Treatment Of Clostridium Difficile-associated Diarrhea Research Articles

Oral faecal microbiota transplantation for the treatment of Clostridium difficile-associated diarrhoea in a dog: a case report

BackgroundSuccessful clinical outcomes of faecal microbiota transplantation (FMT) for recurrent Clostridium difficile infection have been reported in humans and a marmoset. However, it has been unclear whether oral FMT was effective for the treatment of C. difficile-associated diarrhoea in dogs.Case presentationAn 8-month-old, intact male French bulldog was presented with a 4-month history of intermittent large bowel diarrhoea. Physical and clinical examinations did not identify any specific causes for diarrhoea. Real-time PCR analysis and immunochromatography detected C. difficile antigen and toxin A&B genes and proteins in a faecal sample. Based on these findings, diarrhoea in the dog was considered to be induced by C. difficile-associated colitis. The dog was treated with oral FMT, in which a faecal solution obtained from a healthy beagle was orally administered to the subject. Stool consistency and frequency and faecal blood and mucus became normal 2–3 days after oral FMT, and real-time PCR analysis and immunochromatography was negative for C. difficile antigen and toxin A&B genes and proteins. No adverse events were observed.ConclusionThe present case report demonstrated that oral FMT was an effective treatment for C. difficile-associated diarrhoea in a dog. The findings in this report provide a rationale to evaluate clinical efficacy of oral FMT for other gastrointestinal diseases in dogs.

483. Clinical Characteristics of Military Trauma Patients With Clostridium difficile Infections

Background Clostridium difficile-associated diarrhea (CDAD) is an important cause of nosocomial diarrhea with increasing morbidity, mortality, and healthcare costs. There is growing recognition that critically ill trauma patients comprise a unique at risk population. This study describes the clinical epidemiology of CDAD in military trauma patients.MethodsThrough the Trauma Infectious Disease Outcomes Study (TIDOS), patients with a diagnosis of confirmed (laboratory supported) or presumptive (diarrhea with treatment for CDAD in absence of lab confirmation) CDAD (September 2009–February 2014) were analyzed. Patient demographic, injury, and infection data were evaluated. CDAD severity was defined per 2017 IDSA guidelines.ResultsOf 2,660 patients, 19 and four patients with confirmed and presumptive CDAD, respectively, were identified with an incidence of 2.76/10,000 (95% CI: 1.75–4.15) occupied bed days. Sixteen (70%) had blast injuries, four had gunshot wounds, and threehad other injuries. Median age was 24 years (IQR 23, 31). Median injury severity score was 38 (IQR 26, 47). Severe and fulminant CDAD was diagnosed in 8 (35%) and six (26%), respectively. Patients had a median hospitalization of 12 days (IQR 9.5, 34) and threeOR visits (IQR 2, 6) prior to CDAD diagnosis. Nineteen (83%) patients were in the ICU and 17 (74%) were intubated prior to or upon diagnosis. Seventeen patients had ≥1 infection before CDAD diagnosis, largely pneumonia (47%) and skin and soft-tissue infections (47%). Most patients (96%) were on antibiotics pre-CDAD diagnosis: first generation cephalosporins (1GC; 96%), tetracyclines (87%), vancomycin (74%), carbapenems (70%), and fluoroquinolones (FQ; 57%). Five (22%) received clindamycin. Of the 2637 patients without CDAD, 91% received antimicrobials during hospitalization (86% a 1GC, 47% FQ, and 16% clindamycin). Median length of hospital stay after CDAD diagnosis was 34 days (IQR 16, 55). Treatment included only oral metronidazole in 15 patients, IV metronidazole in 2, and some combination of oral vancomycin, metronidazole, and IV metronidazole in 6. No patients died.ConclusionDespite high rates of antimicrobial usage in this severely injured population, CDAD was uncommon. Though CDAD was severe or fulminant in >50%, no patients died.Disclosures All authors: No reported disclosures.

1816. Large-Scale Comparison of Antibiotic Prescription Guidelines Uncovers Disparities Among Stewardship Approaches

BackgroundThe accrediting institution for hospitals in the United States made antimicrobial stewardship programs (ASPs) mandatory in 2017. In part due to the relatively new status of ASPs, standards surrounding the content produced by these programs are still in their infancy. One product of ASPs are antibiotic prescription guidelines, which vary greatly across hospitals in terms of their structure and content.MethodsIn this study, we reviewed 70 publicly available antibiotic prescription guidelines published from 2006 to 2017, originating from 12 countries on four continents to evaluate their coverage and variability.ResultsGuidelines varied greatly in terms of their length, word count, page layout, revision frequency, and number of contributing authors. In terms of content, guidelines were discordant in their inclusion of cost information, restricted antibiotics, disclaimers, and pediatric recommendations. Guidelines also varied in their approach, in that some were focused on how to approach specific diagnoses, while others were focused on the usage of particular antibiotics. Many guidelines made use of decision trees to convey information, especially for the diagnosis and treatment of Clostridium difficile-associated diarrhea, cellulitis, and community-acquired pneumonia; however, the number of decision trees included in a hospital’s guideline varied greatly. A small minority of guidelines included identification trees for classifying bacterial isolates. Guidelines also notably differed in the extent to which they incorporated local antibiotic susceptibility data. Some guidelines did not report antibiogram summaries, while others displayed information for 5 to 34 organisms. Furthermore, we assessed guidelines’ prescription recommendations for 12 common bacterial infections and found large variation in suggested prescribing practices across hospitals.ConclusionTo our knowledge, this study provides the first large-scale analysis of antibiotic prescription guidelines and highlights the extreme variation in approaches to stewardship across hospitals. Furthermore, our analysis provides a baseline of current practices for future comparison, and initiates a discussion into what comprises a model antibiotic prescription guideline.Disclosures All authors: No reported disclosures.

Atypical cause of intractable diarrhea in a hemodialysis patient, masked by Clostridium difficile-associated diarrhea and ischemic colitis: a case report

BackgroundPatients with end-stage kidney disease (ESKD) most commonly complain of gastrointestinal symptoms, such as diarrhea. Diarrhea negatively affects patient quality of life and has miscellaneous etiologies, such as Clostridium difficile-associated diarrhea (CDAD) and ischemic colitis. However, it is sometimes extremely difficult to determine the true etiology given the comorbidities and complications the patients have. A rare cause of diarrhea is ulcerative colitis (UC), which commonly affects the rectum and proximal colon in a continuous fashion. UC with rectal sparing or segmental distribution, although atypical, sometimes leads to misdiagnosis. Herein, we present a case of UC in a patient on hemodialysis with intractable diarrhea; we initially considered that the diarrhea was caused by CDAD and ischemic colitis.Case presentationA 69-year-old man with a history of hypertension, bilateral thalamic hemorrhage, and decreased kidney function was admitted to our hospital because of congestive heart failure. Volume control was impossible due to renal dysfunction and he was started on hemodialysis. Thereafter, he received various antibiotics for bacterial infections. Simultaneously, he experienced continuous watery, and sometimes bloody, diarrhea, which was diagnosed as CDAD owing to a positive stool test for Clostridium difficile toxins. Antibiotic treatment for CDAD did not result in symptom relief. Subsequently, we performed colon biopsy via colonoscopy, and the pathology showed virtually no inflammation with rectal sparing and segmental distributions. These findings favored the presence of ischemic colitis due to arteriosclerosis and ESKD rather than infections. He died of cardiac arrest before the diarrhea was alleviated. Finally, UC was revealed on autopsy as the main cause of the uncontrollable diarrhea.ConclusionsPatients with ESKD have a greater risk of developing CDAD and ischemic colitis, which have clinical features that sometimes overlap with those of UC, as in the present case. This case emphasizes the importance of correctly diagnosing the etiology of intractable diarrhea and the fact that other diarrhea etiologies can obscure the existence of inflammatory bowel disease, which should be considered and treated properly when patients on hemodialysis present with intractable diarrhea.

Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers

BackgroundSurotomycin, a novel, orally administered, cyclic, lipopeptide antibacterial in development for the treatment of Clostridium difficile-associated diarrhea, has demonstrated minimal intestinal absorption in animal models.MethodsSafety, tolerability, and plasma pharmacokinetics of single and multiple ascending oral doses (SAD/MAD) of surotomycin in healthy volunteers were characterized in two randomized, double-blind, placebo-controlled, phase 1 studies.ResultsParticipants were sequentially enrolled into one of four SAD (500, 1000, 2000, 4000 mg surotomycin) or three MAD (250, 500, 1000 mg surotomycin twice/day for 14 days) cohorts. Ten subjects were randomized 4:1 into each cohort to receive surotomycin or placebo. Surotomycin plasma concentrations rose as dose increased (maximum plasma concentration [Cmax]: 10.5, 21.5, 66.6, and 86.7 ng/mL). Systemic levels were generally low, with peak median surotomycin plasma concentrations observed 6–12 h after the first dose. In the MAD study, surotomycin plasma concentrations were higher on day 14 (Cmax: 25.5, 37.6, and 93.5 ng/mL) than on day 1 (Cmax: 6.8, 11.0, and 21.1 ng/mL for increasing doses), indicating accumulation. In the SAD study, <0.01% of the administered dose was recovered in urine. Mean surotomycin stool concentration from the 1000 mg MAD cohort was 6394 μg/g on day 5. Both cohorts were well tolerated with all adverse events reported as mild to moderate.ConclusionBoth SAD and MAD studies of surotomycin demonstrated minimal systemic exposure, with feces the primary route of elimination following oral administration; consistent with observations with similar compounds, such as fidaxomicin. Results of these phase 1 studies support the continued clinical development of surotomycin for the treatment of Clostridium difficile-associated diarrhea.Trial registrationNCT02835118 and NCT02835105. Retrospectively registered, July 13 2016.

Factors Determining Physicians’ Decision Making In Treatment and the Outcomes of Nosocomial Diarrhea in a Tertiary Care Hospital: A Prospective Cohort

Abstract Background: Patients with nosocomial diarrhea (ND) are empirically treated as if they have Clostridium-difficileassociated diarrhea (CDAD), even if their stool tests are negative for C. difficile. We determined the incidence, risk factors, and treatment outcomes of patients with ND in Siriraj Hospital. Methods: All patients with ND were enrolled. Demographic data, clinical and laboratory and stool for C. difficile toxin were collected including severity and outcomes of ND. Descriptive analysis was performed using mean ± SD/ median ± IQR for continuous data and frequency for categorical data. χ2/Fisher’s exact tests were used to compare groups. Predictors that might determine the decision to prescribe empirical treatment were identified using regression analysis. Results: We enrolled 105 patients (mean age 67 years), and 89.5% were non-CDAD. During ND development, 95.7% received antibiotics and 3.2% chemotherapy. Eleven patients had CDAD. Common findings included: fever 42.6%, abdominal pain and hemodynamic instability 7.4%; 11.7% had blood cells in their stools and 85.1% had low serum albumin. Median white blood cell count and serum creatinine were 11-880 cells/mm3 and 1.4 mg/dl, respectively. CDAD treatment was prescribed in 48.9% regardless of the toxin result; 95.7% received metronidazole and 4.3% vancomycin. Response outcomes did not differ significantly between the two groups. Conclusion: Incidence of ND was 4.7%, and 10.6% of these had CDAD. 43.8% of patients with ND were treated as CDAD although they were negative for C. difficile toxin. There were no significant differences in clinical and laboratory features and outcomes between treated and untreated groups. Further study is needed to determine if empirical treatment of CDAD is justified in all cases of ND.

A Subgroup Analysis of Patients Undergoing Autologous and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Deflect-1: A Double-Blind, Randomized Study of Fidaxomicin Vs. Placebo for Prophylaxis Against C. Difficile Infection

Introduction: Clostridium difficile-associated diarrhea (CDAD) is a common complication during HSCT that has been associated with increased morbidity and mortality. CDAD has been reported to occur in 6 to 30% of HSCT patients. An ideal agent for prevention of CDAD has not been established. Fidaxomicin (FDX) is bactericidal against C. difficile, has low systemic absorption, provides a prolonged post-antibiotic effect, and is currently approved for the treatment of CDAD. The efficacy and safety of low dose FDX (200mg once daily) for prevention of CDAD were evaluated in both autologous (AUTO) and allogenic (ALLO) HSCT patients receiving fluoroquinolone (FQ) prophylaxis.Methods: HSCT patients were randomized to receive FDX 200 mg once daily (QD) or placebo (PLA) from start of conditioning therapy or FQ prophylaxis until 7 days after post-transplant engraftment (ANC >500/mm3) or completion of FQ prophylaxis. Randomization was stratified by type of HSCT (AUTO vs. ALLO). Patients were contacted twice weekly for 30 days and then weekly through 60 days post-prophylaxis for symptoms; CDAD was confirmed by toxin testing or PCR. The incidence of CDAD from start of prophylaxis up to 30 days and 60 days post-treatment were primary and secondary endpoints, respectively. For the primary analysis, failures were defined as patients with confirmed CDAD, as well as those who had missing data for the primary endpoint assessment (due to death or discontinuations resulting from adverse events, protocol non-compliance, lost follow-up, or any other reasons) and those who received any CDAD-effective medication (without confirmed CDAD). Sensitivity analyses, including an analysis that defined failure as confirmed CDAD, were prospectively defined for the overall population. These same analyses were performed for the ALLO and AUTO subgroups.Results: Of 611 enrolled patients, 600 were evaluable: 352 (59%) in AUTO and 248 (41%) in ALLO subgroups. The primary analysis for the primary endpoint did not show a significant reduction in incidence of CDAD with FDX prophylaxis (28.6% FDX vs. 30.8% PLA, p = 0.28). Secondary endpoint results were similar. However, the incidence of confirmed CDAD for up to 30 days was significantly lower in AUTO, ALLO, and overall in HSCT patients receiving prophylactic FDX versus PLA (see table). There were similar trends for 60 day post-treatment results. Overall, serious adverse events (AEs) and AEs resulting in death were more frequent in the ALLO vs. AUTO subgroup. In both subgroups, no differences in drug-related serious and non-serious AEs were seen between FDX and PLA.TableIncidence of Confirmed CDAD, 30d Post-treatmentAUTOALLOTotalFDX (%)5/176 (2.8%)8/125 (6.4%)13/301 (4.3%)PLA (%)14/176 (8.0%)18/123 (14.6%)32/299 (10.7%)PLA-FDX, %5.18.26.4Wald p-value0.01630.01660.0014Incidence of Confirmed CDAD, 60d Post-treatmentFDX (%)6/176 (3.4%)11/125 (8.8%)17/301 (5.6%)PLA (%)14/176 (8.0%)18/123 (14.6%)32/299 (10.7%)PLA-FDX, %4.55.85.1Wald p-value0.03210.07590.0117Conclusions: For the primary endpoint (failure of prophylaxis due to confirmed CDAD or non-CDAD events), the efficacy of FDX and PLA were similar. However, in both AUTO and ALLO HSCT patients, prophylactic FDX significantly reduced the incidence of confirmed CDAD and was not associated with drug-related adverse events. DisclosuresDugan:Cubist/Merck & Co., Inc.: Research Funding. Winston:Cubist/Merck & Co., Inc.: Research Funding. Morris:Cubist/ Merck & Co., Inc.: Research Funding. Williams:Merck & Co., Inc.: Employment. Broyde:Merck & Co., Inc.: Employment. Sears:Merck & Co., Inc.: Employment.

Cadazolid Does Not Promote Intestinal Colonization of Vancomycin-Resistant Enterococci in Mice.

The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side effect during treatment of Clostridium difficile-associated diarrhea (CDAD), resulting from disturbances in gut microbiota. Cadazolid (CDZ) is an investigational antibiotic with potent in vitro activity against C. difficile and against VRE and is currently in clinical development for the treatment of CDAD. We report that CDZ treatment did not lead to intestinal VRE overgrowth in mice.

Effect of Treatment Variation on Outcomes in Patients with Clostridium difficile

PurposeNew guidelines for the treatment of Clostridium difficile-associated diarrhea were published by the Infectious Disease Society of America (IDSA) in 2010, however, there has been no literature evaluating the effectiveness of these guidelines. The purpose of this study was to examine the clinical outcomes of Clostridium difficile infection including death, C difficile infection recurrence, toxic megacolon, and surgery between patients who received guideline-concordant therapy vs guideline-discordant therapy. MethodsRetrospective case-control study of hospitalized adults with C difficile infection presenting to a 420-bed tertiary care referral county teaching hospital. Patients were identified by International Classification of Diseases-9th Revision codes, and included if they were ≥18 years of age and treated for C difficile infection during their hospital visit. Complication rates (death, infection recurrence, toxic megacolon, and surgery) of patients with C difficile infection were measured to determine if following the IDSA guidelines improves outcomes. ResultsOnly 51.7% of the patients' prescribers followed the 2010 IDSA guidelines. Patients whose prescribers followed the IDSA guidelines experienced fewer complications than patients whose prescribers strayed from the guidelines (17.2% vs 56.3%, P <.0001). This difference was mainly due to a reduction in mortality (5.4% vs 21.8%, P = .0012) and infection recurrence (14% vs 35.6%, P = .0007). Patients who presented with severe and complicated disease received guideline-based therapy significantly less often than patients with mild disease (19.7%, 35.3%, and 81.2%, respectively, P <.0001). ConclusionsThere was a significant reduction in C difficile infection recurrence and mortality when prescribers followed the IDSA/Society for Healthcare Epidemiology of America guidelines for treatment of C difficile infection.

Surotomycin demonstrates low in vitro frequency of resistance and rapid bactericidal activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium.

Surotomycin (CB-183,315) is an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide in phase 3 development for the treatment of Clostridium difficile-associated diarrhea. The aim of this study was to evaluate the emergence of resistance in C. difficile (ATCC 700057 and three recent clinical isolates from the restriction endonuclease analysis groups BI, BK, and K), vancomycin-susceptible (VS) Enterococcus faecalis (ATCC 49452), vancomycin-resistant (VR) E. faecalis (ATCC 700802), VS Enterococcus faecium (ATCC 6569), and VR E. faecium (ATCC 51559) under anaerobic conditions. The rate of spontaneous resistance was below the limit of detection (<10(-8) to <10(-9)) for surotomycin at 16 and 32× the MIC for all isolates tested. Under selective pressure by serial passage, C. difficile grew in a maximum of 4 μg/ml surotomycin (final MICs of 2 to 8 μg/ml [4- to 16-fold higher than those of the naive control]) at day 15, with the exception of the C. difficile BK strain, which grew in 16 to 32 μg/ml (final MICs of 8 to 32 μg/ml [16- to 64-fold higher than those of the naive control]). Enterococci remained relatively unchanged over 15 days, growing in a maximum of 8 μg/ml surotomycin (final MICs of 2 to 16 μg/ml [8- to 64-fold higher than those of the naive control]). Of the isolates tested, no cross-resistance to vancomycin, rifampin, ampicillin, metronidazole, or moxifloxacin was observed. Surotomycin at 20× MIC demonstrated equally rapid bactericidal activity (≥ 3-log-unit reduction in CFU/ml in ≤ 8 h) against naive and reduced-susceptibility isolates of C. difficile, VS Enterococcus (VSE), and VR Enterococcus (VRE), except for C. difficile BK (2.6-log-unit reductions for both). These results suggest that emergence of resistance to surotomycin against C. difficile, E. faecalis, and E. faecium is likely to be rare.

Comparative Microbiological Studies of Transcription Inhibitors Fidaxomicin and the Rifamycins in Clostridium difficile

Fidaxomicin (FDX) is a narrow-spectrum antibiotic for the treatment of Clostridium difficile-associated diarrhea. While FDX and rifamycins share the same target (RNA polymerase), FDX exhibits a unique mode of action distinct from that of rifamycins. In comparative microbiological studies with C. difficile, FDX interacted synergistically with rifamycins, demonstrated a lower propensity for the development of resistance to rifamycins, and exhibited no cross-resistance with rifamycins. These results highlight differences in the mechanisms of action of FDX and rifamycins.

Is co-prescribing a multi-strain probiotic the solution for treating and preventing proton pump inhibitor (PPIs) induced Clostridium difficile associated diarrhoea (CDAD) while maintaining evidence based pharmacotherapy?

A recent study investigating faecal transplants to eliminate Clostridium difficile infections has elicited further interest regarding the pharmacobiotic potential of the human gastrointestinal microbiome. Probiotic preparations may exhibit significant potential for the treatment of CDAD. Probiotics are defined as living organisms in food and dietary supplements that, upon ingestion, can improve the health of the host beyond their inherent basic nutritional content. The human–microbial gastrointestinal tract (GIT) interface is an ecosystem that participates in a variety of important roles in human health and disease. Maintaining this ecosystem in a balanced state is a critical requisite for the control of pathogenic bacteria and the associated toxin load produced in the small and large bowel. Pharmacotherapy induced adverse metabolic conditions that ensue can disrupt the GIT homeostasis and contribute toward a dysbiotic burden that increases the risk of CDAD.

Fidaxomicin: A new fight against clostridium difficile-associated diarrhea

Clostridium difficile-associated diarrhea (CDAD) occurs commonly as a side effect of broad-spectrum antibiotics. Drugs approved for CDAD are only two of them, metronidazole and vancomycin. Most promising drug for treatment of CDAD is vancomycin, but due to emergence of hypervirulent strains, outcomes have become poor. Fidaxomicin has being approved lately for treatment of CDAD, which has shown good results as compared to vancomycin. Fidaxomicin inhibits protein synthesis by inhibiting transcription carried out by sigma subunit of RNA polymerase. Fidaxomicin has been seen to be a well tolerated, with minimal adverse effects. Clinical trials has showed that fidaxomicin has similar results to vancomycin in showing clinical response, whereas it was superior to vancomycin in having sustained clinical effect, in CDAD.

Investigations of the Mode of Action and Resistance Development of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

Cadazolid is a new oxazolidinone-type antibiotic currently in clinical development for the treatment of Clostridium difficile-associated diarrhea. Here, we report investigations on the mode of action and the propensity for spontaneous resistance development in C. difficile strains. Macromolecular labeling experiments indicated that cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA synthesis was also observed, albeit only at substantially higher concentrations of the drug. Strong inhibition of protein synthesis was also obtained in strains resistant to linezolid, in agreement with low MICs against such strains. Inhibition of protein synthesis was confirmed in coupled transcription/translation assays using extracts from different C. difficile strains, including strains resistant to linezolid, while inhibitory effects in DNA topoisomerase assays were weak or not detectable under the assay conditions. Spontaneous resistance frequencies of cadazolid were low in all strains tested (generally <10(-10) at 2× to 4× the MIC), and in multiple-passage experiments (up to 13 passages) MICs did not significantly increase. Furthermore, no cross-resistance was observed, as cadazolid retained potent activity against strains resistant or nonsusceptible to linezolid, fluoroquinolones, and the new antibiotic fidaxomicin. In conclusion, the data presented here indicate that cadazolid acts primarily by inhibition of protein synthesis, with weak inhibition of DNA synthesis as a potential second mode of action, and suggest a low potential for spontaneous resistance development.

Hypersensitivity Reactions Associated With Fidaxomicin Use

We report hypersensitivity reactions associated with fidaxomicin, an antibacterial drug approved for the treatment of Clostridium difficile-associated diarrhea. These reactions are viewed as significant because of severity and unexpected because fidaxomicin is minimally absorbed. The fidaxomicin labeling was revised to include information about the possibility of hypersensitivity reactions.

Cadazolid, a novel antibiotic with potent activity against Clostridium difficile: safety, tolerability and pharmacokinetics in healthy subjects following single and multiple oral doses

Current treatment options for Clostridium difficile-associated diarrhoea (CDAD) leave a high unmet medical need for new therapies. Cadazolid is a new antibiotic in development for the treatment of CDAD. The objectives of this study were to evaluate its tolerability and pharmacokinetics following single ascending doses (AC-061-101) and multiple ascending doses (AC-061-102). Single and multiple (twice daily for 10 days) oral doses of cadazolid between 30 mg and 3000 mg, or placebo, were tested in a total of 64 healthy male subjects. Safety assessments were conducted at regular intervals. Blood, urine and faeces were sampled, and cadazolid concentrations were measured. Cadazolid was well tolerated up to 3000 mg given twice daily for 10 days. The most common adverse event was headache, with no observed relationship between dose or treatment duration and adverse events. Plasma concentrations of cadazolid were low. No plasma concentrations >3.3 ng/mL were observed after single doses or >6.9 ng/mL after 10 days of multiple doses. Food increased the mean C(max) from 0.73 to 1.87 ng/mL and mean AUC(0-t) from 3.13 to 15.69 ng ·h/mL after a single 300 mg dose. The increase in systemic exposure to cadazolid across doses was less than dose-proportional. The mean cumulative faecal recovery was 81.0%-93.5%. Urinary recovery of unchanged compound was <0.015%. Cadazolid was well tolerated and its systemic exposure was low. The majority of compound was recovered unchanged in the faeces, thus resulting in high concentrations at the site of action (colon).

Diagnosis and Management of Clostridium difficile Infection

Clostridium difficile infection (CDI) is increasing in frequency and severity in and out of the hospital, with a high probability of recurrence after treatment. The recent literature on CDI was reviewed using PubMed to include recent publications dealing with diagnosis and therapy. Real-time polymerase chain reaction is a sensitive and useful diagnostic test for CDI but there are growing concerns of false-positive test results if the rate of CDI is low in the patient population providing samples and/or if the population being studied commonly includes people with C difficile colonization. Recommended therapy of CDI includes oral metronidazole for milder cases of CDI and oral vancomycin or fidaxomicin for more severe cases, each given for 10 days. Colectomy is being performed more frequently in patients with fulminant CDI. For treatment of first recurrences the drug used in the first bout can be used again and for second recurrences longer courses of vancomycin often are given in a tapered dose or intermittently to allow gut flora reconstitution, or other treatments including fidaxomicin may be used. Bacteriotherapy with fecal transplantation is playing an increasing role in therapy of recurrent cases. Metagenomic studies of patients with CDI during successful therapy are needed to determine how best to protect the flora from assaults from antibacterial drugs and to develop optimal therapeutic approaches. Immunotherapy and immunoprophylaxis offer opportunities to prevent CDI, to speed up recovery from CDI, and to eliminate recurrent infection. Humanized monoclonal antitoxin antibodies and active immunization with vaccines against C difficile or its toxins are both in development and appear to be of potential value.

Fidaxomicin in the Treatment of Clostridium difficile-Associated Diarrhoea

We read with interest the correspondence by Greig com-paring outlays for fidaxomicin for the treatment of allprimary cases of Clostridium difficile-associated diarrhoea(CDAD), in persons aged [65 years, and for persons inreceipt of concomitant antimicrobial pharmacotherapy,with mean expenditures for hospitalization for CDAD inthe UK [1].We agree with Greig that the fiscal benefits ofemploying fidaxomicin in the treatment of CDAD extendbeyond the acquisition cost of medication, and that thepotential to reduce transmission of disease will afford amore robust financial profile in favour of fidaxomicin.Our research comparing outlays for fidaxomicin versusvancomycin for the treatment of CDAD, with an end-pointof warranted price from the perspective of the US health-care system, concluded fidaxomicin represented value formoney [2]. To examine this issue, we employed the num-ber-needed-to-treat (NNT) as derived from the registrationstudies with the US Food and Drug Administration(NNT = 7.1). Moreover, to discern the fiscal utility offidaxomicin in both primary and secondary cases ofCDAD, we employed the methodology developed byO’Brien et al. [3] for attribution of hospital outlays due toCDAD in secondary cases. This approach resulted in amore conservative hurdle for fidaxomicin. Finally, itshould be noted that our research employed national (US)data for both primary and secondary cases of CDAD [4].Greig is correct to note that there are limited compara-tive data as regards the use of vancomycin versus metro-nidazole in the treatment of CDAD. That said, from apolicy perspective, results reported by Greig [1] and Sclaret al. [2] indicate that fidaxomicin represents a judiciousfiscal choice among select populations hospitalized forCDAD.References

Detailed methodological recommendations for the treatment of Clostridium difficile-associated diarrhea with faecal transplantation

The incidence of Clostridium difficile associated enteral disease shows dramatic increase worldwide, with appallingly high treatment costs, mortality figures, recurrence rates and treatment refractoriness. It is not surprising, that there is significant interest in the development and introduction of alternative therapeutic strategies. Among these only stool transplantation (or faecal bacteriotherapy) is gaining international acceptance due to its excellent cure rate (≈92%), low recurrence rate (≈6%), safety and cost-effectiveness. Unfortunately faecal transplantation is not available for most patients, although based on promising international results, its introduction into the routine clinical practice is well justified and widely expected. The authors would like to facilitate this process, by presenting a detailed faecal transplantation protocol prepared in their Institution based on the available literature and clinical rationality. Officially accepted national methodological guidelines will need to be issued in the future, founded on the expert opinion of relevant professional societies and upcoming advances in this field.

Fidaxomicin in the Treatment of Clostridium difficile-Associated Diarrhoea

Fidaxomicin in the Treatment of Clostridium difficile-Associated Diarrhoea