“C. diff”: What Is It?
Clostridium difficile (C. diff) is a bacteria in the Clostridia family, which also includes C. perfringens (gas gangrene), C. tetani (tetanus), and C. botulinum (botulism). The Clostridia bacteria are spore-forming anaerobic gram positive bacilli which are particularly virulent because of the toxins they produce.
Clinically, “C. diff” refers to an overgrowth of C. difficile in the colon which can manifest as diarrhea, sometimes profound, colitis, or toxic megacolon, sometimes complicated by dehydration, colonic perforation, and/or death. The overgrowth of C. diff in the colon usually results from alterations in the normal colonic flora associated with use of antibiotics.
A Serious Problem Reported to PA-PSRS
C. diff is documented in almost half the reports submitted to PA-PSRS under the Event Type code “Nosocomial infection: antibiotic-associated diarrhea.” However, of greatest concern is the number of reports involving patient deaths in which C. diff is mentioned as a major contributing factor. PA-PSRS has received 15 such reports to date. Diagnoses include sepsis/septic shock, toxic megacolon, colitis, diarrhea, and abdominal pain. Most patients in these reports (86%) were age 70 or older.
Several reports indicate that patients treated with antibiotics prophylactically for an elective surgical procedure developed symptoms of C. diff infection in the community after discharge. They failed to return to the healthcare system until their disease had progressed significantly. From the patient’s perspective, the relatively routine nature of the surgery in several cases (e.g., knee replacement, repair of a hip or ankle fracture, hysterectomy) may have obscured the connection between the gastrointestinal symptoms of C. diff infection and their recent treatment.
The following reports submitted to PA-PSRS illustrate this point.
A 72-year-old patient came to the ED complaining of a near syncopal episode. He had been discharged two weeks before, after being treated for community-acquired pneumonia. He was taking an antibiotic upon discharge and finished the full course of medication at home. The patient also complained of diarrhea, nausea, and abdominal discomfort over the previous week. The patient arrived, in fact, in septic shock. Fecal testing was positive for C. diff. Despite aggressive intervention, the patient died of C. diff sepsis within 16 hours of returning to the ED.
An 87-year-old patient was discharged to a rehabilitation facility after repair of a hip fracture and receipt of antibiotic therapy. Eighteen days later, the patient returned to the hospital in septic shock associated with C. diff. The patient died the day she returned to the hospital despite aggressive intervention.
The Bottom Line
The message for the healthcare community is to avoid complacency about the risk of C. diff infection and to help patients to understand when they need to return to the healthcare system for additional treatment, especially for diarrhea complicating antibiotic use. The risks of surgical complications may overshadow the risks of prophylactic antibiotics not only in the minds of patients and their families but also among healthcare workers.
C. Diff Infections
While much attention has been focused on such hospital-acquired infections as MRSA (Methicillin-resistant Staphylococcus aureus) and VRE (Vancomycin-resistant enterococcus), C. diff has become a growing concern. C. diff-associated diseases cause significant morbidity and mortality. Patients with C. diff-associated diarrhea (CDAD) have hospital stays that are, on average, 3.6 days longer, and each patient results in additional hospital costs of an average of $3,669.1 A conservative estimate of the cost of this disease in the US is over $1 billion annually.1
In its spore form, C.diff can withstand drying and heat, and is resistant to many disinfectants. The spores can survive up to five months in the environment.2,3 It can be transmitted from person-to-person, as well as by persons touching objects contaminated with the organism.3 In the healthcare environment, C. diff has been cultured in rooms of infected individuals up to 40 days post discharge. Objects from which C. diff has been cultured include: scales, call buttons, telephones, floors, bedpans, toilets/commodes, bed frames, bathing tubs, and electronic thermometers.2-4 It has also been cultured from healthcare workers’ shoes, fingernails and fingertips, as well as the underside of rings.2,3
For the organism to cause disease, C. diff must be in the gastrointestinal system. Then, there must be a change in the normal colonic flora to allow the organism to grow and flourish. Finally, the C. diff must produce toxins.2 The organism produces two toxins. Toxin A is an enterotoxin that causes excretion of large amounts of fluid from the bowel. Toxin B is cytotoxic, attacking and disintegrating cells of the intestines. In addition, C. diff produces tissue- degradative enzymes.3,5 These processes elicit a profound inflammatory response within the colon that can result in a spectrum of diseases.
Spectrum of Disease
At one end of the spectrum, C. diff can reside in the gut asymptomatically.2,3 Many patients colonized with C. diff do not develop clinical signs of the disease.6,7 This organism can be isolated in up to 3% of healthy adults in the general population and from 50% to 80% of healthy newborns and infants.2,3
C. diff also causes simple antibiotic-associated diarrhea.2,3 C. diff is a leading cause of nosocomial diarrhea in the US,8 accounting for nearly 20% of antibiotic-associated diarrhea.9,10 While there is evidence of community-acquired C.diff-related diarrhea, it is rare;2 only about 20,000 cases are diagnosed in the outpatient setting annually.3 The diarrhea is watery and may contain mucus.
More serious manifestations of infection are colitis and pseudomembranous colitis.2,3,6 In addition to diarrhea, there may be loss of appetite, nausea, and abdominal tenderness or pain.3,7 C. diff is responsible for 50-70% of antibiotic-related colitis.10
Approximately 1-3% of patients with C. diff infection develop fulminant colitis.11 Symptoms include severe diarrhea, marked leukocytosis, high fever, chills, and severe lower quadrant or diffuse abdominal pain.11 The colon may become so compromised that a paralytic ileus may develop,2 in which case diarrhea is absent,2,11 and constipation may be apparent.12,13 Abdominal distension may develop.11
Toxic megacolon may ensue;11 this is a life-threatening complication of colitis with an acute dilatation of all or a substantial portion of the colon to a diameter larger than 6 cm. It is associated with systemic toxicity.14 Surgery is required in 65-71% of these cases.14The literature indicates that subtotal colectomy is the procedure of choice to reduce mortality.14 Colonic perforation can occur,6,11 and the protein-losing enteropathy can lead to hypoalbuminemia and ascites.2,11
Death is also a reported complication of C. diff infection.3,6 Mortality associated with active C. diff infections is 0.6% for those with pseudomembranous colitis and 57% in patients requiring colectomy for toxic megacolon. The mortality rate for fulminant C. diff colitis is also high. This may be due to a failure to diagnose this disease in its early, more subtle stages, particularly if diarrhea is not present and abdominal findings are unclear.11 Overall, studies have reported mortality rates associated with CDAD ranging from 0.6%9 to 3%.1
The incidence and severity of C. diff infection and related diseases appears to be increasing in developed countries, such as the US, UK, and Canada, probably due to increased use of broad-spectrum antibiotics, such as third-generation cephalosporins, during the past 20 years.6
A Canadian study describing cases of CDAD in one institution over a 13-year period found that incidence increased from 35.6 per 100,000 population in 1991 to 156.3 per 100,000 in 2003. In the patients aged 65 years or older, the rate increased from 102.0 to 866.5 during the same period. Complicated cases of C. diff infection increased from 7.1% to 18.2%. The proportion of patients who died within 30 days after diagnosis of C. diff infection increased from 4.7% to 13.8%.15
A study in the US Pacific Northwest describing a single institution’s 20-year experience with C. diff colitis found that the number of cases rose by more than 30% when comparing the first and last 10-year periods. The mortality rate increased from 3.5% to 15.3%.16
A study conducted in Pennsylvania indicated that incidence of fulminant C. diff colitis increased from 0% in 1990 to 3.2% in 2000.17 Another study in a Pennsylvania teaching hospital18 found an increase in the incidence of nosocomial C. diff from 2.7 to 6.8 cases per 1,000 discharges from 1999 to 2000-01. Further, 0.15 cases per 1,000 discharges of severe C. diff-related disease in 1999 rose to 0.60 in 2000-01. Some severe cases resulted in colectomy and death.
Recent case studies and anecdotal reports indicate that the course of C. diff-related disease may be changing. There appears to be a trend of more debilitating disease from this infection, higher mortality rates, and an increased need for operative treatment16—from an organism that has previously been considered relatively innocuous and responsive to treatment.17
Once C. diff becomes resident in the gastrointestinal tract, the predominant risk factor for developing disease is treatment with antibiotics, particularly broad-spectrum antibiotics.2,6-8,10,16,19 Though disease may occur in the absence of a history of antibiotic therapy,2 the use of the following antibiotics are most frequently associated with the development of C. diff-associated disease: cephalosporins, penicillins (ampicillin and amoxicillin), and clindamycin.3,7,16 More recently, there have been reports of fluoroquinolone-associated CDAD,6,8,18 including ciprofloxacin8 and levofloxacin.18 Antibiotic use, whether for prophylaxis or treatment, is a more important risk factor for C. diff-related disease and potentially poor outcomes than horizontal transmission via exposure to contaminated surfaces.16
Other general factors that determine whether C. diff-related disease develops include the type and timing of antibiotic exposure, the virulence of the strain of C. diff, and susceptibility or immune status of the patient.3
A multitude of patient factors may place patients at higher risk for C. diff-associated disease, increased mortality and morbidity, and recurrent infection. These include: advanced age;2,6-8,19 severity of co-morbid conditions;2,19 renal disease;2,6,12,13 cancer;2 diabetes mellitus;16 diseases that compromise the immune system;7,16 patients in intensive care units;2,19 and patients with a low serum albumin.19 In these situations, patients’ ability to mount an immune response against the bacteria is compromised.8
Hospitalization is a risk factor. Studies indicate that from 13-31% of inpatients are colonized with C. diff if hospitalized more than one week, and 56% of these develop CDAD.1,3 Those hospitalized more than four weeks may have a rate of acquisition of 50%.3
Gastrointestinal surgery is associated with increased risk of C. diff-associated disease. Procedures include: recent gastrointestinal (GI)/bowel surgery or manipulation of the GI tract;7 non-surgical GI procedures;19 presence of nasogastric tube/tube feedings.2,19
Patients with C. diff colitis and a markedly elevated leukocyte could have a poor prognosis and higher mortality rate than those without a leukemoid reaction.20
In the northern hemisphere during winter, CDAD outbreaks are more likely.
The following interventions can be implemented once a C. diff-associated disease is diagnosed:
Discontinuing the offending antibiotic.2-4
Administering another antibiotic only if continued antimicrobial therapy is needed and using antimicrobics that are less frequently associated with the C.diff-associated disease.3
Providing supportive measures to correct fluid loss and electrolyte imbalances.3
Implementing enteric isolation precautions for infected patients.3
Treating the infection with vancomycin, metronidazole, or bacitracin as first line therapy.1-3 Treatment is more likely to be successful if administered orally for 10 days.4 However, use of vancomycin continues to be restricted because of the risk of developing vancomycin-resistant enterococcus. Ordinarily, oral vancomycin is reserved for patients with metronidazole intolerance. Metronidazole continues to be the drug of choice for CDAD.3
If a patient receiving metronidazole therapy develops a white blood cell count greater than 20,000 cells/mm3 and/or an elevated creatinine level, it may be an indication of more severe C. diff-related outcomes. Based on limited observational data, vancomycin treatment may be indicated in such cases.15,21,22 Large, prospective, randomized controlled trials are needed, however, to confirm the effectiveness of such a change in therapy.
In patients with refractory or recurrent C. diff colitis, a recently published uncontrolled study of 103 patients indicated that the rate of successful treatment was about the same whether prolonged metronidazole therapy or vancomycin was used.23
Avoiding peristaltic agents3 and antidiarrheal/antiperistaltic agents. Antidiarrheal agents such as loperamide may delay clearance of C. diff toxins from the patient’s colon and may predispose the patient to toxic megacolon.4,7
Healthcare workers can provide supportive care; observe and document bowel habits and changes; document the characteristics of bowel movements; and educate patients/relatives about infection control procedures, such as handwashing and wearing of gloves and gowns if directly involved with the patient’s incontinence care or toileting needs.2 Several other approaches to the management and prevention of C. diff are being studied, as well, such as drugs (tinidazole or
nitazoxanide), immunotherapy, vaccine, and probiotics (Lactobacillus species or
Several interventions can help prevent C. diff transmission in the healthcare environment.
The Centers for Disease Control and Prevention (CDC) guidelines for hand hygiene in healthcare
settings21 contains information concerning: handwashing and hand antisepsis, hand hygiene technique, surgical hand antisepsis, selection of hand hygiene agents, and skin care. These guidelines include information that can be applied to preventing transmission of C. diff by healthcare workers.
C. diff spores have been shown to be present on clinicians’ hands, which may become contaminated through contact with infected fixtures, equipment, and patients and may then be instruments of contamination themselves.2
No agent used in antiseptic handwash or antiseptic hand-rub preparations is reliably sporicidal against C. diff (chlorhexidine, hexachlorophene, iodophors, alcohols, PCMX, triclosan). Spores may be physically removed from contaminated hand surfaces by washing hands vigorously with either non-antimicrobial or antimicrobial soap and water.21
While gloves are worn when caring for patients with C. diff diarrhea, after glove removal, hands are washed with a non-antimicrobial or an antimicrobial soap and water, or are disinfected with an alcohol-based hand rub. During outbreaks of C. diff-related infections, washing with soap and water after removing gloves is prudent, as frequent use of alcohol-based hand rubs may dry the skin, making it more vulnerable to breakdown.21
Handwashing also reduces contamination by the vegetative state of C. diff. Technique is important, however, if this decontamination process is to be effective in preventing transmission. Such techniques are described in Figure 1.2,3,7,21
The Veterans Administration’s National Center for Patient Safety has recently recommended that when C. diff is suspected, caregivers’ hands hygiene includes increasing glove use to protect hands from contamination and handwashing with soap and water for decontamination.25
Instituting contact and enteric precautions3,26 until the patient has formed stools—ideally for 48 hours after diarrhea ceases.2
Placing the patient in a private room with private toilet6,24 or placing patients with C. diff-associated disease in the same room (cohorting).26
Using disposable equipment and dedicating reusable equipment solely for that patient.7,26
Personal Protective Equipment
Wearing gloves when entering patients’ rooms and when providing care to a patient with C. diff-associated disease.3,26
Wearing gowns when there is a possibility that the clinician’s clothing might become soiled while caring for the patient.7,26
If the patient is experiencing explosive CDAD, using goggles might be prudent during incontinence care.
Thorough cleaning of surfaces, equipment, reusable devices, and the hospital environment prevents C. diff transmission, acquisition, infection, and reinfection.7,26 For example:
After cleaning surfaces and reusable devices according to label instructions, using an EPA-registered hypochlorite-based disinfectant,3,6,24 alkaline gluteraldehyde, or ethylene oxide.3
Generic sources of hypochlorite, such as household chlorine bleach, may be diluted and used as labeled.26
Cleaning with a hypochlorite disinfectant has been found to be more effective than using a neutral detergent to decrease the incidence of C. diff contamination.6
Carefully cleaning/disinfecting environmental surfaces and items that are likely to be contaminated with fecal material and/or that are frequently touched.7,26
Following manufacturer instructions for disinfection of endoscopes and other devices.26
Alcohol-based disinfectants are not effective against C. diff and are therefore inappropriate for disinfection of environmental surfaces.26
Prudent Antibiotic Use
Some healthcare facilities have changed antibiotic policies to limit use of broad spectrum antibiotics associated with C. diff infection.2 The restriction of fluoroquinolone use among inpatients has been shown to decrease CDAD rates.8 In one study, a formulary restriction of clindamycin was associated with a decrease in the incidence of CDAD.27 Restricting the use of fluoroquinolones, however, needs to be balanced with the drug’s advantages such as efficacy of oral administration and convenient dosing.8
Several hospitals in the UK have implemented antibiotic policies in which later-generation cephalosporins have been replaced with narrow-spectrum penicillins, fluoroquinolones, clarithromycin, pipericillin-tazobactam, metronidazole, trimethoprim, and/or aminoglycosides. Diseases treated were pneumonias, severe sepsis/septic shock, urinary tract infections, H. influenzae. The number of CDAD cases decreased significantly after the implementation of such policies.6,28,29
An important factor in encouraging the prevention of C. diff transmission is education.8 Healthcare workers can receive information about the disease, its epidemiology, methods of preventing transmission, handwashing techniques, personal protective equipment, cleaning/disinfection, as well as the potential for severe sequelae from C. diff infection.
Healthcare workers can also teach patients, family members, and visitors about effective handwashing techniques, as well as use of personal protective equipment if family is to become involved in incontinence care/toileting of an infected patient.2,7 The CDC has fact sheets for healthcare providers and the general public that describe the disease and how to prevent transmission.24,30
Both patients and healthcare workers also can develop awareness that if a patient with current or recent antibiotic use develops diarrhea or abdominal symptoms, it may be indicative of C. diff-associated disease with the potential for serious, life-threatening ramifications.11
While antibiotic use precedes almost all cases of C. diff-associated disease, 11 the onset of such diseases may occur during or several weeks after therapy.3 C. diff-associated diseases are no longer exclusively hospital-acquired infections,2 and symptoms do not necessarily begin during a hospital stay. Inpatient hospital stays continue to grow shorter, pre- and post- operative/procedure antibiotic therapy is conducted outside of the healthcare facility. The number of procedures conducted in ambulatory surgery centers continues to rise. Fluoroquinolones are prescribed for patients in the community because they can be taken orally.
All of these factors contribute to the likelihood of patients experiencing initial symptoms of C. diff-associated disease in a community setting. At least half of the C. diff-associated deaths reported to PA-PSRS indicated that the onset of diarrhea occurred outside the acute hospital setting.
Patients, family members, referring physicians, and healthcare workers in all settings can benefit from recognition that antibiotic use has the potential of causing substantial morbidity and even mortality. If the index of suspicion is raised about this link, medical intervention for evaluation and early treatment of C. diff-associated diseases may be sought in a more timely manner, thus helping to prevent serious negative outcomes.
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Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile.
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Jenkins L. The prevention of Clostridium difficile associated diarrhea in hospital.
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Hurley BW, Nguyen CC. The spectrum of pseudomembranous enterocolitis and antibiotic-associated diarrhea.
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Gerding DN, Johnson S, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis.
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Naaber P, Mikelsaar M. Interactions between Lactobacilli and antibiotic-associated diarrhea.
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McCuster ME, Harris AD, Perencevich E, et al. Fluoroquinolone use and Clostridium difficile-associated diarrhea. Emerging Infectious Diseases [online]. 2003 Jun [cited 2004 Dec 15].
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Miller MA, Hyland M, Ofner-Agostini M, et al. Morbidity, mortality, and healthcare burden of nosocomial Clostridium difficile-associated diarrhea in Canadian hospitals.
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Koehler R, Mone M, Kimball E, et al. Clostridium difficile pericarditis complicating pseudomembranous colitis in a trauma patient.
J Trauma 2003 Oct;55(4):771-3.
Longo WE, Mazuski JE, Virgo KS, et al. Outcome after colectomy for Clostridium difficile colitis.
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Kovithavongs T. Clostridium difficile colitis associated with chronic renal failure.
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Dobson G, Hickey C, Trinder J. Clostridium difficile colitis causing toxic megacolon, severe sepsis and multiple organ dysfunction syndrome.
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Pepin J, Valiquette L, Alary ME, et al. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity.
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Morris AM, Jobe BA, Stoney M, et al. Clostridium difficile colitis.
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Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications.
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Muto CA, Pokrywka M, Shutt K, et als. A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increase fluoroquinolone use.
Infection Control and Hospital Epidemiology 2005 Mar;26(3):273-80.
Eckel F, Huber W, Weiss W, et al. Recurrent pseudomembranous colitis as a cause of recurrent severe sepsis.
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Marinella MA, Burdette SD, Bedimo R, et al. Leukemoid reactions complicating colitis due to Clostridium difficile.
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Emerging Strain of Clostridium Difficile
On April 11, 2005, at the annual meeting of the Society for Healthcare Epidemiology of America, infectious disease experts presented information concerning a new, highly toxic, strain of
Clostridium difficile. This emerging strain is associated not only with severe diarrhea and colitis, but also colectomy and death.
The strain contains a mutation on a gene that regulates production of toxins A and B and which also may produce an additional toxin. The strain produces a higher level of toxin than most other strains, and it is also resistant to fluoroquinolones.
Since 2001, this strain has been identified in outbreaks in at least seven US hospitals in six states, as well as in Sherbrooke and Montreal in Quebec, Canada.
The hospital in Sherbrooke has substantially reduced the use of antibiotics known to be associated with C. diff infection. This was followed by a 33-50% reduction in C. diff-associated disease.
In May 2005, a Pennsylvania facility submitted a report to PA-PSRS indicating that the CDC had confirmed a genetically altered virulent strain of C. diff in a patient’s specimen. A 30-year-old patient with multiple trauma received antibiotics, then developed a C. diff infection, which was treated with Flagyl. However, the patient developed pseudomembranous colitis and required an emergent total colectomy. Fortunately, the patient survived.
Canadian Press. Quebec C. difficile strain has high toxin levels. [online]. 2005 Apr 11 [cited 2005 May 16]. Available from Internet:
Acambis. Emerging strain of common bacteria Clostridium difficile is highly toxic. [online]. 2005 Apr 11 [cited 2005 May 16]. Available from Internet:
International Society for Infectious Diseases. Researchers report emergence of epidemic strain of C. difficile. Archive number 20041004.2735. [online]. 2004 Oct 3 [cited 2005 May 16]. Available from Internet:
When using soap and water:
- First, wet the hands with water
- Apply the manufacturer-recommended amount of the product to the hands
- Rub hands together vigorously at least 15 seconds
- Cover all fingers and surfaces of the hands
- Rinse hands thoroughly with water
- Dry completely with a disposable towel
- Turn off the faucet with the towel
- Avoid using hot water because repeated exposure to hot water may increase the risk of dermatitis
When decontaminating with an alcohol-based hand rub:
- Apply the product to the palm of one hand
- Rub hands together
- Cover all hand and finger surfaces until the hands are dry
- Follow the manufacturer’s recommendations regarding the volume of the product to use