Clostridium difficile associated diarrhea


Also known as pseudomembranous enterocolitis.

When the natural colon flora is altered by antibiotics this organism induces inflammation of the mucosa and lamina propria of the bowel with associated diarrhea.

Exposure to broad spectrum antibiotics is the main risk factor for C. difficile infection, leading to compositional and functional changes in the gastrointestinal microbiome.

The most common healthcare associated infection in the US.

Associated with approximately 450,000 infections annually with a direct mortality of 5% and all-cause mortality is 15 to 20%.

Other risk factors include: old age, female sex, the presence of coexisting conditions, the use of proton pump inhibitors, and a history of recurrence.

With a healthy microbiome, spore forming bacteria of the phylum Firmicutes modulate production and consumption of metabolites important for host defense and colonization resistance.

Antibiotic induced  loss of beneficial Firmicutes bacterial leads to increases in primary bile acid concentration, which allows C. difficile spore germination in a cycle of recurrent disease.

antibiotics used to treat CDI targets resident commensal gut bacteria, which is a major risk factor for CDI recurrences.

They create a favorable environment for C. difficile growth and toxin production, and alter the gut metabolite pool.

A durable clinical response depends on the resilience of the microbiome, and the recovery of these beneficial resident bacteria after discontinuation of antibiotic therapy.

Most recurrences occur within days to a few weeks after completion of  antibiotics.

Most initial CDI episodes respond to antibiotic treatment, but up to 25% of patients experience a first recurrence, and the risk for subsequent recurrence can exceed 60%.

Antibiotic therapy is necessary but not sufficient to achieve assisting clinical response, suggesting the need for an approach that includes microbiome repair.

Dysbiosis of the gut microbiome leads to asymptomatic carriage of C. difficile.

Asymptomatic carriage of C. difficle worsens dysbiosis and increases the risk of continued or subsequent colonization, increasing the risk of symptomatic infection.

Managing asymptomatic colonization is not recommended.

The leading cause of infectious nosocomial diarrhea in industrial countries worldwide.

Gram positive, spore-forming, anaerobic bacillus.

The prevalence of hospital acquired Clostridium difficle infection has doubled in the past 20 years.

Nucleic acid amplification tests (NAATs) is a major contributor to the rising incidence seen in recent years.
In recent years there has been a decline in C. difficile infection and associated hospitalizations, but  recurrent CDI has increased.

An estimated 453,000 cases occur each year, and approximately 83,000 recurrences and 29,300 deaths



Economic burden of C difficile infection (CDI) is estimated to be $4.8 billion in excess medical community-acquired infection, but the incidence and recurrence rates of CDI are increasing


both in health-care settings and the community.

Incidence of hospital acquired CDI has increased by 2-2.5 fold from the late 1990s, and this increase is more pronounced in the elderly.

Most commonly identified health care pathogen.

Contact precautions should be implemented during treatment of patients who have suspected or confirmed CDI.

CDI one of the most common healthcare-associated infections in the US.

C. Difficile infections costs acute care facilities over $6.3 billion dollars yearly.

Treating CDI costs $24,205 per patient.

The rising incidence and virulence is explained at least by inappropriate antibiotic usage, outbreaks in healthcare facilities, and diffusion of hypervirulent and resistant strains belonging to the 027 ribotype.

Recurrent CDI is increasing disproportionately to primary CDI.

In some areas of the US has surpassed MRSA as the most common health care- associated infection.

CDI extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.

Causes as many as 460,000 illnesses each year in the US.

Linked to 20,000 deaths each year.

Most common cause of health care associated infectious diarrhea.

C. difficile infection in US hospitals affects almost 1% percent of hospitalized patients each year.

Increasing molecular evidence exists, and based on genomic sequence, indicates that asymptomatic patients colonized with C. difficile and can contribute to transmission of the disease.

To cause the disease, the bacterium requires, presence in the human intestine and dysbiosis which occurs when host microbiota loses its balance.

Dysbiosis occurs when there is recent use of antibiotics, long-term use of proton pump inhibitors, older age, hospitalization, and immune suppression.

Clinical outcomes are suboptimal because current treatments do not address the two phase lifecycle of this pathogen or the disease pathogenesis.

Vancomycin and fidaxomin lead to symptom relief by killing toxin producing C. difficile bacteria that cause chronic inflammation and debilitating diarrhea, however, they do not kill C. difficile spores which can rapidly germinate into toxin producing vegetative bacteria after treatment discontinuation.

Adults ≥65 years are particularly susceptible to infection, and have the highest rates of infection and mortality.

Hospital fatality has decreased more than two fold in the last decade, despite increasing infection.

The mean length of Hospital stay decreased by more than one day in the last decade.

In the absence of dysbiosis, C. difficile does not usually pass into a vegetative form.

Incident CDI cases are as frequently linked to transmission from asymptomatic carries as to symptomatic patients.

In 2011 C. difficile accounted for 12% of all US healthcare associated infections, surpassing Staphylococcus aureus as the most common cause of infection..

Studies show that 10 to 40% risk reduction in the most physically active study participants when compared to least active participants.

Hospitalized patients with CDI are a recognized source of healthcare associated transmission, and a primary control measure is to limit the spread of the organism from symptomatic patients.

In vulnerable patients CD infections (CDI) associated with high incidence of medical and surgical complications, and mortality.

Critically ill patients admitted to the ICU with CDI associated with increased death rates.

Classification of CDI by mode of acquisition includes A)community acquired if symptoms of onset occurs in the community or within 48 hours of admission to a hospital, after no hospitalization in the past 12 weeks; B) hospital acquired if onset of symptoms occurs more than 48 Hours after admission to or less than four weeks after discharge from a healthcare facility; C) indeterminate if symptoms onset occur in the community between 4 andb12 weeks after discharge from the hospital.

Deaths secondary to CD infections estimated to be 14,000 during 2006-2007.

Most cases nosomial and iatrogenic.

Two type of endotoxins A and B which share amino acid sequence and functional homologies, but are antigenically different.

Both endotoxins cause gastrointestinal cell pathology with mucosal injury and marked inflammatory response.

A normal colonic microflora confers colonization resistance against this organism.

1-4% of healthy adults carry this organism.

About 50% of newborns colonized by C. difficile without causing illness.

In adults loss of colonization resistance is most often secondary to antimicrobial treatment.

Rates of death associated with this infection are increasing.

The clinical aspects of infection has worsened during the past decade, with increased cases, increased morbidity, increased incidence of complications requiring colectomy and increasing mortality.

Outcomes are worse for patients with marked leukocytosis or acute kidney injury than patients with CDI. without these abnormalities.

Some communities have increased cases outside the hospital.

CDI now being described in populations traditionally considered at low risk, such as children and community dwellers.

The increased incidence of CVI in the community may reflect an increase prevalence of asymptomatic colonizers.

An estimated 20-20% of CDI is community associated, with an incidence 20-50 cases per hundred thousand population.

C diff can colonize the stool of 1 to 3% of healthy adults and as many as 30% of infants.

Presently community prevalence 5-60 per 100,000 individuals.

Patients with cancer have a high risk for both primary and recurrent CDI, along with complications such as toxic megacolon and treatment failure likely due to underlying immunosuppression and frequent use of broad-spectrum antibiotics.

Chemotherapy can lead to altered micribiome and promote CDI even in the absence of antibiotic drug exposure.

C difficile in asymptomatic carriers have a role in spore dissemination:they outnumber patients with CDI, can contaminate the environment and caregiver’s hands, and are not placed in isolation precautions.

Hand hygiene should be maintain with soap and water or an alcohol-based hand hygiene product before and after contact with the patient who has CDI.
C. difficile spores are resistant to alcohol, so hand washing with soap and water may be more effective for infection control in hyperendemic settings.

Isolating carriers of C diff decreases the incidence of health care associated C. diff infections.

Approximately 40% of patients with community acquired CDI were not exposed to antibiotics.

Infection rate is increasing in populations that were previously at low risk such as the young, healthy persons in the community and peripartum women.

High levels of antibodies to C. difficle toxins protects against infection.

The incidence and severity of the process is increasing and that has been ascribed to the the emergence of hyper virulent C. difficle strain, North American Pulsed Field type I (NAP1) , restriction-endonuclease (REA) type B1, or polymerase chain reaction ribotype 027 (referred to collectively as the NAP1/B1/027 strain).

CDI can be classified as mild, moderate, or severe.

NAP1 strain associated with increase virilence and anti-microbial resistance, and its widespread emergence is partly attributed to the increasing use of fluoroquinolones in US Healthcare facilities.

NAP-1 Strain produces as much is 10 times more toxin than other C. difficile strains, causing more severe infections.

Neonates lack established flora and may have C. difficile colonization but rarely have diarrhea.

Prescribing antibiotics, often inappropriately, increases risk of C. Difficile infection in children.

Incidence of C. difficile infection among hospitalized children since 1997.

Most children become carriers of C. difficile in first few months of life, with 73% of children having asymptomatic colonization by 6 months.

3% or less of children are carriers of C.difficile by age 3,

California Department of Public Health found C. difficile infections in children aged 1-17: incidence highest in 1 year-olds, at 66.3 per 100,000 children, and decreased to 13.8 per 100,000 at age 6 years, and up to 8.8-25.6 per 100,000 from ages 13-17 years.

Risk associated with different antibiotics is variable and results from a complex process of their concentration in the bowel lumen, is effects on intestinal flora, and activity against this organism.

All antibiotics can induce anti-microbial agent colitis.

Proton pump use associated with increases in the risk of Clostridium difficile infections reflects importance of gastric acid in protecting against infection with this agent.

There is a correlation between the increase in proton pump inhibitor use and the increase in hospital acquired C. Difficile infection incidence.

Patients with continuous PPI use have elevated risk of CDI recurrence and that cessation of unnecessary PPI should be considered at the time of CDI (McDonald EG et al).

Oncology patients have a higher rate of both primary and recurrent CDI along with complications such as toxic megacolon and treatment failure as compared with non oncology patients.

Increase length of stay in hospitals and the extended care facilities by oncology patients, as well as the underlying immunosuppression together with multiple exposures to broad-spectrum antibiotics, all increase the risk of infection in these patients.

Antineoplastic chemotherapy can alter the gut microbiota and promote CDI even in the absence of antibiotic exposure.

More acidic gastric juices are more effective than less acidic gastric juices in killing C. difficile and neutralizing its toxin (Gurian L et al).

Studies show as many as 36% of patients with CDI were taking gastric suppressive medications (Khanna et al).

Increasing pharmacologic acid suppression is associated with increased risks of nosocomial C. difficile infections: compared with no acid suppression proton pump inhibitor daily administration was associated with more than a 70% increase in the odds of developing a C. difficile infection (Howell MD et al).

C difficile infection is increased by an estimated 53% in patients receiving histamine-2 receptor antagonists, 74% for those patients receiving daily proton pump inhibitors, and double in patients receiving more frequent PPI dosing than patients not receiving acid suppression therapy (Linsky A et al).

Proton pump inhibitor use during CD infection treatment associated with a 42% increase in risk of recurrent disease (Linsky A et al).

The leading cause of nosocomial diarrhea.

Approximately 15-20% of hospital acquired diarrhea linked to C. difficile infection.

Use of probiotics increases effectiveness of C.difficile infection treatment.

Co-administration of probiotics and antibiotics is associated with a lower risk for CDI versus placebo or no treatment.

Among outpatients only 1 in every 100,000 patients who undergo antibiotic therapy get C.difficile colitis.

Affects three million people in the U.S. each year.

In the community based setting clostridium diarrhea complicates fewer than 1 in 5000 antimicrobial prescriptions leading to 7.6 cases per 100,000 person/ years.

Complicates 0.5-1.0% of hospitalizations.

The leading cause of hospital associated gastrointestinal illness.

The number of hospital discharges with CDAD more than doubled from 2000 to 2009, from approximately 139,000 to 336,000, and the number with primary CDI tripled from 33,000 to 111.000 (Lucado J et al).

Healthcare facilities are contaminated by C. difficile spores.

Infection occurs often in healthcare settings as antibiotics are prescribed there and symptomatic patients, a significant source of transmission, are located.

Spread from by fecal oral route.

Spores resistant to drying, many antiseptic agents, temperature fluctuations and can remain viable for long periods in the environment.

Spores, the infective form, can persist on fomites and environmental surfaces for months.

Associated mortality 1-2.5%.

Proportion of healthy persons who carry this organism in North America ranges from 4-6%.

Infants and young children may harbor the organism in their intestinal flora.

Gram positive rod that is widespread in the environment.

Associated diarrhea primarily a nosocomial disease associated with antibiotic use.

While most cases of infection occur during or shortly after antimicrobial use, it can be delayed 2 to as much as 3 months later.

Infection may be associated with other processes than antimicrobial therapy such as bowel preparation for colonoscopy or surgery, or related to cytotoxic chemotherapy and colitis related to inflammatory bowel disease.

C. difficile infection is the infection is most commonly associated with inflammatory bowel disease, and it frequently exacerbates severity of the disease.

Pseudomembranous colitis in a patient with recent antibiotic exposure is almost always due to this infection.

Pseudomembranous colitis can progress to toxic megacolon, sepsis, and death.

Incidence in ambulatory patients estimated at 7 to 12 cases per 100,000 person-years.

Common use of broad spectrum antibiotics has led to an increase in the incidence in hospital and outpatient settings.

Increase in incidence and mortality due to spread of a hypervirulent strain of C. difficile that produces increased virulence toxins A and B, enhancing virulence.

Clindamycin impairs colonization and induces infection with this agent.

All isolates of this agent are resistant to cephalosporins.

Increased frequency of fluoroquinolone resistance in C. difficile isolates.

Commonly associated with recurrences or relapses.

Initial response rates to antibiotics are high, however, the recurrence rate in 1 to 8 weeks can be as high as 35%, with subsequent recurrences after retreatment occurring in 50-65% of patients.

The presence of C. difficile infections in hospitalized patients has an overall mortality rate is high as 23% at 30 days (Matilla E et al).

Each incidence of hospital-acquired C. Difficile infection Is associated with a 9.3% mortality rate(LessaF).

Multiple recurrences are associated with increased disability with diarrhea, weight loss, and progressive weakness, and the potential for the need for colectomy or the possibility of death.

Surgical patients comprise 55-75% of all patients with C.difficile diarrheal disease.

More common in elderly adults, particularly older women.

Hypothesized that early colonization results in an immune memory that wanes with age

Symptoms may range from mild abdominal pain and diarrhea to toxic megacolon and death.

1.5%-5.7% of hospitalized patients that acquire Clostridium dIfficile associated infection die and surviving patients at increased length of hospital stay (Zilberber MD et al.).

In a retrospective observational study hospital acquired Clostridium difficile infection was independently associated with an increased risk of in-hospital death, and that for every 10 patients acquiring infection one person died (Oake N etal.).

The risk of acquiring Clostridium difficile infection during a hospital admission is one in 100 (Oake N et al.).

The risk of acquiring Clostridium difficle infection during a hospital admission is lower in patients who have a low baseline mortality risk.

Populations at high risk include elderly, patients with uremia, burns, abdominal surgery or cesarean section, and cancer patients or those in ICU’s.

Uncommon in healthy adults (1%-3%) but is common in debilitated patients and antibiotic treated hospitalized adults (15-25%), including those who received 1 dose of antibiotic before surgery.

All antibiotics can induce antimicrobial agent-associated colitis.

Appears in every 100-200 hospitalized patients.

Among out-patients, the disease in infrequent, appearing in 1 patient in every 100,000 who undergo antibiotic therapy.

Toxins A and B are produced by pathogenic strains.

Binary toxin, a new toxin, identified may be related to increases in aggressiveness of the infection.


The initial management of clostridium difficile infection includes classification of disease severity, fluid resuscitation, correction of electrolyte abnormalities as needed.
It is pertinent to stop unnecessary antibiotics when associated with diarrhea.

Early diagnosis is essential to implement isolation to curb transmission.

Standard of treatment metronidazole or oral vancomycin, but new guidelines recommend vancomycin or fidaxomicin as preferred: metronidazole is recommended it allergy, intolerance or financial considerations preclude vancomycin or fidaxomicin.

Metronidazole may be associated with higher current rates compared with vancomycin and adverse effects include peripheral neuropathy, nausea and with concurrent alcohol use a disulfiram like reaction, including nausea and metallic taste.

Guidelines recommend discontinuing the inciting antibiotic as soon as possible, because continued exposure increases the risk of recurrent CDI.

Oral metronidazole highly effective against clostridium species.

Relapse rate with metronizadole only 7%.

Observational studies have shown infection failure rate of metronidazole may be as high as 50%.

Studies of patients with severe infections have revealed vancomycin has a significantly higher response rate than metronidazole (97% versus 76%, respectively).

Patients with a history of more than one recurrent should be treated with oral vancomycin and treatment should conclude in a tapered manner to prevent further recurrence.

Patients with severe and complicated infections should be treated with intravenous metronidazole and oral vancomycin, with or without rectal vancomycin administration.

Nucleic acid amplification testing can detect CDI with a sensitivity twice enzyme immuno-assays.

Oral vancomycin an alternative to metronidazole but is expensive, selects for resistant gram-positive cocci and has a relapse rate of 18%.

Intravenous metronidazole is also an alternative to oral agents although non-conclusively proven.

Fidaxomicin Is a macro cyclic antibiotic which is more active in vitro than vancomycin by a factor of approximately 8 compared to vancomycin, and treatment and phase 2 and phase 3 trials shows good clinical response and low rate of recurrence.

In a study of 629 patients with this infection treated with oral fidaxomicin or oral vancomycin: the rate of clinical cure for fidaxomicin was not inferior to those treated with vancomycin, and there was a significantly lower rate of recurrence with the non-North American Pulsed Field type I strains (Louie TJ et al).

Prevention of CDI include improving antibiotic use, earlier detection of the disease process, isolation of infected patients, and reducing contamination of C, difficile contamination of health care environment surfaces.

Antibiotic treatment for initial CDI does not induce a durable response in approximately 15-26% of cases.

Effective management of recurrent CDI not presently available.

Generally, recurrent infection of CDI treated with repeated courses of vancomycin.

60% of first recurrences of CDI treated successfully with repeat course of vancomycin, and the proportion of successfully treated patients declines with further recurrences.

Recurrences of CDI due to persistence of CD spores,decreased antibody response to clostridium toxin and persistent abnormal intestinal microbacterial flora.

About 20% of patients experience 1 or more recurrences.

Infusion of donor feces into the duodenum in treating recurrent CDI is more effective than use of vancomycin (van Nood E et al).

In a comparison of frozen versus fresh fecal transplant for recurrent or refractory C difficile infection similar proportion of patients had clinic resolution of diarrhea at 13 weeks (Lee CH et al).

Molecular typing has demonstrated 10-50% of recurrent CDI may be attributable to reinfections rather than recurrence of the initial infection, suggesting a perturbed microbiota may play a role in facilitating reinfection.

Fecal microbiota transplantation refers to the transfer of normal intestinal flora from a healthy donor to a person with intestinal dysbiosis.

Fecal microbiota transplantation in controlled trials has revealed more than 90% efficaciousness in resolving relapsing and recurrent C. difficile infection.

Fecal microbiota transplantation caries risk of transmission of undetected or emerging pathogens that may lead to hospitalization or death.

Fewer than one in six patients treated with antibiotics for a Clostridium Difficile infection actually have lab-confirmed infections despite high costs and negative outcomes of unnecessary treatments.

The anaerobic, spore-forming bacterium C. Difficile is responsible for anywhere between 15% to 25% of antibiotic-related diarrhea cases.

Studies also have found that 96% of patients with symptomatic C. Diff infections had received antibiotics within 14 days of experiencing diarrhea, and the other 4% had taken antibiotics within 3 months of symptom onset.

Stool culture is considered to be the most sensitive test.

As a secondary option, performing an Enzyme Immuno-Assay (EIA) for toxin A and B is fast, but not as accurate as cell cytotoxin assays.

The recommendation is a two-step method for EIA for glutamate dehydrogenase (GDH) plus cytotoxin.

Not recommended to test for C. Diff in asymptomatic patients.

Not all strains of C. difficile produce toxins and nontoxigenoc strains are found in colonized patients and hospital environment and are usually asymptomatic.

Oral administration of spores of nontoxigenic C. difficile -M3 can safely colonize the GI tract and reduce CDI (Gerding DN et al).

Recurrent CDI is the complete resolution of symptoms on appropriate therapy followed by subsequent relapse and return of symptoms within eight weeks of treatment completion after the initial episode.

Approximate 10-20% of cases of CDI recur after the initial episode, but further recurrence rates increase 40-65% after the first recurrent episode.

Diagnosis requires documentation of the presence of toxigenic C. difficile along with compatible clinical syndrome, which typically includes diarrhea of three or more unformed stools in 24 hours.

SER-109, an oral microbiome therapeutic compound of live purified Firmacutes bacterial spores reduces the risk of C. difficile infection recurrence.

Studies using VE303 a microbiome directed therapy composed of non-pathogenic, nontoxigenic, commensal strains of Clostridia can reduce the likelihood of CDI recurrence.

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