Clostridium difficile

Clostridium difficile ; a group of spore forming, toxin forming, gram positive anerobel is implicated in hospital associated diarrhea and is the causative agent of infectious diarrhea. It is the most common hospital associated infection in Europe and North America, and is presumed to be as prevalent in the rest of the world.There has been emergence of new virulent strain of C. difficile, identified as BI, NAP1, and toxinotype III and ribotype 027 (subsequently known as BI/NAP1/027) by various typing method in recent years, implicated in dramatic increase in C. difficile infections.Diagnosis is established by presence of C. difficile toxin or C. difficile toxin gene in stool. Lab testing does not distinguish C. difficile infection and asymptomatic carriage. Clinical suspicion and positive stool study confirms a diagnosis.Clostridium Difficile infection, is most common health care associated infection in Europe and North America, and the available studies show it may have similar prevalence in Nepal. Literature review does not reveal any significant study being conducted in Nepal as of now. It warrants further study to exactly determine the incidence/prevalence and its impact in current health care in Nepal. Clinicians need increased awareness and prompt diagnosis to reduce morbidity and further prevention of transmission.Nepalese Medical Journal, vol.1, No. 1, 2018, page: 43-47

Clostridium difficile is group of spore forming, toxin forming, gram positive anerobe that is implicated in hospital associated diarrhea and is the causative agent of infectious diarrhea in hospitalized patients.2][3] A meta analytical study from 2017 suggest, the prevalence of Clostridium difficile infection in Asia to be similar to Europe and North America implicating immediate need of proper clinical and microbiological diagnosis and treatment to further reduce morbidity and mortality.Here we discuss a general idea about the pathogen, risk factors, transmissions, prevention, and current recommendations for treatment. 4

MICROBIOLOGY, PATHOGENESIS AND EPIDEMIOLOGY
It is an anerobic gram positive bacillus, first described in 1935 in intestine of healthy newborn. 1 It exists in spore forms in an adverse environment and in vegetative form in colonic environment.The spores are resistant to heat, acid, and antibiotics and was found abundant on hospital surfaces (bedding, telephones), on the hands and stethoscopes of health care workers. 5Clostridium Difficile is transmitted by feco-oral route. 6The organism is non-invasive and colonizes the large intestine.Host intestinal microorganism prevents colonization.The loss of intestinal microorganism with exposure to antibiotics, along with presence of virulent strain and poor host immune response leads to clinical expression of the disease.The organism releases two different types of exotoxins (TcdA and Tcd B), which subsequently inhibits Rho

INTRODUCTION
family of guanosine triphosphatases (GTPases), causing death of colonocyte, leading to loss of intestinal barrier and neutrophilic colitis. 7ere has been emergence of new virulent strain of C. difficile, identified as BI, NAP1, and toxinotype III and ribotype 027 (subsequently known as BI/NAP1/027) by various typing method in recent years, implicated in dramatic increase in C. difficile infections. 8This particular strain is characterized by effective spore formation, high toxin production, higher mortality rate, and resistance to fluoroquinolones.This strain is presumed to have a global reach and is found in diverse hospital settings. 9 difficile infection rate in Asia is similar to the rates reported from Europe and North America.Infections from the hypervirulent strain (BI/NAP1/027) were, however, rare as per that study.C.difficile infection related mortality was 8.9% in Asia. 4 Community acquired C. difficile infection is defined as disease in an individual who has not stayed overnight in a health care facility within 12 weeks before infection.Disease tends to be of less severity, but the recurrence rates are similar compared to hospital acquired infection.It tends to occur mostly in younger individual and the pathogenesis is not clearly defined as they have not had exposure to antibiotics or have other risk factors.10

RISK FACTORS
The most important risk factor is antibiotic use which disrupts fecal microbiota.Other risk factors are advanced age, severe illness, and hospitalizations. 11Earliest cases were attributed to use of Clindamycin.However, with widespread use of penicillin and fluoroquinolone, it has been associated with use of almost all antibiotics.Some of the antibiotic (e.g., metronidazole) can both incite the disease and provide effective treatment. 13der age (>65 years) has higher risk of contracting the illness.
Prevalence is >10 times as high as younger population, for some uncertain etiology.This is presumed to be related to poor host immune response. 13e associations between uses of acid suppressive medications/ proton pump inhibitors and C. difficile infection remains uncertain.The spores of C. difficile, which are vector of infection, are resistant to acid. 14,15[18]

Clinical manifestations
Non severe illness: watery diarrhea is the cardinal symptom.Other associated symptoms are lower abdominal pain/cramps, low grade fever, nausea and vomiting.Stool may contain mucus and blood, but frank hematochezia is rare. 19Unexplained leukocytosis in hospitalized patient could be related to C. difficile infections. 20evere Clostridium Difficile infection: Described as white blood cell count of >15,000 cells/ml or serum creatinine >1.5 mg/dl.It is associated with hypovolemia, lactic acidosis, fever, sepsis, abdominal distension.Fulminant colitis may present with severe hypotension with multi-organ failure.It can present with ileus and toxic megacolon. 21,22

Laboratory evaluation
Diagnosis is established by presence of C. difficile toxin or C. difficile toxin gene in stool.Lab testing does not distinguish C. difficile infection and asymptomatic carriage.Clinical suspicion and positive stool study confirms a diagnosis. 23,24 udomembranes can also be seen on radiographic and colonoscopic evaluations.Endoscopic evaluation is not recommended in routine evaluation.It is performed to rule out other underlying pathology.Not all patients with C. difficile infection will have pseudomembranes.Presence of pseudomembranes does not confirm a diagnosis of C. difficile infection. 25 difficile is currently diagnosed by either enzyme linked immunoassay (EIA) for glutamate dehydrogenase antigen and toxins A and B or by nucleic acid amplification tests (NAATs).23,24 Enzyme linked immunoassay for GDH: GDH is produced by C. difficile isolates and this test has good sensitivity.However, it cannot distinguish between toxigenic and nontoxigenic strains.26 Enzyme linked immunoassay for toxins A and B: It has relatively high false negative rate, as the organism does not always produce toxin.28 It has high specificity of 99%, but is 75% sensitive. 27 Nueic acid amplification tests (NAATs): DNA based tests, includes polymerase chain reaction.It has very high sensitivity and specificity.Some DNA-based tests also detect BI/NAP1/027 strain.It detects toxigenic strains, but is only recommended to be tested on unformed strain, as it cannot distinguish asymptomatic carriage of toxin producing C. difficile strain.23,24 Anaerobic culture and cell culture cytotoxic assay: They are resource intensive and time consuming.Culture followed by strain testing for toxin is the Gold Standard for diagnosis if C. difficile.29 Fecal leukocyte testing is not helpful in testing for C. difficile infection. 30

PREVENTION
As Clostridium difficile is abundant in health care facilities.Prevention of initial occurrence: Limited use of antibiotic, prevention of spread of infection in health care facility with proper infection control measures, and use of probiotics.Clostridium difficile spores are resistant to alcohol based hand sanitizers.Limit transmission between patients by keeping patient in an isolated room.Health care professionals should wear proper gown and gloves and wash hands with soap and water.Use of probiotic has shown mixed results in prevention of C. difficile infection. 31,32econdary prevention; prevention of recurrence: Concomitant use of enteral vancomycin in patient with history of Clostridium difficile infection may help reduce the rate of recurrence.Administration of nontoxigenic C. difficile strain was associated with lower risk of recurrence some studies. 34zlotoxumab, a human monoclonal antibody against C. difficile toxin B, was associated with substantially lower rate of recurrent infection among participants receiving antibiotic treatment for primary or recurrent C. difficile infection.However, Actoxumab, a monoclonal antibody against C. difficile toxin A, did not improve efficacy. 35

TREATMENT
It is mostly based on type of illness, which is broadly categorized into 3: Non severe CDI: WBC <15,000 cells/cumm and serum creatinine <1.5 mg /dl Severe CDI: WBC >15,000 cells/cumm or serum creatinine -1.5 mg/dl Fulminant colitis: Presence of hypotension, shock or megacolon Non severe CDI: Oral metronidazole, vancomycin or fidaxomicin have been recommended to use in non severe illness.
Other antibiotics that have activity against C. difficile are rifaximin, nitazoxanide, ramoplanin, teicoplanin, and tigecycline. 36,37cal microbial transplantation: Antibiotic use can cause rapid decline in fecal microbiota and may take up to 12 weeks or longer to recover.The human colonic microbiota is the barrier that prevents Clostridium difficile colonization and infection.Fecal microbial transplantation, initially reported in 1958, is emerging modality of treatment in cases of recurrent C. difficile infections.[41] Immunizations C. difficile toxoid vaccines are in developmental phase.Vaccination against the toxins of C. difficile offers the possibility of an effective approach for prevention.Small studies have shown some promising results.

CONCLUSIONS
Clostridium Difficile infection, is most common health care associated infection in Europe and North America, and the available studies show it may have similar prevalence in Nepal.Literature review does not reveal any significant study being conducted in Nepal as of now.It warrants further study to exactly determine the incidence/prevalence and its impact in current health care in Nepal.Clinicians need increased awareness and prompt diagnosis to reduce morbidity and further prevention of transmission.

Definition Treatment Non Severe initial episode
Vancomycin 125 mg 4 times daily, by mouth, for 10 days, OR Fidaxomicin 200 mg, 2 times daily, by mouth, for 10 days Alternative, if above agents are not available, then Metronidazole 500 mg 3 times daily by mouth for 10 days First recurrence Vancomycin 125 mg 4 times daily, by mouth, for 10 days if Metronidazole was used in initial episode, OR Tapered and Pulsed regimen of vancomycin if standard regimen was used initially, OR Fidaxomicin 200 mg, 2 times daily, by mouth, for 10 days if vancomycin was used in initial phase.Second or Subsequent recurrence Vancomycin in tapered or pulsed regimen , OR Vancomycin 100 mg 4 times daily, by mouth, for 10 days followed by Rifaximin 400 mg 3 times daily, by mouth, for 20 days, OR Fidaxomicin 200 mg 2 times daily, by mouth, for 10 days, OR Fecal microbiota transplantation Adapted from: McDonald LC, Gerding DN, Johnson S, et al.Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).https://academic.oup.com/cid/article/66/7/e1/4855916