Diagnostic Approach and Management of Clostridioides difficile Infection

Clostridioides difficile infection (CDI) was first viewed as a nosocomial infection as it is associated with antibiotics administration. But since antibiotics are more frequently to be prescribed in the community setting, clinicians should investigate the probability of all antibiotics-associated diarrhea as CDI. Diagnostic of CDI should be conducted cautiously as the manifestation of CDI varies from asymptomatic to fatal consequences and is associated with morbidity, mortality, recurrence risk, outbreak possibility, and low quality of life. Management of this infection should include infection prevention and control, stopping the offending antibiotics, and administration of specific antimicrobials. Clinicians should also recognize the risk of recurrence and the higher probability of less efficacious specific antimicrobials in each episode of recurrence.


INTRODUCTION
Clostridioides difficile is a Gram-positive bacterium that has the potential to cause infection along the intestinal tract, with variability clinical symptoms, ranging from asymptomatic to fatal consequences.Due to its variable presentation, clinical approach to diagnose this condition should be done cautiously. 1 Clostridioides difficile infection (CDI) poses 2-sided health issues, as it causes a burden both on the individual aspect (regarding its morbidity, mortality, and its impact on quality of life) and on the community aspect (regarding the recurrence risk, outbreak possibility, and socioeconomic burden).][4][5] CDI was first viewed as a nosocomial infection as it first was found more prevalent in the hospital environment where antibiotics were frequently prescribed.But as the prescription of antibiotics became more deliberately used in the community, the paradigm where CDI was placed among nosocomial infections had to be shifted.Hensgens et al reported that CDI was predicted to cause 390-730 cases of diarrhea in the community annually in the Netherlands.While Bartlett et al reported that CDI was responsible as the third most cause of community diarrhea (causing about 30% of community diarrhea).In 2011, CDC predicted that CDI might cause about 29,000 cases of death.][4][5] This study was written to bring another perspective to better diagnose and manage CDI in the appropriate clinical setting.

Microbiological Aspect of Clostridioides difficile
Clostridioides difficile is a Gram-positive bacterium that can produce toxins, associated with colitis.The colonization of C. difficile is reported to be associated with antibiotics usage.The virulence factor of these obligate anaerobic bacteria was identified in 1935, determined by the production of its toxin: Clostridial toxin A (TcdA) and toxin B (TcdB).C. difficile is differentiated from other species based on its ability to decarboxylase parahydroxyphenylacetate acid, creating p-cresol, which enables C. difficile to produce porcine scent. 2,3. difficile is transmitted via oral-fecal route.The spore of these bacteria is formed as a dormant cell, highly resistant to environmental conditions, such as disinfectant and antimicrobial agents.Ingested spore then travels through the stomach into the duodenum.In the duodenum, spore develops due to exposure of primary bile acids, produced by liver, such as taurocholic.On the other hand, secondary bile acid, which is produced by intestinal bacteria, has a restrictive property against C. difficile growth.][3] The ability of the spore to grow and colonize the intestine is influenced by the imbalance and dysbiosis of gut microbiota and metabolomics of normal flora.The usage of antibiotics causes this dysbiosis, creating an environment suitable for C. difficile to grow.[3]

Pathological Aspect of Clostridioides difficile
The mechanism of host immune response to CDI is initiated by the production of antimicrobial compounds, such as lysozyme and cationic antimicrobial peptides.The further involvement of innate immune response is the production of proinflammatory cytokines and chemokines via nuclear factor κβ (NF-κβ) pathway and transcription factor AP-1.The affecter of innate immune response is triggered by C. difficile toxin, flagellin protein of the bacilli, surface protein (SlpA), and bacteria cell wall. 2,3he clinical manifestation of CDI is mainly influenced by the PaLoc locus containing the bacteria genomic profile.PaLoc is the pathogenic locus that encodes clostridial toxin, both TcdA and TcdB, along with 3 other proteins, associated with the regulation of production and secretion of that two-toxin homolog (TcdR, TcdE, and TcdC).The mechanism of these three proteins influencing the regulation of production and secretion of clostridial toxin has not yet been elucidated. 2,3,6hen TcdA and TcdB are secreted into the intestinal lumen, these two-homolog toxins will attach to the epithelial cells, inducing immune response to produce chemokine, proinflammatory cytokines, inflammatory cells migration, tight junction disruption, and epithelial cell death.Though TcdA and TcdB are homologs, TcdA is reported to be more potent in the small intestine, while the latter shows more potency in the colon segment. 2,3esides these two toxins, several strains of C. difficile can produce C. difficile transferase (CDT or binary toxin).Unlike the two former toxins, CDT is encoded by 2 genes, cdtA and cdtB, which are located in different loci.Although this binary toxin is reported to be associated with severe manifestation of CDI, the mechanism by which this toxin causes such impact has not been well understood.CDT is thought to be related to the disruption of actin cytoskeleton causing epithelial cell death, bacilli adherence, and C. difficile colonization. 2

Epidemiology of Clostridioides difficile Infection (CDI)
CDI was first viewed as a nosocomial infection as it is associated with antibiotics usage.But as antibiotics were more deliberately used in community settings, CDI was found more frequently in the community.A study in the US reported that the incidence of this infection reaches up to 120 cases per 100,000 population annually.In the Netherlands, the incidence was reported to reach 730 cases per 100,000 population annually.CDI was also reported to be the third most frequent cause of community diarrhea (causing 30% of diarrhea cases).This number of cases should be viewed as an iceberg phenomenon because CDI is likely to go underdiagnosed. 5,7,8lthough CDI is closely related to antibioticsassociated diarrhea, a prospective study reported that C. difficile caused about 30% of antibioticsassociated diarrhea cases.In addition to this bacillus, Staphylococcus aureus, Clostridioides perfringens, Clostridioides sordelli, and Klebsiella oxytoca were reported to be the pathogenic causes of antibioticsassociated diarrhea. 1,5,7,8

Clinical Manifestation of Clostridioides difficile Infection (CDI)
Clinical manifestation of CDI varies from selflimiting diarrhea, fulminant colitis, pseudomembranous colitis, toxic megacolon, bowel perforation, and sepsis with/without multiple organ dysfunction syndrome.Several risk factors reported to be associated with CDI were history of hospital admission, underlying bowel condition, elderly, and antibiotics administration.Every class of antibiotics should be suspected to cause CDI, but among them, clindamycin, cephalosporin, and quinolone were the most frequently reported antibiotics to be associated with.In addition to antibiotics class, dosage and duration administered were reported to influence the manifestation of CDI.This finding was supported by the observation that dysbiosis of gut microbiota could occur and sustain for more than 3 months after antibiotics treatment.Aside from antibiotics, proton pump inhibitors (PPI) were reported to be associated with CDI, though the mechanism was still under investigation. 1,2pecial attention is needed in the case where C. difficile causes asymptomatic colonization, as asymptomatic individuals are still able to transmit the clostridial spore into their environment.This asymptomatic colonization can be caused by both toxin-producing strains and negative toxin-producing strains.Asymptomatic colonization of non-toxigenic C. difficile was reported to be a protective factor against other C. difficile isolate infections.However, this finding has to be interpreted cautiously as nontoxigenic C. difficile strains can become toxigenic through horizontal gene transfer. 1,2,6

Diagnostic Approach to Clostridioides difficile Infection (CDI)
Diagnosis of CDI has to be built upon clinical manifestation and microbiological study.][11] Diagnostic tests detecting bacteria components are possible to indicate colonization, while tests detecting toxins are methods with a higher probability to assess CDI.Thus, diagnostic effort built solely upon microbiological study is deemed to be irrational and generally ends up in overdiagnosis and overtreatment. 2,8,10valuation of treatment using toxin studies is not recommended as toxins may remain detected during treatment, and sometimes until the patient has reached clinical cure.If the toxin is not detected from a stool sample, CDI is highly unlikely.However, if bacteria material is found in the stool sample while the toxin study is negative, CDI still cannot be excluded.Therefore, diagnosis of CDI must be built upon a 2-step algorithm, where toxin study and microbiological study have to be performed simultaneously. 3,11,12

Management of Clostridioides difficile Infection (CDI)
Management of CDI has to be initiated by infection prevention and control, which includes antibiotics stewardship, patient isolation, universal precautions, active disinfection, and education.Stopping offending antibiotics is the mainstay treatment of CDI.Antibiotics currently available to eliminate Clostridioides difficile are metronidazole, vancomycin, and fidaxomicin.Patients with mild to moderate symptoms of CDI may be treated with oral metronidazole, while oral vancomycin is necessitated by those with severe symptoms or those with complications.This choice of antibiotics is reported to be supported by clinical trials, which showed that metronidazole was inferior to vancomycin in intention to treat analysis (clinical cure rate 72.7% in those with metronidazole and 81.1% with vancomycin).][12][13] Aside from stopping offending antibiotics and administration of specific antimicrobials, pharmacological management in the setting of CDI should include stopping anti-motility and evaluation of PPI.In patients with ileus or toxic megacolon indication, where oral antibiotics cannot reach the site of infection, rectal vancomycin combined with intravenous metronidazole may be recognized. 7,11n fulminant CDI, surgical management by total abdominal colectomy may be recognized, especially when the patient is present with septic, severe organ dysfunction, acute abdomen, ileus, leukocytosis, and hyperlactatemia (> 5.0 mM). 3

Recurrence of Clostridioides difficile Infection (CDI)
Those with CDI are reported to be prone to relapse up to 15-25% in 8 weeks after the first episode.Those with the first and second recurrences of CDI face the risk of the third recurrence of up to 65%.This recurrence is reported to be associated with immune response dysregulation due to clostridial toxin and/ or dysbiosis of gut microbiota.The recurrence rate is reported to be lower in those treated with oral fidaxomicin (13%) compared to oral vancomycin (25%).Factors attributed to recurrence are age > 65 years old, concomitant antibiotics use, renal failure, history of CDI, antacid usage, and CDI severity. 2,3

Alternative Treatment of Clostridioides difficile Infection (CDI)
Probiotics administration was reported as the alternative therapy in treating recurrence CDI as CDI is caused by dysbiosis of gut microbiota, but clinical evidence supporting its prescription is still limited. 7,14nother alternative in the management of recurrent CDI is fecal microbiota transplantation (FMT), especially in the setting where the episode of CDI occurs more than twice, in which the efficacy of specific antibiotics drops below 30%.Van Nood et al reported that FMT was efficacious in treating CDI with multiple recurrences.British Society of Gastroenterology (BSG) recommended that FMT could be an optional treatment in patients with a history of at least two episodes of CDI. 2,7,14,15

CONCLUSION
Clinicians should shift their view about Clostridioides difficile infection as solely a nosocomial infection to antibiotics-associated diarrhea which can be found in the community setting.Therefore, diagnostic evaluation to confirm CDI in patients with antibiotics-associated diarrhea is important to avoid underdiagnosis and undertreatment.However, the diagnostic approach must be conducted cautiously as the implication of CDI affects not only individual aspects but also community aspects.Management should include infection prevention and control, stopping offending antibiotics, and administration of specific antimicrobial agents to achieve clinical cure and reduce the risk of recurrence.

Figure 1 .
Figure 1.Clinical approach to suspected CDI cases