Clostridium Difficile infection

Clostridium difficile was first described as a cause of diarrhoea in the late 1970’s and since that time it has had a significant impact with increasing incidence and severity in both hospital and community settings. There has also been an increase in severe outcomes from C. difficile infection (CDAD). Over this time there has also been considerable increase in our understanding of the disease. Several treatment options are available for CDAD apart from metronidazole and vancomycin, including newer drugs such as fidaxomicin and other options such as stool transplantation (FMT).

Introduction

Clostridium difficile is a gram-positive spore forming bacterium, originally isolated in 1935 and surprisingly as a cause of diarrhoea in 1978 in a patient with pseudomembranous colitis, In the past three decades, C. difficile has reached an epidemic state with increasing incidence and severity in both healthcare and community settings. C. difficile infection (CDAD) is now among one of the most common causes of hospital-acquired infection (HAI) along with methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci (MRSA), and is the commonest cause of infectious diarrhoea in hospitals and long-term care settings Recently, new risk factors for CDAD have emerged, and more recently a more virulent strain of C. difficile has been identified. This finding may explain this increase in more severe outcomes. There have been several advances with the development of newer diagnostic modalities and treatment options such as new drugs and stool transplantation (FMT). Despite advances in both drug treatment and infection control practices, there continues to be an increase in the rates of complications from CDAD such as severe complicated infection, treatment failure and recurrence rates which are associated with increasing mortality and healthcare costs.

Epidemiology and Risk Factors

Epidemiological data derived from US databses, hospital-based reports and population based studies have shown a two to four fold increase in the incidence of CDAD in the past two decades, especially in the elderly. Hospital outbreak reporting over recent years has shown increasing severity and a high mortality rate of between 4-7 % . There have been relatively few studies describing the epidemiology of community-acquired CDAD. A population- based study from Olmsted County, MN, showed that the incidence of both community acquired increased by 5.3 fold from 1991 to 2005, and a large proportion of cases (41%) were community- acquired. Studies in the paediatric population have shown that the incidence in children has increased up to 12.5- fold in the last two decades. Adult patients with community acquired CDAD are younger, have fewer comorbidities and less frequently have severe disease than patients with hospital-acquired infection Hence, CDAD is now commonly being identified in populations that were previously considered to be low-risk such as children and community dwellers who lack traditional risk factors for CDAD. The traditional risk factors for CDAD include age >65 years, recent hospitalisation, increased length of hospital stay, long-term healthcare facility residence, antibiotic exposure, and comorbidities including malignancy, chronic kidney disease, inflammatory bowel disease and immunosuppression. Additional risk factors include contact with active carriers, consumption of contaminated food products such as processed meats, hypoalbuminaemia, use of proton-pump inhibitors (PPIs), gastrointestinal endoscopic procedures and enteral tube feeding. There is often a lack of traditional risk factors in patients with community- acquired CDAD, such as antibiotic exposure, older age and recent hospitalisation, which suggests alternate novel risk factors for CDAD and newer modes of transmission of CDAD in the community. Studies have shown that patients with community-acquired CDAD are likely to have a recent healthcare exposure other than hospitalisation, with up to 94% of patients having had a recent outpatient visit, thus suggesting that a short duration of healthcare exposure without hospitalisation may also be a risk factor for CDAD. Potential risk factors explaining an increase in the incidence of community-acquired CDAD include contaminated food consumption, person-to-person, environment-to-person and potentially animal- to-person spread. Person-to-person spread is important both in hospitals and outside the hospitals. Recent practice guidelines have suggested that visitors to hospital rooms harboring patients with CDAD should practice the same isolation precautions as healthcare personnel. Exposure to infants and children who may be asymptomatically colonized with C. difficile may be a risk factor for recurrent CDAD in mothers in the postnatal period. Another potential mechanism for acquisition of CDAD in the community is exposure to colonized or infected persons, such as healthcare workers, and studies have shown that family members of patients with recent infection have a higher risk of CDAD. Factors associated with Adverse Outcomes Adverse outcomes from CDAD include severe and severe-complicated infection, treatment failure and recurrent infection. According to guidelines from the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA), severe CDAD is defined as peripheral white cell count ≥15,000 cells/μl or an increase in serum creatinine ≥1.5 times above baseline. Severe-complicated infection is defined by: hypotension, shock and sepsis, which may require intensive care unit level of care; ileus, megacolon and perforation, which may necessitate surgery (colectomy); or death secondary to CDAD. Studies have assessed additional predictors of severe and severe-complicated CDAD, which include increasing age, concomitant antibiotic and antimotility medication use, hypoalbuminemia, more severe diarrhoea, acute kidney injury, comorbidities such as chronic kidney disease, presence of fever and presence of pseudomembranes or megacolon. It is important to identify patients with severe or severe-complicated infection, as treatment recommendations are based on disease severity. Gastric acid suppression medications, such as PPIs, have been implicated as a risk factor for CDAD, but use of these medications has not been associated with severe CDAD or treatment failure in patients with CDAD The data on the risk of recurrent CDAD with gastric acid suppression are controversial.

Clinical Diagnosis

The clinical diagnosis of CDAD requires an appropriate clinical presentation, which includes watery diarrhoea (defined as ≥3 loose stools in 24 hours) with or without abdominal pain, fever or ileus. This should be supported by an appropriate positive laboratory test for C. difficile or the endoscopic presence of pseudomembranes, which are highly suggestive of CDAD. Stool tests vary in their sensitivity and specificity for the diagnosis of CDAD. Stool culture is the most sensitive test and is regarded as the gold standard for C. difficile diagnosis, but has the limitation of time to run the test. Enzyme based immunoassay (EIA) to detect toxins A and B produced by C. difficile is a rapid test, but it lacks sensitivity. EIA for glutamate dehydrogenase enzyme is very sensitive but not very specific and is being adopted by some laboratories as a screening test in combination with another more specific confirmatory test. Molecular analysis with Polymerase chain reaction (PCR) to detect genes tcdB, which encodes the toxin and/or tcdC, which negatively regulates the toxin produced by C. difficile is rapidly becoming the alternative gold standard to stool culture with studies demonstrating excellent sensitivity, specificity and test retest reliability. PCR takes less time to obtain a result, which is crucial in terms of initiating early treatment and effective isolation procedures. The yield of repeat PCR testing for C. difficile is low. In a study evaluating over 15,000 stool PCR tests for C. difficile, repeat testing within 2 weeks of an initial test was uncommon and happened in less than 13% of all tests. Increased age, male sex and inpatient location were predictors of repeat testing. After an initial negative test, the percentage of patients having a subsequent positive test was very low (2.7% in 7 days and 3.2% in 14 days). It is of utmost importance that stool testing for C. difficile be performed only in patients who exhibit signs and symptoms of CDAD. Patients who are colonized with C. difficile and do not exhibit symptoms should not be tested. Treating asymptomatic patients with medications for CDAD may potentially disrupt gut microflora and it is not recommended to eradicate colonization in these patients due to lack of any perceived benefit.

Gastric Acid Suppression and CDAD

The role of gastric acid in the pathogenesis of CDAD is controversial. Recent data have suggested that circumventing the potential protective effect of gastric acid by PPIs or histamine-2 (H2) receptor blockers may be a risk factor for the acquisition of CDAD However, there is conflicting evidence as to whether acid does or does not kill C. difficile spores. Furthermore, studies have found that after controlling for important confounders, the use of PPI and H2 blockers have not been associated with the risk of CD or adverse outcomes from CDAD. Thus, it is not clear if acid suppressing drugs are independent risk factors for CDAD, although the US Food and Drug Administration (FDA) did issue a warning that PPI are associated with an increased risk of CDAD. Three retrospective studies suggested an increased risk of recurrent CDAD in patients on PPIs, although a subgroup analysis of a large randomized controlled trial did not demonstrate a difference in the rates of recurrent CDAD in patients with or without exposure to PPI and H2-receptor antagonists. In a population-based study, patients taking acid suppressive medications were more likely to have severe (34.2% versus 23.6%, p = 0.03) or severe complicated CDAD (4.4% versus 2.6%, p = 0.006) than patients not on acid suppression on univariate analysis. However, patients on acid suppression medications were significantly older and had more comorbid conditions, and on multivariate analysis after controlling for comorbidities and age, acid suppression medication use was not associated with severe or severe-complicated CDAD. In addition, there was no relationship between acid suppression and treatment failure and recurrent CDAD. Therefore, in CDAD patients who have an absolute indication for gastric acid suppression medications, these agents may be continued during treatment of CDAD. However, consideration may be made to stop these medications if there is no absolute indication for their use.

Management of CDAD

General Measures; Supportive care is an essential component of therapy for CDAD. As for any diarrhoeal illness, initial therapy includes careful management of fluid and electrolyte balance. After initial stabilization, data must be obtained to categorize severity and history of prior CDAD episodes must be obtained as therapy depends on these parameters. Anti-motility agents, such as narcotics and loperamide, should be stopped, as these are associated with adverse outcomes. Studies have suggested that the use of concomitant systemic antibiotics is associated with a decreased cure rate and an increased risk of recurrent. Therefore, concomitant systemic antibiotics should ideally be discontinued if possible, and if ongoing antibiotic therapy is absolutely needed, targeted narrow spectrum agents should be used for the shortest duration possible. These decisions may be guided by culture and sensitivities for the systemic infection to choose the appropriate systemic antibiotics. In elderly and severely ill patients, with a high clinical suspicion of CDAD, empirical antibiotic treatment for CDAD may be started whilst confirmatory test results are awaited. Measures for infection control include placing patients in isolation with contact precautions, including the use of gloves and gowns, hand washing with soap and water, and the use of chlorine containing agents for disinfection. Daily cleaning of hospital rooms with germicidal bleach wipes in wards with a high incidence of hospital acquired CDAD reduces infection rates and prolongs the time between hospital-acquired CDAD cases Detailed guidelines for infection prevention for CDAD have been published by SHEA and IDSA . Metronidazole, Vancomycin and Fidaxomicin According to the IDSA/SHEA guidelines, patients with the first infection or first recurrent episode of mild to moderate CDAD should be treated with metronidazole in the absence of contraindications. Randomized controlled trials comparing vancomycin and metronidazole for treatment of CDAD demonstrated cure rates of over 90% and there were no differences in differences when metronidazole was compared to vancomycin. The treatments in these trials were not stratified by disease severity. Metronidazole is an inexpensive, effective treatment but the FDA does not approve its use for CDAD. In mild-to-moderate CDAD, oral metronidazole (e.g. 250–500 mg 3–4 times a day for 10–14 days) is considered equivalent to vancomycin. CDAD may be more refractory to metronidazole treatment than in the past. In one study, from 1991–2002, the rate of metronidazole failure was 9.6%, but during an outbreak in 2003–2004, that rose to almost 26% [Pepin et al. 2005a], a rate close to that reported from Houston where 22% of patients treated with metronidazole had continued symptoms after 10 days or more of therapy. Lack of response to initial therapy with metronidazole has been associated with increased mortality . However, at this time there are no models in patients with mild to moderate CDAD to predict metronidazole failure. After adjusting for appropriate confounders, metronidazole is associated with more side effects than vancomycin has more side effects (including nausea, disulfiram-like reaction if drinking alcohol, metallic taste and peripheral neuropathy), and is not recommended for children or during lactation or pregnancy. Patients who do not improve promptly (within 72–96 hours) should be reassessed for alternative causes of diarrhoea. If other pathologies have been ruled out, metronidazole should be switched to vancomycin. Vancomycin is a reliable but more expensive treatment and was the first drug approved by the FDA for the management of CDAD. According to the IDSA/SHEA guidelines, oral vancomycin is recommended for the treatment of severe CDAD and, in combination with metronidazole, for severe complicated infection. Although response rates are similar to metronidazole in mild to moderate disease, vancomycin is the preferred treatment in severely ill patients due to superior cure rates in these patients (97% versus 76%), although subsequent relapse rates were not significantly different between these two treatments. Oral vancomycin is poorly absorbed, and high stool concentrations can be achieved without systemic side effects. The recommended dose is vancomycin 125 mg 4 times a day for 10 days. A higher dose (250–500 mg) is recommended for seriously ill patients with severe-complicated CDAD, along with intravenous metronidazole, and vancomycin enemas if an ileus is present. Patients who do not improve promptly should be reassessed, since failure of vancomycin therapy is quite unusual and additional therapy, including surgery, may be indicated. Fidaxomicin is a macrocyclic antibiotic agent with little or no systemic absorption after oral administration and narrow spectrum against Gram-positive aerobic and anaerobic bacteria, including C. difficile. In vitro studies showed that fidaxomicin was more active than vancomycin against C. difficile. There are no randomized data comparing fidaxomicin with metronidazole for a first episode of mild to moderate CDAD, for which metronidazole remains the first treatment of choice. In addition, fidaxomicin has not been studied for efficacy in recurrent CDAD. Anecdotal experience from small case series has shown that fidaxomicin may be an option in patients with recurrent CDAD. Factors associated with recurrence include increasing age, severe CDAD, concomitant antibiotic use, decreased anti-toxin A immunoglobulin G (IgG) levels and history of prior CDAD. To summarize, patients with the first episode or first recurrence of mild to moderate CDAD should be treated with metronidazole. For severe disease, as defined by leukocytosis or renal dysfunction, and for second or additional recurrences, vancomycin should be the treatment of choice. For patients with severe-complicated CDAD, intravenous metronidazole supplemented by high dose vancomycin is recommended, with close clinical follow up to assess response. In patients who cannot take oral medications (e.g. ileus), vancomycin should be administered via nasogastric tube and/or enema. In rare instances, where patients have a primary treatment failure to more than one medication regimens, FMT may be an alternative management strategy. Prolonged Vancomycin Treatment Regimens If the initial episode was treated with vancomycin, a tapered and pulsed regimen or just a pulsed regimen of vancomycin can be tried; none of these recommendations for extended vancomycin regimens have been studied in randomized controlled trials. In a small study, 22 patients with recurrent CDAD underwent a tapering dose of oral vancomycin for 21 days and a pulse dose of vancomycin for 21 days and had no recurrences in a mean follow up of 6 months (range 2–12 months). Data analysed from a clinical trial of a probiotic adjunct to antibiotic therapy in patients who had one or more CDAD recurrences demonstrated that longer, tapered, pulsed vancomycin dosing were more effective than conventional regimens. Patients who received a standard 10–14 day course had higher recurrence rates of up to 54% compared with 31% in those who had tapering regimens (gradually lowered doses) and 14% in those who had pulsed (every 2–3 day) regimens. Other Medication Regimens Additional treatment options for CDAD include rifaximin, nitazoxanide, intravenous immunoglobulin (IVIG), and probiotics. Rifaximin is a broad spectrum antibiotic selective to the gastrointestinal tract, and has activity against most Gram negative and Gram-positive bacteria, as well as anaerobes and aerobes and excellent in vitro activity against C. difficile. Rifaximin is not considered to cause significant alterations to the gut microbiota. It has been shown to be effective for the treatment of CDAD in smaller clinical studies and case reports. A recent randomized controlled trial demonstrated that rifaximin was effective against CDAD but did not meet the non-inferiority definition compared to vancomycin (57% for rifaximin versus 64% for vancomycin) to attain a clinical success (absence of fever, abdominal pain or diarrhoea) and was similar to vancomycin for resolution of diarrhoea and rates of recurrence. Rifaximin is currently not recommended as a monotherapy for CDAD, but may be used for recurrent CDAD following treatment with oral vancomycin (125 mg orally 4 times a day for 14 days) in the form of a ‘rifaximin chaser (400 mg orally twice daily for 14 days). IVIG has been used to treat recurrent CDAD with variable success. There are no randomized controlled trials showing a benefit of IVIG for CDAD. It is believed that the mechanism of action for IVIG may include the presence of antibodies against C. difficile toxin A and toxin B. In a large, randomized, controlled study of monoclonal antibodies against C. difficile toxins A and B in addition to antibiotic therapy, the rate of CDAD recurrence was lower among patients treated with monoclonal antibodies (7% versus 25%; p < 0.001). A phase III study is underway to further establish the safety and efficacy of monoclonal antibody treatment for CDAD. Probiotics in CDAD There is limited evidence for the use of concomitant probiotics for treatment of CDAD or for prevention of recurrent CDAD. Saccharomyces boulardii has been studied in several clinical trials in combination with oral therapies for CDAD and has been associated with decreased CDAD recurrences in those with recurrent CDAD. A randomized controlled trial of Lactobacillus rhamnosus did not show efficacy in treatment of recurrent CDAD. A recent meta-analysis suggested that there is strong evidence from numerous large trials for efficacy in prevention of antibiotic-associated diarrhoea for S. boulardii; the evidence for efficacy of S. boulardii in the treatment of C. difficile is weak. A Cochrane analysis concluded that there was lack of sufficient evidence to recommend probiotics, as an adjunct to antibiotics in the treatment of CDAD. Therefore, there are no strong data to support the use of concomitant probiotics for the treatment of CDAD. There are no data to support the use of probiotics in the treatment of severe CDAD. Stool Transplantation (FMT) Antibiotic usage disrupts the normal gut flora and leads to an increased predisposition to CDAD. The risk of recurrent CDAD after initial treatment of the first infection is approximately 20–25% and is further increased up to 60% with the use of additional systemic antibiotics and subsequent CDAD recurrences. The pathophysiology of recurrent CDAD involves ongoing disruption of the normal faecal flora and an inadequate host immune response. Standard CDAD treatment with antibiotics such as metronidazole and vancomycin further disrupts colonic microbial communities that normally keep expansion of C. difficile populations in check. Since C. difficile spores are resistant to antibiotic therapy for CDAD, they can germinate to vegetative forms after treatment has been discontinued and lead to recurrent CDAD. FMT is being used as an alternative to standard antibiotic therapy for recurrent CDAD due to the ability to restore the colonic flora via infusion of a liquid suspension of intestinal microorganisms from the stool of a healthy donor. A randomized controlled trial compared an initial high dose vancomycin regimen (500 mg orally 4 times per day for 4 days) followed by FMT through a nasoduodenal tube to a full course of high dose vancomycin (500 mg orally 4 times per day for 14 days) or a high dose vancomycin regimen with bowel lavage alone. The primary endpoint was the resolution of diarrhoea associated with CDAD without relapse after 10 weeks. Of 16 patients in the FMT group, 13 (81%) had resolution of CDAD after the first infusion. The three remaining patients received a second infusion with faeces from a different donor, with resolution in two patients (for an overall success rate of 94%). Resolution of CDAD occurred in 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) receiving vancomycin with bowel lavage (p < 0.001 for both comparisons with the FMT group). No significant differences in adverse events among the three study groups were observed except for mild diarrhoea and abdominal cramping in the FMT group on the infusion day. A systematic review of 27 studies and case reports, including 317 patients with recurrent CDAD treated with FMT, showed an overall success rate of 92%, with 89% of patients responding after a single treatment. In these studies, 35% of patients received FMT by enema, with a response rate of 95%, 23% by the nasogastric route, with a response rate of 76%, and 19% by colonoscopy, with a response rate of 89%. Another study reporting FMT via colonoscopy in 43 patients with recurrent CDAD included patients with underlying inflammatory bowel disease. The overall rate of infection clearance was 86% in response to a single infusion and there were no differences in outcomes relative to donor source and no serious adverse effects were reported. Another recent study reported experience with FMT via colonoscopy for 70 patients with recurrent CDAD. During the initial 12-week follow-up period, FMT resulted in the resolution of symptoms in all patients with non-hypervirulent C. difficile strain and in 89% of those infected with the hypervirulent strain There have been no studies of FMT for prophylaxis in patients at a high risk of recurrence after a first episode of CDAD, and there has been no head to head comparison of FMT with conventional CDAD treatments. Therefore, existing literature suggests that stool transplant is safe and effective with over 500 cases of recurrent CDAD with no serious adverse events reported to date. FMT appears to be an appropriate treatment option for multiple CDAD recurrences and may be considered for refractory moderate to severe C. difficile diarrhoea, failing standard therapy. Approach to Severe and Severe-complicated CDAD At the time of presentation, risk factors for development of severe and severe-complicated CDAD must be ascertained. These include older age, presence of comorbidities and the concomitant use of certain medications such as immunosuppression, antibiotics, narcotics and anti-peristaltic medications. Other features include the presence of fever, severe abdominal pain and deranged laboratory parameters suggesting severe infection. These include and elevated white blood cell count (≥15, 000/μl), elevated creatinine (≥1.5 times above baseline) and possibly low albumin. Patients with mild to moderate CDAD should be treated with metronidazole. Those with laboratory markers of severity at presentation or who develop these markers during treatment with metronidazole should be switched to oral vancomycin. It may be reasonable to treat patients with prior episodes of severe CDAD with oral vancomycin instead of metronidazole even if their current episode does not meet the definition of severe infection. Additionally, patients with multiple risk factors for development of severe or severe-complicated CDAD may be treated with oral vancomycin to prevent complications. Clinical features defining severe-complicated CDAD include admission to intensive care unit for CDAD, presence of systemic inflammatory response syndrome (SIRS) criteria, hypotension with or without required use of vasopressors, ileus or megacolon, mental status changes, elevated serum lactate or presence of end-organ failure. These patients should be managed with a combination of high dose oral vancomycin (500 mg 4 times a day) and intravenous metronidazole. It is advisable to perform abdominal imaging and serial abdominal examinations to evaluate for the presence of megacolon in these patients. If there is ileus or megacolon, rectal infusion of vancomycin by retention enemas must be added to oral vancomycin and intravenous metronidazole. Early surgical consultation must be obtained on all patients with severe complicated CDAD. Surgical management may consist of total colectomy with end-ileostomy or diverting loop ileostomy and intracolonic lavage with polyethylene glycol followed by liquid vancomycin. Mortality rates from surgery for CDAD are high and studies have shown that outcomes from early surgery are better than outcomes from delayed surgery. It has been shown that intraoperative colonic lavage with polyethylene glycol and postoperative colonic vancomycin flushes led to colon preservation in over 90% of patients and had significantly improved survival compared with historical controls who had undergone colectomy. Approach to Recurrent CDAD The management of recurrent CDAD remains a major challenge due to a paucity of clinical trials and hence evidence-based management guidelines. Recurrent CDAD is defined as the recurrence of CDAD symptoms within 8 weeks after symptom resolution, confirmed with a positive stool test. The risk of recurrence after an initial episode of CDAD is 20% and increased up to 60% after the third episode. The risk of recurrence is higher with older age, concomitant antibiotic exposure, and presence of comorbidities and deceased levels of serum IgG anti-toxin A. The first recurrence is treated the same as the first episode, stratified by severity. A second recurrence is treated with a 6–week taper of oral vancomycin. Several treatment options are available for future recurrences, which include FMT, vancomycin followed by rifaximin chaser or IVIG. A case series of three patients demonstrated that fidaxomicin might be an option for patients with multiple recurrences of CDAD who have failed other therapies. Although these options have not been compared in randomized clinical trials, faecal transplantation appears to be the most successful modality for recurrent CDAD.

Table 1. Treatment options for recurrent C. difficile infection.

First recurrence: • Mild to moderate; oral metronidazole 500 mg 3 times a day for 10–14 days • Mild to moderate CDAD (no response to oral metronidazole/severe CDAD previously or Severe CDAD; oral vancomycin 125 mg 4 times a day for 10–14 days Second recurrence: Oral vancomycin tapered over 7 weeks • 125 mg 4 times daily for 14 days • 125 mg twice daily for 7 days • 125 mg once daily for 7 days • 125 mg once every other day for 8 days • 125 mg once every third days for 15 days Future recurrences • Stool transplantation • Oral vancomycin 125 mg 4 times a day for 14 days, followed by rifaximin 400 mg twice daily for 14 days • Consider intravenous immunoglobulin, 400 mg/kg, repeated up to 3 times at 3-week intervals. • Consider combination therapy with oral vancomycin and oral rifaximin

Conclusion

Over the past decade, the incidence and severity of both hospital- and community-acquired CDAD has increased significantly. There is an emerging population who may contract CDAD without the traditional risk factors and several new risk factors have been identified. PCR based testing is highly sensitive and repeat testing is usually not advised after an initial negative test, or to confirm clearance after treatment in a patient who has responded symptomatically. In a patient with recurrent diarrhoea, repeat testing should be performed to distinguish recurrent infection from other causes, such as post-infectious irritable bowel syndrome. Treatment strategies are based on severity and severe infection must be treated with oral vancomycin. Recurrent infection continues to be a major challenge and newer treatment options such as stool transplantation may become the mainstay for individuals with recurrent/relapsing CDAD.