Arnold Lentnek

Fidaxomicin versus Vancomycin for Clostridium difficile Infection

BACKGROUND Clostridium difficile infection is a serious diarrheal illness associated with substantial morbidity and mortality. Patients generally have a response to oral vancomycin or metronidazole; however, the rate of recurrence is high. This phase 3 clinical trial compared the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection. METHODS Adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test were eligible for study entry. We randomly assigned patients to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence). RESULTS A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non–North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies. CONCLUSIONS The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non–North American Pulsed Field type 1 strains. (Funded by Optimer Pharmaceuticals; ClinicalTrials.gov number, NCT00314951.)

Inhibition of Granulocyte Adherence by Ethanol, Prednisone, and Aspirin, Measured with an Assay System

Abstract A simple, rapid, in vitro assay was developed to study granulocyte adherence, an important component of the inflammatory reaction. Heparinized whole blood is filtered through nylon fiber packed in Pasteur pipettes, and the percentage of granulocytes adhering is calculated. Test variability from morning to evening, before and after meals, and on successive days is less than 10 per cent. In vitro exposure of whole blood to ethanol concentrations varying from 100 to 1000 mg per 100 ml caused a dose-dependent, significant inhibition of adherence (16–87 per cent, p<0.05), but incubation with sodium salicylate (5 to 50 mg per 100 ml) or hydrocortisone sodium succinate (500 to 3000 μg per 100 ml) had no effect. In all volunteers receiving 40 mg of prednisone or 1.2 g of aspirin, impaired adherence developed, suggesting that glucocorticoids and salicylates may affect adherence in vivo by inducing an inhibitor. The anti-inflammatory effect of salicylates, hydrocortisone and ethanol may be secondary to the...

Telavancin Versus Vancomycin for the Treatment of Complicated Skin and Skin-Structure Infections Caused by Gram-Positive Organisms

BACKGROUND Telavancin is an investigational, rapidly bactericidal lipoglycopeptide with a multifunctional mechanism of action. METHODS We conducted 2 parallel, randomized, double-blind, active-control, phase 3 studies with a prespecified pooled analysis design. Patients aged > or = 18 years who had complicated skin and skin-structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin (10 mg/kg intravenously every 24 h) or vancomycin (1 g intravenously every 12 h). RESULTS A total of 1867 patients were randomized and received > or = 1 dose of study medication. In the clinically evaluable population, at 7-14 days after receipt of the last antibiotic dose, success was achieved in 88% and 87% of patients who received telavancin and vancomycin, respectively (95% confidence interval for the difference, -2.1 to 4.6). Methicillin-resistant Staphylococcus aureus was isolated at baseline from samples from 579 clinically evaluable patients. Among these patients with methicillin-resistant S. aureus infection, cure rates were 91% among patients who received telavancin and 86% among patients who received vancomycin (95% confidence interval for the difference, -1.1 to 9.3). Microbiologic eradication among patients infected with methicillin-resistant S. aureus was 90% in the telavancin treatment group and 85% in the vancomycin treatment group (95% confidence interval for the difference, -0.9 to 9.8). Therapy was discontinued because of adverse events in 8% and 6% of patients who received telavancin and vancomycin, respectively. Except for mild taste disturbance, nausea, vomiting, and serum creatinine concentration elevation in the telavancin treatment group and pruritus in the vancomycin treatment group, adverse events were similar between groups with regard to type and severity. CONCLUSIONS Telavancin given once daily is at least as effective as vancomycin for the treatment of patients with complicated skin and skin-structure infections, including those infected with methicillin-resistant S. aureus.

Telavancin versus Vancomycin for Hospital-Acquired Pneumonia due to Gram-positive Pathogens

The results from two methodologically identical double-blind studies indicate that telavancin is noninferior to vancomycin based on clinical response in the treatment of hospital-acquired pneumonia due to Gram-positive pathogens.

Efficacy and Safety of Weekly Dalbavancin Therapy for Catheter-Related Bloodstream Infection Caused by Gram-Positive Pathogens

BACKGROUND Catheter-related bloodstream infections (CR-BSIs) are associated with substantial mortality, prolongation of hospital stay, and increased cost of care. Dalbavancin, a new glycopeptide antibiotic with unique pharmacokinetic properties that have allowed clinical development of a weekly dosing regimen, possesses excellent activity against clinically important gram-positive bacteria, suggesting utility in the treatment of patients with CR-BSIs. METHODS A phase 2, open-label, randomized, controlled, multicenter study of 75 adult patients with CR-BSIs compared treatment with intravenous dalbavancin, administered as a single 1000-mg dose followed by a 500-mg dose 1 week later, with intravenous vancomycin, administered twice daily for 14 days. Gram-positive bacteria isolated in this study included coagulase-negative staphylococci (CoNS) and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). RESULTS Infected patients who received weekly dalbavancin (n=33) had an overall success rate (87.0%; 95% confidence interval [CI], 73.2%-100.0%) that was significantly higher than that of those who received vancomycin (n=34) (50.0%; 95% CI, 31.5%-68.5%). Adverse events and laboratory abnormalities were generally mild and were comparable for the 2 drugs. CONCLUSIONS Dalbavancin thus appears to be an effective and well-tolerated treatment option for adult patients with CR-BSIs caused by CoNS and S. aureus, including MRSA.

Efficacy of Fidaxomicin Versus Vancomycin as Therapy for Clostridium difficile Infection in Individuals Taking Concomitant Antibiotics for Other Concurrent Infections

Concomitant antibiotic (CA) use compromised initial response to Clostridium difficile infection therapy and durability of that response. Fidaxomicin was significantly more effective than vancomycin in achieving clinical cure in the presence of CAs and preventing recurrence regardless of CA use.

Derivation and validation of a simple clinical bedside score (ATLAS) for Clostridium difficile infection which predicts response to therapy

BackgroundClostridium difficile infection (CDI) continues to be a frequent and potentially severe infection. There is currently no validated clinical tool for use at the time of CDI diagnosis to categorize patients in order to predict response to therapy.MethodsSix clinical and laboratory variables, measured at the time of CDI diagnosis, were combined in order to assess their correlation with treatment response in a large CDI clinical trial database (derivation cohort). The final categorization scheme was chosen in order to maximize the number of categories (discrimination) while maintaining a high correlation with clinical cure assessed two days after the end of therapy. Validation of the derived scoring scheme was done on a second large CDI clinical trial database (validation cohort). A third comparison was done on the two pooled databases (pooled cohort).ResultsIn the derivation cohort, the best discrimination and correlation with cure was seen with a five-component ATLAS score (age, treatment with systemic antibiotics, leukocyte count, albumin and serum creatinine as a measure of renal function), which divided CDI patients into 11 groups (scores of 0 to 10 inclusive) and was highly correlated with treatment outcome (R2=0.95; P<0.001). This scheme showed excellent prediction of cure in the validation cohort (overall Kappa=95.2%; P<0.0001), as well as in the pooled cohort, regardless of treatment (fidaxomicin or vancomycin).ConclusionsA combination of five simple and commonly available clinical and laboratory variables measured at the time of CDI diagnosis, combined into a scoring system (ATLAS), are able to accurately predict treatment response to CDI therapy. The ATLAS scoring system may be useful in stratifying CDI patients so that appropriate therapies can be chosen to maximize cure rates, as well as for categorization of patients in CDI therapeutic studies in order allow comparisons of patient groups.

Effect of Age on Treatment Outcomes in Clostridium difficile Infection

To determine the effect of advancing age on the clinical outcomes of Clostridium difficile (CDI) treatment.

751a Opt-80 Versus Vancomycin in Clostridium difficile Infection: Results of a Randomized Clinical Trial

Background & Aims: Lysophosphatidic acid (LPA), a naturally produced phospholipid, mediates multiple effects that are vital to disease process, including cancer and inflammation. The expression of LPA receptor 2 (LPA2) is up-regulated in several types of cancer, including ovary and colon cancer (CC), but the importance of LPA and LPA2 in the development and progression of CC is unclear. Chronic inflammation is also a risk factor for CC. In this study, we sought to determine whether LPA and LPA2 regulate the progression of CC using animal models of CC. Methods: We examined the potential effects of LPA in CC progression by administering LPA to ApcMin/+ mice. We determined the role of LPA2 in colon tumorigenesis by examining the loss of LPA2 function. We treated LPA2-/mice with azoxymethane (AOM) and dextran sulfate sodium (DSS). Furthermore, we examined the role of LPA2 in modulating intestinal adenoma formation by crossing LPA2-/mice with ApcMin/+ mice. Results: We found that LPA treatment by gavage increased the number of adenomas in small intestine in Apcmin/+ mice. The difference in body weight and mortality suggested that the absence of LPA2 protected animals from the AOM/DSS treatment. LPA2-/mice treated with AOM/DSS showed significantly fewer and smaller tumors in the colon than wild-type (WT) mice. There was no difference in number and size of tumors between LPA2+/and WT mice. We observed reduced epithelial cell proliferation and decreases in β-catenin, Kruppel-like factor 5 (KLF5), and cyclooxygenase-2 (COX-2) expression in LPA2-/mice compared to WT. Compared to WT mice, induction of monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF) was significantly abrogated in LPA2-/mice with reduced infiltration by macrophages. The absence of LPA2 expression in ApcMin/ + mice resulted in a significant decrease in adenomas. At 5 month, ApcMin/+/LPA2-/mice developed an average of 22 adenomas in the small intestine compared with 38 in ApcMin/ +/LPA2+/+ and 43 in ApcMin/+/LPA2+/mice. Consistently, the average number of adenomas in the colon was 2.67, 1.75, and 0.64 for ApcMin/+/LPA2+/+, ApcMin/+/LPA2+/-, and ApcMin/ +/LPA2-/respectively. Adenomas larger than 2 mm accounted for 18% for ApcMin/+/LPA2-/mice in contrast to 38% for ApcMin/+/LPA2+/+. Conclusion: The absence of LPA2 attenuates several effects that may contribute to tumorigenesis In Vivo. Hence, our studies identify LPA2 as a modulator of intestinal tumorigenesis.