Special Issue "Clostridium difficile Infection: Unmet Needs and Unsolved Questions"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Epidemiology & Public Health".

Deadline for manuscript submissions: 31 May 2021.

Special Issue Editor

Dr. Nicola Petrosillo
Website
Guest Editor
Clinical and Research Department for Infectious Diseases, Unit Systemic and Immunedepression-Associated Infections, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy
Interests: healthcare associated infections; multidrug resistant organisms; antimicrobial stewardship; infection prevention and control; emerging infectious diseases; Clostridioides difficile infection

Special Issue Information

Dear Colleagues,

The current picture of Clostridioides difficile infection (CDI) is alarming with a recurrence rate ranging from 12% to 40% and a not negligible mortality rate, i.e., between 3% and 15%. Despite the great efforts made over the past 10 years to face the CDI burden, there are still grey areas in our knowledge on CDI management.

Major issues affecting the management of CDI include the high rate of CDI underdiagnosis, the unacceptably high rate of CDI recurrence, and the difficulties faced in reducing the spread of CD among hospitalized patients.

The underdiagnosis of CDI is a recognized issue, either because of suboptimal laboratory diagnostic methods or because of absence of clinical suspicion. There are unsolved questions, such as why the rate of underdiagnosis differs among countries and among hospitals in the same countries, and there is a need to elucidate the reasons for its high rate. In this regard, community-acquired CDI are increasingly represented in the literature, but in “real life”, they are poorly studied, and their underdiagnosis has been hypothesized.

A further critical issue in the management of CD regards the high recurrence rate observed with the currently available CDI therapy. Importantly, in the last few years, many advances in the field of pathogenesis of CDI and on the role of intestinal microbiota have been made, and new strategies for the treatment and prevention of CDI are being studied.

Undeniably, more efforts are needed in order to reduce the spread of CDI, especially among hospitalized patients. Asymptomatic CD carriers might represent a “submerged iceberg” that significantly contributes to the CD hospital spread. Understanding the role asymptomatic carriers play in perpetuating CD transmission in healthcare settings as well as defining the usefulness of contact isolation for them is crucial but also particularly challenging to examine.

Dr. Nicola Petrosillo
Guest Editor

Manuscript Submission Information

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Published Papers (10 papers)

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Editorial

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Open AccessEditorial
Clostridioides difficile Infection: A Room for Multifaceted Interventions
J. Clin. Med. 2020, 9(12), 4114; https://doi.org/10.3390/jcm9124114 - 20 Dec 2020
Abstract
Clostridioides difficile (CD) continues to be the number one health care-associated infectious pathogen in the United States [...] Full article
(This article belongs to the Special Issue Clostridium difficile Infection: Unmet Needs and Unsolved Questions)

Research

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Open AccessArticle
The Relative Role of Toxins A and B in the Virulence of Clotridioides difficile
J. Clin. Med. 2021, 10(1), 96; https://doi.org/10.3390/jcm10010096 - 30 Dec 2020
Abstract
Most pathogenic strains of C. difficile possess two large molecular weight single unit toxins with four similar functional domains. The toxins disrupt the actin cytoskeleton of intestinal epithelial cells leading to loss of tight junctions, which ultimately manifests as diarrhea in the host. [...] Read more.
Most pathogenic strains of C. difficile possess two large molecular weight single unit toxins with four similar functional domains. The toxins disrupt the actin cytoskeleton of intestinal epithelial cells leading to loss of tight junctions, which ultimately manifests as diarrhea in the host. While initial studies of purified toxins in animal models pointed to toxin A (TcdA) as the main virulence factor, animal studies using isogenic mutants demonstrated that toxin B (TcdB) alone was sufficient to cause disease. In addition, the natural occurrence of TcdA−/TcdB+ (TcdA−/B+)mutant strains was shown to be responsible for cases of C. difficile infection (CDI) with symptoms identical to CDI caused by fully toxigenic (A+/B+) strains. Identification of these cases was delayed during the period when clinical laboratories were using immunoassays that only detected TcdA (toxA EIA). Our hospital laboratory at the time performed culture as well as toxA EIA on patient stool samples. A total of 1.6% (23/1436) of all clinical isolates recovered over a 2.5-year period were TcdA−/B+ variants, the majority of which belonged to the restriction endonuclease analysis (REA) group CF and toxinotype VIII. Despite reports of serious disease due to TcdA−/B+ CF strains, these infections were typically mild, often not requiring specific treatment. While TcdB alone may be sufficient to cause disease, clinical evidence suggests that both toxins have a role in disease. Full article
(This article belongs to the Special Issue Clostridium difficile Infection: Unmet Needs and Unsolved Questions)
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Open AccessArticle
Real-World Experience with Bezlotoxumab for Prevention of Recurrence of Clostridioides difficile Infection
J. Clin. Med. 2021, 10(1), 2; https://doi.org/10.3390/jcm10010002 - 22 Dec 2020
Abstract
Bezlotoxumab is marketed for the prevention of recurrent Clostridioides difficile infection (rCDI). Its high cost could be determining its prescription to a different population than that represented in clinical trials. The objective of the study was to verify the effectiveness and safety of [...] Read more.
Bezlotoxumab is marketed for the prevention of recurrent Clostridioides difficile infection (rCDI). Its high cost could be determining its prescription to a different population than that represented in clinical trials. The objective of the study was to verify the effectiveness and safety of bezlotoxumab in preventing rCDI and to investigate factors related to bezlotoxumab failure in the real world. A retrospective, multicentre cohort study of patients treated with bezlotoxumab in Spain was conducted. We compared the characteristics of cohort patients with those of patients treated with bezlotoxumab in the pivotal MODIFY trials. We assessed recurrence rates 12 weeks after completion of treatment against C. difficile, and we analysed the factors associated with bezlotoxumab failure. Ninety-one patients were included in the study. The cohort presented with more risk factors for rCDI than the patients included in the MODIFY trials. Thirteen (14.2%) developed rCDI at 12 weeks of follow-up, and rCDI rates were numerically higher in patients with two or more previous episodes (25%) than in those who had fewer than two previous episodes of C. difficile infection (CDI) (10.4%); p = 0.09. There were no adverse effects attributable to bezlotoxumab. Despite being used in a more compromised population than that represented in clinical trials, we confirm the effectiveness of bezlotoxumab for the prevention of rCDI. Full article
(This article belongs to the Special Issue Clostridium difficile Infection: Unmet Needs and Unsolved Questions)
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Open AccessArticle
Characterization of Clostridioides difficile Strains, the Disease Severity, and the Microbial Changes They Induce
J. Clin. Med. 2020, 9(12), 4099; https://doi.org/10.3390/jcm9124099 - 18 Dec 2020
Abstract
Background: Clostridioides difficile infection (CDI) is a major nosocomial disease. The characteristics of different strains, the disease severity they cause, their susceptibility to antibiotics, and the changes they inflict on gut microbiome, have not been comprehensively studied in Israel. Methods: A severity score [...] Read more.
Background: Clostridioides difficile infection (CDI) is a major nosocomial disease. The characteristics of different strains, the disease severity they cause, their susceptibility to antibiotics, and the changes they inflict on gut microbiome, have not been comprehensively studied in Israel. Methods: A severity score was calculated for 70 patients. Stool samples were tested for toxins presence using a special kit. Bacteria were isolated, identified by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) and antibiotic susceptibility tests were performed for several antibiotics. Strains were classified by Multi-locus sequence typing (MLST), and changes in gut microbiome were tested. Results: ST04 (22.5%) and ST37 (12.7%) were the most frequent strains. Clade (phylogenetic lineage) 1 was the most (81.4%) prevalent. We found significant associations between ST and age (p = 0.024) and between ST and moxifloxacin susceptibility (p = 0.001). At the clade level, we found significant associations with binary toxin gene occurrence (p = 0.002), and with susceptibility to both metronidazole and vancomycin (p = 0.024, 0.035, respectively). Differences in intestine microbiome were affected by age, clades’ distribution and STs. Conclusions: By defining the characteristics of the different strains and clades, clinicians can choose medical interventions based on the predicted response or disease severity associated with each strain, enabling new advances in the field of personalized medicine. Full article
(This article belongs to the Special Issue Clostridium difficile Infection: Unmet Needs and Unsolved Questions)
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Open AccessArticle
The Burden of Clostridioides Difficile Infection during the COVID-19 Pandemic: A Retrospective Case-Control Study in Italian Hospitals (CloVid)
J. Clin. Med. 2020, 9(12), 3855; https://doi.org/10.3390/jcm9123855 - 27 Nov 2020
Cited by 1
Abstract
Data on the burden of Clostridioides difficile infection (CDI) in Coronavirus Disease 2019 (COVID-19) patients are scant. We conducted an observational, retrospective, multicenter, 1:3 case (COVID-19 patients with CDI)-control (COVID-19 patients without CDI) study in Italy to assess incidence and outcomes, and to [...] Read more.
Data on the burden of Clostridioides difficile infection (CDI) in Coronavirus Disease 2019 (COVID-19) patients are scant. We conducted an observational, retrospective, multicenter, 1:3 case (COVID-19 patients with CDI)-control (COVID-19 patients without CDI) study in Italy to assess incidence and outcomes, and to identify risk factors for CDI in COVID-19 patients. From February through July 2020, 8402 COVID-19 patients were admitted to eight Italian hospitals; 38 CDI cases were identified, including 32 hospital-onset-CDI (HO-CDI) and 6 community-onset, healthcare-associated-CDI (CO-HCA-CDI). HO-CDI incidence was 4.4 × 10,000 patient-days. The percentage of cases recovering without complications at discharge (i.e., pressure ulcers, chronic heart decompensation) was lower than among controls (p = 0.01); in-hospital stays was longer among cases, 35.0 versus 19.4 days (p = 0.0007). The presence of a previous hospitalisation (p = 0.001), previous steroid administration (p = 0.008) and the administration of antibiotics during the stay (p = 0.004) were risk factors associated with CDI. In conclusions, CDI complicates COVID-19, mainly in patients with co-morbidities and previous healthcare exposures. Its association with antibiotic usage and hospital acquired bacterial infections should lead to strengthen antimicrobial stewardship programmes and infection prevention and control activities. Full article
(This article belongs to the Special Issue Clostridium difficile Infection: Unmet Needs and Unsolved Questions)
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Open AccessArticle
An Outbreak of Clostridium (Clostridioides) difficile Infections within an Acute and Long-Term Care Wards Due to Moxifloxacin-Resistant PCR Ribotype 176 Genotyped as PCR Ribotype 027 by a Commercial Assay
J. Clin. Med. 2020, 9(11), 3738; https://doi.org/10.3390/jcm9113738 - 20 Nov 2020
Abstract
We aimed to characterize Clostridioides difficile isolates cultured during a six-month single-center study from stool samples of patients with C. difficile infection (CDI) genotyped by the Xpert®C. difficile/Epi assay by polymerase chain reaction (PCR) ribotyping, toxin genes’ detection and multi-locus [...] Read more.
We aimed to characterize Clostridioides difficile isolates cultured during a six-month single-center study from stool samples of patients with C. difficile infection (CDI) genotyped by the Xpert®C. difficile/Epi assay by polymerase chain reaction (PCR) ribotyping, toxin genes’ detection and multi-locus variable number tandem repeats analysis (MLVA). The susceptibility to metronidazole, vancomycin and moxifloxacin was determined by agar dilution. In addition, the presence of Thr82Ile in the GyrA and a single nucleotide deletion at position (Δ117) in the tcdC gene were investigated. Between January 1 and June 30, 2016, of 114 CDIs, 75 cases were genotyped as presumptive PCR ribotype (RT) 027 infections using a commercial assay. C. difficile isolates cultured from presumptive RT027 stool samples belonged to RT176. These isolates carried genes for toxin A (tcdA), B (tcdB), binary (cdtA/B) and had Δ117 in the tcdC gene. Using MLVA, the 71/75 isolates clustered into two clonal complexes (CCs). Of these, 39 isolates (54.9%) were from patients hospitalized in acute care and 32 isolates (45.1%) were isolated from patients hospitalized in the long-term care department. All isolates were susceptible to metronidazole and vancomycin, and 105 isolates were resistant to moxifloxacin (92%) carrying Thr83Ile in the GyrA. An outbreak of RT176 CDIs, suspected as RT027, was recognized in a Slovakian hospital. In order to monitor the emergence and spread of RT027-variants, the identification of a presumptive RT027 CDI should be confirmed at a strain level by PCR ribotyping. Full article
(This article belongs to the Special Issue Clostridium difficile Infection: Unmet Needs and Unsolved Questions)
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Open AccessArticle
Characterization of Non-Toxigenic Clostridioides difficile Strains Isolated from Preterm Neonates and In Vivo Study of Their Protective Effect
J. Clin. Med. 2020, 9(11), 3650; https://doi.org/10.3390/jcm9113650 - 13 Nov 2020
Abstract
In a previous monocentric study in preterm neonates (PN), we described a high Clostridioides difficile colonization rate (74%) with two uncommon non-toxigenic strains (NTCD) belonging to PCR-ribotype (RT) (CE)847 and (CE)032. To determine the extent of carriage of both NTCD in other spatio-temporal [...] Read more.
In a previous monocentric study in preterm neonates (PN), we described a high Clostridioides difficile colonization rate (74%) with two uncommon non-toxigenic strains (NTCD) belonging to PCR-ribotype (RT) (CE)847 and (CE)032. To determine the extent of carriage of both NTCD in other spatio-temporal settings, strains isolated in PN stools from two multicenter cohorts were characterized by PCR-ribotyping, MLVA and MLST. We also evaluated the protective role of two NTCD from these RT against C. difficile infection in a hamster caecitis model. Animals were administered either each NTCD alone (n = 7), or followed by a 027 strain (n = 9). A control group received only the 027 strain (n = 8). Clinical activity and colonization by C. difficile in stools were monitored daily until death or sacrifice at D20. We isolated 18 RT(CE)032 (ST-83) strains and 2 RT(CE)847 (ST-26) strains among 247 PN from both cohorts. Within each RT, strains were genetically related. The survival rate was significantly increased when animals received a RT(CE)847 or (CE)032 strain before the 027 strain (4/9 deaths, p = 0.029; 1/9 death, p = 0.0004, respectively). We describe two predominant uncommon NTCD strains, in a PN population from different healthcare facilities. Both NTCD provide a potential protection against C. difficile infection. Full article
(This article belongs to the Special Issue Clostridium difficile Infection: Unmet Needs and Unsolved Questions)
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Open AccessArticle
Enhanced Humoral Immune Responses against Toxin A and B of Clostridium difficile is Associated with a Milder Disease Manifestation
J. Clin. Med. 2020, 9(10), 3241; https://doi.org/10.3390/jcm9103241 - 10 Oct 2020
Abstract
The role of the humoral immune response to Clostridium difficile in modulating the severity of C. difficile infection (CDI) is unclear. We compared the levels of serum immunoglobulin G (IgG) and immunoglobulin A (IgA) against toxin A (TcdA) and toxin B (TcdB) of [...] Read more.
The role of the humoral immune response to Clostridium difficile in modulating the severity of C. difficile infection (CDI) is unclear. We compared the levels of serum immunoglobulin G (IgG) and immunoglobulin A (IgA) against toxin A (TcdA) and toxin B (TcdB) of C. difficile between CDI and control patients and according to disease severity. The levels of IgG and IgA antibodies against TcdA and TcdB were measured in sera from patients with CDI (n = 50; 19 had severe CDI) and control patients (n = 52), using ELISA. Patients with CDI had higher levels of IgG antibodies against TcdA and TcdB than controls (p = 0.001 and p = 0.04, respectively). Higher IgG levels against TcdA and TcdB were found in patients with mild vs. severe CDI 7–14 days after the diagnosis (p = 0.004 and 0.036, respectively). A factor analysis included both IgA and IgG levels against both toxins into one composite variable, which was of higher values in patients with mild vs. severe CDI (p = 0.026). In conclusion, the systemic humoral immune responses against TcdA and TcdB might modulate the severity of CDI. These preliminary findings provide a basis for future large-scale studies and support the development and evaluation of active and passive immunotherapies for CDI management. Full article
(This article belongs to the Special Issue Clostridium difficile Infection: Unmet Needs and Unsolved Questions)
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Review

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Open AccessReview
Clostridioides difficile Infection, Still a Long Way to Go
J. Clin. Med. 2021, 10(3), 389; https://doi.org/10.3390/jcm10030389 - 20 Jan 2021
Abstract
Clostridioides difficile is an increasingly common pathogen both within and outside the hospital and is responsible for a large clinical spectrum from asymptomatic carriage to complicated infection associated with a high mortality. While diagnostic methods have considerably progressed over the years, the optimal [...] Read more.
Clostridioides difficile is an increasingly common pathogen both within and outside the hospital and is responsible for a large clinical spectrum from asymptomatic carriage to complicated infection associated with a high mortality. While diagnostic methods have considerably progressed over the years, the optimal diagnostic algorithm is still debated and there is no single diagnostic test that can be used as a standalone test. More importantly, the heterogeneity in diagnostic practices between centers along with the lack of robust surveillance systems in all countries and an important degree of underdiagnosis due to lack of clinical suspicion in the community, hinder a more accurate evaluation of the burden of disease. Our improved understanding of the physiopathology of CDI has allowed some significant progress in the treatment of CDI, including a broader use of fidaxomicine, the use of fecal microbiota transplantation for multiples recurrences and newer approaches including antibodies, vaccines and new molecules, already developed or in the pipeline. However, the management of CDI recurrences and severe infections remain challenging and the main question remains: how to best target these often expensive treatments to the right population. In this review we discuss current diagnostic approaches, treatment and potential prevention strategies, with a special focus on recent advances in the field as well as areas of uncertainty and unmet needs and how to address them. Full article
(This article belongs to the Special Issue Clostridium difficile Infection: Unmet Needs and Unsolved Questions)
Open AccessReview
Clostridioides difficile Infection in Chronic Kidney Disease—An Overview for Clinicians
J. Clin. Med. 2021, 10(2), 196; https://doi.org/10.3390/jcm10020196 - 07 Jan 2021
Abstract
Increased incidence of Clostridioides difficile infection (CDI), occurrence of severe and complicated CDI, and more frequent occurrence of drug-resistant, recurrent or non-hospital CDI has become a worldwide clinical problem. CDI is more common in patients with chronic kidney disease (CKD) than in the [...] Read more.
Increased incidence of Clostridioides difficile infection (CDI), occurrence of severe and complicated CDI, and more frequent occurrence of drug-resistant, recurrent or non-hospital CDI has become a worldwide clinical problem. CDI is more common in patients with chronic kidney disease (CKD) than in the general population. CDI seems to be associated with frequent hospitalization, frequently used antibiotic therapy, dysbiosis, and abnormalities of the immune system observed in CKD patients. Dysbiosis is a common disorder found in CKD patients. It may be related to insufficient fiber content in the diet, reduced amount of consumed fluids and often reduced physical activity, constipation, impaired gastrointestinal motility, multidrug pharmacotherapy, and uremic milieu in CKD stage 5. In patients with CKD the clinical manifestations of CDI are similar to the general population; however, more frequent recurrence of CDI and higher prevalence of severe CDI are reported. Moreover, the increase in CDI related mortality is observed more in CKD patients than in the general population. The aim of this review paper is to summarize the current knowledge concerning the epidemiology, pathogenesis, clinical picture, and prevention and treatment in CKD patients. Full article
(This article belongs to the Special Issue Clostridium difficile Infection: Unmet Needs and Unsolved Questions)
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