Clostridioides difficile Infection

Introduction

Many infections have emerged with increased virulence in the recent years. Clostridioides difficile (formerly Clostridium difficile) infection causes disease in presence of exposure to antibiotics either during or after treatment. It results in antibioticassociated diarrhoea, antibiotic-associated colitis and pseudo-membranous colitis. The infection occurs due to the disturbance of normal intestinal flora.

History

Antibiotic-associated colitis occurs as an off-shoot of use of antibiotics and is noted specially in surgical patients. A prospective study carried out by Tedesco and his colleagues in 1974 on 200 consecutive patients receiving clindamycin showed occurrence of diarrhoea in 41 patients. Twenty (10%) of them who received clindamycin exhibited pseudo-membranous colitis.¹ Three years later, Bartlett and colleagues found antibiotic-associated pseudo-membranous colitis to be due to toxin-producing Clostridium.² Since then, C. difficile has been the most commonly recognized microbial cause of nosocomial diarrhoea.

Aetiology

Clostridium difficile is a gram-positive, anaerobic, sporeforming bacillus. It may be part of the normal intestinal microbiota in healthy babies. Transmission occurs via the oral-faecal route. It spreads in hospitalized patients who have been exposed to antimicrobial agents and to an environment contaminated by C. difficile spores. It happens to be the only anaerobe posing such a threat by producing toxin in the colon.

There is an increase in incidence of C. difficile associated disease in US, Canada and Europe in the recent years due to emergence of an epidemic strain with increased virulence, antibiotic resistance or both. A nationwide-Swedish study revealed an increased mortality after the age of 60 years in C. difficile associated diarrhoea.³ The risk factors were age over 65 years and receipt of fluroquinolones in the cases reported from Quebec, Canada.⁴ There were many deaths from C. difficile-associated disease in Pittsburgh, US. It was noted following fluoroquinolone use and it required colectomy in many cases.⁵ The increase appears to be due to emergence of a new strain of C. difficile. In 187 C. difficile isolates collected from eight outbreaks at US health care facilities occurring between 2000 and 2003, a previously uncommon strain of C. difficile with variations in toxin genes that has been more resistant to fluoroquinolones was encountered.⁶ The strain belonged to toxinotype III and was positive for binary toxin.

Loo et al., in another microbial analysis with C. difficile associated enteritis in 1703 patients at 12 hospitals in the year 2004 in Quebec, Canada noted most strains to be resistant to fluoroquinolones and most of them had a binary toxin.⁷ There was a very high incidence and mortality associated with increasing age. These data have proved that more virulent strains of C. difficile are responsible for epidemics in selected locations. They are responsible for more severe disease, often associated with complications necessitating colectomy, and death.

Indian scenario

The first report on C. difficile came from New Delhi in 1985 where the organism was isolated from 25% of patients with diarrhoea.⁸ In a prospective study on 156 patients and 54 healthy controls, Dhawan and co-workers assessed the incidence of C. difficile associated diarrhoea (CDAD) in an Indian hospital and found average disease incidence to be 15% proving that CDAD is an emerging problem in Indian hospitals.⁹

Clostridium difficile has been recognized as an important nosocomial enteric pathogen and has been considered to be an important cause for antibiotic-associated diarrhoea. In a study carried out in Puducherry, the prevalence was found to be 4% and the toxin positive cases were in the age range between 50 and 60 years.¹⁰

In a cross-sectional study in Delhi, of 791 patients with nosocomial diarrhoea, CDAD was diagnosed in 48 (6%) patients. Malignancy was underlying pathologic condition in 15 (31%) patients and the most common antibiotic taken was third generation cephalosporin in 27 (56.7%) patients.¹¹

Vaishnavi and co-workers found the incidence of C. difficile infection in 17% patients of all age groups in Punjab. Fever (41%) and abdominal pain (37.9%) were the predominant features.¹² Justin and colleagues in coastal Karnataka in a prospective study in paediatric age group found the incidence of C. difficile infection in 10.9% of patients.¹³ Fever was presenting complaint in 40% of patients. Kaneria and Paul in a prospective study in Tamil Nadu found occurrence of C. difficile infection in 10% of all age groups tested by ELISA. 40% patients exhibited leucocytosis.¹⁴ Ingle and colleagues in a prospective study in Mumbai found the incidence of C. difficile infection in 17% of all age groups tested by ELISA and fever (47%) and abdominal pain (41%) were the predominant features.¹⁵ Verma and Makharia have shown that there is a wide prevalence of C. difficile infection (CDI) ranging from 7 to 30% among patients with diarrhoea.¹⁶

Of 145 stool samples of patients with diarrhoea, C. difficile was found in 37% in Mysuru. It was nosocomial in 66% of cases and in remaining, it was community acquired.¹⁷ Chakraborty and colleagues found CDI prevalence of 19.8% among patients with antibioticassociated diarrhoea in Kolkata.¹⁸

In a study conducted in Puducherry involving 75 patients with hospital-acquired diarrhoea, 18.67% were positive for toxigenic Clostridioides difficile and 4% patients were positive for nontoxigenic C. difficile. Addition of GeneXpert yielded toxin detection in 5/14 patients. The risk factors included prolonged hospital stay, especially in intensive care unit, diabetes mellitus and exposure to antibiotics such as carbapenems and glycopeptides.¹⁹

Pathogenesis

C. difficile is usually hospital-acquired. The infection gets established when antibiotic therapy disrupts the normal colonic bacterial flora. The condition can develop in debilitated patients who have not received antibiotic therapy. Only about 3% of healthy adults and up to 20-40% of elderly persons may carry C. difficile and remain asymptomatic carriers.²⁰ In healthy persons, the organism remains in a metabolically inactive spore form and its colonization is not ordinarily harmful. The disturbance in the intestinal flora by the antibiotic or surgical interference facilitates its conversion to vegetative forms that replicate and produce toxins.

Exposure to antibiotics is the chief precipitant of C. difficile-associated diseases. Though any antibiotic with an antibacterial spectrum can result in severe intestinal disorder, the most commonly implicated antibiotics are clindamycin, cephalosporins and fluoroquinolones.^2,4 The virulence of the organisms is due to the two exotoxins (A and B) that are cytotoxic and inflammatory. They are encoded by the genes tcdA and tcdB.²¹ These toxins bind to the intestinal epithelial cells and get internalized and disrupts the cells significantly by uridine 5’-diphosphate glucose dependent glucosylation of Rho proteins.²² A binary toxin elaborated by C. difficile encoded by two chromosomal genes cdtA and cdtB mediate cell-surface binding and disrupt the assembly of actin-filaments and results in cell death.²³ However, it is intriguing how some persons carry them without any clinical manifestations.

Pathology

The infection is associated with focal areas of inflammation and ulceration. In fulminant cases, the ulcers are covered by a creamy-white adherent pseudomembrane comprising polymorphs, fibrin and debris. The bowel wall gets thickened. There can be toxic megacolon and perforation.

Clinical features

The infection commonly develops in elderly patients often ailing with other diseases. These patients exhibit symptoms in the first week of receiving antibiotics. However, the development of the condition may be delayed up to six weeks. The therapy would have been stopped by the time the manifestation becomes apparent.

The manifestations begin insidiously. The patients exhibit lower abdominal pain, fever and frequent passage of profuse, watery stools. Often there are cramps. There can be ileus, toxic dilatation of colon and perforation. Some may remain as asymptomatic carriers.

In mild-to-moderate infection of C. difficile, there will be watery diarrhoea 3 to 5 times a day and mild abdominal cramps and tenderness. Severe infection with C. difficile is associated with severe inflammation of colon. There will be watery diarrhoea 10 to 15 times a day, severe abdominal pain and cramps, fever, nausea, anorexia, headache, presence of blood or pus in the stool, tachycardia and dehydration.

Diagnosis

Colitis must be suspected in any patient receiving antibiotics or has received antibiotics recently, when present with diarrhoea. There is leucocytosis and hypoalbuminaemia. Radiologic imaging of abdomen may reveal dilated small intestine and colon without any free air. Sigmoidoscopy reveals erythema of the rectum and colon, ulceration and presence of white plaques or an adherent pseudo-membrane. Biopsy of the area must be used for histopathologic study. C. difficile organisms may be isolated in stool culture. The positivity is higher in those exhibiting pseudo-membranous colitis compared to those having antibiotic-associated diarrhoea. Cell cytotoxin assay helps in isolation of toxins A and B.

Management

The administration of the offending antibiotic should be stopped immediately following development of diarrhoea. The patient must be isolated. The hydration of the patient has to be maintained by administration of intravenous fluids.

The patients who are severely ill, and exhibit ileus, colonic dilatation or pseudo-membranous colitis need antibiotic therapy. The patients must receive them orally. Metronidazole 400 mg should be given orally for ten days. Metronidazole may be administered intravenously. If the response is not satisfactory, vancomycin 125 mg, six-hourly should be given for ten days. These agents control the manifestations after 2-3 days and they may be repeated if there is recurrence of the manifestations. 20,000 units of Bacitracin orally and 300 mg of Fusidic acid orally every 6 hours are the other drugs that can be utilized in the management for a week. Fulminant cases are treated with intravenous immunoglobulin, and some cases may require colectomy.

An international panel of experts from the World Society of Emergency Surgery (WSES) has updated the guidelines in 2019 for the management of CDI in surgical patients.²⁴ According to the guidelines, there should be discontinuation of unnecessary antimicrobial agents and they should be discontinued if CDI is suspected. In case the treatment of primary infection needs antibiotics, it is advised to use those antibiotics which are less frequently implicated with CDI such as parenteral aminoglycosides, macrolides, vancomycin or tetracycline.

Oral metronidazole in a dose of 500 mg thrice a day for 10 days, is the drug of choice for the initial episode of mild and moderate CDI. Vancomycin in a dose of 125 mg four times a day for 10 days is advised for those who do not respond to metronidazole. A combination of metronidazole and vancomycin can be given. For severe cases, vancomycin appears better than metronidazole and is recommended. It can even be administered as a retention enema if oral antibiotics cannot reach the colon. Fidaxomicin 200 mg may be given orally twice daily for 10 days as an alternative to vancomycin.

In situations of fulminant colitis exhibiting systemic toxicity with increasing abdominal pain, distension, diarrhoea, and altered mental status need surgical intervention leading to total colectomy with end ileostomy. They should receive high doses of vancomycin in combination with intravenous metronidazole (500 mg, 8 hourly).

Prevention

It is necessary to maintain proper hygiene of the ward. Periodic disinfection of the hospital environment and cleaning with dilute bleach should be carried out to eliminate C. difficile spores. Proper washing of hands with soap and water must be stressed. Health care workers should wear gloves and gowns when entering the room of patient. Judicious use of antibiotics is an important way to reduce the incidence of C. difficile infection. The use of epidemiologically implicated antibiotics such as clindamycin, second and third generation cephalosporins or fluoroquinolones are to be restricted in surgical cases. Proton pump inhibitors, also may increase the risk of C. difficile infection. The patients must be isolated and treated.

The recent surge in outbreaks shows that known pathogens can alter their behaviour and pose new threats with increased virulence, antimicrobial resistance or both.

Conflict of interest

None