarrhea. This ability is more important when there is an imbalance in the intestinal microbiota caused by previous antibiotic treatment (Smits et al. 2016; Czepiel et al. 2019). A reduction in microbiome complexity creates space for C. difficile to proliferate. Since 2000, hospital strains of C. difficile are common hyperproducers of toxins (ribotypes 027, 176, and 001) (Persson et al. 2011). These strains often colonize elderly polymorbid patients, complicating their primary diagnosis and causing life-threatening infections (Beneš et al. 2012).
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Whole-genome sequencing and ribotyping in the Czech Republic is preferably carried out by university hospitals (quaternary medical facility). Tertiary health care facilities, such as Liberec Regional Hospital, had few resources (personnel, financial, and instrumentation) for molecular epidemiology (ribotyping and whole-genome sequencing). This was changed by the SARS-CoV-2 pandemic, which caused a significant development of regional PCR laboratories. The majority of regional laboratories are now able to analyze C. difficile strains in more detail. In our study, we use ribotyping to detect outbreaks of CDI in Liberec Regional Hospital.
PCR toxinotyping revealed that 43 (44.8%) strains carried the genes for toxins A and B (tcdA and tcdB) only, 33 (34.4%) strains carried the genes for both major toxins and the binary toxin (tcdA, tcdB, cdtA, and cdtB), and only 2 (2.1%) strains only carried the genes for toxin B and the binary toxin (tcdB, cdtA, and cdtB). Fourteen (14.6%) strains were non-toxigenic, and in 4 (4.2%) cases, toxinotyping failed or the presence of C. difficile was not confirmed. Based on PCR confirmation, the incidence of CDI in Liberec Regional Hospital was 4.2 cases per 10 000 patient-bed days.
The incidence of C. difficile infections in the Liberec Regional Hospital in 2017 and 2018 ranged from 5.5 to 4.2 cases per 10,000 patient-bed days. Both incidence rates correspond to the CDI incidence in the Czech Republic (6.1 to 4.5 cases per 10,000 patient-bed days) (Krutova et al. 2016) and in Europe (4.1 to 3.98 cases per 10,000 patient-bed days) (Bauer et al. 2011).
Since publication of the 2017 Clinical Practice Guidelines for Clostridioides (formerly Clostridium) difficile infection (CDI) , new relevant evidence has emerged for treatment options in the management of CDI in adults. The previous guidelines included pediatric treatment recommendations, but the scope of this focused update is restricted to adults and includes new data for fidaxomicin and for bezlotoxumab, a monoclonal antibody targeting toxin B produced by C. difficile. Both of these agents have increased clinical efficacy and other advantages over older agents, but implementation may be challenging because of initial monetary cost and logistics. In addition, the shift towards more sensitive diagnostic strategies emphasizes the importance of selecting appropriate patient populations and establishing the correct diagnosis when considering the use of these agents. While additional data have been published for other treatment entities, the quality of the data was determined not sufficient to alter our current treatment recommendations. New estimates on the burden of CDI have also been reported by the Centers for Disease Control and Prevention . While the adjusted estimate for total CDI burden nationally decreased by 24% from the previous report, they still estimated 462 100 cases annually and the burden of first CDI recurrences was unchanged. Recurrent CDI remains one of the most important treatment challenges for clinicians, with estimates of 31 300 and 38 500 recurrences for community-associated and healthcare-associated cases, respectively, in 2017 .
Clostridioides difficile infection (CDI) is associated with high recurrence rates impacting health-related quality of life (HrQOL). However, patient-reported data are lacking particularly in the outpatient setting. We assessed changes in HrQOL over time in patients treated with bezlotoxumab at US infusion centers and determined clinical factors associated with HrQOL changes.
The C. difficile quality of life survey (Cdiff32) was developed to quantify disease-specific changes to HrQOL in patients with CDI . This survey consists of 32 questions, including three domains and five sub-domains, designed to assess CDI-related changes to the physical, mental, and social status of CDI patients. During the development and validation of Cdiff32, the authors determined that the anxiety sub-domain, which is part of the mental domain, was significantly different in patients with primary CDI compared to patients with recurrent CDI (rCDI) . The 2017 Clinical Practice Guidelines for CDI published by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) have recognized patient-reported outcomes as an important endpoint in clinical research . However, no disease-specific changes to HrQOL over time in patients with CDI have been reported. We used an adapted Cdiff32 instrument to assess HrQOL over time in patients who received bezlotoxumab for prevention of rCDI in outpatient infusion centers. Previously, we reported the use of bezlotoxumab in infusion centers, which provided an opportunity to investigate HrQOL in patients with confirmed CDI .
Clostridioides (Clostridium) difficile is an important pathogen of healthcare- associated diarrhea, however, an increase in the occurrence of C. difficile infection (CDI) outside hospital settings has been reported. The accumulation of antimicrobial resistance in C. difficile can increase the risk of CDI development and/or its spread. The limited number of antimicrobials for the treatment of CDI is matter of some concern.
We searched five bibliographic databases: (MEDLINE [PubMed], Scopus, Embase, Cochrane Library and Web of Science) for studies that focused on antimicrobial susceptibility testing in C. difficile and were published between 1992 and 2019. The weighted pooled resistance (WPR) for each antimicrobial agent was calculated using a random- effects model.
Resistance to metronidazole, vancomycin, fidaxomicin, meropenem and piperacillin/tazobactam is reported rarely. From the alternative CDI drug treatments, tigecycline had a lower resistance rate than rifampin. The high-risk antimicrobials for CDI development showed a high level of resistance, the highest was seen in the second generation of fluoroquinolones and clindamycin; amoxicillin/clavulanate showed almost no resistance. Tetracycline resistance was present in one fifth of human clinical C. difficile isolates.
Clostridium difficile, recently reclassified as Clostridioides difficile , is an important pathogen of healthcare-associated diarrhea . Recently, however, an increase in the occurrence of CDI outside hospital settings has been reported [3, 4].
Previous antibiotic use was recognized as one of the risk factors for developing CDI through an alteration of gut microbiota. The accumulation of antimicrobial resistance mechanisms may provide an advantage to C. difficile as it is not affected by antimicrobials present in the gut .
In addition to humans, C. difficile has been cultured from livestock, food and the environment . Tetracycline is one of the most commonly used antimicrobials in agriculture providing antimicrobial selective pressure in this sphere. This is supported by observations of a high prevalence of the tetracycline resistance gene tetM in livestock-associated C. difficile ribotype 078 isolates . Moreover, the zoonotic transmission of C. difficile between farm animals and humans has been demonstrated .
Carbapenems are antimicrobials used for the treatment of infections caused by multidrug-resistant gram-negative pathogens. However, some carbapenem resistance mechanisms are transferable to other bacterial species . Hence, the monitoring of carbapenem resistance in C. difficile is justified.
We aimed to review the data on the resistance of antimicrobials to C. difficile that have been recommended for CDI treatment; alternative drugs for CDI treatment; high-risk antimicrobials associated with CDI development; agriculture-related antimicrobials; and antimicrobials reserved for the treatment of multidrug pathogens.
All selected studies were reviewed by three authors independently: Ebrahim Kouhsari, Behnam Ahmadzadeh and Abbas Maleki. Studies were excluded if they met the following conditions: (1) C. difficile antibiotic resistance was not presented; (2) resistance rates were not clearly reported; (3) no human clinical C. difficile strain was tested; (4) it was a meta-analysis and systematic review or a review article or not an original research article; (5) a duplicated report using the same database; (6) a conference abstract and article without the full text upon request from the author; (7) less than 5 isolates were tested. Any discrepancies and inconsistencies with the selection of an article were resolved through discussion, and a fourth author (Nourkhoda Sadeghifard) acted as arbiter.
The information extracted from each included study was: (1) author; (2) publication year; (3) study period; (4) number of C. difficile isolates; (5) antimicrobial susceptibility methods; (6) interpretation of resistance; (7) resistance rates (Supplementary Data 1). 041b061a72