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.

Impact of a division-wide bundle on hospital-acquired Clostridioides difficile cases, antibiotic days of therapy, testing appropriateness, and associated financial costs.

INTRODUCTION: Updated international guidelines recommend the use of a two-step algorithm (glutamate dehydrogenase [GDH] or nucleic-acid amplification test [NAAT] plus toxin) rather than NAAT alone for the diagnosis of Clostridioides difficile (formerly Clostridium difficile) infections. The goal of our project was to evaluate the impact of a new bundle on the rate of hospital-acquired C. difficile infections (CDIs), hospital-acquired CDI standardized infection ratio (SIR), antibiotic days of therapy (DOT), and financial cost. MATERIALS AND METHODS: The new bundle was implemented in April 2018. This bundle was implemented across five hospitals in Catholic Health Initiatives (CHI) Texas Division. The bundle included a switch from NAAT to a two-step process (GDH and toxin). We placed the new test in an order panel which included enteric isolation and required indications for C. difficile testing. We used quarterly data pre- and post-intervention to calculate SIR and DOT. RESULTS: In the pre-intervention period, 15.5% of the total 3513 C. difficile NAAT was positive. In the post-intervention period, 5.7% of a total of 2845 GDH and toxin assays was positive for both GDH and toxin (P < 0.0001). SIR, which adjusts for denominator and change in testing methodology, also dropped from 1.02 to 0.43. The estimated cost associated with positive C. difficile cases dropped from 1,932,150 USD to 1,113,800 USD with an estimated yearly cost saving of 794,150 USD. Compliance with enteric isolation improved from 73.1% to 92.5% (P = 0.008). CONCLUSION: The new testing bundle led to a marked reduction in hospital-acquired CDI and unnecessary treatment, reduction in C. difficile testing, an increase in compliance with enteric isolation, and significant cost savings.

Noroviruses as a cause of diarrhea in travelers to Guatemala, India, and Mexico.

Noroviruses (NoVs) are increasingly being recognized as an important enteric pathogen of gastroenteritis worldwide. The prevalence of NoVs as a cause of diarrhea acquired by travelers in developing countries is not well known. We examined the prevalence and importance of NoV infection in three international traveler cohorts with diarrhea acquired in three developing regions of the world, Mexico, Guatemala, and India. We also characterized the demographics and symptoms associated with NoV diarrhea in these travelers. Stool samples from 571 international travelers with diarrhea were evaluated for traditional enteropathogens. NoVs were identified using reverse transcription-PCR and probe hybridization. NoVs were identified in 10.2% of cases of travelers' diarrhea and, overall, was the second most common pathogen, following diarrheagenic Escherichia coli. The detection of NoV diarrhea significantly varied over the three study time periods in Guadalajara, Mexico, ranging from 3 of 98 (3.0%) diarrheal stools to 12 of 100 (12.0%) fecal specimens (P=0.03). The frequency of NoV diarrhea was also dependent upon the geographic region, with 17 of 100 (17.0%) travelers to Guatemala, 23 of 194 (11.9%) travelers to India, and 3 of 79 (3.8%) travelers to Mexico testing positive for NoVs from 2002 to 2003 (P=0.02). NoVs are important pathogens of travelers' diarrhea in multiple regions of the world. Significant variation in the prevalence of NoV diarrhea and in the predominant genogroup infecting travelers was demonstrated, dependent upon the specific geographic location and over time.

Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases.

PURPOSE OF REVIEW: Rifaximin is gaining attention for its potential activity in a multitude of gastrointestinal diseases. We review the unique pharmaceutical properties of this antibiotic and the published evidence in the literature regarding the use of rifaximin for different gastrointestinal disorders. RECENT FINDINGS: Rifaximin is a gastrointestinal-selective antibiotic with a broad spectrum of antimicrobial activity, an excellent safety profile, minimal drug interactions, and negligible impact on the intestinal microbiome. Rifaximin is currently approved in the United States for the treatment of travelers' diarrhea caused by noninvasive diarrheagenic Escherichia coli and is approved in more than 30 other countries for a variety of gastrointestinal disorders. Considerable research with this medication has been conducted for the treatment and prevention of travelers' diarrhea, the treatment of portal systemic encephalopathy, Clostridium difficile infection, small bowel intestinal overgrowth, irritable bowel syndrome, inflammatory bowel disease, pouchitis, and colonic diverticular disease. SUMMARY: Rifaximin is effective for the treatment of travelers' diarrhea and can be considered as the treatment of choice for uncomplicated travelers' diarrhea. When invasive travelers' diarrhea pathogens are suspected, an alternative antibiotic should be administered. Rifaximin appears promising as a chemoprophylaxis for travelers' diarrhea and as a treatment of portal systemic encephalopathy. This antibiotic may be effective for other gastrointestinal diseases, but more well designed clinical studies are needed to confirm its efficacy for these off-label indications. Future studies will determine whether the development of significant bacterial resistance will limit rifaximin use.

Antimotility agents for the treatment of Clostridium difficile diarrhea and colitis.

Antimotility agent use for the treatment of Clostridium difficile infection (CDI) is discouraged. We reviewed the literature and unpublished postmarketing surveillance reports regarding antimotility treatment of CDI. Twenty reports met inclusion criteria, describing 55 patients with CDI who were exposed to antimotility agents. All studies were case reports or series, with the exception of 1 retrospective review. Nineteen patients (35%) improved, with clinical resolution. Nine patients (16%) died, and 27 patients (49%) had unknown outcomes. Seventeen patients (31%) with CDI developed colonic dilation; 5 of these patients with severe CDI died. However, all patients who experienced complications or died were given antimotility agents alone initially, without an appropriate antibiotic. Twenty-three patients who received metronidazole or vancomycin coadministered with the antimotility agent experienced no complications. Evidence supporting the hypothesis that worsened outcomes are associated with antimotility therapy of CDI is lacking. Further study of the role of antimotility agents in providing symptomatic relief and reducing environmental contamination with infectious stool may be warranted.

A nosocomial outbreak of norovirus infection masquerading as clostridium difficile infection.

Noroviruses (NoVs) are increasingly being recognized as important enteric pathogens. At a university-based hospital, we investigated a nosocomial outbreak of NoV infection that was originally attributed to Clostridium difficile. We describe here the unique challenges of the identification of NoVs as the true etiologic pathogen in an outbreak occurring in a health care setting, where C. difficile infection is endemic, as well as the important lessons learned.

Coliform contamination of vegetables obtained from popular restaurants in Guadalajara, Mexico, and Houston, Texas.

Food is the primary vehicle of transmission for traveler's diarrhea. We evaluated coliform contamination of vegetables from popular restaurants in Guadalajara, Mexico, and Houston, Texas. Contamination of vegetables in Guadalajara restaurants was widespread. Prevention of traveler's diarrhea by avoidance of "high-risk" foods may be unsuccessful, because contamination of foods may occur regardless of how they are prepared.

Drug-drug interaction between itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis.

Although there is a presumed drug-drug interaction between itraconazole and nonnucleoside reverse-transcriptase inhibitors, the medical literature lacks such documentation. We describe a drug-drug interaction between itraconazole and efavirenz in a patient with disseminated histoplasmosis and acquired immunodeficiency syndrome (AIDS). The drug combination resulted in persistently elevated urinary Histoplasma antigen levels and subtherapeutic plasma itraconazole concentrations. Changing treatment from efavirenz to a protease inhibitor was accompanied by improvements in the desired urinary Histoplasma antigen level and plasma itraconazole concentration.

Real-world performance of a microarray-based rapid diagnostic for Gram-positive bloodstream infections and potential utility for antimicrobial stewardship.

The Verigene Gram-positive blood culture assay (BC-GP) is a microarray-based rapid diagnostic test, which includes targets for 12 bacterial species and 3 resistance determinants. We prospectively compared the diagnostic accuracy of the BC-GP to routine microbiologic methods and evaluated the potential of the BC-GP for antimicrobial stewardship programs. A total of 143 consecutive patients with Gram-positive bacteremia were included in the analysis. BC-GP correctly identified 127/128 (99.2%) of organisms from monomicrobial blood cultures and 9/14 (64.3%) from polymicrobial, including all methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Stewardship interventions were possible in 51.0% of patients, most commonly stopping or preventing unnecessary vancomycin or starting a targeted therapy. In Monte Carlo simulations, unnecessary antibiotics could be stopped at least 24 hours earlier in 65.6% of cases, and targeted therapy could be started at least 24 hours earlier in 81.2%. BC-GP is a potentially useful test for antibiotic stewardship in patients with Gram-positive bacteremia.

Echinocandin use in hospitalized patients: a multi-institutional study.

BACKGROUND: The echinocandin antifungals are recommended as initial therapy in hospitalized patients with candidemia. Contemporary usage rates and indication for use of echinocandins have not been studied in the United States. The purpose of this study was to evaluate echinocandin usage patterns in community and academic teaching hospitals over time and to evaluate dose, duration of therapy and indications for use. METHODS: This study used hospital pharmacy databases from academic and community hospitals to collect information on adult inpatients given systemic antifungal agents from 2008 to 2012. Patient medical information was also obtained from randomly selected patients given an echinocandin over the same time period. RESULTS: Echinocandin use was determined for 4 academic and 34 community hospitals. A significant increase in echinocandin use was observed in academic and community hospitals during the time period (P < 0.001). Two hundred forty-two randomly selected patients receiving an echinocandin were retrospectively reviewed. Indications for echinocandin use did not change during the time period and included empiric therapy in a high-risk patient without subsequent mycologic confirmation from a normally sterile site (55%), systemic candidiasis (43%) and prophylactic (2%). Fifty-six percent of patients had at least 1 anatomic site of mycologic growth; most commonly urine only (14%), respiratory only (12%) or blood only (7%). In patients with candidemia, the hospital treatment course with an echinocandin averaged 8.4 ± 7.9 days (range, 1-35 days). CONCLUSIONS: This study provides useful benchmark data on antifungal use and indications for use that could be used for antifungal stewardship program comparisons.

A hospital-based study of the clinical characteristics of Clostridium difficile infection in children.

BACKGROUND: Clostridium difficile infection (CDI) is an increasingly important cause of morbidity in hospitalized children. We describe the recent epidemiology of pediatric CDI at a children's hospital, compare community-associated (CA) and hospital-associated (HA) infections and identify risk factors for severe disease. METHODS: Children with CDI at Texas Children's Hospital were identified from February 1, 2011, to October 31, 2011. Severe CDI was defined as the presence of a CDI-related complication or ≥2 clinical features: fever, bloody stools, leukocytosis, hypoalbuminemia or elevated creatinine. Standard epidemiologic definitions were used. RESULTS: One-hundred and nine unique patients 1-21 years of age with CDI were identified throughout the study period. The proportions of CA-CDI (41%) and HA-CDI (46%) were similar, whereas community-onset indeterminate CDI (13%) was less common. Children with malignancy or solid organ transplantation were more likely to have HA-CDI. Conversely, all children with inflammatory bowel disease had CA-CDI. Twenty-three patients (21%) met criteria for severe disease and 8 experienced a CDI-related complication, including 1 death attributable to CDI. On multivariate analysis, the presence of a gastrostomy tube (adjusted odds ratio: 3.09; 95% confidence interval: 1.07-8.94) and having community-onset indeterminate disease (adjusted odds ratio: 4.62; 95% confidence interval: 1.28-16.67) were found to be associated with severe CDI. CONCLUSIONS: A substantial proportion of pediatric CDI is CA and there are clinical differences between children with CA-CDI and HA-CDI. Children with CDI frequently experience severe disease, whereas complications are uncommon. Early identification and treatment of CDI should be pursued in children with gastrostomy tube and recent hospitalization.

Colonic immunopathogenesis of Clostridium difficile infections.

There are major gaps in our understanding of the immunopathogenesis of Clostridium difficile infections (CDIs). In this study, 36 different biomarkers were examined in the stools of CDI and non-CDI patients using the Proteome Profiler human cytokine array assay and quantitative enzyme-linked immunosorbent assay. Diarrheal stools from patients with CDI (CDI-positive diarrheal stools) showed higher relative amounts of the following inflammatory markers than the diarrheal stools from CDI-negative patients (CDI-negative diarrheal stools): C5a, CD40L, granulocyte colony-stimulating factor, I-309, interleukin-13 (IL-13), IL-16, IL-27, monocyte chemoattractant protein 1, tumor necrosis factor alpha, and IL-8. IL-8 and IL-23 were present in a larger number of CDI-positive diarrheal stools than CDI-negative diarrheal stools. Th1 and Th2 cytokines were not significantly different between the CDI-positive and CDI-negative diarrheal stools. Lactoferrin and calprotectin concentrations were also higher in the CDI-positive diarrheal stools. Our results demonstrate that CDI elicits a proinflammatory host response, and we report for the first time that IL-23 is a major marker in CDI-positive diarrheal stools. IL-23 may explain the lack of a robust immunological response exhibited by a proportion of CDI patients and may relate to recurrence; the IL-23 levels induced during CDI in these patients may be inadequate to sustain the cellular immunity conferred by this cytokine in promoting the induction and proliferation of effector memory T cells.

Real-time polymerase chain reaction detection of asymptomatic Clostridium difficile colonization and rising C. difficile-associated disease rates.

OBJECTIVE: To evaluate the accuracy of real-time polymerase chain reaction (PCR) for Clostridium difficile-associated disease (CDAD) detection, after hospital CDAD rates significantly increased following real-time PCR initiation for CDAD diagnosis. DESIGN: Hospital-wide surveillance study following examination of CDAD incidence density rates by interrupted time series design. SETTING: Large university-based hospital. PARTICIPANTS: Hospitalized adult patients. METHODS: CDAD rates were compared before and after real-time PCR implementation in a university hospital and in the absence of physician and infection control practice changes. After real-time PCR introduction, all hospitalized adult patients were screened for C. difficile by testing a fecal specimen by real-time PCR, toxin enzyme-linked immunosorbent assay, and toxigenic culture. RESULTS: CDAD hospital rates significantly increased after changing from cell culture cytotoxicity assay to a real-time PCR assay. One hundred ninety-nine hospitalized subjects were enrolled, and 101 fecal specimens were collected. C. difficile was detected in 18 subjects (18%), including 5 subjects (28%) with either definite or probable CDAD and 13 patients (72%) with asymptomatic C. difficile colonization. CONCLUSIONS: The majority of healthcare-associated diarrhea is not attributable to CDAD, and the prevalence of asymptomatic C. difficile colonization exceeds CDAD rates in healthcare facilities. PCR detection of asymptomatic C. difficile colonization among patients with non-CDAD diarrhea may be contributing to rising CDAD rates and a significant number of CDAD false positives. PCR may be useful for CDAD screening, but further study is needed to guide interpretation of PCR detection of C. difficile and the value of confirmatory tests. A gold standard CDAD diagnostic assay is needed.

Noroviruses: The Most Common Pediatric Viral Enteric Pathogen at a Large University Hospital After Introduction of Rotavirus Vaccination.

We conducted an 8.5-year study examining enteric viruses at Texas Children's Hospital (TCH) before and after rotavirus vaccine introduction. Norovirus prevalence was 10.9%. Rotavirus prevalence decreased 64% after vaccine licensure. Noroviruses are the most common TCH enteropathogen and will likely eclipse rotaviruses as the most important US pediatric gastroenteritis pathogen.

Paradoxical immune reconstitution inflammatory syndrome due to toxoplasmic encephalitis: two cases and review of initiation of antiretroviral timing in toxoplasmic encephalitis IRIS.

Toxoplasma encephalitis immune reconstitution inflammatory syndrome (TE-IRIS) is rare and usually occurs in an unmasking, rather than paradoxical form. To the best of our knowledge, only two cases of paradoxical TE-IRIS and nine cases of unmasking TE-IRIS have been previously described. We present two additional cases of histopathology-consistent paradoxical TE-IRIS, after early initiation of antiretroviral therapy (ART), and review the literature on TE-IRIS. Three of the four reported cases of paradoxical TE-IRIS were associated with early (within one week) initiation of ART, an issue that was not addressed in the 2009 US Department of Health and Human Services guidelines for the treatment of opportunistic infections.

Rifaximin therapy of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal pain and altered bowel habits in the absence of specific organic pathology. Although the underlying pathogenesis of IBS is not well-understood, small intestinal bacterial overgrowth (SIBO) or other abnormalities in the gut flora is believed to contribute to the development of a subset of IBS cases. Rifaximin is a poorly absorbed antimicrobial with activity against enteric pathogens. A number of studies have shown a significant improvement in IBS symptoms with antibiotic therapy including rifaximin. In this review, we discuss the pharmacokinetics, in vitro susceptibility profile, and efficacy and safety data from clinical trials of rifaximin treatment of IBS.

Clostridium difficile: an emerging pathogen in children.

Clostridium difficile is emerging as an important enteric pathogen in children. Historically considered as an asymptomatic colonizer of the gastrointestinal tract, C. difficile infection (CDI) has not been well-studied in pediatric populations. While asymptomatic carriage remains high among infants, recent epidemiological surveillance has demonstrated a rise in the prevalence of CDI in both healthcare and community settings, particularly in children 1-5 years of age. The pathogenesis of pediatric CDI, including the factors underlying the absence of toxin-mediated effects among colonized infants, remains ill-defined. Studies suggest that traditional adult CDI risk factors such as antibiotic and healthcare exposure may not be as important for children who acquire CDI in the community. As recognition of the significant impact of CDI in children increases, the pressing need for deepening our understanding of this disease and identifying optimal therapeutic and preventative strategies is becoming apparent.

Norovirus gastroenteritis successfully treated with nitazoxanide.

Infectious diarrhea is a common occurrence in the immunosuppressed population. We present a 43-year-old individual with large-volume stool output Norovirus acute gastroenteritis in the setting of relapsed refractory acute myelogenous leukemia, hematopoietic stem cell transplantation, and biopsy-proven cutaneous and pulmonary graft-versus-host disease. Therapeutic options such as intravenous immunoglobulin or reduction of immunosuppressants were not a feasible choice. A prompt clinical cure was achieved with nitazoxanide, a broad-spectrum antimicrobial agent. Nitazoxanide may be a safe therapeutic alternative, in which a reduction in immunosuppression may not be a viable option.