Retrospective evaluation of fidaxomicin versus oral vancomycin for treatment of Clostridium difficile infections in allogeneic stem cell transplant

Objective/background

Clostridium difficile infection (CDI) is a potential complication during hematopoietic stem cell transplantation (HSCT), and no specific recommendations exist regarding treatment of CDI in allogeneic SCT patients. Use of metronidazole and oral vancomycin has been associated with clinical failure. Fidaxomicin has previously been found noninferior to the use of oral vancomycin for the treatment of CDI, and no studies have compared the use of oral vancomycin with fidaxomicin for the treatment of CDI in allogeneic SCT.

Clinical approach to severe Clostridium difficile infection: update for the hospital practitioner

The rising incidence of Clostridium difficile (C. difficile) infection or CDI is now a problem of pandemic proportions. The NAP1 hypervirulent strain of C. difficile is responsible for a majority of recent epidemics and the widespread use of fluoroquinolone antibiotics may have facilitated the selective proliferation of this strain. The NAP1 strain also is more likely to cause severe and fulminant colitis characterized by marked leukocytosis, renal failure, hemodynamic instability, and toxic megacolon. No single test suffices to diagnose severe CDI, instead; the clinician must rely on a combination of clinical acumen, laboratory testing, and radiologic and endoscopic modalities. Although oral vancomycin and metronidazole are considered standard therapies in the medical management of CDI, recently it has been demonstrated that vancomycin is the more effective antibiotic in cases of severe disease. Moreover, early surgical consultation is necessary in patients who do not respond to medical therapy or who demonstrate rising white blood cell counts or hemodynamic instability indicative of fulminant colitis. Subtotal colectomy with end ileostomy is the procedure of choice for fulminant colitis. When applied to select patients in a judicious and timely fashion, surgery can be a life-saving intervention. In addition to these therapeutic approaches, several investigational treatments including novel antibiotics, fecal bacteriotherapy and immunotherapy have shown promise in the care of patients with severe CDI.     

Reducing the risk of severe complications among patients with Clostridium difficile infection

BACKGROUND:

The incidence and severity of Clostridium difficile infections are increasing, and there is a need to optimize the prevention of complicated disease.

OBJECTIVE:

To identify modifiable processes of care associated with an altered risk of C difficile complications.

METHODS:

A retrospective cohort study (with prospective case ascertainment) of all C difficile infections during 2007/2008 at a tertiary care hospital was conducted.

RESULTS:

Severe complications were frequent (occurring in 97 of 365 [27%] C difficile episodes), with rapid onset (median three days postdiagnosis). On multivariable analysis, nonmodifiable predictors of complications included repeat infection (OR 2.67), confusion (OR 2.01), hypotension (OR 0.97 per increased mmHg) and elevated white blood cell count (OR 1.04 per 10⁹ cells/L). Protection from complications was associated with initial use of vancomycin (OR 0.24); harm was associated with ongoing use of exacerbating antibiotics (OR 3.02).

CONCLUSION:

C difficile infections often occur early in the disease course and are associated with high complication rates. Clinical factors that predicted a higher risk of complications included confusion, hypotension and leukocytosis. The most effective ways to improve outcomes for patients with C difficile colitis are consideration of vancomycin as first-line treatment for moderate to severe cases, and the avoidance of unnecessary antibiotics.     

Models for the study of Clostridium difficile infection

Models of Clostridium difficile infection (C. difficile) have been used extensively for Clostridium difficile (C. difficile) research. The hamster model of C. difficile infection has been most extensively employed for the study of C. difficile and this has been used in many different areas of research, including the induction of C. difficile, the testing of new treatments, population dynamics and characterization of virulence. Investigations using in vitro models for C. difficile introduced the concept of colonization resistance, evaluated the role of antibiotics in C. difficile development, explored population dynamics and have been useful in the evaluation of C. difficile treatments. Experiments using models have major advantages over clinical studies and have been indispensible in furthering C. difficile research. It is important for future study programs to carefully consider the approach to use and therefore be better placed to inform the design and interpretation of clinical studies.     

Clostridium difficile infection worsens the prognosis of ulcerative colitis

BACKGROUND:

The impact of Clostridium difficile infections among ulcerative colitis (UC) patients is well characterized. However, there is little knowledge regarding the association between C difficile infections and postoperative complications among UC patients.

OBJECTIVE:

To determine whether C difficile infection is associated with undergoing an emergent colectomy and experiencing postoperative complications.

METHODS:

The present population-based case-control study identified UC patients admitted to Calgary Health Zone hospitals for a flare between 2000 and 2009. C difficile toxin tests ordered in hospital or 90 days before hospital admission were provided by Calgary Laboratory Services (Calgary, Alberta). Hospital records were reviewed to confirm diagnoses and to extract clinical data. Multivariate logistic regression analyses were performed among individuals tested for C difficile to examine the association between C difficile infection and emergent colectomy and diagnosis of any postoperative complications and, secondarily, an infectious postoperative complication. Estimates were presented as adjusted ORs with 95% CIs.

RESULTS:

C difficile was tested in 278 (58%) UC patients and 6.1% were positive. C difficile infection was associated with an increased risk for emergent colectomy (adjusted OR 3.39 [95% CI 1.02 to 11.23]). Additionally, a preoperative diagnosis of C difficile was significantly associated with the development of postoperative infectious complications (OR 4.76 [95% CI 1.10 to 20.63]).

CONCLUSION:

C difficile diagnosis worsened the prognosis of UC by increasing the risk of colectomy and postoperative infectious complications following colectomy. Future studies are needed to explore whether early detection and aggressive management of C difficile infection will improve UC outcomes.     

The potential for emerging therapeutic options for Clostridium difficile infection

Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review.     

Clinical Predictors of Fulminant Colitis in Patients with Clostridium difficile Infection

Background/Aim:

Clostridium difficile infection (CDI) can affect up to 8% of hospitalized patients. Twenty-five percent CDI patients may develop C. difficile associated diarrhea (CDAD) and 1–3% may progress to fulminant C. difficile colitis (FCDC). Once developed, FCDC has higher rates of complications and mortality.

Patients and Methods:

A 10-year retrospective review of FCDC patients who underwent colectomy was performed and compared with randomly selected age- and sex-matched non-fulminant CDAD patients at our institution. FCDC (n=18) and CDAD (n=49) groups were defined clinically, radiologically, and pathologically. Univariate analysis was performed using Chi-square and Student''s t test followed by multivariate logistic regression to compute independent predictors.

Results:

FCDC patients were significantly older (77 ± 13 years), presented with triad of abdominal pain (89%), diarrhea (72%), and distention (39%); 28% had prior CDI and had greater hemodynamic instability. In contrast, CDAD patients were comparatively younger (65 ± 20 years), presented with only 1 or 2 of these 3 symptoms and only 5% had prior CDI. No significant difference was noted between the 2 groups in terms of comorbid conditions, use of antibiotics, or proton pump inhibitor. Leukocytosis was significantly higher in FCDC patients (18.6 ± 15.8/mm³ vs 10.7 ± 5.2/mm³; P=0.04) and further increased until the point of surgery. Use of antiperistaltic medications was higher in FCDC than CDAD group (56% vs 22%; P=0.01).

Conclusions:

Our data suggest several clinical and laboratory features in CDI patients, which may be indicative of FCDC. These include old age (>70 years), prior CDI, clinical triad of increasing abdominal pain, distention and diarrhea, profound leukocytosis (>18,000/mm³), hemodynamic instability, and use of antiperistaltic medications.     

Toxic megacolon associated Clostridium difficile colitis

Toxic megacolon is a severe complication of Clostridium difficile (C. difficile) colitis. As the prevalence of C. difficile colitis increases and treatments become more refractory, clinicians will encounter more patients with C. difficile associated toxic megacolon in the future. Here, we review a case of toxic megacolon secondary to C. difficile colitis and review the current literature on diagnosis and management. We identify both clinical and radiologic criteria for diagnosis and discuss both medical and surgical options for management. Ultimately, we recommend using the Jalen criteria in conjunction with daily abdominal radiographs to help establish the diagnosis of toxic megacolon and to make appropriate treatment recommendations. Aggressive medical management using supportive measures and antibiotics should remain the mainstay of treatment. Surgical intervention should be considered if the patient does not clinically improve within 2-3 d of initial treatment.     

A cohort study for the derivation and validation of a clinical prediction scale for hospital-onset Clostridium difficile infection

OBJECTIVE:

To develop and validate a clinical prediction scale for hospital-onset Clostridium difficile infection (CDI).

METHODS:

A community-based, 360-bed hospital located in the suburbs of a metropolitan area in the United States served as the setting for the present retrospective cohort study. The cohort consisted of patients admitted to the adult medical service over a six-year period from October 2005 to September 2011. The cohort was divided into derivation (October 2005 to September 2009) and validation (October 2009 to September 2011) groups. The primary outcome measure was hospital-onset CDIs identified as stool positive for C difficile after 48 h of hospital admission ordered for new-onset unformed stool by the treating physician.

RESULTS:

In the derivation phase, 35,588 patients were admitted to the medical service and 21,541 stayed in hospital beyond 48 h. A total of 266 cases of CDI were identified, 121 of which were hospital onset. The developed clinical prediction scale included the onset of unformed stool (5 points), length of hospital stay beyond seven days (4 points), age >65 years (3 points), long-term care facility residence (2 points), high-risk antibiotic use (1 point) and hypoalbuminemia (1 point). The scale had an area under the receiver operating curve (AUC) of 0.93 (95% CI 0.82 to 0.94) in predicting hospital-onset CDI, with a sensitivity of 0.94 (95% CI 0.88 to 0.97) and a specificity of 0.80 (95% CI 0.79 to 0.80) at a cut-off score of 9 on the scale. During the validation phase, 16,477 patients were admitted, of whom 10,793 stayed beyond 48 h and 58 acquired CDI during hospitalization. The predictive performance of the score was maintained in the validation cohort (AUC 0.95 [95% CI 0.93 to 0.96]) and the goodness-to-fit model demonstrated good calibration.

CONCLUSION:

The authors developed and validated a simple clinical prediction scale for hospital-onset CDI. This score can be used for periodical evaluation of hospitalized patients for early initiation of contact precautions and empirical treatment once it is validated externally in a prospective manner.     

Recurrent Clostridium difficile infections: The importance of the intestinal microbiota

Clostridium difficile infections (CDI) are a leading cause of antibiotic-associated and nosocomial diarrhea. Despite effective antibiotic treatments, recurrent infections are common. With the recent emergence of hypervirulent isolates of C. difficile, CDI is a growing epidemic with higher rates of recurrence, increasing severity and mortality. Fecal microbiota transplantation (FMT) is an alternative treatment for recurrent CDI. A better understanding of intestinal microbiota and its role in CDI has opened the door to this promising therapeutic approach. FMT is thought to resolve dysbiosis by restoring gut microbiota diversity thereby breaking the cycle of recurrent CDI. Since the first reported use of FMT for recurrent CDI in 1958, systematic reviews of case series and case report have shown its effectiveness with high resolution rates compared to standard antibiotic treatment. This article focuses on current guidelines for CDI treatment, the role of intestinal microbiota in CDI recurrence and current evidence about FMT efficacy, adverse effects and acceptability.     

Clinical update for the diagnosis and treatment of Clostridium difficile infection

Clostridium difficile infection(CDI)presents a rapidly evolving challenge in the battle against hospitalacquired infections.Recent advances in CDI diagnosis and management include rapid changes in diagnostic approach with the introduction of newer tests,such as detection of glutamate dehydrogenase in stool and polymerase chain reaction to detect the gene for toxin production,which will soon revolutionize the diagnostic approach to CDI.New medications and multiple medical society guidelines have introduced changing concepts in the definitions of severity of CDI and the choice of therapeutic agents,while rapid expansion of data on the efficacy of fecal microbiota transplantation heralds a revolutionary change in the management of patients suffering multiple relapses of CDI.Through a comprehensive review of current medical literature,this article aims to offer an intensive review of the current state of CDI diagnosis,discuss the strengths and limitations of available laboratory tests,compare both current and future treatments options and offer recommendations for best practice strategies.     

Incidence and Clinical Outcomes of Clostridium difficile Infection after Treatment with Tuberculosis Medication

Background/Aims

To determine the incidence and clinical characteristics of tuberculosis (TB) medication-associated Clostridium difficile infection.

Methods

This multicenter study included patients from eight tertiary hospitals enrolled from 2008 to 2013. A retrospective analysis was conducted to identify the clinical features of C. difficile infection in patients who received TB medication.

Results

C. difficile infection developed in 54 of the 19,080 patients prescribed TB medication, representing a total incidence of infection of 2.83 cases per 1,000 adults. Fifty-one of the 54 patients (94.4%) were treated with rifampin. The patients were usually treated with oral metronidazole, which produced improvement in 47 of the 54 patients (87%). Twenty-three patients clinically improved with continuous rifampin therapy for C. difficile infection. There were no significant differences in improvement between patients treated continuously (n=21) and patients in whom treatment was discontinued (n=26).

Conclusions

The incidence of C. difficile infection after TB medication was not low considering the relatively low TB medication dosage compared to other antibiotics. It may not be always necessary to discontinue TB medication. Instead, decisions concerning discontinuation of TB medication should be based on TB status.     

Clostridium difficile Infection: A Worldwide Disease

Clostridium difficile, an anaerobic toxigenic bacterium, causes a severe infectious colitis that leads to significant morbidity and mortality worldwide. Both enhanced bacterial toxins and diminished host immune response contribute to symptomatic disease. C. difficile has been a well-established pathogen in North America and Europe for decades, but is just emerging in Asia. This article reviews the epidemiology, microbiology, pathophysiology, and clinical management of C. difficile. Prompt recognition of C. difficile is necessary to implement appropriate infection control practices.     

Physician attitudes toward the use of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection

BACKGROUND:

Fecal microbiota transplantation (FMT) is a safe and effective, yet infrequently used therapy for recurrent Clostridium difficile infection (CDI).

OBJECTIVE:

To characterize barriers to FMT adoption by surveying physicians about their experiences and attitudes toward the use of FMT.

METHODS:

An electronic survey was distributed to physicians to assess their experience with CDI and attitudes toward FMT.

RESULTS:

A total of 139 surveys were sent and 135 were completed, yielding a response rate of 97%. Twenty-five (20%) physicians had treated a patient with FMT, 10 (8%) offered to treat with FMT, nine (7%) referred a patient to receive FMT, and 83 (65%) had neither offered nor referred a patient for FMT. Physicians who had experience with FMT (performed, offered or referred) were more likely to be male, an infectious diseases specialist, >40 years of age, fellowship trained and practicing in an urban setting. The most common reasons for not offering or referring a patient for FMT were: not having ‘the right clinical situation’ (33%); the belief that patients would find it too unappealing (24%); and institutional or logistical barriers (23%). Only 8% of physicians predicted that the majority of patients would opt for FMT if given the option. Physicians predicted that patients would find all aspects of the FMT process more unappealing than they would as providers.

CONCLUSIONS:

Physicians have limited experience with FMT despite having treated patients with multiple recurrent CDIs. There is a clear discordance between physician beliefs about FMT and patient willingness to accept FMT as a treatment for recurrent CDI.     

Clostridium difficile and inflammatory bowel disease: Role in pathogenesis and implications in treatment

Clostridium difficile(C.difficile)is the leading cause of antibiotic associated colitis and nosocomial diarrhea.Patients with inflammatory bowel disease(IBD)are at increased risk of developing C.difficile infection(CDI),have worse outcomes of CDI-including higher rates of colectomy and death,and experience higher rates of recurrence.However,it is still not clear whether C.difficile is a cause of IBD or a consequence of the inflammatory state in the intestinal environment.The burden of CDI has increased dramatically over the past decade,with severe outbreaks described in many countries,which have been attributed to a new and more virulent strain.A parallel rise in the incidence of CDI has been noted in patients with IBD.IBD patients with CDI tend be younger,have less prior antibiotic exposure,and most cases of CDI in these patients represent outpatient acquired infections.The clinical presentation of CDI in these patients can be unique-including diversion colitis,enteritis and pouchitis,and typical findings on colonoscopy are often absent.Due to the high prevalence of CDI in patients hospitalized with an IBD exacerbation,and the prognostic implications of CDI in these patients,it is recommended to test all IBD patients hospitalized with a disease flare for C.difficile.Treatment includes general measures such as supportive care and infection control measures.Antibiotic therapy with either oral metronidazole,vancomycin,or the novel antibiotic-fidaxomicin,should be initiated as soon as possible.Fecal macrobiota transplantation constitutes another optional treatment for severe/recurrent CDI.The aim of this paper is to review recent data on CDI in IBD:role in pathogenesis,diagnostic methods,optional treatments,and outcomes of these patients.     

Glucosyltransferase activity of Clostridium difficile Toxin B is essential for disease pathogenesis

Clostridium difficile TcdB harbors a glucosyltransferase that targets host Rho GTPases. However, the role of the enzyme activity in the induction of host intestinal disease has not been demonstrated. In this study, we established a mouse acute intestinal disease model by cecum injection of wild type and glucosyltransferase-deficient TcdB and a chronic model by delivering toxin intraluminally via engineered surrogate host Bacillus megaterium. We demonstrated, for the first time, that the glucosyltransferase activity of TcdB is essential for inducing disease symptoms and intestinal pathological responses that resemble human disease, highlighting the importance of targeting toxin glucosyltransferase activity for future therapy.     

Ulcerative colitis worsened after Clostridium difficile infection:Efficacy of infliximab

The incidence of Clostridium difficile(C.difficile)infection(CDI)is 1.8%-5.7%in admitted patients with ulcerative colitis(UC).CDI can worsen UC and increase the risk for colectomy or even death,thus necessitating therapy escalation,such as increasing the corticoid therapy or starting a biologic treatment.Several reported cases with infliximab therapy have provided favorable outcomes in UC patients with CDI,suggesting that infliximab treatment may be protective;however,the optimal infliximab treatment regimen for UC patients with CDI remains to be established.Here,we report a case of worsening UC in the presence of recurrent CDI.The patient had received prior ciprofloxacin and immunosuppressive therapy during a prolonged hospital stay.The deterioration in the patient’s condition likely resulted from the ability of C.difficile to promote relapsing of UC by activating the immune response.Ultimately,the patient was treated with a high dose of infliximab after a low trough level of infliximab at week 8was identified,yielding better clinical results.Infliximab was found to be safe after repetitive episodes of CDI.The trough level of infliximab was therefore a useful indicator to guide therapy and correlated well with the patient’s outcome.     

Lactic acid production by Streptococcus thermophilus alters Clostridium difficile infection and in vitro Toxin A production

Antibiotic treatment to treat specific infections has the potential to effectively target the offending microbe as well as other microbes that colonize sites within a host. Antibiotic-associated diarrhea (AAD) is a classic example resulting from disruption of host microbial communities; 20% of patients with AAD are likely to become colonized with Clostridium difficile. Restoration of a “normal” microbial community within the host using probiotic bacteria is one approach to circumvent AAD and C. difficile infection. The goals of this study were to assess the interactions between Streptococcus thermophilus, a potential probiotic organism and C. difficile using both in vitro and in vivo systems. Exposure of C. difficile to filtered supernatants from S. thermophilus showed a dose-dependent, bactericidal effect due to lactic acid. Additional studies show that levels of lactic acid (10 mM) that did not inhibit bacterial growth had the potential to decrease tcdA expression and TcdA release into the extracellular milieu. In vivo, treatment with viable S. thermophilus significantly increased luminal levels of lactate in the cecum compared with UV-irradiated S. thermophilus. In the context of infection with C. difficile, mice treated with viable S. thermophilus exhibited 46% less weight loss compared with untreated controls; moreover, less pathology, diarrhea, and lower detectable toxin levels in cecal contents were evident more often in S. thermophillus treated mice. A significant, inverse correlation (Spearman r = -0.942, p = 0.017) between the levels of luminal lactate and abundance of C. difficile were noted suggesting that lactate produced by S. thermophilus is a factor impacting the progression of C. difficile infection in the murine system.