Clostridium difficile is a gram‐positive, spore‐forming, toxin‐producing, anaerobic bacillus that was established as the causative pathogen of most cases of antibiotic‐associated colitis in 1978. 1, 2 The spectrum of possible clinical presentations of C. difficile range from asymptomatic colonization, uncomplicated diarrhea, severe pseudomembranous colitis, paralytic ileus, to sepsis and death, with a mortality rate upwards of 80% in fulminant cases requiring colectomy. 3

Vegetative C. difficile cells die rapidly on dry surfaces, but they have been found to remain viable for up to 6 hours on moist surfaces in room air. 4 Spores shed from the gastrointestinal (GI) tract, however, are highly resistant to common hospital disinfectants, and can survive in the environment for many months. 2 C. difficile spores are primarily transmitted from patient to patient on the hands or equipment of healthcare workers. 2 Once spores are ingested and reach the GI tract, they germinate in the vegetative form. 2, 5 In the GI tract, C. difficile causes disease by the production of toxins, primarily toxins A and B, both of which cause severe inflammation. 5 Toxin A attracts neutrophils and monocytes, and toxin B breaks down colonic epithelial cells. 5 Both of these mechanisms lead to colitis, formation of pseudomembranes, and watery diarrhea. 5

After alteration of the healthy colonic bacterial flora, the immune response to C. difficile toxins appears to play a major role in determining host susceptibility to C. difficile infection (CDI). 5, 6 Those with antitoxin immunity are more likely to become symptomless carriers than patients without preexisting immunity. 3 More than 60% of healthy adults have protective immunity against a primary CDI, demonstrated by detectable serum IgG and IgA to both toxins A and B, as a consequence of childhood immunity or frequent exposure to C. difficile in the environment. 3 After a primary episode of CDI, many patients acquire protective immunity against C. difficile toxins, seen as significantly higher serum concentrations of IgM against C. difficile toxin by the third day from onset of diarrhea, and significantly higher serum concentrations of IgG against toxin A by the 12th day. 7 Patients who experience recurrent CDI lack development of this protective immunity to C. difficile. 6, 7

CDI INCIDENCE IS ON THE RISE

During the past decade, rates of CDI have increased steadily to levels not previously seen. A report published by the Agency of Healthcare Research and Quality demonstrated that the number of CDI diagnoses on hospital discharge more than doubled in the United States from 139,000 to 301,200 between 2000 and 2005 (Figure 1). 8 Examination of a more recent Nationwide Inpatient Sample (NIS) indicates continuation of this trend, with nearly 350,000 CDI diagnoses recorded upon discharge from acute care hospitals in 2008. 9 Of note, in 2006 the state of Ohio mandated CDI reporting from both hospitals and nursing homes. It was estimated there were more than 18,000 cases of CDI during this year, of which more than 60% were diagnosed in nursing homes. 10 Based on the 2008 NIS data and the data from Ohio, it is conceivable there were as many as 1 million cases of CDI in the US in 2008.

Figure 1

This increased incidence of CDI contrasts with several other healthcare‐associated infections, which have declined in incidence over the last decade. 1113 C. difficile is the most common causative agent of healthcare‐associated infections in some areas. A cohort study of common infections among inpatients at 30 community hospitals in the Duke Infection Control Outreach Network conducted between January 1, 2008 and June 30, 2009 found the incidence of CDI cases was 0.26 cases per 1000 patient‐days, which was higher than the incidence of methicillin‐resistant Staphylococcus aureus (MRSA) at 0.22 cases per 1000 patient‐days. 14 Another study utilizing the NIS data found that, while vancomycin‐resistant enterococcus and pseudomonas infections remained stable, CDI increased in many areas of the country and was more common than MRSA in some areas. 15

HYPERVIRULENT STRAIN OF C. DIFFICILE

In the early 2000s, an epidemic and hypervirulent strain of C. difficile emerged in North America and Europe that altered the epidemiology of CDI. 16 Due to multiple different methods for molecular typing of C. difficile, this strain has several names depending on the method of typing performed. The most common names for this strain are BI (REA typing), NAP1 (pulsed field gel electrophoresis), and 027 (PCR‐ribotyping). This strain has become the predominant strain of C. difficile in some areas, accounting for more than 80% of CDI cases in some areas. 3

The characteristics of this particular strain epidemic in North America typically include:

• A deletion in the tcd gene that downregulates toxin production, which renders the gene nonfunctional in the epidemic strain. Some in vitro data have demonstrated that this epidemic strain produces 16‐fold higher concentrations of toxin A and 23‐fold higher concentrations of toxin B than nonepidemic strains of C. difficile. 17

• Production of a third toxin, called binary toxin CDT. The role of this toxin in the pathogenesis of CDI is not clear, but the presence of this toxin has been associated with more severe CDI‐related diarrhea. 2, 16

• High‐level resistance to fluoroquinolones, including moxifloxacin and gatifloxacin. 5, 16 It has been theorized that increasing use of fluoroquinolones during the past decade may have provided a selective advantage for the BI/NAP1/027 strain to predominate. 2

• Production of more spores than other strains of C. difficile. 17, 18 This may increase its ability to contaminate the environment and be transmitted in a healthcare facility.

CDI SEVERITY IS INCREASING

Paralleling the increased prevalence of CDI, C. difficile infections are generally becoming more severe. In Sherbrooke, Quebec, Canada, which experienced a dramatic outbreak of CDI associated with increased CDI severity, the cumulative 1‐year attributable mortality was nearly 37% (60 of 161 CDI cases) in a hospital case review of nonsurgical admissions between January 2003 and June 2004. 19 In St Louis, Missouri in 2003, a 5.7% 180‐day mortality rate was reported in an endemic setting. 20 Among the 24% of patients readmitted within 180 days of discharge (4207 of 17,492) in this retrospective case review, patients with CDI were more than twice as likely as non‐CDI patients to be readmitted to the hospital (52% vs 23%, N = 4207). 20 Furthermore, patients with CDI were significantly more likely to require discharge to a long‐term care facility (32%) than non‐CDI controls (23%). 19

Based on NIS data for CDI‐related hospitalizations between 2000 and 2005, the crude, age‐adjusted case‐fatality rate rose from 1.2% in 2000 to 2.2% in 2004. 21 This increase was mirrored by a doubling of CDI cases admitted for hospitalization during the same 6‐year period. 21 According to the investigators, these findings indirectly confirm that the doubling in CDI deaths is attributable to an increase in C. difficile virulence. 21 A 6‐month prospective surveillance of CDI patient outcomes in 29 Canadian hospitals was conducted by the Canadian Nosocomial Infection Surveillance Program (CNISP) beginning in November 2004. 22 At 30 days after onset of CDI, the percentage of deaths directly or indirectly attributable to CDI was 5.7%, which represented an almost 4‐fold increase over CDI‐attributable deaths recorded in the 1997 CNISP survey. 22 Overall 30‐day mortality was retrospectively analyzed among patients with CDI in a St Louis, Missouri 1200‐bed teaching hospital intensive care unit (ICU) over a 2‐year period (20042005). 23 The 30‐day crude mortality among 278 patients admitted to the ICU with CDI was 37% (n = 102), and mortality directly attributable to CDI in these critically ill patients was 6%. 23 The number of deaths in the United States due to CDI increased sharply from 793 patients in 1999 to 6225 patients in 2006. 24 In 2006, it ranked among the top 20 causes of death for those aged 65 years and older. 24

INCREASE IN TREATMENT FAILURES

In addition to being more severe, there have been several reports of increases in CDI treatment failures and/or increases in recurrent CDI. 6 Recent studies indicate there may be more metronidazole treatment failures regardless of whether the infecting strain is the BI/NAP1/027 strain, despite a lack of laboratory evidence indicating resistance to metronidazole. 2529 Regardless of the initial therapy chosen, patients must be carefully monitored to ensure they are responding appropriately to treatment and their condition is not deteriorating. 29 Some of the original trials of CDI treatments found relapse rates as low as 5% to 15%. 30 More recent data indicate relapse occurs after 30% of initial CDI episodes, and as frequent as 65% if the patient has had multiple prior CDI episodes. 3, 6, 31

COMMUNITY‐ASSOCIATED CDI

The epidemiology of community‐associated CDI may also be changing. Virulent strains, which cause more severe disease in high‐risk patients, may also cause more frequent, severe disease in populations previously thought to be at low risk. Some studies have found an increase in community‐associated CDI in otherwise healthy individuals with little or no exposure to a healthcare facility. Although antimicrobial exposure remains the most important risk factor for community‐associated CDI, antimicrobial exposure is less common in community‐associated CDI than healthcare‐associated CDI. 3235

In a Canadian study, the rate of diagnosed community‐acquired CDI cases was stable at about 22 cases per 100,000 patient‐years per calendar year between 1998 and 2002, but rose steadily for the next 2 years to 53 cases per 100,000 patient‐years in 2004. 33 Similar results were seen in the United Kingdom, with an exponential increase from fewer than 1 case per 100,000 person‐years in 1994 to 22 cases per 100,000 person‐years in 2004. 32 There are currently no comprehensive longitudinal studies in the United States investigating the incidence of purely community‐acquired CDI where a patient had no prior hospital exposure. However, regional surveys have reported an incidence of community‐acquired CDI of 12 cases per 100,000 person‐years during 1992 to 1994, 36 7.6 cases per 100,000 person‐years in 2005, 37 and 6.9 cases per 100,000 person‐years in 2006. 34, 37

One patient population generally thought to be at low risk for CDI that may be at increased risk for severe CDI is pregnant women. In one study 419 infectious disease consultants who responded to a survey conducted by the Emerging Infections Network had seen or were aware of 55 cases of CDI in peripartum women. 38 There were 21 cases with complications, including 10 relapses and 5 cases of toxic megacolon. 38 In a prior report of severe CDI among 10 peripartum women, 3 women died and 3 infants (2 were twins) were stillborn. 38 This data emphasizes why clinicians must have a high index of suspicion for CDI, and should be aware of the potential for severe outcomes, even in patients traditionally considered to be at low risk. 38

ECONOMIC IMPACT OF CDI

The economic burden of CDI in the United States is staggering, with estimates ranging from $1.1 to $3.2 billion annually (Table 1). 3941 These estimates are based on the cost of caring for patients with CDI in acute care facilities and are primarily driven by increased length of stay in the hospital due to CDI. These data also predate the emergence of the BI/NAP1/027 strain. Therefore, the costs of CDI are likely higher than these estimates due to the increases in CDI severity seen since these studies were performed. It is important to note that these studies did not include patients diagnosed and treated in nursing homes or the community, nor the increase in costs due to discharge to a long‐term care facility. 39

SUMMARY

C. difficile infections are becoming more prevalent and more severe. The issue is sufficiently serious that healthcare‐onset CDI has recently been called a major public health threat. 42 For this reason, efforts to combat virulent C. difficile should include good antimicrobial stewardship, effective infection control, and control of environmental factors that promote transmission. 35 Healthcare professionals who oversee the care of inpatients should act as catalysts for improvement by taking a leadership role in the multidisciplinary approach needed to reduce the morbidity, mortality, and cost burden for patients and the healthcare system.

Clostridium difficile is a gram‐positive, spore‐forming, toxin‐producing, anaerobic bacillus that was established as the causative pathogen of most cases of antibiotic‐associated colitis in 1978. 1, 2 The spectrum of possible clinical presentations of C. difficile range from asymptomatic colonization, uncomplicated diarrhea, severe pseudomembranous colitis, paralytic ileus, to sepsis and death, with a mortality rate upwards of 80% in fulminant cases requiring colectomy. 3

Vegetative C. difficile cells die rapidly on dry surfaces, but they have been found to remain viable for up to 6 hours on moist surfaces in room air. 4 Spores shed from the gastrointestinal (GI) tract, however, are highly resistant to common hospital disinfectants, and can survive in the environment for many months. 2 C. difficile spores are primarily transmitted from patient to patient on the hands or equipment of healthcare workers. 2 Once spores are ingested and reach the GI tract, they germinate in the vegetative form. 2, 5 In the GI tract, C. difficile causes disease by the production of toxins, primarily toxins A and B, both of which cause severe inflammation. 5 Toxin A attracts neutrophils and monocytes, and toxin B breaks down colonic epithelial cells. 5 Both of these mechanisms lead to colitis, formation of pseudomembranes, and watery diarrhea. 5

After alteration of the healthy colonic bacterial flora, the immune response to C. difficile toxins appears to play a major role in determining host susceptibility to C. difficile infection (CDI). 5, 6 Those with antitoxin immunity are more likely to become symptomless carriers than patients without preexisting immunity. 3 More than 60% of healthy adults have protective immunity against a primary CDI, demonstrated by detectable serum IgG and IgA to both toxins A and B, as a consequence of childhood immunity or frequent exposure to C. difficile in the environment. 3 After a primary episode of CDI, many patients acquire protective immunity against C. difficile toxins, seen as significantly higher serum concentrations of IgM against C. difficile toxin by the third day from onset of diarrhea, and significantly higher serum concentrations of IgG against toxin A by the 12th day. 7 Patients who experience recurrent CDI lack development of this protective immunity to C. difficile. 6, 7

CDI INCIDENCE IS ON THE RISE

During the past decade, rates of CDI have increased steadily to levels not previously seen. A report published by the Agency of Healthcare Research and Quality demonstrated that the number of CDI diagnoses on hospital discharge more than doubled in the United States from 139,000 to 301,200 between 2000 and 2005 (Figure 1). 8 Examination of a more recent Nationwide Inpatient Sample (NIS) indicates continuation of this trend, with nearly 350,000 CDI diagnoses recorded upon discharge from acute care hospitals in 2008. 9 Of note, in 2006 the state of Ohio mandated CDI reporting from both hospitals and nursing homes. It was estimated there were more than 18,000 cases of CDI during this year, of which more than 60% were diagnosed in nursing homes. 10 Based on the 2008 NIS data and the data from Ohio, it is conceivable there were as many as 1 million cases of CDI in the US in 2008.

Figure 1

This increased incidence of CDI contrasts with several other healthcare‐associated infections, which have declined in incidence over the last decade. 1113 C. difficile is the most common causative agent of healthcare‐associated infections in some areas. A cohort study of common infections among inpatients at 30 community hospitals in the Duke Infection Control Outreach Network conducted between January 1, 2008 and June 30, 2009 found the incidence of CDI cases was 0.26 cases per 1000 patient‐days, which was higher than the incidence of methicillin‐resistant Staphylococcus aureus (MRSA) at 0.22 cases per 1000 patient‐days. 14 Another study utilizing the NIS data found that, while vancomycin‐resistant enterococcus and pseudomonas infections remained stable, CDI increased in many areas of the country and was more common than MRSA in some areas. 15

HYPERVIRULENT STRAIN OF C. DIFFICILE

In the early 2000s, an epidemic and hypervirulent strain of C. difficile emerged in North America and Europe that altered the epidemiology of CDI. 16 Due to multiple different methods for molecular typing of C. difficile, this strain has several names depending on the method of typing performed. The most common names for this strain are BI (REA typing), NAP1 (pulsed field gel electrophoresis), and 027 (PCR‐ribotyping). This strain has become the predominant strain of C. difficile in some areas, accounting for more than 80% of CDI cases in some areas. 3

The characteristics of this particular strain epidemic in North America typically include:

• A deletion in the tcd gene that downregulates toxin production, which renders the gene nonfunctional in the epidemic strain. Some in vitro data have demonstrated that this epidemic strain produces 16‐fold higher concentrations of toxin A and 23‐fold higher concentrations of toxin B than nonepidemic strains of C. difficile. 17

• Production of a third toxin, called binary toxin CDT. The role of this toxin in the pathogenesis of CDI is not clear, but the presence of this toxin has been associated with more severe CDI‐related diarrhea. 2, 16

• High‐level resistance to fluoroquinolones, including moxifloxacin and gatifloxacin. 5, 16 It has been theorized that increasing use of fluoroquinolones during the past decade may have provided a selective advantage for the BI/NAP1/027 strain to predominate. 2

• Production of more spores than other strains of C. difficile. 17, 18 This may increase its ability to contaminate the environment and be transmitted in a healthcare facility.

CDI SEVERITY IS INCREASING

Paralleling the increased prevalence of CDI, C. difficile infections are generally becoming more severe. In Sherbrooke, Quebec, Canada, which experienced a dramatic outbreak of CDI associated with increased CDI severity, the cumulative 1‐year attributable mortality was nearly 37% (60 of 161 CDI cases) in a hospital case review of nonsurgical admissions between January 2003 and June 2004. 19 In St Louis, Missouri in 2003, a 5.7% 180‐day mortality rate was reported in an endemic setting. 20 Among the 24% of patients readmitted within 180 days of discharge (4207 of 17,492) in this retrospective case review, patients with CDI were more than twice as likely as non‐CDI patients to be readmitted to the hospital (52% vs 23%, N = 4207). 20 Furthermore, patients with CDI were significantly more likely to require discharge to a long‐term care facility (32%) than non‐CDI controls (23%). 19

Based on NIS data for CDI‐related hospitalizations between 2000 and 2005, the crude, age‐adjusted case‐fatality rate rose from 1.2% in 2000 to 2.2% in 2004. 21 This increase was mirrored by a doubling of CDI cases admitted for hospitalization during the same 6‐year period. 21 According to the investigators, these findings indirectly confirm that the doubling in CDI deaths is attributable to an increase in C. difficile virulence. 21 A 6‐month prospective surveillance of CDI patient outcomes in 29 Canadian hospitals was conducted by the Canadian Nosocomial Infection Surveillance Program (CNISP) beginning in November 2004. 22 At 30 days after onset of CDI, the percentage of deaths directly or indirectly attributable to CDI was 5.7%, which represented an almost 4‐fold increase over CDI‐attributable deaths recorded in the 1997 CNISP survey. 22 Overall 30‐day mortality was retrospectively analyzed among patients with CDI in a St Louis, Missouri 1200‐bed teaching hospital intensive care unit (ICU) over a 2‐year period (20042005). 23 The 30‐day crude mortality among 278 patients admitted to the ICU with CDI was 37% (n = 102), and mortality directly attributable to CDI in these critically ill patients was 6%. 23 The number of deaths in the United States due to CDI increased sharply from 793 patients in 1999 to 6225 patients in 2006. 24 In 2006, it ranked among the top 20 causes of death for those aged 65 years and older. 24

INCREASE IN TREATMENT FAILURES

In addition to being more severe, there have been several reports of increases in CDI treatment failures and/or increases in recurrent CDI. 6 Recent studies indicate there may be more metronidazole treatment failures regardless of whether the infecting strain is the BI/NAP1/027 strain, despite a lack of laboratory evidence indicating resistance to metronidazole. 2529 Regardless of the initial therapy chosen, patients must be carefully monitored to ensure they are responding appropriately to treatment and their condition is not deteriorating. 29 Some of the original trials of CDI treatments found relapse rates as low as 5% to 15%. 30 More recent data indicate relapse occurs after 30% of initial CDI episodes, and as frequent as 65% if the patient has had multiple prior CDI episodes. 3, 6, 31

COMMUNITY‐ASSOCIATED CDI

The epidemiology of community‐associated CDI may also be changing. Virulent strains, which cause more severe disease in high‐risk patients, may also cause more frequent, severe disease in populations previously thought to be at low risk. Some studies have found an increase in community‐associated CDI in otherwise healthy individuals with little or no exposure to a healthcare facility. Although antimicrobial exposure remains the most important risk factor for community‐associated CDI, antimicrobial exposure is less common in community‐associated CDI than healthcare‐associated CDI. 3235

In a Canadian study, the rate of diagnosed community‐acquired CDI cases was stable at about 22 cases per 100,000 patient‐years per calendar year between 1998 and 2002, but rose steadily for the next 2 years to 53 cases per 100,000 patient‐years in 2004. 33 Similar results were seen in the United Kingdom, with an exponential increase from fewer than 1 case per 100,000 person‐years in 1994 to 22 cases per 100,000 person‐years in 2004. 32 There are currently no comprehensive longitudinal studies in the United States investigating the incidence of purely community‐acquired CDI where a patient had no prior hospital exposure. However, regional surveys have reported an incidence of community‐acquired CDI of 12 cases per 100,000 person‐years during 1992 to 1994, 36 7.6 cases per 100,000 person‐years in 2005, 37 and 6.9 cases per 100,000 person‐years in 2006. 34, 37

One patient population generally thought to be at low risk for CDI that may be at increased risk for severe CDI is pregnant women. In one study 419 infectious disease consultants who responded to a survey conducted by the Emerging Infections Network had seen or were aware of 55 cases of CDI in peripartum women. 38 There were 21 cases with complications, including 10 relapses and 5 cases of toxic megacolon. 38 In a prior report of severe CDI among 10 peripartum women, 3 women died and 3 infants (2 were twins) were stillborn. 38 This data emphasizes why clinicians must have a high index of suspicion for CDI, and should be aware of the potential for severe outcomes, even in patients traditionally considered to be at low risk. 38

ECONOMIC IMPACT OF CDI

The economic burden of CDI in the United States is staggering, with estimates ranging from $1.1 to $3.2 billion annually (Table 1). 3941 These estimates are based on the cost of caring for patients with CDI in acute care facilities and are primarily driven by increased length of stay in the hospital due to CDI. These data also predate the emergence of the BI/NAP1/027 strain. Therefore, the costs of CDI are likely higher than these estimates due to the increases in CDI severity seen since these studies were performed. It is important to note that these studies did not include patients diagnosed and treated in nursing homes or the community, nor the increase in costs due to discharge to a long‐term care facility. 39

SUMMARY

C. difficile infections are becoming more prevalent and more severe. The issue is sufficiently serious that healthcare‐onset CDI has recently been called a major public health threat. 42 For this reason, efforts to combat virulent C. difficile should include good antimicrobial stewardship, effective infection control, and control of environmental factors that promote transmission. 35 Healthcare professionals who oversee the care of inpatients should act as catalysts for improvement by taking a leadership role in the multidisciplinary approach needed to reduce the morbidity, mortality, and cost burden for patients and the healthcare system.

Clostridium difficile is a gram‐positive, spore‐forming, toxin‐producing, anaerobic bacillus that was established as the causative pathogen of most cases of antibiotic‐associated colitis in 1978. 1, 2 The spectrum of possible clinical presentations of C. difficile range from asymptomatic colonization, uncomplicated diarrhea, severe pseudomembranous colitis, paralytic ileus, to sepsis and death, with a mortality rate upwards of 80% in fulminant cases requiring colectomy. 3

Vegetative C. difficile cells die rapidly on dry surfaces, but they have been found to remain viable for up to 6 hours on moist surfaces in room air. 4 Spores shed from the gastrointestinal (GI) tract, however, are highly resistant to common hospital disinfectants, and can survive in the environment for many months. 2 C. difficile spores are primarily transmitted from patient to patient on the hands or equipment of healthcare workers. 2 Once spores are ingested and reach the GI tract, they germinate in the vegetative form. 2, 5 In the GI tract, C. difficile causes disease by the production of toxins, primarily toxins A and B, both of which cause severe inflammation. 5 Toxin A attracts neutrophils and monocytes, and toxin B breaks down colonic epithelial cells. 5 Both of these mechanisms lead to colitis, formation of pseudomembranes, and watery diarrhea. 5

After alteration of the healthy colonic bacterial flora, the immune response to C. difficile toxins appears to play a major role in determining host susceptibility to C. difficile infection (CDI). 5, 6 Those with antitoxin immunity are more likely to become symptomless carriers than patients without preexisting immunity. 3 More than 60% of healthy adults have protective immunity against a primary CDI, demonstrated by detectable serum IgG and IgA to both toxins A and B, as a consequence of childhood immunity or frequent exposure to C. difficile in the environment. 3 After a primary episode of CDI, many patients acquire protective immunity against C. difficile toxins, seen as significantly higher serum concentrations of IgM against C. difficile toxin by the third day from onset of diarrhea, and significantly higher serum concentrations of IgG against toxin A by the 12th day. 7 Patients who experience recurrent CDI lack development of this protective immunity to C. difficile. 6, 7

CDI INCIDENCE IS ON THE RISE

During the past decade, rates of CDI have increased steadily to levels not previously seen. A report published by the Agency of Healthcare Research and Quality demonstrated that the number of CDI diagnoses on hospital discharge more than doubled in the United States from 139,000 to 301,200 between 2000 and 2005 (Figure 1). 8 Examination of a more recent Nationwide Inpatient Sample (NIS) indicates continuation of this trend, with nearly 350,000 CDI diagnoses recorded upon discharge from acute care hospitals in 2008. 9 Of note, in 2006 the state of Ohio mandated CDI reporting from both hospitals and nursing homes. It was estimated there were more than 18,000 cases of CDI during this year, of which more than 60% were diagnosed in nursing homes. 10 Based on the 2008 NIS data and the data from Ohio, it is conceivable there were as many as 1 million cases of CDI in the US in 2008.

Figure 1

This increased incidence of CDI contrasts with several other healthcare‐associated infections, which have declined in incidence over the last decade. 1113 C. difficile is the most common causative agent of healthcare‐associated infections in some areas. A cohort study of common infections among inpatients at 30 community hospitals in the Duke Infection Control Outreach Network conducted between January 1, 2008 and June 30, 2009 found the incidence of CDI cases was 0.26 cases per 1000 patient‐days, which was higher than the incidence of methicillin‐resistant Staphylococcus aureus (MRSA) at 0.22 cases per 1000 patient‐days. 14 Another study utilizing the NIS data found that, while vancomycin‐resistant enterococcus and pseudomonas infections remained stable, CDI increased in many areas of the country and was more common than MRSA in some areas. 15

HYPERVIRULENT STRAIN OF C. DIFFICILE

In the early 2000s, an epidemic and hypervirulent strain of C. difficile emerged in North America and Europe that altered the epidemiology of CDI. 16 Due to multiple different methods for molecular typing of C. difficile, this strain has several names depending on the method of typing performed. The most common names for this strain are BI (REA typing), NAP1 (pulsed field gel electrophoresis), and 027 (PCR‐ribotyping). This strain has become the predominant strain of C. difficile in some areas, accounting for more than 80% of CDI cases in some areas. 3

The characteristics of this particular strain epidemic in North America typically include:

• A deletion in the tcd gene that downregulates toxin production, which renders the gene nonfunctional in the epidemic strain. Some in vitro data have demonstrated that this epidemic strain produces 16‐fold higher concentrations of toxin A and 23‐fold higher concentrations of toxin B than nonepidemic strains of C. difficile. 17

• Production of a third toxin, called binary toxin CDT. The role of this toxin in the pathogenesis of CDI is not clear, but the presence of this toxin has been associated with more severe CDI‐related diarrhea. 2, 16

• High‐level resistance to fluoroquinolones, including moxifloxacin and gatifloxacin. 5, 16 It has been theorized that increasing use of fluoroquinolones during the past decade may have provided a selective advantage for the BI/NAP1/027 strain to predominate. 2

• Production of more spores than other strains of C. difficile. 17, 18 This may increase its ability to contaminate the environment and be transmitted in a healthcare facility.

CDI SEVERITY IS INCREASING

Paralleling the increased prevalence of CDI, C. difficile infections are generally becoming more severe. In Sherbrooke, Quebec, Canada, which experienced a dramatic outbreak of CDI associated with increased CDI severity, the cumulative 1‐year attributable mortality was nearly 37% (60 of 161 CDI cases) in a hospital case review of nonsurgical admissions between January 2003 and June 2004. 19 In St Louis, Missouri in 2003, a 5.7% 180‐day mortality rate was reported in an endemic setting. 20 Among the 24% of patients readmitted within 180 days of discharge (4207 of 17,492) in this retrospective case review, patients with CDI were more than twice as likely as non‐CDI patients to be readmitted to the hospital (52% vs 23%, N = 4207). 20 Furthermore, patients with CDI were significantly more likely to require discharge to a long‐term care facility (32%) than non‐CDI controls (23%). 19

Based on NIS data for CDI‐related hospitalizations between 2000 and 2005, the crude, age‐adjusted case‐fatality rate rose from 1.2% in 2000 to 2.2% in 2004. 21 This increase was mirrored by a doubling of CDI cases admitted for hospitalization during the same 6‐year period. 21 According to the investigators, these findings indirectly confirm that the doubling in CDI deaths is attributable to an increase in C. difficile virulence. 21 A 6‐month prospective surveillance of CDI patient outcomes in 29 Canadian hospitals was conducted by the Canadian Nosocomial Infection Surveillance Program (CNISP) beginning in November 2004. 22 At 30 days after onset of CDI, the percentage of deaths directly or indirectly attributable to CDI was 5.7%, which represented an almost 4‐fold increase over CDI‐attributable deaths recorded in the 1997 CNISP survey. 22 Overall 30‐day mortality was retrospectively analyzed among patients with CDI in a St Louis, Missouri 1200‐bed teaching hospital intensive care unit (ICU) over a 2‐year period (20042005). 23 The 30‐day crude mortality among 278 patients admitted to the ICU with CDI was 37% (n = 102), and mortality directly attributable to CDI in these critically ill patients was 6%. 23 The number of deaths in the United States due to CDI increased sharply from 793 patients in 1999 to 6225 patients in 2006. 24 In 2006, it ranked among the top 20 causes of death for those aged 65 years and older. 24

INCREASE IN TREATMENT FAILURES

In addition to being more severe, there have been several reports of increases in CDI treatment failures and/or increases in recurrent CDI. 6 Recent studies indicate there may be more metronidazole treatment failures regardless of whether the infecting strain is the BI/NAP1/027 strain, despite a lack of laboratory evidence indicating resistance to metronidazole. 2529 Regardless of the initial therapy chosen, patients must be carefully monitored to ensure they are responding appropriately to treatment and their condition is not deteriorating. 29 Some of the original trials of CDI treatments found relapse rates as low as 5% to 15%. 30 More recent data indicate relapse occurs after 30% of initial CDI episodes, and as frequent as 65% if the patient has had multiple prior CDI episodes. 3, 6, 31

COMMUNITY‐ASSOCIATED CDI

The epidemiology of community‐associated CDI may also be changing. Virulent strains, which cause more severe disease in high‐risk patients, may also cause more frequent, severe disease in populations previously thought to be at low risk. Some studies have found an increase in community‐associated CDI in otherwise healthy individuals with little or no exposure to a healthcare facility. Although antimicrobial exposure remains the most important risk factor for community‐associated CDI, antimicrobial exposure is less common in community‐associated CDI than healthcare‐associated CDI. 3235

In a Canadian study, the rate of diagnosed community‐acquired CDI cases was stable at about 22 cases per 100,000 patient‐years per calendar year between 1998 and 2002, but rose steadily for the next 2 years to 53 cases per 100,000 patient‐years in 2004. 33 Similar results were seen in the United Kingdom, with an exponential increase from fewer than 1 case per 100,000 person‐years in 1994 to 22 cases per 100,000 person‐years in 2004. 32 There are currently no comprehensive longitudinal studies in the United States investigating the incidence of purely community‐acquired CDI where a patient had no prior hospital exposure. However, regional surveys have reported an incidence of community‐acquired CDI of 12 cases per 100,000 person‐years during 1992 to 1994, 36 7.6 cases per 100,000 person‐years in 2005, 37 and 6.9 cases per 100,000 person‐years in 2006. 34, 37

One patient population generally thought to be at low risk for CDI that may be at increased risk for severe CDI is pregnant women. In one study 419 infectious disease consultants who responded to a survey conducted by the Emerging Infections Network had seen or were aware of 55 cases of CDI in peripartum women. 38 There were 21 cases with complications, including 10 relapses and 5 cases of toxic megacolon. 38 In a prior report of severe CDI among 10 peripartum women, 3 women died and 3 infants (2 were twins) were stillborn. 38 This data emphasizes why clinicians must have a high index of suspicion for CDI, and should be aware of the potential for severe outcomes, even in patients traditionally considered to be at low risk. 38

ECONOMIC IMPACT OF CDI

The economic burden of CDI in the United States is staggering, with estimates ranging from $1.1 to $3.2 billion annually (Table 1). 3941 These estimates are based on the cost of caring for patients with CDI in acute care facilities and are primarily driven by increased length of stay in the hospital due to CDI. These data also predate the emergence of the BI/NAP1/027 strain. Therefore, the costs of CDI are likely higher than these estimates due to the increases in CDI severity seen since these studies were performed. It is important to note that these studies did not include patients diagnosed and treated in nursing homes or the community, nor the increase in costs due to discharge to a long‐term care facility. 39

SUMMARY

C. difficile infections are becoming more prevalent and more severe. The issue is sufficiently serious that healthcare‐onset CDI has recently been called a major public health threat. 42 For this reason, efforts to combat virulent C. difficile should include good antimicrobial stewardship, effective infection control, and control of environmental factors that promote transmission. 35 Healthcare professionals who oversee the care of inpatients should act as catalysts for improvement by taking a leadership role in the multidisciplinary approach needed to reduce the morbidity, mortality, and cost burden for patients and the healthcare system.

The incidence and severity of Clostridium difficile infections (CDI) have increased steadily over the past decade, paralleling the emergence of an epidemic strain of C. difficile in North America, the North American pulsed field type 1 (NAP1), restriction‐endonuclease analysis type BI, polymerase‐chain‐reaction ribotype 027, commonly referred to as NAP1/BI/027. The reduced responsiveness of CDI to standard antibiotic therapy, and increased death rate attributable to CDI, present a significant challenge to clinicians. 1 This is a brief review of clinical strategies for effective management of initial CDI for hospital‐based physicians.

Effective management of CDI requires a multidisciplinary effort that includes identification of patients at risk, rapid implementation of contact isolation for patients suspected of having CDI, and implementation of early and appropriate treatment based on current clinical evidence. 2 Early recognition is, in large part, based on suspecting CDI anytime a patient develops antibiotic‐associated diarrhea. An understanding of traditional and emerging risk factors for CDI can help clinicians identify this serious condition early.

CASE STUDY

A.L. is an 87‐year‐old woman in a rehabilitation facility who is recovering from left hip replacement surgery performed 3 weeks ago. Her past medical history is positive for heart failure, atrial fibrillation, type 2 diabetes mellitus, and chronic obstructive pulmonary disease. During her hospitalization, she was treated preoperatively with cephalexin for prophylaxis. She was recently started on ciprofloxacin for a urinary tract infection, and has been taking this for 6 days.

During morning rounds, her nurse reports that A.L. has had diarrhea for 2 days. She is currently afebrile, and her white blood cell (WBC) count is 11,400/L. Ciprofloxacin was discontinued and a stool test for C. difficile toxin was ordered.

RISK FACTORS FOR CDI

The risk of developing CDI depends on 3 groups of factors: impairment of colonization resistance, risk of exposure to toxigenic C. difficile or its spores, and host health and immune status.

RISK FACTORS FOR RECURRENT CDI

The incidence of recurrent CDI within 60 to 90 days of initial CDI resolution following a course of treatment with metronidazole, vancomycin, or both is mostly 19% to 29%, but was 50% in 1 report. 11 The risk for CDI recurrence increases with each recurrent episode 12: Patients with 1 prior episode of recurrent CDI have a >40% risk for an additional recurrence, and those with 2 or more episodes have a >60% risk. 13, 14 Two likely mechanisms that predispose patients to recurrent CDI are an inadequate immune response to C. difficile toxins and persistent disruption of the normal colonic flora due to therapy with metronidazole, vancomycin, or other concomitant antibiotics. 15 Recurrent CDI is seldom due to resistance of vegetative cells of C. difficile to vancomycin or metronidazole. 14 Two other important factors associated with recurrence are infection with a hypervirulent strain of C. difficile, and the fact that the current hospital population generally consists of older and sicker patients who have been treated with many broad‐spectrum antibiotics. 16

Specific patient risk factors associated with recurrent CDI include 14, 17, 18:

• Previous history of recurrence.

• Increased age (>65).

• Severe underlying disease.

• Renal impairment.

• Conditions or treatments that lead to immunocompromise.

• Hospital admission (especially prolonged hospital stay).

• Use of additional antibiotics.

As noted above, ongoing treatment with antibiotics plays an important role in the risk for recurrence. Hu and colleagues found that concomitant antibiotic use after a diagnosis of CDI was associated with a 10‐fold increased risk for recurrence (odds ratio [OR], 10.0; 95% confidence interval [CI], 1.5‐68.3). 12 Johnson and colleagues found that the rate of sustained response to CDI therapy, without subsequent recurrence, was higher in patients able to stop all other antibiotics and be treated with only fidaxomicin or vancomycin than it was in a group of patients treated with 1 of these agents plus an additional antibiotic (91.9% and 76.1%, respectively). 19 In general, patients who require concomitant antibiotics have more comorbidities and are sicker, so the entire difference cannot be attributed to antibiotics. However, clinicians should carefully consider the ongoing need for antibiotics if CDI is suspected or confirmed.

Continued exposure to C. difficile in the hospital or home environment often leads to reinfection when vancomycin and metronidazole concentrations have decreased. Data show that at least half of clinical recurrences are reinfection with a different strain, and half are due to persisting intestinal infection with the original infecting strain. 20 Therefore, patients with CDI should be educated about appropriate hygiene at home.

CLINICAL MANIFESTATIONS OF CDI

CDI has a wide range of clinical manifestations, ranging from a mild and self‐limited diarrheal illness to fulminant, life‐threatening colitis. The onset of symptoms usually occurs within 3 to 7 days of antibiotic exposure, but may not arise for up to 10 weeks after stopping antibiotics. 5 CDI is associated with watery diarrhea that is often accompanied by cramping abdominal pain and low‐grade fever. Systemic symptoms generally increase with the degree of colitis. Patients with severe disease may also progress to having an ileus, or toxic megacolon or acute abdomen. 5

Up to 20% of critically ill patients have ileus or toxic megacolon, and therefore may not present with diarrhea; this, combined with a limited ability to communicate among some critically ill patients makes early diagnosis of CDI in this patient population extremely challenging. Therefore, physicians and other clinical staff must be vigilant about evaluating patients for the presence of CDI based on physical exam and laboratory findings. For example, fever, abdominal pain, and abdominal distention are likely to be present in patients with severe colitis. In addition, patients often have significant leukocytosis (often >20,000 cells/mm 3) with bandemia. In advanced cases, an elevated serum lactate dehydrogenase may be seenthis is a nonspecific finding for gastrointestinal disease, but provides a clue to the presence of CDI. Because these findings often precede multiorgan dysfunction, the presence of CDI must be determined quickly and appropriate treatment initiated. 5

PRINCIPLES OF DIAGNOSIS

C. difficile infection should be suspected in patients with antimicrobial‐associated diarrhea. Confirmatory testing should be performed, but only on watery or loose stools because the rate of symptomless colonization with C. difficile in hospitalized patients is high; a positive result on a normal stool sample proves only that the patient is colonized with C. difficile, but not necessarily infected. 14 A notable exception is when CDI is suspected in a patient with ileus; as many laboratories will not accept solid stool for C. difficile testing, the clinician should notify the laboratory about the specific request and reasons for suspecting CDI. 21 Stool testing for eradication of C. difficile during or after therapy is not advised, as many successfully treated patients will continue to shed the organism and its spores. 2 This symptomless carriage does not require additional treatment.

CASE STUDY CONTINUED

A.L. was empirically started on oral metronidazole, 500 mg 3 times a day, pending results of the stool C. difficile test.

On rounds the following day, diarrhea was less frequent (decreased from 9 to 4 loose bowel movements in 24 hours). She reported mild abdominal discomfort and nausea, but was tolerating oral intake. Her temperature was 100.8F.

Her lab results returned later in the afternoon were:

• WBC: 18,600 cells/L.

• Potassium: 3.2 mEq/mL.

• Creatinine: 2.4 mg/dL (up from 1.1).

• Stool C. difficile test: negative.

There are a variety of tests for C. difficile, each with advantages and disadvantages (Table 2). 2, 3, 21 Factors to consider when selecting a diagnostic test include turnaround time, sensitivity, specificity, cost, whether there is an ongoing outbreak, and the availability of particular tests. 21 Recent guidelines for CDI management jointly developed by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA) note that stool culture is the gold standard, but recognize the clinical limitations of its long turnaround time. 2 Enzyme immunoassay (EIA) is noted to be a suboptimal alternative approach for diagnosis than the cell cytotoxin assay. 2 Therefore, because EIA is most often used in clinical practice, it is important to be aware that a high clinical suspicion for CDI may warrant empiric therapy or repeat testing with a more sensitive test in a patient with an initial negative test result. 3, 21

CURRENT STRATEGIES FOR CDI MANAGEMENT

While current guidelines recommend that treatment of CDI be based on disease severity, 2, 22 determination of severity is challenging, in part, because standard definitions are lacking and because the illness varies along a continuum of symptoms. 5 In general, CDI can be categorized as: mild to moderate, severe, and severe disease with complications. Mild to moderate CDI is characterized by diarrhea and abdominal cramping, only without systemic symptoms. 5, 21 Severe CDI is distinguished by abundant diarrhea, severe abdominal pain/distension, leukocytosis, fever, or other systemic symptoms (Table 3). 5, 21, 2326 Patients with severe disease and other complications may present with a wide range of gastrointestinal symptoms accompanied by paralytic ileus, toxic megacolon, or other life‐threatening conditions. 5, 21 CDI may progress in severity rapidly, even after initiation of treatment, so ongoing assessment of the patient's condition and disease category is important. 5, 21

In 2010, SHEA/IDSA published evidence‐based guidelines for managing CDI based on severity of illness (summarized in Table 4). 2 The first and most important step in the effective management of CDI in all patients, regardless of severity, is to discontinue the causative antibiotic(s). 1 Data show that when all antibiotics are stopped, about 25% of patients with mild CDI who are otherwise healthy have resolution of diarrhea within 48 hours 27; most importantly, recurrent CDI is unlikely. Many hospitalized patients, especially in the intensive care setting, have serious concomitant infections, and therefore it may not be appropriate to discontinue the inciting antibiotic. In these patients, the regimen and available culture and sensitivity results should be thoughtfully reviewed, and change made when possible to a more narrow‐spectrum regimen less likely to cause or exacerbate CDI (Table 1).

The next step, as discussed above, is to send a stool sample for C. difficile testing. Based on the patient's clinical circumstances, the decision must be made whether or not to begin empiric therapy. In general, beginning treatment without testing for C. difficile is not recommended, because, at most, only about a third of hospitalized patients with diarrhea have CDI, even in an epidemic setting. 21 If a patient is severely ill or has a rapidly deteriorating clinical course and is at high risk for CDI, empiric therapy may be appropriate while awaiting test results. 21

In patients with severe CDI and complications, reduced or absent bowel motility can reduce the amount of orally administered vancomycin that reaches the site of infection. Intracolonic administration of vancomycin may be indicated in these cases, or when oral therapy cannot be tolerated. 28 Higher doses of oral vancomycin may also be used, with the goal of increasing fecal concentrations, however this strategy has not been studied. 5 In all patients, antiperistaltic agents are usually avoided because of unproven concerns that they might mask symptoms and/or increase the risk for toxic megacolon. 2

Fidaxomicin, a new macrolide antibiotic in the macrocyclic group, has a narrow‐spectrum and excellent activity against C. difficile. The US Food and Drug Administration approved fidaxomicin for treatment of adults for C. difficileassociated diarrhea (CDAD) in May 2011. 29 Approval was based on 2 phase III trials involving 1105 patients with CDAD in which fidaxomicin was shown to have similar initial clinical efficacy and safety as vancomycin. 30 In addition, more patients treated with fidaxomicin had a sustained response 25 days following discontinuation of treatment than patients treated with vancomycin. 31 The recommended dosage of fidaxomicin is one 200‐mg tablet orally twice daily for 10 days. 31

In a phase III trial (N = 596) of fidaxomicin (200 mg orally every 12 hours) versus vancomycin (125 mg orally every 6 hours) for 10 days, fidaxomicin was shown to be noninferior to vancomycin in achieving an initial clinical response and significantly better at preventing recurrent CDI. 32 The rates of initial clinical response, the primary endpoint, and rates of recurrent CDI are shown in Table 5. The significant difference in recurrence may be explained by the fact that metronidazole and vancomycin impact commensal microflora populations that normally mediate competitive exclusion of C. difficile. Compared with vancomycin, fidaxomicin has less effect on the composition of the fecal microbiota, in particular some clostridial clusters and Bifidobacterium. 33 While acquisition costs for this new antibiotic are a consideration, they may be offset by a reduction in recurrent CDI, especially in high‐risk patients.

FOCUS ON FULMINANT/REFRACTORY CDI

Management of CDI that is fulminant and/or refractory can be extremely challenging. 3 In clinical practice, these conditions often overlap. Clinical characteristics that may help identify fulminant CDI include abdominal pain and tenderness, colonic distension, and signs of sepsis. Diarrhea may be absent or minimal due to ileus. Furthermore, a diagnosis of CDI is easy to miss, as these symptoms are also consistent with ischemic bowel or a perforated viscus. 3 Gentle, flexible sigmoidoscopy or colonoscopy (without bowel preparation and with minimal air insufflation) may be extremely valuable to allow for immediate identification of pseudomembranous colitis, which speeds appropriate medical and surgical management. 3

First‐line treatment for fulminant or refractory CDI is oral or intragastric vancomycin 500 mg every 6 hours. 2, 3 Intravenous (IV) metronidazole 500 mg every 6 hours should be added to the treatment regimen in those with ileus or megacolon. For patients with complete ileus, vancomycin can be administered rectally as 500 mg in 100 mL of normal saline every 6 hours. 3 Normal pooled IV immunoglobulin has been used with mixed success, in patients with fulminant and/or refractory CDI, in an attempt to avert surgery or death by providing passive immunotherapy against C. difficile toxins A and B. 34 In a study of monoclonal antibodies to toxins A and B that included 200 patients, recurrence rates among those with the epidemic NAP1/BI/027 strain were 8% for the antibody group and 32% for the placebo group (P = 0.06); in a subset with more than 1 previous episode of CDI, recurrence rates were 7% and 38%, respectively (P = 0.006). 35

Some patients with fulminant or refractory CDI are best managed with subtotal colectomy, which may be lifesaving. 36 However, the optimal timing of surgery is difficult to establish, and the decision to proceed with this course can be difficult because patients with severe CDI are typically poor surgical candidates. 3 Delaying surgery until the development of a systemic inflammatory response syndrome with concomitant severe disease, such as multisystem organ failure, immunocompromise, or hemodynamic instability, usually results in a poor outcome. 37, 38 The best approach is to get a surgical consult early, when the course of CDI starts to deteriorate, so that management decisions can be based on input from a multidisciplinary team of clinicians. 3

CASE STUDY CONTINUED

A.L. was subsequently transferred to an acute care facility. Her therapy for C. difficile was switched to oral vancomycin, 125 mg 4 times daily. On arrival in the emergency department, the following findings were noted:

• No further diarrhea, but abdominal distention noted.

• Temperature: 101.4F.

• Fall in blood pressure (BP) to 90/48 mmHg during transfer, which responded to a fluid bolus, and increased to 108/74.

• WBC: 27,000/L.

• Abdominal computed tomography (CT) showed thickening of descending and sigmoid colon, and the rectum.

• Proctoscopy confirmed pseudomembranous colitis.

Oral vancomycin was increased to 500 mg 4 times daily, and IV metronidazole 500 mg every 8 hours was added. C. difficile infection responded to this regimen and she was subsequently discharged to home care.

The incidence and severity of Clostridium difficile infections (CDI) have increased steadily over the past decade, paralleling the emergence of an epidemic strain of C. difficile in North America, the North American pulsed field type 1 (NAP1), restriction‐endonuclease analysis type BI, polymerase‐chain‐reaction ribotype 027, commonly referred to as NAP1/BI/027. The reduced responsiveness of CDI to standard antibiotic therapy, and increased death rate attributable to CDI, present a significant challenge to clinicians. 1 This is a brief review of clinical strategies for effective management of initial CDI for hospital‐based physicians.

Effective management of CDI requires a multidisciplinary effort that includes identification of patients at risk, rapid implementation of contact isolation for patients suspected of having CDI, and implementation of early and appropriate treatment based on current clinical evidence. 2 Early recognition is, in large part, based on suspecting CDI anytime a patient develops antibiotic‐associated diarrhea. An understanding of traditional and emerging risk factors for CDI can help clinicians identify this serious condition early.

CASE STUDY

A.L. is an 87‐year‐old woman in a rehabilitation facility who is recovering from left hip replacement surgery performed 3 weeks ago. Her past medical history is positive for heart failure, atrial fibrillation, type 2 diabetes mellitus, and chronic obstructive pulmonary disease. During her hospitalization, she was treated preoperatively with cephalexin for prophylaxis. She was recently started on ciprofloxacin for a urinary tract infection, and has been taking this for 6 days.

During morning rounds, her nurse reports that A.L. has had diarrhea for 2 days. She is currently afebrile, and her white blood cell (WBC) count is 11,400/L. Ciprofloxacin was discontinued and a stool test for C. difficile toxin was ordered.

RISK FACTORS FOR CDI

The risk of developing CDI depends on 3 groups of factors: impairment of colonization resistance, risk of exposure to toxigenic C. difficile or its spores, and host health and immune status.

RISK FACTORS FOR RECURRENT CDI

The incidence of recurrent CDI within 60 to 90 days of initial CDI resolution following a course of treatment with metronidazole, vancomycin, or both is mostly 19% to 29%, but was 50% in 1 report. 11 The risk for CDI recurrence increases with each recurrent episode 12: Patients with 1 prior episode of recurrent CDI have a >40% risk for an additional recurrence, and those with 2 or more episodes have a >60% risk. 13, 14 Two likely mechanisms that predispose patients to recurrent CDI are an inadequate immune response to C. difficile toxins and persistent disruption of the normal colonic flora due to therapy with metronidazole, vancomycin, or other concomitant antibiotics. 15 Recurrent CDI is seldom due to resistance of vegetative cells of C. difficile to vancomycin or metronidazole. 14 Two other important factors associated with recurrence are infection with a hypervirulent strain of C. difficile, and the fact that the current hospital population generally consists of older and sicker patients who have been treated with many broad‐spectrum antibiotics. 16

Specific patient risk factors associated with recurrent CDI include 14, 17, 18:

• Previous history of recurrence.

• Increased age (>65).

• Severe underlying disease.

• Renal impairment.

• Conditions or treatments that lead to immunocompromise.

• Hospital admission (especially prolonged hospital stay).

• Use of additional antibiotics.

As noted above, ongoing treatment with antibiotics plays an important role in the risk for recurrence. Hu and colleagues found that concomitant antibiotic use after a diagnosis of CDI was associated with a 10‐fold increased risk for recurrence (odds ratio [OR], 10.0; 95% confidence interval [CI], 1.5‐68.3). 12 Johnson and colleagues found that the rate of sustained response to CDI therapy, without subsequent recurrence, was higher in patients able to stop all other antibiotics and be treated with only fidaxomicin or vancomycin than it was in a group of patients treated with 1 of these agents plus an additional antibiotic (91.9% and 76.1%, respectively). 19 In general, patients who require concomitant antibiotics have more comorbidities and are sicker, so the entire difference cannot be attributed to antibiotics. However, clinicians should carefully consider the ongoing need for antibiotics if CDI is suspected or confirmed.

Continued exposure to C. difficile in the hospital or home environment often leads to reinfection when vancomycin and metronidazole concentrations have decreased. Data show that at least half of clinical recurrences are reinfection with a different strain, and half are due to persisting intestinal infection with the original infecting strain. 20 Therefore, patients with CDI should be educated about appropriate hygiene at home.

CLINICAL MANIFESTATIONS OF CDI

CDI has a wide range of clinical manifestations, ranging from a mild and self‐limited diarrheal illness to fulminant, life‐threatening colitis. The onset of symptoms usually occurs within 3 to 7 days of antibiotic exposure, but may not arise for up to 10 weeks after stopping antibiotics. 5 CDI is associated with watery diarrhea that is often accompanied by cramping abdominal pain and low‐grade fever. Systemic symptoms generally increase with the degree of colitis. Patients with severe disease may also progress to having an ileus, or toxic megacolon or acute abdomen. 5

Up to 20% of critically ill patients have ileus or toxic megacolon, and therefore may not present with diarrhea; this, combined with a limited ability to communicate among some critically ill patients makes early diagnosis of CDI in this patient population extremely challenging. Therefore, physicians and other clinical staff must be vigilant about evaluating patients for the presence of CDI based on physical exam and laboratory findings. For example, fever, abdominal pain, and abdominal distention are likely to be present in patients with severe colitis. In addition, patients often have significant leukocytosis (often >20,000 cells/mm 3) with bandemia. In advanced cases, an elevated serum lactate dehydrogenase may be seenthis is a nonspecific finding for gastrointestinal disease, but provides a clue to the presence of CDI. Because these findings often precede multiorgan dysfunction, the presence of CDI must be determined quickly and appropriate treatment initiated. 5

PRINCIPLES OF DIAGNOSIS

C. difficile infection should be suspected in patients with antimicrobial‐associated diarrhea. Confirmatory testing should be performed, but only on watery or loose stools because the rate of symptomless colonization with C. difficile in hospitalized patients is high; a positive result on a normal stool sample proves only that the patient is colonized with C. difficile, but not necessarily infected. 14 A notable exception is when CDI is suspected in a patient with ileus; as many laboratories will not accept solid stool for C. difficile testing, the clinician should notify the laboratory about the specific request and reasons for suspecting CDI. 21 Stool testing for eradication of C. difficile during or after therapy is not advised, as many successfully treated patients will continue to shed the organism and its spores. 2 This symptomless carriage does not require additional treatment.

CASE STUDY CONTINUED

A.L. was empirically started on oral metronidazole, 500 mg 3 times a day, pending results of the stool C. difficile test.

On rounds the following day, diarrhea was less frequent (decreased from 9 to 4 loose bowel movements in 24 hours). She reported mild abdominal discomfort and nausea, but was tolerating oral intake. Her temperature was 100.8F.

Her lab results returned later in the afternoon were:

• WBC: 18,600 cells/L.

• Potassium: 3.2 mEq/mL.

• Creatinine: 2.4 mg/dL (up from 1.1).

• Stool C. difficile test: negative.

There are a variety of tests for C. difficile, each with advantages and disadvantages (Table 2). 2, 3, 21 Factors to consider when selecting a diagnostic test include turnaround time, sensitivity, specificity, cost, whether there is an ongoing outbreak, and the availability of particular tests. 21 Recent guidelines for CDI management jointly developed by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA) note that stool culture is the gold standard, but recognize the clinical limitations of its long turnaround time. 2 Enzyme immunoassay (EIA) is noted to be a suboptimal alternative approach for diagnosis than the cell cytotoxin assay. 2 Therefore, because EIA is most often used in clinical practice, it is important to be aware that a high clinical suspicion for CDI may warrant empiric therapy or repeat testing with a more sensitive test in a patient with an initial negative test result. 3, 21

CURRENT STRATEGIES FOR CDI MANAGEMENT

While current guidelines recommend that treatment of CDI be based on disease severity, 2, 22 determination of severity is challenging, in part, because standard definitions are lacking and because the illness varies along a continuum of symptoms. 5 In general, CDI can be categorized as: mild to moderate, severe, and severe disease with complications. Mild to moderate CDI is characterized by diarrhea and abdominal cramping, only without systemic symptoms. 5, 21 Severe CDI is distinguished by abundant diarrhea, severe abdominal pain/distension, leukocytosis, fever, or other systemic symptoms (Table 3). 5, 21, 2326 Patients with severe disease and other complications may present with a wide range of gastrointestinal symptoms accompanied by paralytic ileus, toxic megacolon, or other life‐threatening conditions. 5, 21 CDI may progress in severity rapidly, even after initiation of treatment, so ongoing assessment of the patient's condition and disease category is important. 5, 21

In 2010, SHEA/IDSA published evidence‐based guidelines for managing CDI based on severity of illness (summarized in Table 4). 2 The first and most important step in the effective management of CDI in all patients, regardless of severity, is to discontinue the causative antibiotic(s). 1 Data show that when all antibiotics are stopped, about 25% of patients with mild CDI who are otherwise healthy have resolution of diarrhea within 48 hours 27; most importantly, recurrent CDI is unlikely. Many hospitalized patients, especially in the intensive care setting, have serious concomitant infections, and therefore it may not be appropriate to discontinue the inciting antibiotic. In these patients, the regimen and available culture and sensitivity results should be thoughtfully reviewed, and change made when possible to a more narrow‐spectrum regimen less likely to cause or exacerbate CDI (Table 1).

The next step, as discussed above, is to send a stool sample for C. difficile testing. Based on the patient's clinical circumstances, the decision must be made whether or not to begin empiric therapy. In general, beginning treatment without testing for C. difficile is not recommended, because, at most, only about a third of hospitalized patients with diarrhea have CDI, even in an epidemic setting. 21 If a patient is severely ill or has a rapidly deteriorating clinical course and is at high risk for CDI, empiric therapy may be appropriate while awaiting test results. 21

In patients with severe CDI and complications, reduced or absent bowel motility can reduce the amount of orally administered vancomycin that reaches the site of infection. Intracolonic administration of vancomycin may be indicated in these cases, or when oral therapy cannot be tolerated. 28 Higher doses of oral vancomycin may also be used, with the goal of increasing fecal concentrations, however this strategy has not been studied. 5 In all patients, antiperistaltic agents are usually avoided because of unproven concerns that they might mask symptoms and/or increase the risk for toxic megacolon. 2

Fidaxomicin, a new macrolide antibiotic in the macrocyclic group, has a narrow‐spectrum and excellent activity against C. difficile. The US Food and Drug Administration approved fidaxomicin for treatment of adults for C. difficileassociated diarrhea (CDAD) in May 2011. 29 Approval was based on 2 phase III trials involving 1105 patients with CDAD in which fidaxomicin was shown to have similar initial clinical efficacy and safety as vancomycin. 30 In addition, more patients treated with fidaxomicin had a sustained response 25 days following discontinuation of treatment than patients treated with vancomycin. 31 The recommended dosage of fidaxomicin is one 200‐mg tablet orally twice daily for 10 days. 31

In a phase III trial (N = 596) of fidaxomicin (200 mg orally every 12 hours) versus vancomycin (125 mg orally every 6 hours) for 10 days, fidaxomicin was shown to be noninferior to vancomycin in achieving an initial clinical response and significantly better at preventing recurrent CDI. 32 The rates of initial clinical response, the primary endpoint, and rates of recurrent CDI are shown in Table 5. The significant difference in recurrence may be explained by the fact that metronidazole and vancomycin impact commensal microflora populations that normally mediate competitive exclusion of C. difficile. Compared with vancomycin, fidaxomicin has less effect on the composition of the fecal microbiota, in particular some clostridial clusters and Bifidobacterium. 33 While acquisition costs for this new antibiotic are a consideration, they may be offset by a reduction in recurrent CDI, especially in high‐risk patients.

FOCUS ON FULMINANT/REFRACTORY CDI

Management of CDI that is fulminant and/or refractory can be extremely challenging. 3 In clinical practice, these conditions often overlap. Clinical characteristics that may help identify fulminant CDI include abdominal pain and tenderness, colonic distension, and signs of sepsis. Diarrhea may be absent or minimal due to ileus. Furthermore, a diagnosis of CDI is easy to miss, as these symptoms are also consistent with ischemic bowel or a perforated viscus. 3 Gentle, flexible sigmoidoscopy or colonoscopy (without bowel preparation and with minimal air insufflation) may be extremely valuable to allow for immediate identification of pseudomembranous colitis, which speeds appropriate medical and surgical management. 3

First‐line treatment for fulminant or refractory CDI is oral or intragastric vancomycin 500 mg every 6 hours. 2, 3 Intravenous (IV) metronidazole 500 mg every 6 hours should be added to the treatment regimen in those with ileus or megacolon. For patients with complete ileus, vancomycin can be administered rectally as 500 mg in 100 mL of normal saline every 6 hours. 3 Normal pooled IV immunoglobulin has been used with mixed success, in patients with fulminant and/or refractory CDI, in an attempt to avert surgery or death by providing passive immunotherapy against C. difficile toxins A and B. 34 In a study of monoclonal antibodies to toxins A and B that included 200 patients, recurrence rates among those with the epidemic NAP1/BI/027 strain were 8% for the antibody group and 32% for the placebo group (P = 0.06); in a subset with more than 1 previous episode of CDI, recurrence rates were 7% and 38%, respectively (P = 0.006). 35

Some patients with fulminant or refractory CDI are best managed with subtotal colectomy, which may be lifesaving. 36 However, the optimal timing of surgery is difficult to establish, and the decision to proceed with this course can be difficult because patients with severe CDI are typically poor surgical candidates. 3 Delaying surgery until the development of a systemic inflammatory response syndrome with concomitant severe disease, such as multisystem organ failure, immunocompromise, or hemodynamic instability, usually results in a poor outcome. 37, 38 The best approach is to get a surgical consult early, when the course of CDI starts to deteriorate, so that management decisions can be based on input from a multidisciplinary team of clinicians. 3

CASE STUDY CONTINUED

A.L. was subsequently transferred to an acute care facility. Her therapy for C. difficile was switched to oral vancomycin, 125 mg 4 times daily. On arrival in the emergency department, the following findings were noted:

• No further diarrhea, but abdominal distention noted.

• Temperature: 101.4F.

• Fall in blood pressure (BP) to 90/48 mmHg during transfer, which responded to a fluid bolus, and increased to 108/74.

• WBC: 27,000/L.

• Abdominal computed tomography (CT) showed thickening of descending and sigmoid colon, and the rectum.

• Proctoscopy confirmed pseudomembranous colitis.

Oral vancomycin was increased to 500 mg 4 times daily, and IV metronidazole 500 mg every 8 hours was added. C. difficile infection responded to this regimen and she was subsequently discharged to home care.

The incidence and severity of Clostridium difficile infections (CDI) have increased steadily over the past decade, paralleling the emergence of an epidemic strain of C. difficile in North America, the North American pulsed field type 1 (NAP1), restriction‐endonuclease analysis type BI, polymerase‐chain‐reaction ribotype 027, commonly referred to as NAP1/BI/027. The reduced responsiveness of CDI to standard antibiotic therapy, and increased death rate attributable to CDI, present a significant challenge to clinicians. 1 This is a brief review of clinical strategies for effective management of initial CDI for hospital‐based physicians.

Effective management of CDI requires a multidisciplinary effort that includes identification of patients at risk, rapid implementation of contact isolation for patients suspected of having CDI, and implementation of early and appropriate treatment based on current clinical evidence. 2 Early recognition is, in large part, based on suspecting CDI anytime a patient develops antibiotic‐associated diarrhea. An understanding of traditional and emerging risk factors for CDI can help clinicians identify this serious condition early.

CASE STUDY

A.L. is an 87‐year‐old woman in a rehabilitation facility who is recovering from left hip replacement surgery performed 3 weeks ago. Her past medical history is positive for heart failure, atrial fibrillation, type 2 diabetes mellitus, and chronic obstructive pulmonary disease. During her hospitalization, she was treated preoperatively with cephalexin for prophylaxis. She was recently started on ciprofloxacin for a urinary tract infection, and has been taking this for 6 days.

During morning rounds, her nurse reports that A.L. has had diarrhea for 2 days. She is currently afebrile, and her white blood cell (WBC) count is 11,400/L. Ciprofloxacin was discontinued and a stool test for C. difficile toxin was ordered.

RISK FACTORS FOR CDI

The risk of developing CDI depends on 3 groups of factors: impairment of colonization resistance, risk of exposure to toxigenic C. difficile or its spores, and host health and immune status.

RISK FACTORS FOR RECURRENT CDI

The incidence of recurrent CDI within 60 to 90 days of initial CDI resolution following a course of treatment with metronidazole, vancomycin, or both is mostly 19% to 29%, but was 50% in 1 report. 11 The risk for CDI recurrence increases with each recurrent episode 12: Patients with 1 prior episode of recurrent CDI have a >40% risk for an additional recurrence, and those with 2 or more episodes have a >60% risk. 13, 14 Two likely mechanisms that predispose patients to recurrent CDI are an inadequate immune response to C. difficile toxins and persistent disruption of the normal colonic flora due to therapy with metronidazole, vancomycin, or other concomitant antibiotics. 15 Recurrent CDI is seldom due to resistance of vegetative cells of C. difficile to vancomycin or metronidazole. 14 Two other important factors associated with recurrence are infection with a hypervirulent strain of C. difficile, and the fact that the current hospital population generally consists of older and sicker patients who have been treated with many broad‐spectrum antibiotics. 16

Specific patient risk factors associated with recurrent CDI include 14, 17, 18:

• Previous history of recurrence.

• Increased age (>65).

• Severe underlying disease.

• Renal impairment.

• Conditions or treatments that lead to immunocompromise.

• Hospital admission (especially prolonged hospital stay).

• Use of additional antibiotics.

As noted above, ongoing treatment with antibiotics plays an important role in the risk for recurrence. Hu and colleagues found that concomitant antibiotic use after a diagnosis of CDI was associated with a 10‐fold increased risk for recurrence (odds ratio [OR], 10.0; 95% confidence interval [CI], 1.5‐68.3). 12 Johnson and colleagues found that the rate of sustained response to CDI therapy, without subsequent recurrence, was higher in patients able to stop all other antibiotics and be treated with only fidaxomicin or vancomycin than it was in a group of patients treated with 1 of these agents plus an additional antibiotic (91.9% and 76.1%, respectively). 19 In general, patients who require concomitant antibiotics have more comorbidities and are sicker, so the entire difference cannot be attributed to antibiotics. However, clinicians should carefully consider the ongoing need for antibiotics if CDI is suspected or confirmed.

Continued exposure to C. difficile in the hospital or home environment often leads to reinfection when vancomycin and metronidazole concentrations have decreased. Data show that at least half of clinical recurrences are reinfection with a different strain, and half are due to persisting intestinal infection with the original infecting strain. 20 Therefore, patients with CDI should be educated about appropriate hygiene at home.

CLINICAL MANIFESTATIONS OF CDI

CDI has a wide range of clinical manifestations, ranging from a mild and self‐limited diarrheal illness to fulminant, life‐threatening colitis. The onset of symptoms usually occurs within 3 to 7 days of antibiotic exposure, but may not arise for up to 10 weeks after stopping antibiotics. 5 CDI is associated with watery diarrhea that is often accompanied by cramping abdominal pain and low‐grade fever. Systemic symptoms generally increase with the degree of colitis. Patients with severe disease may also progress to having an ileus, or toxic megacolon or acute abdomen. 5

Up to 20% of critically ill patients have ileus or toxic megacolon, and therefore may not present with diarrhea; this, combined with a limited ability to communicate among some critically ill patients makes early diagnosis of CDI in this patient population extremely challenging. Therefore, physicians and other clinical staff must be vigilant about evaluating patients for the presence of CDI based on physical exam and laboratory findings. For example, fever, abdominal pain, and abdominal distention are likely to be present in patients with severe colitis. In addition, patients often have significant leukocytosis (often >20,000 cells/mm 3) with bandemia. In advanced cases, an elevated serum lactate dehydrogenase may be seenthis is a nonspecific finding for gastrointestinal disease, but provides a clue to the presence of CDI. Because these findings often precede multiorgan dysfunction, the presence of CDI must be determined quickly and appropriate treatment initiated. 5

PRINCIPLES OF DIAGNOSIS

C. difficile infection should be suspected in patients with antimicrobial‐associated diarrhea. Confirmatory testing should be performed, but only on watery or loose stools because the rate of symptomless colonization with C. difficile in hospitalized patients is high; a positive result on a normal stool sample proves only that the patient is colonized with C. difficile, but not necessarily infected. 14 A notable exception is when CDI is suspected in a patient with ileus; as many laboratories will not accept solid stool for C. difficile testing, the clinician should notify the laboratory about the specific request and reasons for suspecting CDI. 21 Stool testing for eradication of C. difficile during or after therapy is not advised, as many successfully treated patients will continue to shed the organism and its spores. 2 This symptomless carriage does not require additional treatment.

CASE STUDY CONTINUED

A.L. was empirically started on oral metronidazole, 500 mg 3 times a day, pending results of the stool C. difficile test.

On rounds the following day, diarrhea was less frequent (decreased from 9 to 4 loose bowel movements in 24 hours). She reported mild abdominal discomfort and nausea, but was tolerating oral intake. Her temperature was 100.8F.

Her lab results returned later in the afternoon were:

• WBC: 18,600 cells/L.

• Potassium: 3.2 mEq/mL.

• Creatinine: 2.4 mg/dL (up from 1.1).

• Stool C. difficile test: negative.

There are a variety of tests for C. difficile, each with advantages and disadvantages (Table 2). 2, 3, 21 Factors to consider when selecting a diagnostic test include turnaround time, sensitivity, specificity, cost, whether there is an ongoing outbreak, and the availability of particular tests. 21 Recent guidelines for CDI management jointly developed by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA) note that stool culture is the gold standard, but recognize the clinical limitations of its long turnaround time. 2 Enzyme immunoassay (EIA) is noted to be a suboptimal alternative approach for diagnosis than the cell cytotoxin assay. 2 Therefore, because EIA is most often used in clinical practice, it is important to be aware that a high clinical suspicion for CDI may warrant empiric therapy or repeat testing with a more sensitive test in a patient with an initial negative test result. 3, 21

CURRENT STRATEGIES FOR CDI MANAGEMENT

While current guidelines recommend that treatment of CDI be based on disease severity, 2, 22 determination of severity is challenging, in part, because standard definitions are lacking and because the illness varies along a continuum of symptoms. 5 In general, CDI can be categorized as: mild to moderate, severe, and severe disease with complications. Mild to moderate CDI is characterized by diarrhea and abdominal cramping, only without systemic symptoms. 5, 21 Severe CDI is distinguished by abundant diarrhea, severe abdominal pain/distension, leukocytosis, fever, or other systemic symptoms (Table 3). 5, 21, 2326 Patients with severe disease and other complications may present with a wide range of gastrointestinal symptoms accompanied by paralytic ileus, toxic megacolon, or other life‐threatening conditions. 5, 21 CDI may progress in severity rapidly, even after initiation of treatment, so ongoing assessment of the patient's condition and disease category is important. 5, 21

In 2010, SHEA/IDSA published evidence‐based guidelines for managing CDI based on severity of illness (summarized in Table 4). 2 The first and most important step in the effective management of CDI in all patients, regardless of severity, is to discontinue the causative antibiotic(s). 1 Data show that when all antibiotics are stopped, about 25% of patients with mild CDI who are otherwise healthy have resolution of diarrhea within 48 hours 27; most importantly, recurrent CDI is unlikely. Many hospitalized patients, especially in the intensive care setting, have serious concomitant infections, and therefore it may not be appropriate to discontinue the inciting antibiotic. In these patients, the regimen and available culture and sensitivity results should be thoughtfully reviewed, and change made when possible to a more narrow‐spectrum regimen less likely to cause or exacerbate CDI (Table 1).

The next step, as discussed above, is to send a stool sample for C. difficile testing. Based on the patient's clinical circumstances, the decision must be made whether or not to begin empiric therapy. In general, beginning treatment without testing for C. difficile is not recommended, because, at most, only about a third of hospitalized patients with diarrhea have CDI, even in an epidemic setting. 21 If a patient is severely ill or has a rapidly deteriorating clinical course and is at high risk for CDI, empiric therapy may be appropriate while awaiting test results. 21

In patients with severe CDI and complications, reduced or absent bowel motility can reduce the amount of orally administered vancomycin that reaches the site of infection. Intracolonic administration of vancomycin may be indicated in these cases, or when oral therapy cannot be tolerated. 28 Higher doses of oral vancomycin may also be used, with the goal of increasing fecal concentrations, however this strategy has not been studied. 5 In all patients, antiperistaltic agents are usually avoided because of unproven concerns that they might mask symptoms and/or increase the risk for toxic megacolon. 2

Fidaxomicin, a new macrolide antibiotic in the macrocyclic group, has a narrow‐spectrum and excellent activity against C. difficile. The US Food and Drug Administration approved fidaxomicin for treatment of adults for C. difficileassociated diarrhea (CDAD) in May 2011. 29 Approval was based on 2 phase III trials involving 1105 patients with CDAD in which fidaxomicin was shown to have similar initial clinical efficacy and safety as vancomycin. 30 In addition, more patients treated with fidaxomicin had a sustained response 25 days following discontinuation of treatment than patients treated with vancomycin. 31 The recommended dosage of fidaxomicin is one 200‐mg tablet orally twice daily for 10 days. 31

In a phase III trial (N = 596) of fidaxomicin (200 mg orally every 12 hours) versus vancomycin (125 mg orally every 6 hours) for 10 days, fidaxomicin was shown to be noninferior to vancomycin in achieving an initial clinical response and significantly better at preventing recurrent CDI. 32 The rates of initial clinical response, the primary endpoint, and rates of recurrent CDI are shown in Table 5. The significant difference in recurrence may be explained by the fact that metronidazole and vancomycin impact commensal microflora populations that normally mediate competitive exclusion of C. difficile. Compared with vancomycin, fidaxomicin has less effect on the composition of the fecal microbiota, in particular some clostridial clusters and Bifidobacterium. 33 While acquisition costs for this new antibiotic are a consideration, they may be offset by a reduction in recurrent CDI, especially in high‐risk patients.

FOCUS ON FULMINANT/REFRACTORY CDI

Management of CDI that is fulminant and/or refractory can be extremely challenging. 3 In clinical practice, these conditions often overlap. Clinical characteristics that may help identify fulminant CDI include abdominal pain and tenderness, colonic distension, and signs of sepsis. Diarrhea may be absent or minimal due to ileus. Furthermore, a diagnosis of CDI is easy to miss, as these symptoms are also consistent with ischemic bowel or a perforated viscus. 3 Gentle, flexible sigmoidoscopy or colonoscopy (without bowel preparation and with minimal air insufflation) may be extremely valuable to allow for immediate identification of pseudomembranous colitis, which speeds appropriate medical and surgical management. 3

First‐line treatment for fulminant or refractory CDI is oral or intragastric vancomycin 500 mg every 6 hours. 2, 3 Intravenous (IV) metronidazole 500 mg every 6 hours should be added to the treatment regimen in those with ileus or megacolon. For patients with complete ileus, vancomycin can be administered rectally as 500 mg in 100 mL of normal saline every 6 hours. 3 Normal pooled IV immunoglobulin has been used with mixed success, in patients with fulminant and/or refractory CDI, in an attempt to avert surgery or death by providing passive immunotherapy against C. difficile toxins A and B. 34 In a study of monoclonal antibodies to toxins A and B that included 200 patients, recurrence rates among those with the epidemic NAP1/BI/027 strain were 8% for the antibody group and 32% for the placebo group (P = 0.06); in a subset with more than 1 previous episode of CDI, recurrence rates were 7% and 38%, respectively (P = 0.006). 35

Some patients with fulminant or refractory CDI are best managed with subtotal colectomy, which may be lifesaving. 36 However, the optimal timing of surgery is difficult to establish, and the decision to proceed with this course can be difficult because patients with severe CDI are typically poor surgical candidates. 3 Delaying surgery until the development of a systemic inflammatory response syndrome with concomitant severe disease, such as multisystem organ failure, immunocompromise, or hemodynamic instability, usually results in a poor outcome. 37, 38 The best approach is to get a surgical consult early, when the course of CDI starts to deteriorate, so that management decisions can be based on input from a multidisciplinary team of clinicians. 3

CASE STUDY CONTINUED

A.L. was subsequently transferred to an acute care facility. Her therapy for C. difficile was switched to oral vancomycin, 125 mg 4 times daily. On arrival in the emergency department, the following findings were noted:

• No further diarrhea, but abdominal distention noted.

• Temperature: 101.4F.

• Fall in blood pressure (BP) to 90/48 mmHg during transfer, which responded to a fluid bolus, and increased to 108/74.

• WBC: 27,000/L.

• Abdominal computed tomography (CT) showed thickening of descending and sigmoid colon, and the rectum.

• Proctoscopy confirmed pseudomembranous colitis.

Oral vancomycin was increased to 500 mg 4 times daily, and IV metronidazole 500 mg every 8 hours was added. C. difficile infection responded to this regimen and she was subsequently discharged to home care.

As noted elsewhere in this supplement, recent studies show a high rate of recurrent Clostridium difficile infection (CDI) despite the availability of evidence‐based guidelines for CDI treatment. 1, 2 Treatment with vancomycin has been associated with recurrence in 25% or more of patients. The risk for recurrence increases with each episode, and is greater than 60% in patients with more than 2 episodes. 1, 3, 4 Identification of patients at risk for recurrence is critical to early diagnosis and prompt treatment. 5 Because recurrent CDI is so widespread, it should be common practice to educate patients about this complication, including:

• The risk for continued exposure to C. difficile in the hospital or home environment and strategies for appropriate hygiene to minimize reinfection.

• When to contact a healthcare professional for recurrent symptoms. 1

CASE STUDY CONTINUED

In the previous article in this supplement, a case study for patient A.L. was presented. A.L. is an 87‐year‐old woman who developed initial inpatient CDI in a rehabilitation facility. She was empirically started on oral metronidazole, 500 mg 3 times a day. Her symptoms improved but she became febrile with an elevated white blood cell (WBC) count. She was transferred to an acute care facility where her treatment was switched to oral vancomycin 125 mg 4 times daily. A proctoscopic exam confirmed pseudomembranous colitis, and her treatment regimen was increased to oral vancomycin 500 mg 4 times daily plus intravenous (IV) metronidazole 500 mg every 8 hours. The CDI responded to therapy and she was discharged to home care.

Ten days after her hospital discharge, A.L. noted a change in the character of her stools, which became looser and increased in frequency, accompanied by a foul odor that she recalls was present during her previous episode. The following day, she developed frank watery stools occurring every 1‐2 hours and had 2 incontinent episodes. Her family brought her to the emergency department because she was also light‐headed, confused, and had increased abdominal cramping. Intravenous fluid resuscitation was started, along with oral vancomycin, 125 mg every 6 hours for 14 days, followed by a vancomycin taper and pulse, which consisted of 125 mg twice daily for 7 days, once daily for 7 days, once every other day for 7 days, then every third day. Stool was sent to the lab for C. difficile testing in the middle of the taper regimen. The result was negative. Ten days after tapering the oral vancomycin regimen to every third day, she developed loose stools with the same odor, followed by increased frequency and frank watery stools.

This case illustrates several aspects of recurrent CDI. First, the recurrent episode may be severe, as evidenced by the need for IV fluid resuscitation in addition to specific anti‐C. difficile treatment. Second, although the patient was treated appropriately with standard 4 times daily vancomycin followed by a taper, subsequent recurrences may still occur, usually near the end of the taper/pulse (as in this case) or shortly after finishing the regimen. Finally, test of cure stool testing (either toxin testing, culture, or polymerase chain reaction [PCR]) may be misleading and is NOT recommended for managing recurrent CDI. Although subsequent management of this case was not addressed, repeating the standard vancomycin regimen, followed again by a taper/pulse would be a realistic option, as vancomycin resistance in C. difficile has not been reported and the patient would be expected to respond. Other management options should also be considered and are discussed below.

SHEA/IDSA RECOMMENDATIONS

There is no strong evidence to support a particular treatment strategy for recurrent CDI. 5 The Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA) guidelines 6 recommends the following:

• When severe or complicated CDI is suspected, initiate empiric treatment as soon as the diagnosis is suspected (C‐III).

• Treatment of the first recurrence is usually with the same regimen as for the initial episode (A‐II), but should be stratified by disease severity (C‐III).

• Do not use metronidazole beyond first recurrence or for long‐term chronic therapy (B‐II).

• Treatment of second or later recurrences with vancomycin using a taper and/or pulse regimen is the preferred next strategy (B‐III).

• No recommendations can be made regarding prevention of recurrent CDI in patients requiring continued antimicrobial therapy (C‐III).

The vancomycin taper/pulse regimen is one of the most widely used regimens for treatment of recurrent CDI. 5 A tapered oral vancomycin regimen consists of a stepwise decrease in dose over a period of time. Intermittent or pulsed vancomycin therapy consists of administering the drug every few days.

A standard course of antibiotic therapy eradicates vegetative cells of C. difficile, but is not effective against spores. Administering antibiotics over an extended time period at decreasing doses (tapered regimen) or intermittent delivery (pulsed regimen) gradually clears C. difficile by eradicating cells as the spores germinate. 5 Thus, a taper/pulse regimen of vancomycin, in theory, leads to a decreased rate of recurrence and may aid restoration of the normal microflora. 5

Evidence for efficacy of the tapered dosage regimen is based on a post hoc analysis of patients treated for recurrence in 2 trials of probiotic treatment with Saccharomyces boulardii. When standard‐dose oral vancomycin (125 mg 4 times daily) was compared with high‐dose vancomycin (500 mg twice daily for 7 to 14 days), recurrence rates were not statistically different. However, a tapered regimen of vancomycin resulted in significantly fewer recurrences (31%, P = 0.01), as did a pulsed dose of vancomycin (14.3%, P = 0.02). 4 One empiric pulsed‐dose regimen consists of oral vancomycin, 125 mg every 6 hours for 14 days, followed by tapering to 125 mg every 12 hours for 7 days, then 125 mg once daily for another 7 days, followed in turn by pulse‐dosed vancomycin (125 mg once every 2 days for 4 doses, then once every 3 days for 5 doses, or longer). 1 Prolonged courses of metronidazole are not recommended because of potential adverse effects, including peripheral neuropathy. 1

Management of patients with multiple recurrences of CDI is difficult, and no regimens are supported by adequate clinical evidence. 5 Various strategies have been tried, including probiotics, antibiotics, toxin binders, and immune‐based treatments. 1 The strategy behind use of probiotics is to augment colonization resistance. The probiotic S. boulardii, 1 g daily for 4 weeks, decreased recurrence compared with placebo in a small study of 60 patients when given during and after standard treatment (ie, metronidazole or vancomycin). In patients receiving high‐dose vancomycin plus S. boulardii, 3 of 18 (16.7%) had a recurrence compared with 7 of 14 (50%) receiving high‐dose vancomycin plus placebo (P = 0.05). 7 However, a larger follow‐up study did not show a significant overall benefit of S. boulardii over placebo. 1, 7 In addition, there have been a few case reports of systemic infections in immunocompromised patients treated with probiotics. 8 Overall, the results of studies with probiotics, including Lactobacilli, have been inconsistent.

Another approach to restoring a normal gastrointestinal microflora is fecal transplantation, where a small amount of fresh feces from a healthy donor (ideally someone who lives with the patient), is suspended in saline, filtered, and administered through a nasogastric tube, by colonoscope, or by enema. In a recent case series of 18 patients, this approach showed a 94% success rate. 9

Another potential strategy to prevent recurrence is to block colonization of pathogenic C. difficile strains by administration of nontoxigenic and nonpathogenic strains of C. difficile. Researchers have identified a nontoxigenic strain that is being developed as a targeted biotherapeutic probiotic for human use. 1 Because patients with recurrent CDI lack a strong immune response to C. difficile toxins, IV immunoglobulin (IVIG) has been used empirically to provide passive immunotherapy. It has shown benefit in some case series of patients with multiple recurrences. 1, 10, 11

Other antibiotics have also been investigated in conjunction with vancomycin for recurrent infection. Rifaximin has good in vitro activity against C. difficile, and is not absorbed from the gastrointestinal tract. Oral rifaximin, 400 to 800 mg daily for 14 days following discontinuation of vancomycin, was shown to prevent further recurrence in 7 of 8 patients with a history of 4 to 8 CDI recurrences. 1, 12 It is important to note that rifaximin resistance has been reported in clinical isolates of C. difficile, and may be more common than initially thought, particularly among epidemic strains. 13

Fidaxomicin, a narrow‐spectrum macrocyclic antibiotic, was also compared with vancomycin in 2 multicenter, randomized, double‐blind Phase 3 clinical trials of 1105 adults with confirmed CDI. 14 Patients were treated with either oral fidaxomicin (200 mg every 12 hours) or oral vancomycin (125 mg every 6 hours) for 10 days. 15, 16 The clinical cure rate with fidaxomicin was comparable to vancomycin in both studies. 14 In the more recent study, 59.8% of subjects (N = 535) were receiving concomitant antibiotics during CDI treatment; among this group, treatment with fidaxomicin was associated with a significantly lower recurrence rate than treatment with vancomycin (17.6% vs 29.5%, P = 0.027). 15 In addition, there was a sustained clinical response. Global cure, also a secondary endpoint, was defined as patients who were cured and did not have a recurrence during a subsequent 4‐week period, compared with treatment with vancomycin (67.5% vs 53.4%, P = 0.020). 15 These results confirm the findings from the first fidaxomicin Phase 3 study 16 and suggest that even when concomitant antibiotics are administered, fidaxomicin may be more effective than vancomycin in preventing CDI recurrence.

SUMMARY

Because hospitalists take a leadership role and often coordinate care for patients with CDI, they can take an active role to ensure that clinicians are aware of evidence‐based treatments for recurrent CDI, and the importance of routine follow‐up and persistence. The most important considerations in managing patients with recurrent CDI are to:

• Continue to try new or previous approaches, beginning with those that are evidence‐based, followed by options that have been shown to work but are not backed by strong clinical evidence.

• Provide consistent follow‐up and ongoing support.

• Be sympatheticbecause this condition has significant detrimental impact on quality of life.

As noted elsewhere in this supplement, recent studies show a high rate of recurrent Clostridium difficile infection (CDI) despite the availability of evidence‐based guidelines for CDI treatment. 1, 2 Treatment with vancomycin has been associated with recurrence in 25% or more of patients. The risk for recurrence increases with each episode, and is greater than 60% in patients with more than 2 episodes. 1, 3, 4 Identification of patients at risk for recurrence is critical to early diagnosis and prompt treatment. 5 Because recurrent CDI is so widespread, it should be common practice to educate patients about this complication, including:

• The risk for continued exposure to C. difficile in the hospital or home environment and strategies for appropriate hygiene to minimize reinfection.

• When to contact a healthcare professional for recurrent symptoms. 1

CASE STUDY CONTINUED

In the previous article in this supplement, a case study for patient A.L. was presented. A.L. is an 87‐year‐old woman who developed initial inpatient CDI in a rehabilitation facility. She was empirically started on oral metronidazole, 500 mg 3 times a day. Her symptoms improved but she became febrile with an elevated white blood cell (WBC) count. She was transferred to an acute care facility where her treatment was switched to oral vancomycin 125 mg 4 times daily. A proctoscopic exam confirmed pseudomembranous colitis, and her treatment regimen was increased to oral vancomycin 500 mg 4 times daily plus intravenous (IV) metronidazole 500 mg every 8 hours. The CDI responded to therapy and she was discharged to home care.

Ten days after her hospital discharge, A.L. noted a change in the character of her stools, which became looser and increased in frequency, accompanied by a foul odor that she recalls was present during her previous episode. The following day, she developed frank watery stools occurring every 1‐2 hours and had 2 incontinent episodes. Her family brought her to the emergency department because she was also light‐headed, confused, and had increased abdominal cramping. Intravenous fluid resuscitation was started, along with oral vancomycin, 125 mg every 6 hours for 14 days, followed by a vancomycin taper and pulse, which consisted of 125 mg twice daily for 7 days, once daily for 7 days, once every other day for 7 days, then every third day. Stool was sent to the lab for C. difficile testing in the middle of the taper regimen. The result was negative. Ten days after tapering the oral vancomycin regimen to every third day, she developed loose stools with the same odor, followed by increased frequency and frank watery stools.

This case illustrates several aspects of recurrent CDI. First, the recurrent episode may be severe, as evidenced by the need for IV fluid resuscitation in addition to specific anti‐C. difficile treatment. Second, although the patient was treated appropriately with standard 4 times daily vancomycin followed by a taper, subsequent recurrences may still occur, usually near the end of the taper/pulse (as in this case) or shortly after finishing the regimen. Finally, test of cure stool testing (either toxin testing, culture, or polymerase chain reaction [PCR]) may be misleading and is NOT recommended for managing recurrent CDI. Although subsequent management of this case was not addressed, repeating the standard vancomycin regimen, followed again by a taper/pulse would be a realistic option, as vancomycin resistance in C. difficile has not been reported and the patient would be expected to respond. Other management options should also be considered and are discussed below.

SHEA/IDSA RECOMMENDATIONS

There is no strong evidence to support a particular treatment strategy for recurrent CDI. 5 The Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA) guidelines 6 recommends the following:

• When severe or complicated CDI is suspected, initiate empiric treatment as soon as the diagnosis is suspected (C‐III).

• Treatment of the first recurrence is usually with the same regimen as for the initial episode (A‐II), but should be stratified by disease severity (C‐III).

• Do not use metronidazole beyond first recurrence or for long‐term chronic therapy (B‐II).

• Treatment of second or later recurrences with vancomycin using a taper and/or pulse regimen is the preferred next strategy (B‐III).

• No recommendations can be made regarding prevention of recurrent CDI in patients requiring continued antimicrobial therapy (C‐III).

The vancomycin taper/pulse regimen is one of the most widely used regimens for treatment of recurrent CDI. 5 A tapered oral vancomycin regimen consists of a stepwise decrease in dose over a period of time. Intermittent or pulsed vancomycin therapy consists of administering the drug every few days.

A standard course of antibiotic therapy eradicates vegetative cells of C. difficile, but is not effective against spores. Administering antibiotics over an extended time period at decreasing doses (tapered regimen) or intermittent delivery (pulsed regimen) gradually clears C. difficile by eradicating cells as the spores germinate. 5 Thus, a taper/pulse regimen of vancomycin, in theory, leads to a decreased rate of recurrence and may aid restoration of the normal microflora. 5

Evidence for efficacy of the tapered dosage regimen is based on a post hoc analysis of patients treated for recurrence in 2 trials of probiotic treatment with Saccharomyces boulardii. When standard‐dose oral vancomycin (125 mg 4 times daily) was compared with high‐dose vancomycin (500 mg twice daily for 7 to 14 days), recurrence rates were not statistically different. However, a tapered regimen of vancomycin resulted in significantly fewer recurrences (31%, P = 0.01), as did a pulsed dose of vancomycin (14.3%, P = 0.02). 4 One empiric pulsed‐dose regimen consists of oral vancomycin, 125 mg every 6 hours for 14 days, followed by tapering to 125 mg every 12 hours for 7 days, then 125 mg once daily for another 7 days, followed in turn by pulse‐dosed vancomycin (125 mg once every 2 days for 4 doses, then once every 3 days for 5 doses, or longer). 1 Prolonged courses of metronidazole are not recommended because of potential adverse effects, including peripheral neuropathy. 1

Management of patients with multiple recurrences of CDI is difficult, and no regimens are supported by adequate clinical evidence. 5 Various strategies have been tried, including probiotics, antibiotics, toxin binders, and immune‐based treatments. 1 The strategy behind use of probiotics is to augment colonization resistance. The probiotic S. boulardii, 1 g daily for 4 weeks, decreased recurrence compared with placebo in a small study of 60 patients when given during and after standard treatment (ie, metronidazole or vancomycin). In patients receiving high‐dose vancomycin plus S. boulardii, 3 of 18 (16.7%) had a recurrence compared with 7 of 14 (50%) receiving high‐dose vancomycin plus placebo (P = 0.05). 7 However, a larger follow‐up study did not show a significant overall benefit of S. boulardii over placebo. 1, 7 In addition, there have been a few case reports of systemic infections in immunocompromised patients treated with probiotics. 8 Overall, the results of studies with probiotics, including Lactobacilli, have been inconsistent.

Another approach to restoring a normal gastrointestinal microflora is fecal transplantation, where a small amount of fresh feces from a healthy donor (ideally someone who lives with the patient), is suspended in saline, filtered, and administered through a nasogastric tube, by colonoscope, or by enema. In a recent case series of 18 patients, this approach showed a 94% success rate. 9

Another potential strategy to prevent recurrence is to block colonization of pathogenic C. difficile strains by administration of nontoxigenic and nonpathogenic strains of C. difficile. Researchers have identified a nontoxigenic strain that is being developed as a targeted biotherapeutic probiotic for human use. 1 Because patients with recurrent CDI lack a strong immune response to C. difficile toxins, IV immunoglobulin (IVIG) has been used empirically to provide passive immunotherapy. It has shown benefit in some case series of patients with multiple recurrences. 1, 10, 11

Other antibiotics have also been investigated in conjunction with vancomycin for recurrent infection. Rifaximin has good in vitro activity against C. difficile, and is not absorbed from the gastrointestinal tract. Oral rifaximin, 400 to 800 mg daily for 14 days following discontinuation of vancomycin, was shown to prevent further recurrence in 7 of 8 patients with a history of 4 to 8 CDI recurrences. 1, 12 It is important to note that rifaximin resistance has been reported in clinical isolates of C. difficile, and may be more common than initially thought, particularly among epidemic strains. 13

Fidaxomicin, a narrow‐spectrum macrocyclic antibiotic, was also compared with vancomycin in 2 multicenter, randomized, double‐blind Phase 3 clinical trials of 1105 adults with confirmed CDI. 14 Patients were treated with either oral fidaxomicin (200 mg every 12 hours) or oral vancomycin (125 mg every 6 hours) for 10 days. 15, 16 The clinical cure rate with fidaxomicin was comparable to vancomycin in both studies. 14 In the more recent study, 59.8% of subjects (N = 535) were receiving concomitant antibiotics during CDI treatment; among this group, treatment with fidaxomicin was associated with a significantly lower recurrence rate than treatment with vancomycin (17.6% vs 29.5%, P = 0.027). 15 In addition, there was a sustained clinical response. Global cure, also a secondary endpoint, was defined as patients who were cured and did not have a recurrence during a subsequent 4‐week period, compared with treatment with vancomycin (67.5% vs 53.4%, P = 0.020). 15 These results confirm the findings from the first fidaxomicin Phase 3 study 16 and suggest that even when concomitant antibiotics are administered, fidaxomicin may be more effective than vancomycin in preventing CDI recurrence.

SUMMARY

Because hospitalists take a leadership role and often coordinate care for patients with CDI, they can take an active role to ensure that clinicians are aware of evidence‐based treatments for recurrent CDI, and the importance of routine follow‐up and persistence. The most important considerations in managing patients with recurrent CDI are to:

• Continue to try new or previous approaches, beginning with those that are evidence‐based, followed by options that have been shown to work but are not backed by strong clinical evidence.

• Provide consistent follow‐up and ongoing support.

• Be sympatheticbecause this condition has significant detrimental impact on quality of life.

As noted elsewhere in this supplement, recent studies show a high rate of recurrent Clostridium difficile infection (CDI) despite the availability of evidence‐based guidelines for CDI treatment. 1, 2 Treatment with vancomycin has been associated with recurrence in 25% or more of patients. The risk for recurrence increases with each episode, and is greater than 60% in patients with more than 2 episodes. 1, 3, 4 Identification of patients at risk for recurrence is critical to early diagnosis and prompt treatment. 5 Because recurrent CDI is so widespread, it should be common practice to educate patients about this complication, including:

• The risk for continued exposure to C. difficile in the hospital or home environment and strategies for appropriate hygiene to minimize reinfection.

• When to contact a healthcare professional for recurrent symptoms. 1

CASE STUDY CONTINUED

In the previous article in this supplement, a case study for patient A.L. was presented. A.L. is an 87‐year‐old woman who developed initial inpatient CDI in a rehabilitation facility. She was empirically started on oral metronidazole, 500 mg 3 times a day. Her symptoms improved but she became febrile with an elevated white blood cell (WBC) count. She was transferred to an acute care facility where her treatment was switched to oral vancomycin 125 mg 4 times daily. A proctoscopic exam confirmed pseudomembranous colitis, and her treatment regimen was increased to oral vancomycin 500 mg 4 times daily plus intravenous (IV) metronidazole 500 mg every 8 hours. The CDI responded to therapy and she was discharged to home care.

Ten days after her hospital discharge, A.L. noted a change in the character of her stools, which became looser and increased in frequency, accompanied by a foul odor that she recalls was present during her previous episode. The following day, she developed frank watery stools occurring every 1‐2 hours and had 2 incontinent episodes. Her family brought her to the emergency department because she was also light‐headed, confused, and had increased abdominal cramping. Intravenous fluid resuscitation was started, along with oral vancomycin, 125 mg every 6 hours for 14 days, followed by a vancomycin taper and pulse, which consisted of 125 mg twice daily for 7 days, once daily for 7 days, once every other day for 7 days, then every third day. Stool was sent to the lab for C. difficile testing in the middle of the taper regimen. The result was negative. Ten days after tapering the oral vancomycin regimen to every third day, she developed loose stools with the same odor, followed by increased frequency and frank watery stools.

This case illustrates several aspects of recurrent CDI. First, the recurrent episode may be severe, as evidenced by the need for IV fluid resuscitation in addition to specific anti‐C. difficile treatment. Second, although the patient was treated appropriately with standard 4 times daily vancomycin followed by a taper, subsequent recurrences may still occur, usually near the end of the taper/pulse (as in this case) or shortly after finishing the regimen. Finally, test of cure stool testing (either toxin testing, culture, or polymerase chain reaction [PCR]) may be misleading and is NOT recommended for managing recurrent CDI. Although subsequent management of this case was not addressed, repeating the standard vancomycin regimen, followed again by a taper/pulse would be a realistic option, as vancomycin resistance in C. difficile has not been reported and the patient would be expected to respond. Other management options should also be considered and are discussed below.

SHEA/IDSA RECOMMENDATIONS

There is no strong evidence to support a particular treatment strategy for recurrent CDI. 5 The Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA) guidelines 6 recommends the following:

• When severe or complicated CDI is suspected, initiate empiric treatment as soon as the diagnosis is suspected (C‐III).

• Treatment of the first recurrence is usually with the same regimen as for the initial episode (A‐II), but should be stratified by disease severity (C‐III).

• Do not use metronidazole beyond first recurrence or for long‐term chronic therapy (B‐II).

• Treatment of second or later recurrences with vancomycin using a taper and/or pulse regimen is the preferred next strategy (B‐III).

• No recommendations can be made regarding prevention of recurrent CDI in patients requiring continued antimicrobial therapy (C‐III).

The vancomycin taper/pulse regimen is one of the most widely used regimens for treatment of recurrent CDI. 5 A tapered oral vancomycin regimen consists of a stepwise decrease in dose over a period of time. Intermittent or pulsed vancomycin therapy consists of administering the drug every few days.

A standard course of antibiotic therapy eradicates vegetative cells of C. difficile, but is not effective against spores. Administering antibiotics over an extended time period at decreasing doses (tapered regimen) or intermittent delivery (pulsed regimen) gradually clears C. difficile by eradicating cells as the spores germinate. 5 Thus, a taper/pulse regimen of vancomycin, in theory, leads to a decreased rate of recurrence and may aid restoration of the normal microflora. 5

Evidence for efficacy of the tapered dosage regimen is based on a post hoc analysis of patients treated for recurrence in 2 trials of probiotic treatment with Saccharomyces boulardii. When standard‐dose oral vancomycin (125 mg 4 times daily) was compared with high‐dose vancomycin (500 mg twice daily for 7 to 14 days), recurrence rates were not statistically different. However, a tapered regimen of vancomycin resulted in significantly fewer recurrences (31%, P = 0.01), as did a pulsed dose of vancomycin (14.3%, P = 0.02). 4 One empiric pulsed‐dose regimen consists of oral vancomycin, 125 mg every 6 hours for 14 days, followed by tapering to 125 mg every 12 hours for 7 days, then 125 mg once daily for another 7 days, followed in turn by pulse‐dosed vancomycin (125 mg once every 2 days for 4 doses, then once every 3 days for 5 doses, or longer). 1 Prolonged courses of metronidazole are not recommended because of potential adverse effects, including peripheral neuropathy. 1

Management of patients with multiple recurrences of CDI is difficult, and no regimens are supported by adequate clinical evidence. 5 Various strategies have been tried, including probiotics, antibiotics, toxin binders, and immune‐based treatments. 1 The strategy behind use of probiotics is to augment colonization resistance. The probiotic S. boulardii, 1 g daily for 4 weeks, decreased recurrence compared with placebo in a small study of 60 patients when given during and after standard treatment (ie, metronidazole or vancomycin). In patients receiving high‐dose vancomycin plus S. boulardii, 3 of 18 (16.7%) had a recurrence compared with 7 of 14 (50%) receiving high‐dose vancomycin plus placebo (P = 0.05). 7 However, a larger follow‐up study did not show a significant overall benefit of S. boulardii over placebo. 1, 7 In addition, there have been a few case reports of systemic infections in immunocompromised patients treated with probiotics. 8 Overall, the results of studies with probiotics, including Lactobacilli, have been inconsistent.

Another approach to restoring a normal gastrointestinal microflora is fecal transplantation, where a small amount of fresh feces from a healthy donor (ideally someone who lives with the patient), is suspended in saline, filtered, and administered through a nasogastric tube, by colonoscope, or by enema. In a recent case series of 18 patients, this approach showed a 94% success rate. 9

Another potential strategy to prevent recurrence is to block colonization of pathogenic C. difficile strains by administration of nontoxigenic and nonpathogenic strains of C. difficile. Researchers have identified a nontoxigenic strain that is being developed as a targeted biotherapeutic probiotic for human use. 1 Because patients with recurrent CDI lack a strong immune response to C. difficile toxins, IV immunoglobulin (IVIG) has been used empirically to provide passive immunotherapy. It has shown benefit in some case series of patients with multiple recurrences. 1, 10, 11

Other antibiotics have also been investigated in conjunction with vancomycin for recurrent infection. Rifaximin has good in vitro activity against C. difficile, and is not absorbed from the gastrointestinal tract. Oral rifaximin, 400 to 800 mg daily for 14 days following discontinuation of vancomycin, was shown to prevent further recurrence in 7 of 8 patients with a history of 4 to 8 CDI recurrences. 1, 12 It is important to note that rifaximin resistance has been reported in clinical isolates of C. difficile, and may be more common than initially thought, particularly among epidemic strains. 13

Fidaxomicin, a narrow‐spectrum macrocyclic antibiotic, was also compared with vancomycin in 2 multicenter, randomized, double‐blind Phase 3 clinical trials of 1105 adults with confirmed CDI. 14 Patients were treated with either oral fidaxomicin (200 mg every 12 hours) or oral vancomycin (125 mg every 6 hours) for 10 days. 15, 16 The clinical cure rate with fidaxomicin was comparable to vancomycin in both studies. 14 In the more recent study, 59.8% of subjects (N = 535) were receiving concomitant antibiotics during CDI treatment; among this group, treatment with fidaxomicin was associated with a significantly lower recurrence rate than treatment with vancomycin (17.6% vs 29.5%, P = 0.027). 15 In addition, there was a sustained clinical response. Global cure, also a secondary endpoint, was defined as patients who were cured and did not have a recurrence during a subsequent 4‐week period, compared with treatment with vancomycin (67.5% vs 53.4%, P = 0.020). 15 These results confirm the findings from the first fidaxomicin Phase 3 study 16 and suggest that even when concomitant antibiotics are administered, fidaxomicin may be more effective than vancomycin in preventing CDI recurrence.

SUMMARY

Because hospitalists take a leadership role and often coordinate care for patients with CDI, they can take an active role to ensure that clinicians are aware of evidence‐based treatments for recurrent CDI, and the importance of routine follow‐up and persistence. The most important considerations in managing patients with recurrent CDI are to:

• Continue to try new or previous approaches, beginning with those that are evidence‐based, followed by options that have been shown to work but are not backed by strong clinical evidence.

• Provide consistent follow‐up and ongoing support.

• Be sympatheticbecause this condition has significant detrimental impact on quality of life.

Infection control is a critical component of an overall management strategy for Clostridium difficile infection (CDI). In fact, preventing patients from acquiring this nosocomial condition in the healthcare setting has been identified as the most essential component.1 In 2008, the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA) published a compendium of strategies to prevent healthcare‐associated infections, including CDI. This guideline includes graded recommendations and provides helpful strategies for applying them in a healthcare facility. An effective and comprehensive preventive program to reduce the incidence and impact of CDI requires several key components:2

• 1

  Communication of responsibilities and accountability.

• 2

  Application of basic recommendations (Table 1).2

• 3

  Application of special recommendations if the incidence of CDI is not adequately controlled with the basic recommendations (Table 2).2

Many healthcare providers are involved in patient care, and therefore each of these departmentsincluding administration, the medical staff, the infection control department, nursing, pharmacy, the clinical laboratory, and environmental controlmust be supportive of, and accountable for, implementing strategies to prevent CDI. Hospital administration must ensure that nursing, environmental services, and infection prevention and control have adequate support. The department of infection prevention and control should take the lead role in designing, implementing, and monitoring the CDI prevention program, including the education of hospital staff.

Clinical staff must comply with infection prevention and control policies, and have a high index of suspicion for rapid identification of patients with CDI, so they can be placed under contact precautions and started on treatment quickly. Nursing and physician leaders must hold personnel accountable for adhering to infection prevention and control policies. Finally, environmental services play a key role and must ensure that housekeeping personnel are appropriately trained and monitored to ensure they are following effective cleaning policies and procedures.

TRANSMISSION OF CDI

Healthcare workers are a primary mode of C. difficile transmission. C. difficile spores end up on multiple hospital surfaces and contaminate healthcare worker hands and medical devices (stethoscopes, thermometers, etc) used on multiple patients. One study found that after caring for a patient with CDI, 59% of healthcare workers had hand contamination regardless of whether or not they actually touched the patient.3 Many studies have shown that patients in adjacent rooms are at equal or higher risk of acquiring CDI as patients admitted to the same room.4, 5 Although a recent study found that admission to an intensive care unit room that previously housed a patient for CDI was a risk factor for developing CDI, 89% of patients who actually developed CDI did not have this risk factor.6 This indicates that most C. difficile acquisitions came from healthcare workers.

CONTACT PRECAUTIONS AND STRICT HAND HYGIENE ARE KEY

The combination of appropriate contact precautions and strict hand hygiene has been reported to reduce the incidence of CDI by as much as 80%.1, 7, 8 The CDI prevention recommendation with the strongest level of evidence is the donning of gloves when caring for a patient with CDI (Table 1).9

The optimal method of hand hygiene after caring for a patient with CDI is a matter of some confusion. Alcohol‐based hand sanitizers did not reduce the amount of C. difficile spores on the hands of volunteers contaminated with a known quantity of C. difficile spores.10 However, studies have not found an increase in CDI with use of alcohol‐based hand sanitizers or a decrease in CDI with use of soap and water.11 In addition, several of these studies have found the use of alcohol‐based hand hygiene products to be associated with decreases in methicillin‐resistant Staphylococcus aureus or vancomycin‐resistant enterococcus. For these reasons, in non‐outbreak settings, hand hygiene with alcohol‐based hand sanitizers, in addition to wearing gloves as a component of contact precautions, is considered an acceptable method of hand hygiene after caring for a patient with CDI.11 In outbreak settings, however, preferential use of soap and water is recommended after caring for a patient with CDI because of the theoretical increase in risk of C. difficile transmission based on the volunteer hand contamination studies.2, 11, 12

DISINFECTION OF EQUIPMENT AND ENVIRONMENT

Environmental services staff must be educated about the incidence, transmission of, and impact of CDI, as well as strategies effective for C. difficile spores, which are resistant to standard cleaning products and may persist in patient rooms for many months.1 During CDI outbreaks, rooms should be cleaned with a chlorine‐based disinfectant (either an Environmental Protection Agency‐approved disinfectant with known sporicidal activity or a 1:10 dilution of household bleach), which rapidly destroys C. difficile spores.1 The sporicidal solution should have a contact time of at least 10 minutes.2 Efforts to control spores in the environment and prevent transmission are even more important considering recent data demonstrating that hypervirulent C. difficile strains may have increased sporulation, which in combination with increased toxin production, pose a major management challenge.13 Identification and removal of other sources of C. difficile, including replacement of electronic rectal thermometers with disposable thermometers, can also reduce the incidence of CDI.12

ANTIMICROBIAL STEWARDSHIP AND RESTRICTION

Interventions to ensure appropriate use of antibiotics, including antimicrobial stewardship programs and antibiotic restriction programs, are also effective. A study during an outbreak of a hypervirulent strain of C. difficile showed that an antimicrobial stewardship program reduced the incidence of CDI by 60%.14 In this study, the antimicrobial stewardship program focused on shifting antimicrobial selection to antimicrobials that were associated with a lower risk of CDI at their institution whenever possible. Reducing unnecessary antimicrobial use was stressed as well. Formal restrictions were not instituted; rather, clinicians received education and pocket guides to assist in antimicrobial selection.

Several studies have found respiratory fluoroquinolones, such as gatifloxacin or moxifloxacin, to be associated with the highest risk of CDI during outbreaks due to the BI/NAP1/027 strain.15, 16 Interestingly, this antimicrobial stewardship program recommended respiratory fluoroquinolones over cephalosporins for community‐acquired pneumonia, as cephalosporins historically have been strongly associated with CDI. Nevertheless, the incidence of CDI decreased after initiation of the antimicrobial stewardship program, despite increased use of respiratory fluoroquinolones. The antimicrobial stewardship program was implemented prior to the identification of the fluoroquinolone‐resistant epidemic strain. This shows that herd protection against CDI can occur by improvements in overall antimicrobial prescribing practices by decreasing the total number of patients at risk for CDI. This, in turn, will decrease the number of patients who develop CDI and contribute to the spread of C. difficile. In addition to using education to improve antimicrobial prescribing, several studies have found that restriction of specific antimicrobials associated with CDI (for example, clindamycin or fluoroquinolones) can result in a decrease in CDI.1, 1720

INSIGHTS ABOUT OPPORTUNITIES FOR IMPROVEMENT

Results of a recent point prevalence survey conducted by the Association for Professionals in Infection Control and Epidemiology, Inc (APIC) provide important insights into knowledge and clinical practice gaps related to early diagnosis and prevention of CDI.21 More than 12,000 APIC members were asked to provide a 1‐day snapshot of patients identified with CDI or colonization at their institutions. Responses from 648 (12.5%) acute care hospitals in the United States, representing 47 states, indicate a clear need to improve infection control practices.21 The following recommendations are based on recent evidence:

• Patients should be placed in contact isolation at the first suspicion of CDI, and kept in isolation for up to 2 days after diarrhea resolves because contamination persists in the environment that long.2 Of note, this differs from the SHEA/IDSA Clinical Practice Guidelines for Clostridium difficile Infection in Adults, which state: Maintain contact precautions for the duration of diarrhea.12 The Centers for Disease Control and Prevention (CDC) currently recommends contact precautions for the duration of illness when caring for patients with CDI.22

• Bleach solution should be used for routine and terminal cleaning during CDI outbreaks, as recommended by SHEA/IDSA and the CDC.

• Hand washing with soap and water is more effective than alcohol‐based hand sanitizers for removal of spores. However, appropriate donning and removal of gloves prevents hand contamination with C. difficile spores, likely explaining why hand washing with soap and water has not been associated with a decrease in CDI compared with alcohol‐based products.

• A formal program to educate environmental services personnel should be implemented to ensure they understand their critical role on the infection control team and effective strategies for cleaning.

SPECIAL APPROACHES

When basic approaches are not effective to reduce the incidence of CDI, the SHEA has recommendations for special approaches, which should be implemented as appropriate for each institution (summarized in Table 2).2 Strategies for prevention of CDI are also available from the CDC and the Institute for Healthcare Improvement (IHI).23, 24

SUMMARY

Effective management and prevention of CDI requires a multidisciplinary approach that includes leaders in hospital administration, clinicians, the infection control department, nursing, pharmacy, and the clinical laboratory, as well as environmental services. All of these professionals must be accountable and take an active role in implementing and complying with evidence‐based strategies to ensure that patients at risk are identified early and managed appropriately, and that effective strategies for prevention are in place. Hospitalists, as front‐line caregivers, physician leaders in their hospitals, and coordinators of patient care, can play a key role in these regards. Care when deciding when and which antimicrobial to use to treat non‐CDI infections; being attuned to symptoms that may be due to CDI, and prompt diagnosis and treatment of CDI; adhering to infection control policies; awareness of cleaning practices; and also being an active member of the infection control committee are all ways that hospitalists may take active roles in preventing CDI.

Infection control is a critical component of an overall management strategy for Clostridium difficile infection (CDI). In fact, preventing patients from acquiring this nosocomial condition in the healthcare setting has been identified as the most essential component.1 In 2008, the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA) published a compendium of strategies to prevent healthcare‐associated infections, including CDI. This guideline includes graded recommendations and provides helpful strategies for applying them in a healthcare facility. An effective and comprehensive preventive program to reduce the incidence and impact of CDI requires several key components:2

• 1

  Communication of responsibilities and accountability.

• 2

  Application of basic recommendations (Table 1).2

• 3

  Application of special recommendations if the incidence of CDI is not adequately controlled with the basic recommendations (Table 2).2

Many healthcare providers are involved in patient care, and therefore each of these departmentsincluding administration, the medical staff, the infection control department, nursing, pharmacy, the clinical laboratory, and environmental controlmust be supportive of, and accountable for, implementing strategies to prevent CDI. Hospital administration must ensure that nursing, environmental services, and infection prevention and control have adequate support. The department of infection prevention and control should take the lead role in designing, implementing, and monitoring the CDI prevention program, including the education of hospital staff.

Clinical staff must comply with infection prevention and control policies, and have a high index of suspicion for rapid identification of patients with CDI, so they can be placed under contact precautions and started on treatment quickly. Nursing and physician leaders must hold personnel accountable for adhering to infection prevention and control policies. Finally, environmental services play a key role and must ensure that housekeeping personnel are appropriately trained and monitored to ensure they are following effective cleaning policies and procedures.

TRANSMISSION OF CDI

Healthcare workers are a primary mode of C. difficile transmission. C. difficile spores end up on multiple hospital surfaces and contaminate healthcare worker hands and medical devices (stethoscopes, thermometers, etc) used on multiple patients. One study found that after caring for a patient with CDI, 59% of healthcare workers had hand contamination regardless of whether or not they actually touched the patient.3 Many studies have shown that patients in adjacent rooms are at equal or higher risk of acquiring CDI as patients admitted to the same room.4, 5 Although a recent study found that admission to an intensive care unit room that previously housed a patient for CDI was a risk factor for developing CDI, 89% of patients who actually developed CDI did not have this risk factor.6 This indicates that most C. difficile acquisitions came from healthcare workers.

CONTACT PRECAUTIONS AND STRICT HAND HYGIENE ARE KEY

The combination of appropriate contact precautions and strict hand hygiene has been reported to reduce the incidence of CDI by as much as 80%.1, 7, 8 The CDI prevention recommendation with the strongest level of evidence is the donning of gloves when caring for a patient with CDI (Table 1).9

The optimal method of hand hygiene after caring for a patient with CDI is a matter of some confusion. Alcohol‐based hand sanitizers did not reduce the amount of C. difficile spores on the hands of volunteers contaminated with a known quantity of C. difficile spores.10 However, studies have not found an increase in CDI with use of alcohol‐based hand sanitizers or a decrease in CDI with use of soap and water.11 In addition, several of these studies have found the use of alcohol‐based hand hygiene products to be associated with decreases in methicillin‐resistant Staphylococcus aureus or vancomycin‐resistant enterococcus. For these reasons, in non‐outbreak settings, hand hygiene with alcohol‐based hand sanitizers, in addition to wearing gloves as a component of contact precautions, is considered an acceptable method of hand hygiene after caring for a patient with CDI.11 In outbreak settings, however, preferential use of soap and water is recommended after caring for a patient with CDI because of the theoretical increase in risk of C. difficile transmission based on the volunteer hand contamination studies.2, 11, 12

DISINFECTION OF EQUIPMENT AND ENVIRONMENT

Environmental services staff must be educated about the incidence, transmission of, and impact of CDI, as well as strategies effective for C. difficile spores, which are resistant to standard cleaning products and may persist in patient rooms for many months.1 During CDI outbreaks, rooms should be cleaned with a chlorine‐based disinfectant (either an Environmental Protection Agency‐approved disinfectant with known sporicidal activity or a 1:10 dilution of household bleach), which rapidly destroys C. difficile spores.1 The sporicidal solution should have a contact time of at least 10 minutes.2 Efforts to control spores in the environment and prevent transmission are even more important considering recent data demonstrating that hypervirulent C. difficile strains may have increased sporulation, which in combination with increased toxin production, pose a major management challenge.13 Identification and removal of other sources of C. difficile, including replacement of electronic rectal thermometers with disposable thermometers, can also reduce the incidence of CDI.12

ANTIMICROBIAL STEWARDSHIP AND RESTRICTION

Interventions to ensure appropriate use of antibiotics, including antimicrobial stewardship programs and antibiotic restriction programs, are also effective. A study during an outbreak of a hypervirulent strain of C. difficile showed that an antimicrobial stewardship program reduced the incidence of CDI by 60%.14 In this study, the antimicrobial stewardship program focused on shifting antimicrobial selection to antimicrobials that were associated with a lower risk of CDI at their institution whenever possible. Reducing unnecessary antimicrobial use was stressed as well. Formal restrictions were not instituted; rather, clinicians received education and pocket guides to assist in antimicrobial selection.

Several studies have found respiratory fluoroquinolones, such as gatifloxacin or moxifloxacin, to be associated with the highest risk of CDI during outbreaks due to the BI/NAP1/027 strain.15, 16 Interestingly, this antimicrobial stewardship program recommended respiratory fluoroquinolones over cephalosporins for community‐acquired pneumonia, as cephalosporins historically have been strongly associated with CDI. Nevertheless, the incidence of CDI decreased after initiation of the antimicrobial stewardship program, despite increased use of respiratory fluoroquinolones. The antimicrobial stewardship program was implemented prior to the identification of the fluoroquinolone‐resistant epidemic strain. This shows that herd protection against CDI can occur by improvements in overall antimicrobial prescribing practices by decreasing the total number of patients at risk for CDI. This, in turn, will decrease the number of patients who develop CDI and contribute to the spread of C. difficile. In addition to using education to improve antimicrobial prescribing, several studies have found that restriction of specific antimicrobials associated with CDI (for example, clindamycin or fluoroquinolones) can result in a decrease in CDI.1, 1720

INSIGHTS ABOUT OPPORTUNITIES FOR IMPROVEMENT

Results of a recent point prevalence survey conducted by the Association for Professionals in Infection Control and Epidemiology, Inc (APIC) provide important insights into knowledge and clinical practice gaps related to early diagnosis and prevention of CDI.21 More than 12,000 APIC members were asked to provide a 1‐day snapshot of patients identified with CDI or colonization at their institutions. Responses from 648 (12.5%) acute care hospitals in the United States, representing 47 states, indicate a clear need to improve infection control practices.21 The following recommendations are based on recent evidence:

• Patients should be placed in contact isolation at the first suspicion of CDI, and kept in isolation for up to 2 days after diarrhea resolves because contamination persists in the environment that long.2 Of note, this differs from the SHEA/IDSA Clinical Practice Guidelines for Clostridium difficile Infection in Adults, which state: Maintain contact precautions for the duration of diarrhea.12 The Centers for Disease Control and Prevention (CDC) currently recommends contact precautions for the duration of illness when caring for patients with CDI.22

• Bleach solution should be used for routine and terminal cleaning during CDI outbreaks, as recommended by SHEA/IDSA and the CDC.

• Hand washing with soap and water is more effective than alcohol‐based hand sanitizers for removal of spores. However, appropriate donning and removal of gloves prevents hand contamination with C. difficile spores, likely explaining why hand washing with soap and water has not been associated with a decrease in CDI compared with alcohol‐based products.

• A formal program to educate environmental services personnel should be implemented to ensure they understand their critical role on the infection control team and effective strategies for cleaning.

SPECIAL APPROACHES

When basic approaches are not effective to reduce the incidence of CDI, the SHEA has recommendations for special approaches, which should be implemented as appropriate for each institution (summarized in Table 2).2 Strategies for prevention of CDI are also available from the CDC and the Institute for Healthcare Improvement (IHI).23, 24

SUMMARY

Effective management and prevention of CDI requires a multidisciplinary approach that includes leaders in hospital administration, clinicians, the infection control department, nursing, pharmacy, and the clinical laboratory, as well as environmental services. All of these professionals must be accountable and take an active role in implementing and complying with evidence‐based strategies to ensure that patients at risk are identified early and managed appropriately, and that effective strategies for prevention are in place. Hospitalists, as front‐line caregivers, physician leaders in their hospitals, and coordinators of patient care, can play a key role in these regards. Care when deciding when and which antimicrobial to use to treat non‐CDI infections; being attuned to symptoms that may be due to CDI, and prompt diagnosis and treatment of CDI; adhering to infection control policies; awareness of cleaning practices; and also being an active member of the infection control committee are all ways that hospitalists may take active roles in preventing CDI.

Infection control is a critical component of an overall management strategy for Clostridium difficile infection (CDI). In fact, preventing patients from acquiring this nosocomial condition in the healthcare setting has been identified as the most essential component.1 In 2008, the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA) published a compendium of strategies to prevent healthcare‐associated infections, including CDI. This guideline includes graded recommendations and provides helpful strategies for applying them in a healthcare facility. An effective and comprehensive preventive program to reduce the incidence and impact of CDI requires several key components:2

• 1

  Communication of responsibilities and accountability.

• 2

  Application of basic recommendations (Table 1).2

• 3

  Application of special recommendations if the incidence of CDI is not adequately controlled with the basic recommendations (Table 2).2

Many healthcare providers are involved in patient care, and therefore each of these departmentsincluding administration, the medical staff, the infection control department, nursing, pharmacy, the clinical laboratory, and environmental controlmust be supportive of, and accountable for, implementing strategies to prevent CDI. Hospital administration must ensure that nursing, environmental services, and infection prevention and control have adequate support. The department of infection prevention and control should take the lead role in designing, implementing, and monitoring the CDI prevention program, including the education of hospital staff.

Clinical staff must comply with infection prevention and control policies, and have a high index of suspicion for rapid identification of patients with CDI, so they can be placed under contact precautions and started on treatment quickly. Nursing and physician leaders must hold personnel accountable for adhering to infection prevention and control policies. Finally, environmental services play a key role and must ensure that housekeeping personnel are appropriately trained and monitored to ensure they are following effective cleaning policies and procedures.

TRANSMISSION OF CDI

Healthcare workers are a primary mode of C. difficile transmission. C. difficile spores end up on multiple hospital surfaces and contaminate healthcare worker hands and medical devices (stethoscopes, thermometers, etc) used on multiple patients. One study found that after caring for a patient with CDI, 59% of healthcare workers had hand contamination regardless of whether or not they actually touched the patient.3 Many studies have shown that patients in adjacent rooms are at equal or higher risk of acquiring CDI as patients admitted to the same room.4, 5 Although a recent study found that admission to an intensive care unit room that previously housed a patient for CDI was a risk factor for developing CDI, 89% of patients who actually developed CDI did not have this risk factor.6 This indicates that most C. difficile acquisitions came from healthcare workers.

CONTACT PRECAUTIONS AND STRICT HAND HYGIENE ARE KEY

The combination of appropriate contact precautions and strict hand hygiene has been reported to reduce the incidence of CDI by as much as 80%.1, 7, 8 The CDI prevention recommendation with the strongest level of evidence is the donning of gloves when caring for a patient with CDI (Table 1).9

The optimal method of hand hygiene after caring for a patient with CDI is a matter of some confusion. Alcohol‐based hand sanitizers did not reduce the amount of C. difficile spores on the hands of volunteers contaminated with a known quantity of C. difficile spores.10 However, studies have not found an increase in CDI with use of alcohol‐based hand sanitizers or a decrease in CDI with use of soap and water.11 In addition, several of these studies have found the use of alcohol‐based hand hygiene products to be associated with decreases in methicillin‐resistant Staphylococcus aureus or vancomycin‐resistant enterococcus. For these reasons, in non‐outbreak settings, hand hygiene with alcohol‐based hand sanitizers, in addition to wearing gloves as a component of contact precautions, is considered an acceptable method of hand hygiene after caring for a patient with CDI.11 In outbreak settings, however, preferential use of soap and water is recommended after caring for a patient with CDI because of the theoretical increase in risk of C. difficile transmission based on the volunteer hand contamination studies.2, 11, 12

DISINFECTION OF EQUIPMENT AND ENVIRONMENT

Environmental services staff must be educated about the incidence, transmission of, and impact of CDI, as well as strategies effective for C. difficile spores, which are resistant to standard cleaning products and may persist in patient rooms for many months.1 During CDI outbreaks, rooms should be cleaned with a chlorine‐based disinfectant (either an Environmental Protection Agency‐approved disinfectant with known sporicidal activity or a 1:10 dilution of household bleach), which rapidly destroys C. difficile spores.1 The sporicidal solution should have a contact time of at least 10 minutes.2 Efforts to control spores in the environment and prevent transmission are even more important considering recent data demonstrating that hypervirulent C. difficile strains may have increased sporulation, which in combination with increased toxin production, pose a major management challenge.13 Identification and removal of other sources of C. difficile, including replacement of electronic rectal thermometers with disposable thermometers, can also reduce the incidence of CDI.12

ANTIMICROBIAL STEWARDSHIP AND RESTRICTION

Interventions to ensure appropriate use of antibiotics, including antimicrobial stewardship programs and antibiotic restriction programs, are also effective. A study during an outbreak of a hypervirulent strain of C. difficile showed that an antimicrobial stewardship program reduced the incidence of CDI by 60%.14 In this study, the antimicrobial stewardship program focused on shifting antimicrobial selection to antimicrobials that were associated with a lower risk of CDI at their institution whenever possible. Reducing unnecessary antimicrobial use was stressed as well. Formal restrictions were not instituted; rather, clinicians received education and pocket guides to assist in antimicrobial selection.

Several studies have found respiratory fluoroquinolones, such as gatifloxacin or moxifloxacin, to be associated with the highest risk of CDI during outbreaks due to the BI/NAP1/027 strain.15, 16 Interestingly, this antimicrobial stewardship program recommended respiratory fluoroquinolones over cephalosporins for community‐acquired pneumonia, as cephalosporins historically have been strongly associated with CDI. Nevertheless, the incidence of CDI decreased after initiation of the antimicrobial stewardship program, despite increased use of respiratory fluoroquinolones. The antimicrobial stewardship program was implemented prior to the identification of the fluoroquinolone‐resistant epidemic strain. This shows that herd protection against CDI can occur by improvements in overall antimicrobial prescribing practices by decreasing the total number of patients at risk for CDI. This, in turn, will decrease the number of patients who develop CDI and contribute to the spread of C. difficile. In addition to using education to improve antimicrobial prescribing, several studies have found that restriction of specific antimicrobials associated with CDI (for example, clindamycin or fluoroquinolones) can result in a decrease in CDI.1, 1720

INSIGHTS ABOUT OPPORTUNITIES FOR IMPROVEMENT

Results of a recent point prevalence survey conducted by the Association for Professionals in Infection Control and Epidemiology, Inc (APIC) provide important insights into knowledge and clinical practice gaps related to early diagnosis and prevention of CDI.21 More than 12,000 APIC members were asked to provide a 1‐day snapshot of patients identified with CDI or colonization at their institutions. Responses from 648 (12.5%) acute care hospitals in the United States, representing 47 states, indicate a clear need to improve infection control practices.21 The following recommendations are based on recent evidence:

• Patients should be placed in contact isolation at the first suspicion of CDI, and kept in isolation for up to 2 days after diarrhea resolves because contamination persists in the environment that long.2 Of note, this differs from the SHEA/IDSA Clinical Practice Guidelines for Clostridium difficile Infection in Adults, which state: Maintain contact precautions for the duration of diarrhea.12 The Centers for Disease Control and Prevention (CDC) currently recommends contact precautions for the duration of illness when caring for patients with CDI.22

• Bleach solution should be used for routine and terminal cleaning during CDI outbreaks, as recommended by SHEA/IDSA and the CDC.

• Hand washing with soap and water is more effective than alcohol‐based hand sanitizers for removal of spores. However, appropriate donning and removal of gloves prevents hand contamination with C. difficile spores, likely explaining why hand washing with soap and water has not been associated with a decrease in CDI compared with alcohol‐based products.

• A formal program to educate environmental services personnel should be implemented to ensure they understand their critical role on the infection control team and effective strategies for cleaning.

SPECIAL APPROACHES

When basic approaches are not effective to reduce the incidence of CDI, the SHEA has recommendations for special approaches, which should be implemented as appropriate for each institution (summarized in Table 2).2 Strategies for prevention of CDI are also available from the CDC and the Institute for Healthcare Improvement (IHI).23, 24

SUMMARY

Effective management and prevention of CDI requires a multidisciplinary approach that includes leaders in hospital administration, clinicians, the infection control department, nursing, pharmacy, and the clinical laboratory, as well as environmental services. All of these professionals must be accountable and take an active role in implementing and complying with evidence‐based strategies to ensure that patients at risk are identified early and managed appropriately, and that effective strategies for prevention are in place. Hospitalists, as front‐line caregivers, physician leaders in their hospitals, and coordinators of patient care, can play a key role in these regards. Care when deciding when and which antimicrobial to use to treat non‐CDI infections; being attuned to symptoms that may be due to CDI, and prompt diagnosis and treatment of CDI; adhering to infection control policies; awareness of cleaning practices; and also being an active member of the infection control committee are all ways that hospitalists may take active roles in preventing CDI.