A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile-associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation.

Background: Clostridium difficile-associated diarrhea (CDAD) is common during hematopoietic stem-cell transplantation (HSCT) and is associated with increased morbidity and mortality. We evaluated fidaxomicin for prevention of CDAD in HSCT patients. Methods: In this double-blind study, subjects undergoing HSCT with fluoroquinolone prophylaxis stratified by transplant type (autologous/allogeneic) were randomized to once-daily oral fidaxomicin (200 mg) or a matching placebo. Dosing began within 2 days of starting conditioning or fluoroquinolone prophylaxis and continued until 7 days after neutrophil engraftment or completion of fluoroquinolone prophylaxis/clinically-indicated antimicrobials for up to 40 days. The primary endpoint was CDAD incidence through 30 days after study medication. The primary endpoint analysis counted confirmed CDAD, receipt of CDAD-effective medications (for any indication), and missing CDAD assessment (for any reason, including death) as failures; this composite analysis is referred to as "prophylaxis failure" to distinguish from the pre-specified sensitivity analysis, which counted only confirmed CDAD (by toxin immunoassay or nucleic acid amplification test) as failure. Results: Of 611 subjects enrolled, 600 were treated and analyzed. Prophylaxis failure was similar in fidaxomicin and placebo recipients (28.6% vs 30.8%; difference 2.2% [-5.1, 9.5], P = .278). However, most failures were due to non-CDAD events. Confirmed CDAD was lower in fidaxomicin vs placebo recipients (4.3% vs 10.7%; difference 6.4% [2.2, 10.6], P = .0014). Drug-related adverse events occurred in 15.0% of fidaxomicin recipients and 20.0% of placebo recipients. Conclusions: While no difference was demonstrated between arms in the primary analysis, results of the sensitivity analysis demonstrated that fidaxomicin significantly reduced the incidence of CDAD in HSCT recipients. Clinical Trials Registration: NCT01691248.

Fidaxomicin versus Vancomycin in the Treatment of Clostridium difficile Infection: Canadian Outcomes.

Background. This analysis examined the efficacy of fidaxomicin versus vancomycin in 406 Canadian patients with Clostridium difficile infection (CDI), based on data from 2 randomized, clinical trials. Methods. Patients received fidaxomicin or vancomycin 1. Patients were assessed for clinical response recurrence of infection and sustained clinical response for 28 days after treatment completion. Patients at increased risk of recurrence were subjected to subgroup analyses. Results. Clinical response rates for fidaxomicin (90.0%) were noninferior to those with vancomycin (92.2%; 95% confidence interval for difference: -7.7, 3.5). However, fidaxomicin-treated patients had lower recurrence (14.4% versus 28.0%, p = 0.001) and higher sustained clinical response (77.1% versus 66.3%, p = 0.016). Compared with vancomycin, fidaxomicin was associated with lower recurrence rates in all subgroups, reaching statistical significance in patients with age ≥ 65 years (16.0% versus 30.9%, p = 0.026), concomitant antibiotic use (16.2% versus 38.7%, p = 0.036), and non-BI strains (11.8% versus 28.3%, p = 0.004). Higher sustained clinical response rates were observed for fidaxomicin compared with vancomycin in all subgroups; this was statistically significant in the non-BI subgroup (82.8% versus 69.1%, p = 0.021). Conclusions. In Canadian patients, fidaxomicin was superior to vancomycin in sustaining clinical response and reducing CDI recurrence.

Whole-genome sequencing demonstrates that fidaxomicin is superior to vancomycin for preventing reinfection and relapse of infection with Clostridium difficile.

Whole-genome sequencing was used to determine whether the reductions in recurrence of Clostridium difficile infection observed with fidaxomicin in pivotal phase 3 trials occurred by preventing relapse of the same infection, by preventing reinfection with a new strain, or by preventing both outcomes. Paired isolates of C. difficile were available from 93 of 199 participants with recurrences (28 were treated with fidaxomicin, and 65 were treated with vancomycin). Given C. difficile evolutionary rates, paired samples ≤2 single-nucleotide variants (SNVs) apart were considered relapses, paired samples >10 SNVs apart were considered reinfection, and those 3-10 SNVs apart (or without whole-genome sequences) were considered indeterminate in a competing risks survival analysis. Fidaxomicin reduced the risk of both relapse (competing risks hazard ratio [HR], 0.40 [95% confidence interval {CI}, .25-.66]; P = .0003) and reinfection (competing risks HR, 0.33 [95% CI, 0.11-1.01]; P = .05).

John G. Bartlett: Contributions to the discovery of Clostridium difficile antibiotic-associated diarrhea.

In 1975 John Bartlett began trials investigating the problem of antibiotic-associated diarrhea and pseudomembranous colitis. His work led the discovery of Clostridium difficile and he identified it as the leading cause of hospital-associated infections.

Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America.

A panel of national experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2005 guidelines for the treatment of skin and soft tissue infections (SSTIs). The panel's recommendations were developed to be concordant with the recently published IDSA guidelines for the treatment of methicillin-resistant Staphylococcus aureus infections. The focus of this guideline is the diagnosis and appropriate treatment of diverse SSTIs ranging from minor superficial infections to life-threatening infections such as necrotizing fasciitis. In addition, because of an increasing number of immunocompromised hosts worldwide, the guideline addresses the wide array of SSTIs that occur in this population. These guidelines emphasize the importance of clinical skills in promptly diagnosing SSTIs, identifying the pathogen, and administering effective treatments in a timely fashion.

Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.

A panel of national experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2005 guidelines for the treatment of skin and soft tissue infections (SSTIs). The panel's recommendations were developed to be concordant with the recently published IDSA guidelines for the treatment of methicillin-resistant Staphylococcus aureus infections. The focus of this guideline is the diagnosis and appropriate treatment of diverse SSTIs ranging from minor superficial infections to life-threatening infections such as necrotizing fasciitis. In addition, because of an increasing number of immunocompromised hosts worldwide, the guideline addresses the wide array of SSTIs that occur in this population. These guidelines emphasize the importance of clinical skills in promptly diagnosing SSTIs, identifying the pathogen, and administering effective treatments in a timely fashion.

Renal impairment and clinical outcomes of Clostridium difficile infection in two randomized trials.

BACKGROUND/AIMS: Patients with chronic kidney disease (CKD) have increased risk for Clostridium difficile infection (CDI) and for subsequent mortality. We determined the effect of CKD on response to treatment for CDI. METHODS: This is a post hoc analysis of two randomized controlled phase 3 trials that enrolled patients with CDI. Patients received either fidaxomicin 200 mg b.i.d. or vancomycin 125 mg q.i.d. for 10 days. Univariate and multivariate analyses compared end points by treatment received and CKD stage. RESULTS: At baseline, 27, 21, and 9% of the patients had stage 2 (60-89 ml/min/1.73 m(2)), stage 3 (30-59), and stage 4 or higher (<30) CKD. Cure rates were similar for normal (91%) and stage 2 CKD (92%), but declined to 80% for stage 3 and to 75% for stage 4 CKD (p < 0.001 for trend). Time to resolution of diarrhea (TTROD) increased with stage 3 and stage 4 CKD. CDI recurrence rates 4 weeks after treatment were 16, 20, 27, and 24% for normal, stage 2, stage 3, and stage 4 or higher CKD, respectively. Mortality increased with CKD stage. In multivariate analyses, stage 3 or higher CKD correlated with lower odds of cure, greater chance of recurrence, and lower odds of sustained response 28 days after treatment. Initial cure rates were similar in the vancomycin or fidaxomicin groups; however, the rate of recurrence was higher following vancomycin treatment independent of renal function. The presence of immunosuppression did not alter this effect. CONCLUSION: Progressive CKD is associated with increased TTROD, lower cure rates, and higher recurrence rates with treatment of CDI.

Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin.

Recurrence of Clostridium difficile infection (CDI) occurs in approximately 25% of successfully treated patients. Two phase 3 randomized, double-blind trials were conducted at 154 sites in the United States, Canada, and Europe to compare fidaxomicin vs vancomycin in treating CDI. Patients with CDI received fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times daily for 10 days. The primary end point was clinical cure of CDI at end of treatment, and a secondary end point was recurrence during the 28 days following clinical cure. In all, 1164 subjects were enrolled, of which a subgroup of 128 in the per-protocol population had another recent episode of CDI prior to the CDI diagnosis at study enrollment. In the analysis of this subgroup, initial response to therapy was similar for both drugs (>90% cure). However, recurrence within 28 days occurred in 35.5% of patients treated with vancomycin and 19.7% of patients treated with fidaxomicin (-15.8% difference; 95% confidence interval, -30.4% to -0.3%; P = .045). Early recurrence (within 14 days) was reported in 27% of patients treated with vancomycin and 8% of patients treated with fidaxomicin (P = .003). In patients with a first recurrence of CDI, fidaxomicin was similar to vancomycin in achieving a clinical response at end of therapy but superior in preventing a second recurrence within 28 days.

Renal failure and leukocytosis are predictors of a complicated course of Clostridium difficile infection if measured on day of diagnosis.

Nonsevere Clostridium difficile infection (CDI) and severe CDI, which carries a higher risk than nonsevere CDI for treatment failure and CDI recurrence, are difficult to distinguish at the time of diagnosis. To investigate the prognostic value of 3 markers of severe CDI suggested by recent guidelines (fever, leukocytosis, and renal failure), we used the database of 2 randomized controlled trials, which contained information for 1105 patients with CDI. Leukocytosis (risk ratio [RR], 2.29; 95% confidence interval [CI], 1.63-3.21) and renal failure (RR, 2.52; 95% CI, 1.82-3.50) were associated with treatment failure. Fever, although associated with treatment failure (RR, 2.45; 95% CI, 1.07-5.61), was rare. Renal failure was the only significant predictor of recurrence (RR, 1.45; 95% CI, 1.05-2.02). Different timing of measurements of leukocyte count and serum creatinine level around the CDI diagnosis led to a different severity classification in many cases. In conclusion, both leukocytosis and renal failure are useful predictors, although timing of measurement is important.

Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials.

Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.

Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections.

BACKGROUND: Treatment guidelines recommend stopping all implicated antibiotics at the onset of Clostridium difficile infection (CDI), but many individuals have persistent or new infections necessitating the use of concomitant antibiotics (CAs). We used data from 2 phase 3 trials to study effects of CAs on response to fidaxomicin or vancomycin. METHODS: Subjects with CDI were treated for 10 days with fidaxomicin 200 mg every 12 hours or vancomycin 125 mg every 6 hours, assessed for resolution of symptoms, and followed up for an additional 4 weeks for evidence of recurrence. Rates of cure, recurrence, and global cure (cure without recurrence) were determined for subgroups of subjects defined by CA use and treatment group. RESULTS: CAs were prescribed for 27.5% of subjects during study participation. The use of CAs concurrent with CDI treatment was associated with a lower cure rate (84.4% vs 92.6%; P < .001) and an extended time to resolution of diarrhea (97 vs 54 hours; P < .001). CA use during the follow-up was associated with more recurrences (24.8% vs 17.7%; not significant), and CA administration at any time was associated with a lower global cure rate (65.8% vs 74.7%; P = .005). When subjects received CAs concurrent with CDI treatment, the cure rate was 90.0% for fidaxomicin and 79.4% for vancomycin (P = .04). In subjects receiving CAs during treatment and/or follow-up, treatment with fidaxomicin compared with vancomycin was associated with 12.3% fewer recurrences (16.9% vs 29.2%; P = .048). CONCLUSIONS: Treatment with CAs compromised initial response to CDI therapy and durability of response. Fidaxomicin was significantly more effective than vancomycin in achieving clinical cure in the presence of CA therapy and in preventing recurrence regardless of CA use.

Relationship between essential amino acids and muscle mass, independent of habitual diets, in pre- and post-menopausal US women.

The purpose of this secondary analysis was to examine the relationship between protein and essential amino acids (EAAs) intake with the level of muscle mass (MM) independent of the diet. Twenty-one omnivores, 22 ovo-lacto-vegetarians and 20 vegans were recruited. MM (urinary creatinine), dietary intake (5-day dietary records) and biochemical analyses (urinary and plasma sex hormones) were obtained. We observed no significant difference between groups for MM, total EAA intake, leucine, isoleucine, age and body mass index. However, we observed a significant difference between groups for total dietary protein intake and total energy intake. Despite significant differences in total dietary protein, the EAA intake was not different, indicating that neither the amount nor the quality of protein in these diets was a limiting factor in determining the amount of MM. Thus, each of these diet patterns appears adequate to maintain MM.

Lessons learned from the anaerobe survey: historical perspective and review of the most recent data (2005-2007).

BACKGROUND: The rationale and lessons learned through the evolution of the National Survey for the Susceptibility of Bacteroides fragilis Group from its initiation in 1981 through 2007 are reviewed here. The survey was conceived in 1980 to track emerging antimicrobial resistance in Bacteroides species. METHODS: Data from the last 11 years of the survey (1997-2007), including 6574 isolates from 13 medical centers, were analyzed for in vitro antimicrobial resistance to both frequently used and newly developed anti-anaerobic agents. The minimum inhibitory concentrations of the antibiotics were determined using agar dilution in accordance with Clinical and Laboratory Standards Institute recommendations. RESULTS: The analyses revealed that the carbapenems (imipenem, meropenem, ertapenem, and doripenem) and piperacillin-tazobactam were the most active agents against these pathogens, with resistance rates of 0.9%-2.3%. In the most recent 3 years of the survey (2005-2007), resistance to some agents was shown to depend on the species, such as ampicillin-sulbactam against Bacteroides distasonis (20.6%) and tigecycline against Bacteroides uniformis and Bacteroides eggerthii ( approximately 7%). Very high resistance rates (>50%) were noted for moxifloxacin and trovafloxacin, particularly against Bacteroides vulgatus. During that period of study, non-B. fragilis Bacteroides species had >40% resistance to clindamycin. Metronidazole-resistant Bacteroides strains were also first reported during that period. CONCLUSIONS: In summary, resistance to antibiotics was greater among non-B. fragilis Bacteroides species than among B. fragilis and was especially greater among species with a low frequency of isolation, such as Bacteroides caccae and B. uniformis. The emergence of resistance among the non-B. fragilis Bacteroides species underscores the need for speciation of B. fragilis group isolates and for clinicians to be aware of associations between species and drug resistance.

Risk factors for cardiovascular disease in children infected with human immunodeficiency virus-1.

OBJECTIVE: To determine risk factors for cardiovascular disease (CVD) in children infected with human immunodeficiency virus (HIV) compared with nationally representative controls from 2003-2004 National Health and Nutrition Examination Survey (NHANES) data. STUDY DESIGN: A prospective, longitudinal analysis of CVD risk factors in 42 HIV-infected children compared with NHANES controls, with multivariable modeling of demographic, disease-specific, and treatment-related factors contributing to cardiac risk in the HIV cohort. RESULTS: The 42 children infected with HIV were initially an average of 10.1 years old; 68% were Centers for Disease Control and Prevention pediatric HIV disease stage B or C, and 76% were receiving highly active antiretroviral therapy (HAART). Compared with age- and sex-adjusted NHANES controls, the children infected with HIV had lower weight (-0.46 standard deviation [SD] vs +0.54 SD; P < .001), height (-0.62 SD vs +0.26 SD; P < .001), and body mass index (-0.09 SD vs +0.51 SD; P < .001), a higher level of triglycerides (136 mg/dL vs 90 mg/dL; P < .001), and a lower level of high-density lipoprotein (HDL) cholesterol (47 mg/dL vs 54 mg/dL; P < .001). Protease inhibitor therapy was independently associated with higher triglyceride (P = .02) and low-density lipoprotein cholesterol levels (P = .04) and lower HDL cholesterol level (P = .02); nonnucleoside reverse-transcriptase inhibitor therapy was associated with lower visceral fat (P = .01) and higher HDL cholesterol level (P = .005). CONCLUSIONS: Children infected with HIV have adverse cardiac risk profiles compared with NHANES controls. Antiretroviral therapy has a significant influence on these factors.

Cystatin C and creatinine in an HIV cohort: the nutrition for healthy living study.

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons have an increased risk of chronic kidney disease (CKD). Serum creatinine level may underestimate the prevalence of CKD in subjects with decreased lean body mass or liver disease. Level of serum cystatin C, an alternative kidney function marker, is independent of lean body mass. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 250 HIV-infected subjects on highly active antiretroviral therapy in the Nutrition for Healthy Living (NFHL) cohort; 2,628 National Health and Nutrition Examination Survey (NHANES) 2001-2002 subjects. PREDICTORS & OUTCOMES: Comparison of serum creatinine levels in NFHL to those in NHANES subjects; comparison of CKD in NFHL subjects ascertained using serum creatinine versus cystatin C levels. MEASUREMENTS: Standardized serum creatinine, serum cystatin C, glomerular filtration rate (GFR) estimated from serum creatinine and cystatin C levels. RESULTS: Creatinine levels were lower in NFHL than NHANES subjects despite greater rates of hepatitis, diabetes, and drug use (mean difference, -0.18 mg/dL; P < 0.001 adjusted for age, sex, and race). Of NFHL subjects, only 2.4% had a creatinine-based estimated GFR less than 60 mL/min/1.73 m(2), but 15.2% had a cystatin-based estimated GFR less than 60 mL/min/1.73 m(2). LIMITATIONS: GFR was estimated rather than measured. Other factors in addition to GFR may affect creatinine and cystatin C levels. Measurements of proteinuria were not available. CONCLUSIONS: Serum creatinine levels may overestimate GFRs in HIV-infected subjects. Kidney disease prevalence may be greater than previously appreciated.

Drug use and other risk factors related to lower body mass index among HIV-infected individuals.

Malnutrition is associated with morbidity and mortality in HIV-infected individuals. Little research has been conducted to identify the roles that clinical, illicit drug use and socioeconomic characteristics play in the nutritional status of HIV-infected patients. This cross-sectional analysis included 562 HIV-infected participants enrolled in the Nutrition for Healthy Living study conducted in Boston, MA and Providence, RI. The relationship between body mass index (BMI) and several covariates (type of drug use, demographic, and clinical characteristics) were examined using linear regression. Overall, drug users had a lower BMI than non-drug users. The BMI of cocaine users was 1.4 kg/m(2) less than that of patients who did not use any drugs, after adjusting for other covariates (p=0.02). The BMI of participants who were over the age of 55 years was 2.0 kg/m(2) less than that of patients under the age of 35, and BMI increased by 0.3 kg/m(2) with each 100 cells/mm(3) increase in CD4 count. HAART use, adherence to HAART, energy intake, AIDS status, hepatitis B and hepatitis C co-infections, cigarette smoking and depression were not associated with BMI in the final model. In conclusion, BMI was lower in drug users than non-drug users, and was lowest in cocaine users. BMI was also directly associated with CD4 count and inversely related to age more than 55 years old. HIV-infected cocaine users may be at higher risk of developing malnutrition, suggesting the need for anticipatory nutritional support.

Probiotics for prevention of antibiotic-associated diarrhea.

Antibiotic-associated diarrhea (AAD) occurs in approximately 25% of patients receiving antibiotics. Hospitalized patients with AAD are at increased risk for nosocomial infections and have a higher mortality. Probiotics are living microorganisms used to restore gut health by changing the intestinal microbiota. Several have been studied for the prevention of AAD. Five meta-analyses of trials of probiotics for the prevention of AAD have been performed. The results showed an overall reduction in the risk of AAD when probiotics were coadministered with antibiotics. McFarland conducted the largest meta-analysis to date analyzing 25 randomized controlled trials of probiotics for the prevention of AAD including 2810 subjects. More than half of the trials demonstrated efficacy of the probiotic. In particular, Lactobacillus GG, Saccharomyces boulardii, and the probiotic mixtures were effective. The Cochrane Database of Systematic Reviews published a review of the literature on the use of probiotics for the prevention of pediatric AAD, including 10 randomized trials testing 1986 children. The per protocol pooled analysis, but not the intent-to-treat analysis, showed that probiotics are effective for preventing AAD with the number needed to treat to prevent 1 case of diarrhea being 10. Lactobacillus GG, Bacillus coagulans, and S. boulardii appeared to be most effective. Probiotics are generally safe, however, they should be used with caution in patients who have compromise of either the immune system or the integrity of the intestinal mucosa, and in the presence of a central venous catheter.

Estimated net acid excretion inversely correlates with urine pH in vegans, lacto-ovo vegetarians, and omnivores.

OBJECTIVE: Diet affects urine pH and acid-base balance. Both excess acid/alkaline ash (EAA) and estimated net acid excretion (NAE) calculations have been used to estimate the effects of diet on urine pH. This study's goal was to determine if free-living vegans, lacto-ovo vegetarians, and omnivores have increasingly acidic urine, and to assess the ability of EAA and estimated NAE calculations to predict urine pH. DESIGN: This study used a cross-sectional design. SETTING AND PARTICIPANTS: This study assessed urine samples of 10 vegan, 16 lacto-ovo vegetarian, and 16 healthy omnivorous women in the Boston metropolitan area. Six 3-day food records from each dietary group were analyzed for EAA content and estimated NAE, and correlations with measured urine pH were calculated. RESULTS: The mean (+/- SD) urine pH was 6.15 +/- 0.40 for vegans, 5.90 +/- 0.36 for lacto-ovo vegetarians, and 5.74 +/- 0.21 for omnivores (analysis of variance, P = .013). Calculated EAA values were not significantly different among the three groups, whereas mean estimated NAE values were significantly different: 17.3 +/- 14.5 mEq/day for vegans, 31.3 +/- 8.5 mEq/day for lacto-ovo vegetarians, and 42.6 +/- 13.2 mEq/day for omnivores (analysis of variance, P = .01). The average deattenuated correlation between urine pH and EAA was 0.333; this value was -0.768 for estimated NAE and urine pH, with a regression equation of pH = 6.33 - 0.014 NAE (P = .02, r = -0.54). CONCLUSIONS: Habitual diet and estimated NAE calculations indicate the probable ranking of urine pH by dietary groups, and may be used to determine the likely acid-base status of an individual; EAA calculations were not predictive of urine pH.