Outcomes associated with Clostridium difficile infection in patients with chronic liver disease.

Patients with chronic liver disease (CLD) have frequent exposure to Clostridium difficile infection (CDI) risk factors but the incidence and aetiology of CDI on this population is poorly understood. The aim of this study was to assess the incidence, disease presentation and outcomes of CDI in patients with underlying CLD. The Health Care and Utilization Project National Inpatient Sample (HCUP-NIS) 2009 dataset was used to identify patients with CLD who developed CDI along with matched non-CLD patients with CDI. Using the NIS dataset, the incidence rate of CDI was 189.4/10 000 discharges in CLD patients vs. 83.7/10 000 discharges in the non-CLD matched cohort (P < 0.001). Compared with non-CLD, comorbidity-matched controls with CDI, CLD patients with CDI had higher likelihood of in-hospital mortality (8.8% vs. 18.6%, P < 0.001), increased length of stay by 1.19 days (P < 0.001) and increased total costs by $8632 (P < 0.001). In separate analyses using a tertiary case database of hospitalised patients in Houston, Texas (2006-2016) with CLD and CDI (n = 41) compared with patients with CDI but not CLD (n = 111), CLD patients had significantly higher Charlson comorbidity index (P < 0.0001) but similar risk factors for CDI and CDI-related disease presentation compared with non-CLD patients. In conclusion, CDI-related risk factors were almost universally present in the CLD population. CDI resulted in worse outcomes in this population.

Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy.

OBJECTIVES: Rezafungin (CD101) is a novel echinocandin currently under development. The purpose of this study was to perform a systematic literature review of published evidence on rezafungin and an antimicrobial stewardship audit of real-world use of echinocandins to determine areas of unmet medical needs and potential places in therapy for rezafungin. METHODS: The systematic literature review identified 8 peer-reviewed manuscripts and 19 separate abstracts. A stewardship audit was performed on hospitalised patients receiving echinocandins to better understand potential future areas of use for rezafungin. RESULTS: Rezafungin is a cyclic hexapeptide with a lipophilic tail derived from anidulafungin, with a choline moiety at the C5 ornithine position resulting in increased in vitro and in vivo stability compared with other echinocandins. Microbiological data showed similar susceptibility and resistance development between rezafungin and other echinocandins. Rezafungin has a long half-life (80h) and a favourable safety profile that allows for high doses (up to 400mg) given once weekly. A phase 2 study is ongoing. The antimicrobial stewardship audit of echinocandin identified several areas of possible use for rezafungin, including patients receiving daily echinocandins for >7 days, patients who remained in the hospital to complete a full course of daily echinocandin therapy, and patients who required an echinocandin scheduled via an infusion clinic after discharge. CONCLUSION: Rezafungin is a novel echinocandin currently in phase 2 studies, differentiated by a long half-life that allows once-weekly dosing and a safety profile that allows higher doses. Several potential areas of use for rezafungin were identified.

A multi-center study of fidaxomicin use for Clostridium difficile infection.

PURPOSE: Fidaxomicin use in real-world clinical practice, especially for severe Clostridium difficile infection (CDI), is mainly based on single-center observational studies. The purpose of this pharmacoepidemiology study was to assess outcomes of patients given fidaxomicin based on episode number and use of concomitant antibiotics. METHODS: Fidaxomicin use over time across included hospitals in the United States was assessed using a large inpatient drug utilization database. A multicenter retrospective chart review was also conducted of hospitalized patients with CDI that received fidaxomicin between 2011 and 2013. Fidaxomicin utilization and clinical outcomes were stratified by use of fidaxomicin for first or second episode (early episodes) versus greater than or equal to episodes (later episodes). RESULTS: The overall fidaxomicin use rate was 2.16 % which increased from 0.22 % in the last two quarters of 2011 to 3.16 % in the first two quarters of 2013. A total of 102 hospitalized patients that received fidaxomicin from 11 hospitals were identified in the multicenter study. Sixty-nine patients received fidaxomicin for early (68 % with severe CDI) and 33 received for later episodes. The majority of patients received other CDI therapy including 61 patients (88 %) for early episodes and 27 (82 %) for later episodes. Concomitant non-CDI antibiotics were received by 48 patients (47 %). Rates of clinical outcomes were similar regardless of CDI episode. CONCLUSION: This study demonstrated a slow but steady increase in fidaxomicin utilization over time; most of which was combined with other systemic antibiotics. Antimicrobial stewardship teams should provide guidance on appropriate use of fidaxomicin to optimize therapy and assess the need to continue other antibiotics during CDI treatment.

Development and Validation of a Clostridium difficile Health-related Quality-of-Life Questionnaire.

GOALS AND BACKGROUND: Patients with Clostridium difficile infection (CDI) can experience long-term symptoms and poor quality of life due to the disease. Despite this, a health-related quality of life (HRQOL) instrument specific for patients with CDI does not exist. The aim of this study was to develop and validate a disease-specific instrument to assess HRQOL in patients with CDI. STUDY: A systematic literature review was conducted to identify HRQOL instruments and questions related to general health (n=3) or gastrointestinal disease (n=12) potentially related to CDI HRQOL. Removing duplicate questions and using direct patient or clinician interviews, a 36-item survey was developed. The survey was then tested using 98 patients with CDI and compared with the RAND Short-Form 36 (SF-36) Health Survey. Psychometric analysis techniques were used to identify domains and remove redundant items. RESULTS: Exploratory factor analysis identified 3 major domains (physical, mental, and social) with 4 associated subdomains. Survey overall and domain scores displayed good internal consistency (Cronbach α coefficient >0.87) and concurrent validity evidenced by significant correlation with SF-36 scores. The C. difficile survey scores were better able than the SF-36 to discriminate quality-of-life score differences in patients with primary versus recurrent CDI and increasing time since last episode of CDI. The final version contained 32 items related to the physical, mental, and social health of CDI patients. CONCLUSION: The properties of the newly developed Cdiff32 should make it appropriate to assess changes over time in HRQOL in patients with CDI.

Multiplex Real-Time PCR Method for Simultaneous Identification and Toxigenic Type Characterization of Clostridium difficile From Stool Samples.

BACKGROUND: The aim of this study was to develop and validate a multiplex real-time PCR assay for simultaneous identification and toxigenic type characterization of Clostridium difficile. METHODS: The multiplex real-time PCR assay targeted and simultaneously detected triose phosphate isomerase (tpi) and binary toxin (cdtA) genes, and toxin A (tcdA) and B (tcdB) genes in the first and sec tubes, respectively. The results of multiplex real-time PCR were compared to those of the BD GeneOhm Cdiff assay, targeting the tcdB gene alone. The toxigenic culture was used as the reference, where toxin genes were detected by multiplex real-time PCR. RESULTS: A total of 351 stool samples from consecutive patients were included in the study. Fifty-five stool samples (15.6%) were determined to be positive for the presence of C. difficile by using multiplex real-time PCR. Of these, 48 (87.2%) were toxigenic (46 tcdA and tcdB-positive, two positive for only tcdB) and 11 (22.9%) were cdtA-positive. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the multiplex real-time PCR compared with the toxigenic culture were 95.6%, 98.6%, 91.6%, and 99.3%, respectively. The analytical sensitivity of the multiplex real-time PCR assay was determined to be 10(3) colony forming unit (CFU)/g spiked stool sample and 0.0625 pg genomic DNA from culture. Analytical specificity determined by using 15 enteric and non-clostridial reference strains was 100%. CONCLUSIONS: The multiplex real-time PCR assay accurately detected C. difficile isolates from diarrheal stool samples and characterized its toxin genes in a single PCR run.

A Multi-Center Prospective Derivation and Validation of a Clinical Prediction Tool for Severe Clostridium difficile Infection.

BACKGROUND AND AIMS: Prediction of severe clinical outcomes in Clostridium difficile infection (CDI) is important to inform management decisions for optimum patient care. Currently, treatment recommendations for CDI vary based on disease severity but validated methods to predict severe disease are lacking. The aim of the study was to derive and validate a clinical prediction tool for severe outcomes in CDI. METHODS: A cohort totaling 638 patients with CDI was prospectively studied at three tertiary care clinical sites (Boston, Dublin and Houston). The clinical prediction rule (CPR) was developed by multivariate logistic regression analysis using the Boston cohort and the performance of this model was then evaluated in the combined Houston and Dublin cohorts. RESULTS: The CPR included the following three binary variables: age ≥ 65 years, peak serum creatinine ≥ 2 mg/dL and peak peripheral blood leukocyte count of ≥ 20,000 cells/µL. The Clostridium difficile severity score (CDSS) correctly classified 76.5% (95% CI: 70.87-81.31) and 72.5% (95% CI: 67.52-76.91) of patients in the derivation and validation cohorts, respectively. In the validation cohort, CDSS scores of 0, 1, 2 or 3 were associated with severe clinical outcomes of CDI in 4.7%, 13.8%, 33.3% and 40.0% of cases respectively. CONCLUSIONS: We prospectively derived and validated a clinical prediction rule for severe CDI that is simple, reliable and accurate and can be used to identify high-risk patients most likely to benefit from measures to prevent complications of CDI.

Healthcare resource utilization for recurrent Clostridium difficile infection in a large university hospital in Houston, Texas.

BACKGROUND: There are limited data examining healthcare resource utilization in patients with recurrent Clostridium difficile infection (CDI). METHODS: Patients with CDI at a tertiary-care hospital in Houston, TX, were prospectively enrolled into an observational cohort study. Recurrence was assessed via follow-up phone calls. Patients with one or more recurrence were included in this study. The location at which healthcare was obtained by patients with recurrent CDI was identified along with hospital length of stay. CDI-attributable readmissions, defined as a positive toxin test within 48 hours of admission and a primary CDI diagnosis, were also assessed. RESULTS: 372 primary cases of CDI were identified of whom 64 (17.2%) experienced at least one CDI recurrence. Twelve of 64 patients experienced 18 further episodes of CDI recurrence. Of these 64 patients, 33 (50.8%) patients with recurrent CDI were readmitted of which 6 (18.2%) required ICU care, 29 (45.3%) had outpatient care only, and 2 (3.1%) had an ED visit. Nineteen (55.9%) readmissions were defined as CDI-attributable. For patients with CDI-attributable readmission, the average length of stay was 6 ± 6 days. CONCLUSION: Recurrent CDI leads to significant healthcare resource utilization. Methods of reducing the burden of recurrent CDI should be further studied.

Clinical practice patterns in hospitalized patients at risk for invasive candidiasis: role of antifungal stewardship programs in an era of rapid diagnostics.

BACKGROUND: Rapid diagnostic tests for Candida are becoming available that may supplement traditional microbiological identification. OBJECTIVE: Assess clinical practice patterns in patients with or at risk of candidiasis who may benefit from the use of rapid diagnostic tests. METHODS: This was a prospective cohort study of patients with candidemia or receiving systemic antifungals conducted at a university-affiliated tertiary care hospital. Time to initiation of therapy, Candida species, time to identification, and indications for antifungal use were assessed. RESULTS: A total of 162 patients with candidemia aged 58 ± 17 years were identified. Average time to yeast identification yeast was 2.2 ± 1.3 days and varied by Candida species (range = 0.6-7.9 days). Average time for patient to start antifungal therapy was 3.5 ± 2.1 days. In Monte Carlo simulations, average time to initiation of antifungal therapy was 0.6 ± 0.2 days for T2Candida, 2.6 ± 1.3 days for PNA-FISH (fluorescence in situ hybridization using peptide nucleic acid probes), and 2.5 ± 1.4 days for MALDI-TOF (matrix-assisted laser desorption/ionization time of flight). Use of T2Candida on the day of the blood culture collection resulted in 3136 to 6078 fewer doses of echinocandins annually per 5000 patients. CONCLUSION: Many interventions are possible for antifungal stewardship programs to improve care of patients at risk for systemic candidiasis, including rapid identification of yeast species and limiting unnecessary antifungal agents. Technology enabling rapid diagnosis of Candida will be paramount to appropriate, cost-effective treatment of patients with or at risk for candidiasis.

Significant publications on infectious diseases pharmacotherapy in 2012.

PURPOSE: The most important articles pertaining to infectious diseases (ID) pharmacotherapy published in 2012, as nominated and ranked by panels of pharmacists and physicians with ID expertise, are summarized. SUMMARY: Members of the Houston Infectious Diseases Network were asked to nominate articles on ID research published in prominent peer-reviewed journals during the period January 1-December 31, 2012, with a major impact in the field of ID pharmacotherapy. A list of 42 nominated articles on general ID-related topics and 8 articles pertaining to human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) was compiled. In a survey conducted in January 2013, members of the Society of Infectious Diseases Pharmacists (SIDP) were asked to select from the list 10 general ID articles and 1 HIV/AIDS-related article that they considered to be the most important. Of the 180 SIDP members surveyed, 100 (55%) and 44 (24%) participated in ranking the general ID and HIV/AIDS-related articles, respectively. Summaries of the highest-ranked articles in both categories are presented here. CONCLUSION: With the volume of published ID-related research growing each year, both ID specialists and nonspecialists are challenged to stay current with the literature. Key ID-related publications in 2012 included updated recommendations on management of diabetic foot infections, articles on promising approaches to prevention and early treatment of HIV disease, and reports on developments in research on pharmacotherapies for methicillin-resistant Staphylococcus aureus bacteremia and Klebsiella pneumoniae infections.

Treatment of Candida famata bloodstream infections: case series and review of the literature.

OBJECTIVES: Candida famata (also known as Debaryomyces hansenii and Torulopsis candida) is a commensal yeast found in cheese, dairy products and the environment. C. famata accounts for 0.2%-2% of invasive candidiasis. The purpose of this study was to provide an overview of the treatment of C. famata bloodstream infections. METHODS: The clinical course of two hospitalized patients who developed C. famata fungaemia within 2 weeks of each other was summarized along with available data regarding in vitro susceptibility patterns, genotyping and clinical outcomes of these cases compared with the published literature. RESULTS AND CONCLUSIONS: C. famata appears to exhibit reduced susceptibility to echinocandins and azoles, particularly in the setting of prior antifungal exposure. The removal of indwelling central venous catheters and prompt initiation of therapy with liposomal amphotericin B is recommended for successful treatment of C. famata fungaemia, particularly in immunocompromised patients. These cases also help provide justification for routine antifungal susceptibility testing in patients with candidaemia to guide optimal antifungal therapy.

Evaluation of a daptomycin dose-optimization protocol.

PURPOSE: The impact of an institutional protocol intended to improve daptomycin dosing for vancomycin-resistant enterococci (VRE) infections was investigated. SUMMARY: Daptomycin has been reported to have optimal activity against VRE at weight-based doses of ≥8 mg/kg. As part of an initiative to optimize daptomycin dosing for all indications and regimens, a large medical center implemented a protocol restricting daptomycin prescribing to infectious-diseases specialists and a nomogram recommending elevated daptomycin dosing for all VRE infections, with baseline and weekly creatinine phosphokinase (CPK) determinations during daptomycin therapy. Protocol implementation was preceded by educational efforts targeting medical and pharmacy staff. A retrospective study was conducted to compare prescribing behavior and safety monitoring rates during the 12 months before and 16 months after protocol implementation; the baseline characteristics of the preimplementation cohort (n = 95) and postimplementation cohort (n = 72) were similar. The mean daptomycin doses before and after the protocol was implemented were 453 mg (6.1 mg/kg) and 576 mg (7.6 mg/kg), respectively. After protocol implementation, there were significant increases in the proportion of patients who received doses of ≥8 mg/kg (52% in the postimplementation period versus 4% in the preimplementation period, p < 0.05) and in the rate of baseline CPK assessment (64% versus 43%, p < 0.05). CONCLUSION: Implementation of a daptomycin dosing protocol by a multidisciplinary antimicrobial stewardship team optimized treatment by increasing the mean dose of daptomycin administered to hospitalized adults with non-urinary VRE infections and improved the rate of safety monitoring.

Impact of prior inappropriate fluconazole dosing on isolation of fluconazole-nonsusceptible Candida species in hospitalized patients with candidemia.

Prior use of fluconazole is a modifiable risk factor for the isolation of fluconazole-nonsusceptible Candida species. Optimization of the use of fluconazole by appropriate dose or duration may be able to minimize the risk of resistance. The objective of this study was to evaluate the effects of prior fluconazole therapy, including the dose and duration, on fluconazole susceptibility among Candida species isolated from hospitalized patients with candidemia. A retrospective cohort study of hospitalized patients with a first occurrence of nosocomial candidemia, from 2006 to 2009, was carried out. The relationships between the initial dose and duration of prior fluconazole therapy and the isolation of fluconazole-nonsusceptible Candida species were assessed. An initial fluconazole dose greater than 2 mg/kg and less than 6 mg/kg of body weight was considered suboptimal. A total of 177 patients were identified, of whom 133 patients aged 61 ± 16 years (56% male, 51% Caucasian, 51% with an APACHE II score of ≥ 15) had candidemia more than 2 days after the hospital admission day. Nine of 107 (8%) patients with fluconazole-susceptible Candida species and 9 of 26 (35%) patients with fluconazole-nonsusceptible Candida species had prior fluconazole exposure (risk ratio [RR], 3.03; 95% confidence interval [95% CI], 1.57 to 5.86; P, 0.0022). Preexposure with an initial dose of fluconazole greater than 2 mg/kg and less than 6 mg/kg occurred in 3 of 9 (33%) and 8 of 9 (89%) patients with fluconazole-susceptible and fluconazole-nonsusceptible Candida species, respectively (P, 0.0498). We conclude that patients with candidemia due to fluconazole-nonsusceptible Candida species were more likely to have received prior fluconazole therapy. Suboptimal initial dosing of prior fluconazole therapy was associated with candidemia with fluconazole-nonsusceptible Candida species.

A real-world evaluation of oral vancomycin for severe Clostridium difficile infection: implications for antibiotic stewardship programs.

STUDY OBJECTIVE: To assess antibiotic treatment patterns and clinical outcomes of patients with Clostridium difficile infection (CDI) based on underlying severity of CDI disease. DESIGN: Retrospective analysis of data from a prospective cohort study. SETTING: Large tertiary care university hospital. PATIENTS: One hundred forty-four patients (mean ± SD age 63 ± 17 yrs) with CDI who received metronidazole (intravenous or oral) or oral vancomycin as their initial therapy option between 2006 and 2008. MEASUREMENTS AND MAIN RESULTS: Patients were stratified by severity of illness and treatment, and outcomes assessed were clinical response, relapse of disease, all-cause inpatient mortality, and length of hospital stay. Mild-moderate CDI disease was present in 85 patients (59%) and severe disease in 59 patients (41%). Overall, oral vancomycin was given to 16 patients (11%); use of this drug did not differ according to severity of infection. Among patients with severe disease, clinical success occurred in 32 (63%) of 51 patients given metronidazole and in all 8 patients (100%) given vancomycin (p=0.04). Inpatient mortality and hospital length of stay were lower in patients with severe CDI who were given oral vancomycin, although these results were not statistically significant. CONCLUSION: Oral vancomycin was not commonly used for severe CDI. An improved clinical response rate was observed in patients with severe CDI given oral vancomycin; this outcome supported results from clinical trials. Antibiotic stewardship teams could play a major role in providing guidance on CDI treatment based on severity.

Significant publications on infectious diseases pharmacotherapy in 2010.

PURPOSE: Important articles on topics pertinent to infectious diseases (ID) pharmacotherapy published in prominent peer-reviewed journals in 2010 are summarized. SUMMARY: At the end of 2010, pharmacists, physicians, and researchers in the Houston Infectious Diseases Network were asked to nominate articles published from January through December 2010 that they perceived as having a significant impact in the field of ID pharmacotherapy. The resulting list, comprising 27 articles relating to human immunodeficiency virus (HIV) disease or acquired immune deficiency syndrome (AIDS) and 52 articles on a broad range of other ID-related topics, was sent to members of the Society of Infectious Diseases Pharmacists (SIDP) for evaluation via an Internet survey. The survey participants were asked to select from the list 10 articles unrelated to HIV or AIDS and 1 HIV- or AIDS-related article that in their view had the most significant impact in the field. Of the 380 SIDP members surveyed, 105 (27.6%) ranked the non-HIV-related papers and 45 (11.8%) ranked the HIV-related papers. The 11 highest-ranked publications-including 2 articles presenting updated practice guidelines-are summarized here. CONCLUSION: Due to the increasing number of articles published each year, it is difficult to maintain a current knowledge of significant publications in the field of ID pharmacotherapy. This review of key publications in 2010 may be helpful to the nonspecialist clinician by lessening this burden.

A randomized, double-blind, placebo-controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with Clostridium difficile infection.

BACKGROUND: Uncontrolled case series have demonstrated decreased Clostridium difficile infection (CDI) recurrence in patients given rifaximin after standard antibiotic therapy. However, clinical trials assessing whether rifaximin decreases recurrent diarrhoea in patients with CDI have not been performed. The purpose of this study was to assess rates of recurrent diarrhoea in patients with CDI given rifaximin versus placebo immediately after standard therapy. METHODS: This was a randomized, double-blind, placebo-controlled pilot study. Patients with CDI and a Horn's index ≥1 were randomized to receive rifaximin 400 mg three times daily or placebo for 20 days given immediately after finishing standard anti-CDI antibiotics. Patients were followed for 3 months and assessed for recurrent diarrhoea that included CDI recurrence (return of diarrhoea with a positive toxin test) and patient self-reported return of non-CDI diarrhoea after a period of wellness. RESULTS: Sixty-eight patients aged 61 ± 18 years (50% male) were given rifaximin (n = 33) or placebo (n = 35). Twenty-four of 68 (35%) patients had recurrent diarrhoea either due to recurrent CDI (23.5%) or self-reported diarrhoea (11.5%). Recurrent diarrhoea occurred in 17 of 35 (49%) patients given placebo and 7 of 33 (21%) given rifaximin (P = 0.018). CDI recurrence occurred in 11 of 35 (31%) patients given placebo and 5 of 33 (15%) patients given rifaximin (P = 0.11). Self-reported diarrhoea occurred in 6 of 35 (17%) of patients given placebo and 2 of 33 (6%) given rifaximin (P = 0.15). CONCLUSIONS: Patients with CDI given a rifaximin chaser regimen experienced a decreased incidence of recurrent diarrhoea compared with placebo.