Clostridium difficile (C Diff): The Cost and the Burden But There Is Hope

Executive Summary

Introduction:

Clostridium difficile (C. diff or CDI) infections represent a significant threat to public health, particularly within healthcare facilities and military settings. The Centers for Disease Control and Prevention (CDC) has highlighted CDI as one of the most dangerous healthcare-associated pathogens, causing severe diarrhea and potentially life-threatening complications. In light of the escalating costs and devastating consequences associated with CDI, urgent measures are needed to prevent and combat its spread.

?

The Danger of C. diff Infections:

C. diff is a highly virulent, antibiotic-resistant bacterium that can lead to deadly diarrhea and colitis. Unlike antibiotic-resistant bacteria, CDI is alarmingly prevalent in healthcare settings, posing a substantial risk to patients, particularly those with compromised immune systems or underlying medical conditions. The recent emergence of hypervirulent strains, such as BI/NAP1/027, has further exacerbated the severity and frequency of CDI outbreaks, leading to increased morbidity and mortality rates.

?

Transmission and Symptoms:

CDI is primarily transmitted through the oral-fecal route, with spores exhibiting remarkable resistance to environmental conditions and disinfectants. Common symptoms of CDI include watery diarrhea, fever, abdominal pain, and nausea, with severe cases progressing to pseudomembranous colitis, toxic megacolon, and even death. The ease of transmission and the wide range of symptoms make CDI a formidable adversary in both healthcare and military settings.

?

Risk Factors and Prevalence:

Numerous factors contribute to the risk of CDI, including antibiotic use, prolonged hospitalization, and underlying medical conditions such as inflammatory bowel disease and weakened immune systems. Alarmingly, CDI is estimated to cause nearly half a million infections in the US annually, with recurrence rates on the rise. Moreover, community-associated cases are on the rise, highlighting the need for comprehensive prevention strategies beyond healthcare facilities.

?

Cost Implications:

The economic burden of CDI is staggering, with studies estimating annual costs exceeding billions of dollars in the US alone. From prolonged hospital stays to increased mortality rates, CDI imposes significant financial strains on healthcare systems, military institutions, and individual patients. Furthermore, the long-term sequelae of CDI, including recurrent infections and chronic gastrointestinal disorders, further amplify the economic toll of this insidious pathogen.

?

The Role of Prevention and Intervention:

Effective prevention measures are paramount in curbing the spread of CDI, encompassing stringent hygiene practices, antimicrobial stewardship, and innovative interventions such as vaccines and microbiome-based therapies. Companies like LIV Process offer promising solutions, such as NTCD-M3, a non-toxigenic strain of C. difficile that prevents CDI recurrence without causing symptoms. Additionally, predictive algorithms like Sentri7's C. diff infection risk score enable early identification of at-risk patients, allowing for timely interventions to prevent infection transmission.

?

Military Implications:

In military settings, where personnel face unique challenges such as prolonged deployments and exposure to trauma, the threat of CDI is particularly concerning. Combat field hospitals must adapt to provide agile and versatile healthcare support, emphasizing early detection and intervention to mitigate the impact of CDI on soldier health and mission readiness. Moreover, military personnel experiencing gastrointestinal symptoms, whether deployed or not, require specialized care to address the long-term consequences of CDI and other gastrointestinal disorders.

?

Conclusion:

Clostridium difficile infections represent a critical public, health, and military concern, with devastating consequences for patients and significant economic ramifications. Urgent action is needed to prevent and combat CDI through comprehensive prevention strategies, innovative interventions, and enhanced healthcare infrastructure. By prioritizing CDI prevention and investing in research and development, we can mitigate the impact of this dangerous pathogen and safeguard the health and well-being of individuals in both civilian and military contexts.

Background

The Centers for Disease Control and Prevention announced that the most threatening infections are those caused by antibiotic-resistant bacteria and Clostridium difficile (C.diff or CDI, will be used interchangeably), which can cause deadly diarrhea. Another report says one out of 25 hospitalized patients gets a healthcare-associated infection, and one in nine of them dies. Antibiotic-resistant bacteria and C. diff cause some of the most threatening infections. Unlike antibiotic-resistant bacteria, CID is the most frequently reported healthcare-associated pathogen in the United States. For reasons that aren’t well understood but that may be linked to widespread use of antibiotics and antimicrobials, C. diff strains have evolved to become more virulent, causing outbreaks in various countries including the United States and sometimes affecting those who aren’t at considerable risk.?

?

C. diff is a gram-positive, anaerobic, spore-forming bacillus that can cause diarrhea. C.diff occurs when C. diff colonizes the colon and the spores concert to the vegetative state releasing toxins that trigger inflammation resulting in diarrhea and colitis. Once the spores are ingested, they may readily pass through the acidic environment of the stomach and then germinate in the bowel as the vegetative form. Patients may then become colonized with the organism, further enhancing transmission. It causes inflammation in the colon leading to fever and severe diarrhea—up to 15 to 30 times daily.

?

CDI is transmitted by the oral-fecal route in either the vegetative or spore form. Vegetative cells die quickly in an aerobic environment. Spores are a survival form and live for a very long time in the environment. The spores are resistant to heat, drying, pressure and nearly all disinfects. They are resistant to all antibiotics as they only act on growing bacteria. Spores survive very well in a hospital environment. In the healthcare setting, environmental contamination and hand carriage from healthcare workers to patients play a significant role in disease outbreaks.

?

Common symptoms of C.diff infection including:

-????????? Watery diarrhea (mild to severe)

-????????? Fever

-????????? Leukocytosis

-????????? Nausea

-????????? Abdominal swollen, pain and distention

?

In cases of mild to moderate Clostridium difficile (C. diff) infection, patients may present solely with diarrhea, which may not immediately suggest the severity of the underlying condition. This symptomatic manifestation is principally due to the release of toxins A and B, and in some instances, an additional binary toxin, all of which contribute to the disruption of the colonic mucosal integrity and incite an inflammatory response.

?

Severe C. diff infections can lead to grave complications, including pseudomembranous colitis, a condition characterized by the formation of plaques in the colon, toxic megacolon, which is a dangerous dilation of the large intestine, and in extreme circumstances, a perforated colon. These conditions can precipitate systemic sepsis and, if not promptly and effectively managed, may result in mortality.

?

The alarming surge in the incidence and severity of CDI in recent times has been linked to the emergence of the BI/NAP1/027 strain. This particular strain is notorious for its overproduction of toxins A and B, exceeding the output of other toxin-producing strains by 16 and 23 times, respectively. The augmented toxin production is theorized to be the consequence of a gene deletion that typically regulates toxin synthesis, thereby removing the intrinsic limits on toxin production. Additionally, the BI/NAP1/027 strain is known to synthesize a binary toxin analogous to that produced by Clostridium perfringens, which may contribute to its virulence. The strain also demonstrates a robust resistance to fluoroquinolone antibiotics and has a heightened ability to sporulate, factors which likely contribute to its widespread and persistent nature in healthcare settings.

Risk Factors

?Risk factors for C. diff encompass a broad spectrum of environmental and clinical settings, with hospitalization and residence in long-term care facilities (LTCFs) identified as primary contributors to increased incidence rates. However, and more alarmingly, recent studies shown prevalence of infection in non-medical and non-LTCFs settings at the same or higher rates.

?

The pervasive nature of C. diff spores within healthcare environments is attributed to their remarkable resilience, adhering to and persisting on a multitude of surfaces such as beds, bed-rails, chairs—with contamination rates reported as high as 58%—and curtains, which can harbor spores on up to 4% of their surfaces. The spores' tenacity is further evidenced by their presence on medical instruments and various other high-contact surfaces, including wheelchairs, where spores can be transferred via hands and equipment, setting the stage for patient-to-patient transmission.

?

C. diff’s risk extends beyond the confines of healthcare institutions. The spores are not exclusive to the hospital or LTCF environments; they have been detected in significant quantities in non-clinical settings, indicating a ubiquitous presence. A study conducted by the University of Houston revealed nearly equivalent levels of C. diff spores in both healthcare and community environments, suggesting that the spread of this pathogen is not limited by the walls of medical facilities. Remarkably, of all community sites tested, shoe soles exhibited the highest positivity rate for C. diff, at 45%. This finding underscores the ease with which spores can be disseminated throughout the community, potentially tracing back to healthcare settings or other contaminated environments.

?

The implications of these findings are profound. The facility-wide distribution of C. diff spores in healthcare settings necessitates rigorous and comprehensive disinfection protocols to mitigate the risk of transmission. The identification of C. diff in community settings requires public health strategies that extend beyond hospitals and LTCFs, acknowledging the potential for community-acquired infections and the need for heightened awareness and hygiene practices among the general public. The ability of spores to hitchhike on personal items such as shoes illustrates the ease of movement across different environments, bridging the gap between community and healthcare-associated infections.

?

To combat the spread of C. diff, there is a need for enhanced surveillance and cleaning protocols, especially in areas of high patient turnover, where the probability of encountering residual spores from previous occupants is elevated. The resilience of C. diff spores against routine cleaning and disinfection underscores the importance of employing sporicidal agents and adhering to strict hand hygiene practices by healthcare workers and visitors alike. In addition to environmental strategies, there is a growing recognition of the need to address the broad dissemination of spores in the community, necessitating public health campaigns that inform on best practices to prevent the spread of this formidable pathogen beyond the traditional healthcare settings.

Community-associated cases are associated with peri-partum, close contact with C.diff, and food. Additional community sources of the organism may include domestic animals, such as cats and dogs, and farm animals. Spores have been detected in a substantial proportion of retail ground meat samples in Canada and in pet foods containing raw turkey, suggesting the possibility of transmission via food products.

?

Among the places that C. diff can be found are:

• Between 25 and 70% of neonates as well children under 2 are colonized with C.diff but are often asymptomatic
• Up to 17.5% of the healthy adult population, as well as a much higher percentage in hospital communities (One study showed that only 43% of healthcare staff regularly used proper PPE).
• About 30% of patients who have already had a CDI. Recurrence rates have grown by about 10%, and the death rate has steadily increased.
• Flood waters

?

The epidemiology of Clostridium difficile (C. diff) infection is intimately connected with the utilization of certain antibiotics that can disrupt the colonic microbiota, rendering patients more susceptible to colonization and infection. Antibiotics such as clindamycin, cephalosporins, penicillins, beta-lactams, and fluoroquinolones are well-documented for their propensity to induce C. diff infections. The mechanism underlying this risk is associated with the broad-spectrum activity of these agents, which can non-selectively eradicate commensal bacterial flora that typically confer protection against C. diff colonization. When the balance of the gut microbiome is compromised, C. diff spores can germinate and proliferate unchecked, leading to infection.

?

Proton-pump inhibitors (PPIs), commonly prescribed for reducing gastric acid secretion in conditions like gastroesophageal reflux disease (GERD), have also been implicated in increasing the risk of C. diff infections. The suppression of gastric acid by PPIs is hypothesized to diminish the natural barrier to ingested pathogens, including C. diff spores, facilitating their survival and subsequent colonization in the gastrointestinal tract. This association is particularly notable in cases of community-acquired CDI where no prior antibiotic exposure is reported, yet a history of PPI use is present.

?

Medical conditions that inherently weaken the body's defenses against infections, such as inflammatory bowel disease (IBD), can predispose patients to C. diff. In the context of IBD, the altered gut mucosa, coupled with the frequent need for antibiotics, can increase the risk of CDI. Similarly, patients with compromised immune systems, whether due to conditions like HIV/AIDS or immunosuppressive treatments such as chemotherapy, are at heightened risk. The therapeutic immunosuppression, while necessary, can impair the body's ability to contain C. diff after colonization.

?

Chronic kidney disease (CKD) is another condition that predisposes patients to CDI, possibly due to alterations in the gut microbiota, changes in intestinal permeability, or the frequent use of antibiotics in this patient population. Procedures involving the digestive tract, ranging from endoscopic interventions to complex surgeries, can disrupt the gut's mucosal barrier and its microbial ecology, providing a niche for C. diff proliferation.

?

Surgeries of the stomach or abdominal area inherently require perioperative antibiotics and often result in alterations to the gastrointestinal microbiome, both of which can significantly increase the risk of subsequent CDI. Facility managers and healthcare providers must recognize these risk factors to implement appropriate preventative strategies, such as judicious antibiotic stewardship, careful patient monitoring, and targeted prophylactic measures to mitigate the incidence of C. diff infections within healthcare environments.

?

Patient Population

?

In the cohort of 629,000 individuals diagnosed with Clostridium difficile (C. diff), approximately 90% successfully resolve the infection after the initial episode. However, around 10% experience a second episode. Within this subset, a concerning 52% may encounter a third episode, representing approximately 5.2% of the initial cohort. Furthermore, the fourth episode is noted in about 5% of these recurrent cases, equating to 0.26% of the original cohort. These figures highlight the recurrent nature of C. diff and the critical need for effective management strategies after the initial infection.

?

The data regarding vaccine uptake among adults over 65 indicates an overall penetration rate of approximately 15%, with variations depending on patient segmentation. The lowest uptake is between 3-5% for primary prophylaxis in adults over 65, rising to 50% among patients with inflammatory bowel disease (IBD). With C. diff responsible for nearly half a million infections in the U.S. annually, the risk factors—age over 65, recent healthcare facility stays, immunocompromised states, and prior CDI episodes—necessitate prioritized preventive measures. Currently, hygiene and disinfection protocols are the mainstays of prevention, but the emerging vaccine developments hold promise for a more robust approach to prevent both primary and recurrent CDI.

?

The interplay between C. diff and IBD is particularly noteworthy. In the U.S., there are an estimated 1.4 million people with IBD, and 70,000 new cases are identified annually. Of these, 100,000 result in hospitalization each year. A significant proportion of IBD patients—75% with Crohn’s disease and 35% with ulcerative colitis—will eventually require surgical intervention. The past two decades have seen a staggering 30% increase in C. diff-related hospitalizations, emphasizing the infection's expanding footprint. High-risk patient groups for C. diff in community settings include those with HIV, chronic obstructive pulmonary disease (COPD), diabetes, and those undergoing procedures like nasogastric tube placement.

?

Surgical patients are especially susceptible to C. diff, likely due to the prevalent use of antibiotics both as prophylaxis and treatment. The implementation of non-toxigenic C. diff (NTCD) strains as a primary prophylactic measure has been investigated as a means to safeguard these at-risk groups. The highly sensitive polymerase chain reaction (PCR) testing for C. diff, while a powerful diagnostic tool, cannot differentiate between active infection and colonization, which may lead to overdiagnosis and increased healthcare costs due to extended hospital stays, unnecessary antibiotic use, and unwarranted isolation practices.

?

The burden of C. diff extends to increased healthcare resource utilization, with an average extension of hospital stays by 2.6 to 4.5 days. Mortality rates are sobering, with a 6.9% death rate at 30 days post-infection, rising to 16.7% after one year. The BI/NAP1/027 strain, known for its virulence, has led to a mortality rate of 16.7% and lengthened hospital stays by an average of 10.7 days. In the context of surgery, colectomy is required in 0.4% to 3.5% of CDI cases, primarily to manage complications such as colonic perforation, toxic megacolon, or severe recurrent disease. The mortality rate associated with surgery can reach 50%.

Fulminant CDI, which may progress to shock, occurs in 3% to 8% of patients and is particularly prevalent among individuals with autoimmune diseases, HIV, recent surgical history, chemotherapy, transplantation, or immunosuppression, and in patients presenting symptoms within two weeks of antibiotic use. Mortality rates in these scenarios can escalate to 30-90%. High-risk assessments based on criteria such as the American Society of Anesthesiology classification, the need for vasopressor support, and low serum albumin are strong predictors of death from fulminant CDI.

Following treatment, CDI recurs in 15-35% of patients after one episode and in 33-65% of those who have experienced multiple episodes. Recurrent CDI poses a substantial challenge in clinical management, with a high likelihood of further episodes in those who have previously recurred. Identification of long-term sequelae in younger cohorts, as well as in historically lower-risk groups such as pregnant women and children, is an emerging concern, underscoring the pressing need for comprehensive prevention and management strategies for C. diff across all demographics.

?

Treatment Options for CDI

?

An array of therapeutic options exists for the treatment of C. diff, detailed comprehensively in the Appendix. Initial strategies often involve the discontinuation of the inciting antibiotics when clinically feasible. Historically, metronidazole and vancomycin have displayed comparable efficacy and relapse rates, with initial response rates around 96% and recurrence rates near 20%. Metronidazole, administered orally or intravenously, exhibits a failure rate between 5-20%, with relapses occurring in about one-fifth of cases. Upon the failure of two metronidazole courses, clinicians typically escalate treatment to vancomycin, partly due to the potential for metronidazole resistance.

?

Fecal microbiota transplantation (FMT) has emerged as a potent intervention for refractory C. diff infections, demonstrating efficacy and cost-effectiveness as recognized by insurance providers. This is contingent on the absence of subsequent antibiotic therapy which could disrupt the restored microbiota. Monoclonal antibodies constitute another therapeutic avenue, offering rapid protection against C. diff reinfection, albeit with considerable cost implications.

?

In the United States, the FDA has sanctioned the use of REBYOTA, a pioneering microbiome-based therapeutic, for the prevention of CDI recurrence in adult patients following antibiotic treatment for recurrent episodes. This authorization is currently exclusive to the U.S. market.

?

Biomictra Fecal Microbiota, another microbiome therapy, has gained approval from the Therapeutic Goods Administration (TGA) in Australia for the treatment of C. diff infection. This treatment is dispensed solely to registered Medical Practitioners, highlighting the controlled and specialized nature of this intervention.

?

Fecal microbiota, live-jslm (marketed as REBYOTA [RBL]), recently received approval in the U.S. for the prevention of recurrent CDI following antibiotic interventions. A post hoc analysis from the phase 3 PUNCH CD3 trial—an extensive, randomized, double-blind, placebo-controlled study—evaluated the effectiveness and health-related quality of life (HRQL) impact of RBL compared to placebo in patients experiencing their first recurrence. The analysis revealed that RBL treatment significantly reduced the odds of recurrence at week 8, with an 81% probability of treatment success compared to 60% with placebo. This corresponds to a 21% absolute and 35% relative improvement in treatment success rates for RBL. Additionally, RBL treatment was linked to notably higher scores in the Clostridioides difficile Quality of Life Survey (Cdiff32), particularly in the mental health domain, from baseline to week 8. These outcomes underscore RBL's efficacy in both preventing further recurrences and enhancing HRQL in patients at their first recurrence of CDI.

?

Drugs Currently in the Pipeline

?

In a strategic move to advance their presence in the North American market, Destiny Pharma entered into an exclusive collaboration and licensing arrangement with Sebela Pharmaceuticals in February 2023. This partnership entails Sebela's commitment to finance all forthcoming clinical developments and oversee the commercialization efforts within the United States. Destiny, in tandem with Sebela, will continue to contribute to the clinical trial processes. A pivotal aspect of this collaboration is Sebela's dedication to meticulously design and conduct Phase 3 trials that will be pivotal for the attainment of a global Marketing Authorization Application (MAA). In pursuit of expanding the reach of their promising therapeutic, Destiny is actively pursuing additional commercial partnerships to introduce NTCD-M3 to markets beyond North American borders.

?

NTCD-M3 represents a non-toxigenic strain of C. difficile that is devoid of the genetic material necessary for toxin production. This innovative oral formulation contains spores of NTCD-M3, which has demonstrated a protective effect against CDI in treated patients. NTCD-M3 operates as a benign colonizer of the intestinal tract, effectively creating a protective barrier against colonization by virulent C. difficile strains following antibiotic therapy. By temporarily establishing itself within the gut, NTCD-M3 offers a symptom-free protective mechanism against the recurrence of CDI during vulnerable post-treatment phases.

In contrast to Destiny's forward momentum, Sanofi in 2017 chose to halt the development of their vaccine candidate for C. diff. This decision reflects the challenging landscape of vaccine development for this complex infection.

To date, no vaccine has been granted approval for the prophylaxis of either primary or recurrent CDI. However, multiple vaccine candidates are in various stages of research and development, targeting the prevention of primary C. diff infections. These investigational vaccines hold the potential to transform the approach to CDI, offering a proactive solution to a disease that currently relies on responsive treatment strategies.

Cost of CDI

CDI continues to present a significant financial burden on healthcare systems, as well as a growing clinical challenge. Research has consistently shown that CDI contributes to an increased length of hospital stay—ranging from an additional three to 20 days per patient—resulting in an excess cost of approximately $1 billion annually in the United States. The aggregate annual costs were estimated at a staggering $6.3 billion in 2016, with prolonged hospitalization following a CDI episode being a major contributor to this expenditure.

?

C. diff represents a relentless drain on healthcare resources and patient quality of life. Data reveal the stark reality: C. diff is associated with an increased odds ratio of 1.5 for 30-day hospital readmissions compared to non-GI conditions. The implication is clear — C. diff patients are more likely to bounce back into hospital beds, straining the already overstretched sinews of healthcare systems. Although not as high as some GI cancers, C. diff treatment costs are significant and contribute to the financial strain on healthcare systems.

?

Hospitalization costs associated with C. diff infections are equally troubling. While not reaching the astronomical heights of some GI cancers, the infection nonetheless commands a significant premium, with hospital charges averaging over $50,000.

?

The numbers are more than mere statistics; they are a clarion call for targeted intervention. Without a robust strategy to prevent initial and recurrent infections, the cycle of treatment and hospitalization due to C. diff will continue unabated. The study highlighted an increased average length of stay by 1.91 days for C. diff patients, further emphasizing the additional resources required for these infections.

?

The data indicates that CDI not only increases the number of hospital days but also has a broader economic impact across various gastrointestinal (GI) indications. As seen in the first image, CDI accounts for a significant number of hospitalizations when compared to other GI conditions. The second image emphasizes that CDI management incurs substantial relative hospital charges, underscoring the high cost of care for these patients. Furthermore, as depicted in the third image, CDI has a marked effect on 30-day readmission rates, with an adjusted odds ratio indicating a higher likelihood of readmission compared to many non-GI conditions.

?

In terms of specific costs, the management of a CDI case and the attributable costs per case were averaging $42,316 and $21,448, respectively, in 2015. The expense for hospital-onset CDI per case was 1.5 times greater than that for community-onset cases. The total annual cost attributable to CDI in the U.S. was estimated to be between $1.9 and $7.0 billion, with nearly 2.4 million inpatient days required for the management of this infection.

?

For pediatric patients, CDI during hospitalization incurred costs ranging from $1,917 to $8,317, with CDI-associated hospitalizations costing 1.6 times more than hospitalizations not associated with CDI. Affected children experienced a longer hospital stay by an average of four days compared to those without CDI, even after adjusting for the propensity to develop the infection.

?

International figures parallel the financial impact observed in the U.S., with the cost of treating a CDI case in Germany approximating €33,840. In Spain, with 7,601 reported cases per year, the annual cost of CDI is around €33 million, averaging €4,395 per case.

?

When considering specific surgical procedures, the risk of developing CDI is notably higher in patients undergoing valvular surgery compared to those receiving coronary artery bypass grafting. The impact of CDI on hospital mortality rates is significant for both types of surgeries, with median hospital stays and costs dramatically increasing in the event of a CDI. For CABG, the length of stay could extend from 7 days to 19 days, and costs could rise from $33,105 to $65,535. Similarly, for valvular surgeries, the duration could increase from 8 days to 24 days, with costs escalating from $41,876 to $95,699.

?

These figures not only reflect the immediate financial implications of CDI but also highlight the necessity for preventive measures and efficient management protocols to mitigate the continued growth in cases and associated costs. It is evident that prevention strategies could lead to substantial cost savings for healthcare facilities and improve patient outcomes.

Case Analysis: Potential Savings of Preventing C Diff

New Jersey's collective potential savings range from $1.7M to $5.1M from just one surgery type, which is a notable figure, emphasizing the broader implications of cost-saving measures on a state-wide scale. This cost reduction could translate into better resource allocation, improved patient care, and overall, a more efficient healthcare system. The data in the table serves as a compelling argument for the adoption of C. diff preventive measures, highlighting the potential to not only save lives but also to conserve valuable healthcare resources.

??

The table provides a detailed breakdown of the potential cost savings that hospitals in various medical systems could realize through the implementation of prevention technology like the LIV Process (https://www.livprocess.com/), a preventive measure for Clostridium difficile (C. diff) infections, specifically in the context of coronary artery bypass grafting (CABG) procedures. The data reflects a hypothetical scenario where the LIV Process could effectively eliminate 25% to 75% of C. diff cases, thereby reducing the extra days in the hospital attributed to such infections. Over 13% of growth in Cdiff hospitalization has been attributed to changes in disease risk.

?

For instance, AtlantiCare Regional MC - Mainland, part of the AtlantiCare system, had a total of 284 CABG procedures in 2019, leading to 60 extra hospital days due to C. diff. With the C diff prevention technology implementation, the estimated average bottom savings—assuming a 25% reduction in cases—could be around $65K, and if a 75% reduction is achieved, the savings could escalate to approximately $196K. Similarly, Hackensack University Medical Center, under the Hackensack Meridian Health system, reported the highest number of extra days due to C. diff at 150, correlating with potential savings between $163K and $490K. These figures underscore the significant financial impact that C. diff infections have on hospital stays and the substantial cost benefits that could be achieved through effective prevention strategies.

?

The data clearly indicates the economic strain C. diff infections place on healthcare facilities, with longer hospital stays increasing operational costs and reducing the availability of beds for other patients. The table includes diverse medical centers, from Jersey Shore University Medical Center, with 863 CABG procedures and the possibility of saving between $199K to $597K, to smaller institutions like St. Mary's General Hospital, where the savings range is between $11K to $33K. Across the board, the implementation of C. diff prevention strategies that includes the LIV Process could lead to a significant decrease in healthcare expenditure.

Appendix A Differential Diagnosis

• Antibiotic-associated diarrhea
• Viral gastroenteritis
• Bacterial gastroenteritis
• Intolerance to lactose
• Traveler's diarrhea
• Inflammatory bowel disease
• Diverticulitis
• Celiac disease
• Diarrhea due to drug
• Ischemic colitis
• Postoperative ileus
• Intra-abdominal infection following surgical procedure
• Tube feeding diet

?

Appendix B Treatment

Treatment Summary

Patients with severe symptoms of Clostridium difficile infection (CDI) should be started on empiric treatment as soon as the diagnosis is suspected and laboratory samples have been obtained. Metronidazole for mild disease and vancomycin for more severe disease are recommended in the treatment of CDI. Antibiotics thought to be causing the disease should be discontinued. Previously, treatment was delayed, as resolution often occurred quickly with this maneuver. Because of the current frequency of fulminant disease, however, specific therapy is generally not postponed except for the very mildest presentations. The European Society of Microbiology and Infectious Diseases (ESCMID) recommend that in non-epidemic situations, non-severe cases of CDI clearly induced by antibiotics may be treated with careful observation for 48 hours after stopping the offending agent, treating with antibiotics those who show any signs of clinical deterioration.

?

Severe CDI may be treated with oral vancomycin or fidaxomicin. Up to 3.5% of patients with CDI will not respond to antibiotics or will have other indications for surgical treatment. Nonresponsive disease with ongoing sepsis, toxic megacolon, or colonic perforation from fulminant CDI are indications for colectomy, the recommended procedure. An alternative to colectomy may be a diverting loop ileostomy with colonic lavage that is combined with intracolonic antegrade vancomycin and IV metronidazole.

?

Recurrent disease may be problematic. The recurrence may be treated with fidaxomicin, vancomycin, or metronidazole. Multiple recurrences may be treated with oral vancomycin or fidaxomicin, and consideration given to fecal transplantation using donor stool, which has been reported to be highly effective in cases of multiple recurrences. Intravenous immunoglobulin (IVIG) may be helpful in select cases, especially those with hypogammaglobulinemia (eg, following solid organ transplant).

?

Evidence is mixed on the efficacy of probiotics for the prevention or treatment of CDI; they are currently not recommended as primary prophylaxis. Antiperistaltic agents may obscure symptoms and have been associated with toxic megacolon; they should not be used. Narcotics should be minimized or avoided, if possible, for similar reasons.