Hospital readmissions are common and costly, and represent a significant burden to the healthcare system. The challenges of postdischarge medication uncertainty, lack of self‐management support, and lack of timely access to health professionals1 are compounded in uninsured and Medicaid individuals by limited access to medications and primary care, financial strain, insecure housing, and limited social support.2

Our hospital cares for a large number of uninsured and low‐income publicly insured patients. The Portland area safety‐net, which consists of a network of 14 federally qualified health centers and free clinics, has limited capacity for uncompensated care. Uninsured patientsand to a lesser degree, Medicaid patientshave difficulty establishing primary care. Prior to the implementation of our program, uninsured and Medicaid patients without a usual source of care were given a list of safety‐net clinics at discharge, but frequently could not access appointments or navigate the complex system. There were no well‐developed partnerships between hospital and outpatient clinics for uninsured or Medicaid patients. The hospital lacked a systematic approach to securing postdischarge follow‐up and peridischarge patient education, and uninsured patients were financially responsible for most medications upon discharge. The costs of uncompensated or undercompensated potentially preventable readmissions for these patients, along with the recognition of gaps in quality, ultimately provided the rationale for a medical center‐funded transitional care intervention for uninsured and low‐income publicly insured patients.

Several transitional care improvement programs have shown effectiveness in reducing hospital readmissions,1, 35 but most have been conducted in settings where patients have secure access to outpatient care, and none have focused specifically on uninsured or Medicaid patients. Moreover, the development of these programs requires time and capital. Transitional care programs that have published results, to date, have been funded through government or private foundation grants1, 35; however, broader implementation of transitional care innovations will require financial and intellectual engagement of healthcare institutions themselves.

This report describes development of the Care Transitions Innovation (C‐TraIn), a multicomponent transitional care intervention for uninsured and low‐income publicly insured adults at a large, urban academic medical center, Oregon Health & Science University (OHSU). Because institutional funding and engagement is critical to the sustainability and scalability of similar programs, we also describe our process for gaining institutional support. Our hypothesis is that C‐TraIn can reduce readmissions and emergency department (ED) use at 30 days after hospital discharge, compared with usual care.

METHODS

PROGRAM EVALUATION

We are conducting a clustered, randomized controlled trial to evaluate C‐TraIn's impact on quality, access, and high‐cost utilization at 30 days after hospital discharge. Results are anticipated in mid‐2012. We chose to perform an analysis clustered by admitting team, because communication between the C‐TraIn nurse, physician team, and pharmacist consult services could introduce secular change effects that could impact the care received by other patients on a given team. There are 5 general medicine resident teams, 1 hospitalist service, and 1 cardiology service, and the physician personnel for each team changes from month to month. Because the cardiology and hospitalist services differ slightly from resident teams, we chose a randomized cross‐over design such that intervention and control teams are redesignated every 3 months. To enhance internal validity, study personnel who enroll patients and administer baseline and 30‐day surveys are blinded to intervention status. We are collecting data on prior utilization, usual source of care, outpatient access, insurance, patient activation,6 functional status,7, 8 self‐rated health,7 health literacy, care transitions education,9 alcohol and substance abuse, and social support.10 Our primary outcome will be self‐reported 30‐day hospital readmission and ED use. We will also evaluate administrative claims data to identify 30‐day OHSU readmission and ED utilization rates. We will assess whether improved access to medications, rates of outpatient follow‐up and time to follow‐up mediate any effect on primary outcomes. Secondary outcomes will include outpatient utilization, patient activation, self‐rated health, and functional status.

Given limited experience with transitional care programs in socioeconomically disadvantaged patients, we are measuring acceptability and feasibility by tracking rates of those declining the intervention, and through semi‐structured interviews at 30 days. We are monitoring fidelity to core elements of the program through chart and checklist reviews, and seeking provider feedback through in‐person meetings with key implementers. To ensure possibility of broader adoption beyond OHSU, we are developing a toolkit that defines core program elements and can be adapted for use in various settings.

DISCUSSION

Using a process of broad stakeholder engagement, exposure of financial incentives, and data‐driven understanding of institutional and population needs, we built consensus and gained institutional financial commitment for implementation of a multicomponent transitional care program for uninsured and Medicaid patients. Our experience is relevant to other hospital systems, and may have particular relevance to academic medical centers, whose tripartite mission of clinical care, research, and education make them a natural place for healthcare reform.11

Several key lessons from our experience may be widely applicable. First, key administrative allies helped us understand institutional priorities and identify key institutional change‐agents. Though initial attempts to gain support were met cautiously, persistent advocacy, development of a strong business case, and support from several administrative allies compelled further leadership support. Second, unlike traditional grant funding cycles, hospital budgets operate in real‐time rapid‐change cycles, necessitating rapid data collection, analysis, and program design. Such demands could potentially threaten the viability of the program itself, or result in premature diffusion of novel practices into disparate populations. Communication with administrative leadership about the value of sound research design within the context of faster‐paced institutional needs was important and allowed time for data‐driven program development and diffusion. Simultaneously, we recognized the need to move quickly, provide regular progress updates, and use existing institutional resources, such as volunteer students and business development office, when possible.

We found that cross‐site hospitalcommunity partnerships are an essential program element. Partnership occurs through a payment agreement and through active engagement in ongoing quality improvement, including clinic representation at monthly team meetings. Clinic partnerships have enabled multidisciplinary cross‐site communication and relationships that facilitate innovation across routinely siloed elements of the system, allowing the team to anticipate and respond to patient problems before they lead to readmissions or poor outcomes. Our experience matches findings from recent program evaluations that found that care coordination attempts are unsuccessful without strong cross‐site linkages.12 These linkages are especially challenging and needed for uninsured and Medicaid patients, given their traditional lack of access and the additional social and financial barriers that influence their care.13

Limitations of our study include: implementation at a single, academic medical center; secular changes (which we mitigate against using randomized trial design); and potential for low power, if readmission rates are lower than anticipated from needs assessment data. Additionally, the need for a willing and invested program champion to coordinate an often messy, complex intervention may limit generalizability.

While transitional care programs continue to proliferate in response to increasingly recognized gaps in a fragmented care system,14, 15 few interventions specifically address the needs of socioeconomically disadvantaged patients. The major study that did5 was conducted in Massachusetts, where many patients received care through a state Free Care program and robust local safety‐net. Others have largely been tested in integrated care settings,1 and target patients who are part of managed care programs.1, 4, 16

To our knowledge, there are no well‐described programs that include explicit purchasing of outpatient medical homes for uninsured patients who would not otherwise have access to care. Our experience shifts the paradigm of the role of hospitals in care for the uninsured and underinsured: instead of a reactive, uncoordinated role, we assert that the hospital's strategic up‐front allocation of resources has a sound business, quality, and ethical foundation. This is especially important, given a new era of payment reform and coordinated care organizations. There is an opportunity to both improve quality for the uninsured and Medicaid patients, control costs, and gain valuable experience that can inform transitional care improvements for broader patient populations. If our study is successful in reducing readmissions, there may be important implications as to how to redefine the hospital's role in outpatient access to care linkages, especially for uninsured and Medicaid patients.

Hospital readmissions are common and costly, and represent a significant burden to the healthcare system. The challenges of postdischarge medication uncertainty, lack of self‐management support, and lack of timely access to health professionals1 are compounded in uninsured and Medicaid individuals by limited access to medications and primary care, financial strain, insecure housing, and limited social support.2

Our hospital cares for a large number of uninsured and low‐income publicly insured patients. The Portland area safety‐net, which consists of a network of 14 federally qualified health centers and free clinics, has limited capacity for uncompensated care. Uninsured patientsand to a lesser degree, Medicaid patientshave difficulty establishing primary care. Prior to the implementation of our program, uninsured and Medicaid patients without a usual source of care were given a list of safety‐net clinics at discharge, but frequently could not access appointments or navigate the complex system. There were no well‐developed partnerships between hospital and outpatient clinics for uninsured or Medicaid patients. The hospital lacked a systematic approach to securing postdischarge follow‐up and peridischarge patient education, and uninsured patients were financially responsible for most medications upon discharge. The costs of uncompensated or undercompensated potentially preventable readmissions for these patients, along with the recognition of gaps in quality, ultimately provided the rationale for a medical center‐funded transitional care intervention for uninsured and low‐income publicly insured patients.

Several transitional care improvement programs have shown effectiveness in reducing hospital readmissions,1, 35 but most have been conducted in settings where patients have secure access to outpatient care, and none have focused specifically on uninsured or Medicaid patients. Moreover, the development of these programs requires time and capital. Transitional care programs that have published results, to date, have been funded through government or private foundation grants1, 35; however, broader implementation of transitional care innovations will require financial and intellectual engagement of healthcare institutions themselves.

This report describes development of the Care Transitions Innovation (C‐TraIn), a multicomponent transitional care intervention for uninsured and low‐income publicly insured adults at a large, urban academic medical center, Oregon Health & Science University (OHSU). Because institutional funding and engagement is critical to the sustainability and scalability of similar programs, we also describe our process for gaining institutional support. Our hypothesis is that C‐TraIn can reduce readmissions and emergency department (ED) use at 30 days after hospital discharge, compared with usual care.

METHODS

PROGRAM EVALUATION

We are conducting a clustered, randomized controlled trial to evaluate C‐TraIn's impact on quality, access, and high‐cost utilization at 30 days after hospital discharge. Results are anticipated in mid‐2012. We chose to perform an analysis clustered by admitting team, because communication between the C‐TraIn nurse, physician team, and pharmacist consult services could introduce secular change effects that could impact the care received by other patients on a given team. There are 5 general medicine resident teams, 1 hospitalist service, and 1 cardiology service, and the physician personnel for each team changes from month to month. Because the cardiology and hospitalist services differ slightly from resident teams, we chose a randomized cross‐over design such that intervention and control teams are redesignated every 3 months. To enhance internal validity, study personnel who enroll patients and administer baseline and 30‐day surveys are blinded to intervention status. We are collecting data on prior utilization, usual source of care, outpatient access, insurance, patient activation,6 functional status,7, 8 self‐rated health,7 health literacy, care transitions education,9 alcohol and substance abuse, and social support.10 Our primary outcome will be self‐reported 30‐day hospital readmission and ED use. We will also evaluate administrative claims data to identify 30‐day OHSU readmission and ED utilization rates. We will assess whether improved access to medications, rates of outpatient follow‐up and time to follow‐up mediate any effect on primary outcomes. Secondary outcomes will include outpatient utilization, patient activation, self‐rated health, and functional status.

Given limited experience with transitional care programs in socioeconomically disadvantaged patients, we are measuring acceptability and feasibility by tracking rates of those declining the intervention, and through semi‐structured interviews at 30 days. We are monitoring fidelity to core elements of the program through chart and checklist reviews, and seeking provider feedback through in‐person meetings with key implementers. To ensure possibility of broader adoption beyond OHSU, we are developing a toolkit that defines core program elements and can be adapted for use in various settings.

DISCUSSION

Using a process of broad stakeholder engagement, exposure of financial incentives, and data‐driven understanding of institutional and population needs, we built consensus and gained institutional financial commitment for implementation of a multicomponent transitional care program for uninsured and Medicaid patients. Our experience is relevant to other hospital systems, and may have particular relevance to academic medical centers, whose tripartite mission of clinical care, research, and education make them a natural place for healthcare reform.11

Several key lessons from our experience may be widely applicable. First, key administrative allies helped us understand institutional priorities and identify key institutional change‐agents. Though initial attempts to gain support were met cautiously, persistent advocacy, development of a strong business case, and support from several administrative allies compelled further leadership support. Second, unlike traditional grant funding cycles, hospital budgets operate in real‐time rapid‐change cycles, necessitating rapid data collection, analysis, and program design. Such demands could potentially threaten the viability of the program itself, or result in premature diffusion of novel practices into disparate populations. Communication with administrative leadership about the value of sound research design within the context of faster‐paced institutional needs was important and allowed time for data‐driven program development and diffusion. Simultaneously, we recognized the need to move quickly, provide regular progress updates, and use existing institutional resources, such as volunteer students and business development office, when possible.

We found that cross‐site hospitalcommunity partnerships are an essential program element. Partnership occurs through a payment agreement and through active engagement in ongoing quality improvement, including clinic representation at monthly team meetings. Clinic partnerships have enabled multidisciplinary cross‐site communication and relationships that facilitate innovation across routinely siloed elements of the system, allowing the team to anticipate and respond to patient problems before they lead to readmissions or poor outcomes. Our experience matches findings from recent program evaluations that found that care coordination attempts are unsuccessful without strong cross‐site linkages.12 These linkages are especially challenging and needed for uninsured and Medicaid patients, given their traditional lack of access and the additional social and financial barriers that influence their care.13

Limitations of our study include: implementation at a single, academic medical center; secular changes (which we mitigate against using randomized trial design); and potential for low power, if readmission rates are lower than anticipated from needs assessment data. Additionally, the need for a willing and invested program champion to coordinate an often messy, complex intervention may limit generalizability.

While transitional care programs continue to proliferate in response to increasingly recognized gaps in a fragmented care system,14, 15 few interventions specifically address the needs of socioeconomically disadvantaged patients. The major study that did5 was conducted in Massachusetts, where many patients received care through a state Free Care program and robust local safety‐net. Others have largely been tested in integrated care settings,1 and target patients who are part of managed care programs.1, 4, 16

To our knowledge, there are no well‐described programs that include explicit purchasing of outpatient medical homes for uninsured patients who would not otherwise have access to care. Our experience shifts the paradigm of the role of hospitals in care for the uninsured and underinsured: instead of a reactive, uncoordinated role, we assert that the hospital's strategic up‐front allocation of resources has a sound business, quality, and ethical foundation. This is especially important, given a new era of payment reform and coordinated care organizations. There is an opportunity to both improve quality for the uninsured and Medicaid patients, control costs, and gain valuable experience that can inform transitional care improvements for broader patient populations. If our study is successful in reducing readmissions, there may be important implications as to how to redefine the hospital's role in outpatient access to care linkages, especially for uninsured and Medicaid patients.

Hospital readmissions are common and costly, and represent a significant burden to the healthcare system. The challenges of postdischarge medication uncertainty, lack of self‐management support, and lack of timely access to health professionals1 are compounded in uninsured and Medicaid individuals by limited access to medications and primary care, financial strain, insecure housing, and limited social support.2

Our hospital cares for a large number of uninsured and low‐income publicly insured patients. The Portland area safety‐net, which consists of a network of 14 federally qualified health centers and free clinics, has limited capacity for uncompensated care. Uninsured patientsand to a lesser degree, Medicaid patientshave difficulty establishing primary care. Prior to the implementation of our program, uninsured and Medicaid patients without a usual source of care were given a list of safety‐net clinics at discharge, but frequently could not access appointments or navigate the complex system. There were no well‐developed partnerships between hospital and outpatient clinics for uninsured or Medicaid patients. The hospital lacked a systematic approach to securing postdischarge follow‐up and peridischarge patient education, and uninsured patients were financially responsible for most medications upon discharge. The costs of uncompensated or undercompensated potentially preventable readmissions for these patients, along with the recognition of gaps in quality, ultimately provided the rationale for a medical center‐funded transitional care intervention for uninsured and low‐income publicly insured patients.

Several transitional care improvement programs have shown effectiveness in reducing hospital readmissions,1, 35 but most have been conducted in settings where patients have secure access to outpatient care, and none have focused specifically on uninsured or Medicaid patients. Moreover, the development of these programs requires time and capital. Transitional care programs that have published results, to date, have been funded through government or private foundation grants1, 35; however, broader implementation of transitional care innovations will require financial and intellectual engagement of healthcare institutions themselves.

This report describes development of the Care Transitions Innovation (C‐TraIn), a multicomponent transitional care intervention for uninsured and low‐income publicly insured adults at a large, urban academic medical center, Oregon Health & Science University (OHSU). Because institutional funding and engagement is critical to the sustainability and scalability of similar programs, we also describe our process for gaining institutional support. Our hypothesis is that C‐TraIn can reduce readmissions and emergency department (ED) use at 30 days after hospital discharge, compared with usual care.

METHODS

PROGRAM EVALUATION

We are conducting a clustered, randomized controlled trial to evaluate C‐TraIn's impact on quality, access, and high‐cost utilization at 30 days after hospital discharge. Results are anticipated in mid‐2012. We chose to perform an analysis clustered by admitting team, because communication between the C‐TraIn nurse, physician team, and pharmacist consult services could introduce secular change effects that could impact the care received by other patients on a given team. There are 5 general medicine resident teams, 1 hospitalist service, and 1 cardiology service, and the physician personnel for each team changes from month to month. Because the cardiology and hospitalist services differ slightly from resident teams, we chose a randomized cross‐over design such that intervention and control teams are redesignated every 3 months. To enhance internal validity, study personnel who enroll patients and administer baseline and 30‐day surveys are blinded to intervention status. We are collecting data on prior utilization, usual source of care, outpatient access, insurance, patient activation,6 functional status,7, 8 self‐rated health,7 health literacy, care transitions education,9 alcohol and substance abuse, and social support.10 Our primary outcome will be self‐reported 30‐day hospital readmission and ED use. We will also evaluate administrative claims data to identify 30‐day OHSU readmission and ED utilization rates. We will assess whether improved access to medications, rates of outpatient follow‐up and time to follow‐up mediate any effect on primary outcomes. Secondary outcomes will include outpatient utilization, patient activation, self‐rated health, and functional status.

Given limited experience with transitional care programs in socioeconomically disadvantaged patients, we are measuring acceptability and feasibility by tracking rates of those declining the intervention, and through semi‐structured interviews at 30 days. We are monitoring fidelity to core elements of the program through chart and checklist reviews, and seeking provider feedback through in‐person meetings with key implementers. To ensure possibility of broader adoption beyond OHSU, we are developing a toolkit that defines core program elements and can be adapted for use in various settings.

DISCUSSION

Using a process of broad stakeholder engagement, exposure of financial incentives, and data‐driven understanding of institutional and population needs, we built consensus and gained institutional financial commitment for implementation of a multicomponent transitional care program for uninsured and Medicaid patients. Our experience is relevant to other hospital systems, and may have particular relevance to academic medical centers, whose tripartite mission of clinical care, research, and education make them a natural place for healthcare reform.11

Several key lessons from our experience may be widely applicable. First, key administrative allies helped us understand institutional priorities and identify key institutional change‐agents. Though initial attempts to gain support were met cautiously, persistent advocacy, development of a strong business case, and support from several administrative allies compelled further leadership support. Second, unlike traditional grant funding cycles, hospital budgets operate in real‐time rapid‐change cycles, necessitating rapid data collection, analysis, and program design. Such demands could potentially threaten the viability of the program itself, or result in premature diffusion of novel practices into disparate populations. Communication with administrative leadership about the value of sound research design within the context of faster‐paced institutional needs was important and allowed time for data‐driven program development and diffusion. Simultaneously, we recognized the need to move quickly, provide regular progress updates, and use existing institutional resources, such as volunteer students and business development office, when possible.

We found that cross‐site hospitalcommunity partnerships are an essential program element. Partnership occurs through a payment agreement and through active engagement in ongoing quality improvement, including clinic representation at monthly team meetings. Clinic partnerships have enabled multidisciplinary cross‐site communication and relationships that facilitate innovation across routinely siloed elements of the system, allowing the team to anticipate and respond to patient problems before they lead to readmissions or poor outcomes. Our experience matches findings from recent program evaluations that found that care coordination attempts are unsuccessful without strong cross‐site linkages.12 These linkages are especially challenging and needed for uninsured and Medicaid patients, given their traditional lack of access and the additional social and financial barriers that influence their care.13

Limitations of our study include: implementation at a single, academic medical center; secular changes (which we mitigate against using randomized trial design); and potential for low power, if readmission rates are lower than anticipated from needs assessment data. Additionally, the need for a willing and invested program champion to coordinate an often messy, complex intervention may limit generalizability.

While transitional care programs continue to proliferate in response to increasingly recognized gaps in a fragmented care system,14, 15 few interventions specifically address the needs of socioeconomically disadvantaged patients. The major study that did5 was conducted in Massachusetts, where many patients received care through a state Free Care program and robust local safety‐net. Others have largely been tested in integrated care settings,1 and target patients who are part of managed care programs.1, 4, 16

To our knowledge, there are no well‐described programs that include explicit purchasing of outpatient medical homes for uninsured patients who would not otherwise have access to care. Our experience shifts the paradigm of the role of hospitals in care for the uninsured and underinsured: instead of a reactive, uncoordinated role, we assert that the hospital's strategic up‐front allocation of resources has a sound business, quality, and ethical foundation. This is especially important, given a new era of payment reform and coordinated care organizations. There is an opportunity to both improve quality for the uninsured and Medicaid patients, control costs, and gain valuable experience that can inform transitional care improvements for broader patient populations. If our study is successful in reducing readmissions, there may be important implications as to how to redefine the hospital's role in outpatient access to care linkages, especially for uninsured and Medicaid patients.

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.