Dhara N. Shah

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 Horns 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.

Clostridium difficile infection: update on emerging antibiotic treatment options and antibiotic resistance

Clostridium difficile infection (CDI) is the most common cause of identifiable diarrhea in hospitalized patients. The incidence and severity of CDIs are increasing. The increased incidence and severity of the disease has sparked interest in the optimal treatment of CDI as well as the use of new therapies and drug discovery. Current treatment strategies are inadequate with decreased response rates to metronidazole, and high recurrence rates with the use of metronidazole and oral vancomycin. Although incidence rates continue to be low, in vitro resistance to antibiotics used for the treatment of CDI has been noted. Recently, important data has emerged on new anti-C. difficile antibiotics such as rifaximin, rifalazil, fidaxomicin, nitazoxanide, tigecycline and ramoplanin. The purpose of this review is to provide an update on the in vitro susceptibility and new antibiotic treatment options for CDI. This review will focus primarily on scientific studies published in the last 36 months in order to provide an up-to-date review on the topic.

Evaluation of antifungal therapy in patients with candidaemia based on susceptibility testing results: implications for antimicrobial stewardship programmes

BACKGROUND Definitive antifungal therapy is typically based on Candida species and clinical status, rather than susceptibility reports. Antifungal susceptibility testing is available, but the impact on treatment decisions is unknown. The purpose of this study was to assess antifungal therapy in hospitalized patients with candidaemia during the time period between the start of empirical therapy and after antifungal susceptibility testing reports are available. METHODS A retrospective study of 161 hospitalized patients with candidaemia was conducted. Patients who received fluconazole or an echinocandin were evaluated for changes in empirical antifungal therapy prior to and after susceptibility reporting. RESULTS One hundred and sixty-one patients aged 59 ± 16 years (male, 54%; Caucasian, 52%; APACHE II score ≥ 15, 48%; and intensive care unit, 50%) were identified, of whom 130 (81%) had fluconazole-susceptible candidaemia. Fifty-eight patients (36%) were initiated on fluconazole and 103 (64%) on an echinocandin. The mean time from culture to the susceptibility report was 5 ± 2 days. Prior to availability of the susceptibility report, 20 fluconazole-initiated patients (34%) were switched to an echinocandin, while 14 echinocandin-initiated patients (14%) were switched to fluconazole. Once a susceptibility report was available, 35 of 89 (39%) patients with fluconazole-susceptible candidaemia on an echinocandin were de-escalated to fluconazole. Eleven patients on fluconazole just prior to a susceptibility report were identified with a fluconazole-resistant Candida species. CONCLUSIONS Using antifungal susceptibility testing, patients given fluconazole with fluconazole-resistant Candida species were identified. Less than 40% of echinocandin-treated patients with fluconazole-susceptible organisms were de-escalated to fluconazole. Antifungal susceptibility testing may help to identify patients in need of clinical intervention.

Rifamycin Antibiotics for Treatment of Clostridium difficile–Associated Diarrhea

Objective: To review the existing data on use of the rifamycin class of antibiotics as therapy for Clostridium difficile–associated diarrhea (CDAD). Data Sources: A literature search was performed using PubMed (1996–January 2008), abstracts from the International Conference on Antimicrobial Agents and Chemotherapy (September 2007), the Infectious Diseases Society of America (October 2007), Salix Pharmaceuticals Web site (January 2008), ActivBiotics Web site (January 2008). Google Scholar, and searches of selected bibliographies using the terms rifamycin, ansamycins, rifampin, rifabutin, rifampicin, rifaximin, rifalazil, Clostridium difficile, C. difficile, and CDAD. Study Selection and Data Extraction: In vivo and in vitro studies investigating the use of rifamycins for CDAD were selected, along with all clinical trials using rifamycins in patients with CDAD. Data Synthesis: Nine studies totaling 890 isolates were identified that investigated the in vitro susceptibility of rifampin (6 studies), rifaximin (3 studies), and rifalazil (2 studies). Rifamycins consistently displayed potent activity against tested strains, although strains with decreased susceptibility have been identified. Six published clinical studies involving 81 patients have investigated the use of rifamycins for the treatment of CDAD. These have generally been small studies, although initial positive clinical results have been reported on the use of rifamycins for recurrent CDAD. Conclusions: Preliminary data support the use of rifamycins for treatment of CDAD. With the increased incidence and severity of CDAD, further investigation into this drug class as a treatment regimen for CDAD is warranted.

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.

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.

Impact of Prior Inappropriate Fluconazole Dosing on Isolation of Fluconazole-Nonsusceptible Candida Species in Hospitalized Patients with Candidemia

ABSTRACT 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.

Assessment of treatment patterns and patient outcomes before vs after implementation of a severity-based Clostridium difficile infection treatment policy

BACKGROUND National guidelines recommend oral vancomycin for severe Clostridium difficile infection (CDI) based on results from recent clinical trials demonstrating improved clinical outcomes. However, real-world data to support these clinical trials are scant. AIM To compare treatment patterns and patient outcomes of those treated for CDI before and after implementation of a severity-based CDI treatment policy at a tertiary teaching hospital. METHODS This study evaluated adult patients with a positive C. difficile toxin before and after implementation of a policy where patients with severe CDI given metronidazole were switched to oral vancomycin unless contra-indicated. Patients were stratified according to disease severity using a modified published severity score. Treatment patterns based on CDI severity and rates of refractory CDI were assessed. FINDINGS In total, 256 patients with CDI (mean age 66 years, standard deviation 17, 52% female) were evaluated (before implementation: N = 144; after implementation: N = 112). Use of oral vancomycin for severe CDI increased significantly from 14% (N = 8) to 91% (N = 48) following implementation of the policy (P < 0.0001). Refractory disease in patients with severe CDI decreased significantly from 37% to 15% following implementation of the policy (P = 0.035). No significant differences were noted among patients with mild to moderate CDI. CONCLUSION A severity-based CDI treatment policy at a tertiary teaching hospital increased the use of oral vancomycin and was associated with decreased rates of refractory CDI.

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.

A Real‐World Evaluation of Oral Vancomycin for Severe Clostridium difficile Infection: Implications for Antibiotic Stewardship Programs

To assess antibiotic treatment patterns and clinical outcomes of patients with Clostridium difficile infection (CDI) based on underlying severity of CDI disease.