Safety of long-term use of linezolid: results of an open-label study.

OBJECTIVE: The objective of this study was to assess the long-term safety of linezolid in patients with chronic infections requiring treatment for ≥6 weeks. Enhanced monitoring for optic neuropathy was included to characterize the early development of this side effect and to identify ophthalmologic tests that might be valuable in early detection of this event. METHODS: This was a multicenter, open-label, pilot study of patients aged ≥18 years on long-term linezolid therapy. Matched control patients were included for baseline assessment comparison. Patients were assessed at study entry, monthly while on treatment, at the end of treatment, and 30 days following the last dose. Aggregate ocular safety data were reviewed. Response to treatment was reported. RESULTS: The study was terminated owing to slow enrollment. Twenty-four patients received linezolid; nine patients were included as matched controls. Linezolid was prescribed for a median of 80.5 days (range, 50-254 days). In patients with a reported clinical outcome, the majority were considered improved or cured. Common treatment-related adverse events (AEs) included anemia, peripheral neuropathy, polyneuropathy, vomiting, and asthenia, and were consistent with the known safety profile. Most AEs resolved or stabilized with discontinuation of treatment. Results of ophthalmologic tests in the one case adjudicated as probable linezolid-associated optic neuropathy revealed abnormal color vision, characteristic changes in the optic disk, and central scotomas in each eye. CONCLUSION: In our small population, linezolid was generally well tolerated and AEs were consistent with the known safety profile. Extensive ophthalmologic testing of all 24 linezolid-treated patients identified one case adjudicated as probable, linezolid-associated optic neuropathy.

Novel antifungal drug discovery based on targeting pathways regulating the fungus-conserved Upc2 transcription factor.

Infections by Candida albicans and related fungal pathogens pose a serious health problem for immunocompromised patients. Azole drugs, the most common agents used to combat infections, target the sterol biosynthetic pathway. Adaptation to azole therapy develops as drug-stressed cells compensate by upregulating several genes in the pathway, a process mediated in part by the Upc2 transcription factor. We have implemented a cell-based high-throughput screen to identify small-molecule inhibitors of Upc2-dependent induction of sterol gene expression in response to azole drug treatment. The assay is designed to identify not only Upc2 DNA binding inhibitors but also compounds impeding the activation of gene expression by Upc2. An AlphaScreen assay was developed to determine whether the compounds identified interact directly with Upc2 and inhibit DNA binding. Three compounds identified by the cell-based assay inhibited Upc2 protein level and UPC2-LacZ gene expression in response to a block in sterol biosynthesis. The compounds were growth inhibitory and attenuated antifungal-induced sterol gene expression in vivo. They did so by reducing the level of Upc2 protein and Upc2 DNA binding in the presence of drug. The mechanism by which the compounds restrict Upc2 DNA binding is not through a direct interaction, as demonstrated by a lack of DNA binding inhibitory activity using the AlphaScreen assay. Rather, they likely inhibit a novel pathway activating Upc2 in response to a block in sterol biosynthesis. We suggest that the compounds identified represent potential precursors for the synthesis of novel antifungal drugs.

(1,3)-ß-D-glucan as a prognostic marker of treatment response in invasive candidiasis.

BACKGROUND: (1,3)-ß-D-glucan (BG) is a biomarker for invasive candidiasis (IC). The usefulness of BG level as a prognostic marker of treatment outcome is not well characterized. METHODS: Two hundred fifty-seven patients with proven IC were enrolled in an anidulafungin study. Clinical and microbiological responses at the end of therapy were evaluated. Serial serum BG was measured. Correlation of initial and final BG levels with overall outcome was assessed in each patient. RESULTS: Two hundred three patients had at least 2 BG levels and outcomes assessed. The majority of IC was caused by non-Candida albicans (53%) and found in the blood (84%). Overall, treatment success was 85%. In successfully treated patients, the mean ± SD initial and final BG were 573 ± 681 pg/mL and 499 ± 635 pg/mL (P = .03), respectively; while in treatment-failure patients, the levels were 1224 ± 1585 pg/mL and 1293 ± 1283 pg/mL (P = .29), respectively. A negative slope in BG levels correlated with a successful treatment outcome with a positive predictive value (PPV) of 90%, and a positive slope in BG levels correlated with treatment failure with a negative predictive value (NPV) of 90%. The cutoff value for initial BG <416 pg/mL has potential to predict treatment success with a PPV of 89%. CONCLUSIONS: A decrease in BG levels during therapy is associated with treatment success. An initial BG of <416 pg/mL has potential to predict successful treatment outcomes. Baseline and consecutive serum BG measurements may be useful as prognostic markers of treatment outcome in patients with IC receiving primarily echinocandin therapy.

Identification and hit-to-lead optimization of a novel class of CB1 antagonists.

The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.

Once-daily azithromycin for 3 days compared with clarithromycin for 10 days for acute exacerbation of chronic bronchitis: a multicenter, double-blind, randomized study.

STUDY OBJECTIVES: To compare the efficacy and safety of oral azithromycin 500 mg once daily for 3 days with those of oral clarithromycin 500 mg twice daily for 10 days. DESIGN: Randomized, double-blind, double-dummy, multicenter study. SETTING: Seventy-six study centers in eight countries (Argentina, Brazil, Canada, Chile, Costa Rica, India, South Africa, and USA). PATIENTS: Three hundred and twenty-two adult outpatients with acute exacerbation of chronic bronchitis (AECB) as documented by increased cough or sputum production, worsening dyspnea, and purulent sputum production. INTERVENTIONS: Randomization 1 : 1 to azithromycin 500 mg once daily for 3 days or clarithromycin 500 mg twice daily for 10 days. RESULTS: The primary efficacy endpoint was clinical response at day 21-24, or test of cure (TOC) visit in the modified intent-to-treat (MITT) analysis (n = 318 patients). The TOC clinical cure rates in the MITT population were equivalent in the two treatment groups at 85% with azithromycin and 82% with clarithromycin (95% CI -5.9%, 12.0%). Clinical success rates on day 10-12 were also equivalent at 93% with azithromycin and 94% with clarithromycin (95% CI -7.9%, 4.4%). Clinical cure rates at TOC by pathogen were equivalent for the two treatment groups for Haemophilus influenzae (azithromycin, 85.7%; clarithromycin, 87.5%), Moraxella catarrhalis (91.7% and 80.0%, respectively) and Streptococcus pneumoniae (90.6% and 77.8%, respectively). Bacteriologic success rates were also equivalent between the azithromycin and clarithromycin treatment groups at TOC for S. pneumoniae (90.6% and 85.2%, respectively), H. influenzae (71.4% and 81.3%, respectively) and M. catarrhalis (100% and 86.7%, respectively). The overall incidence of treatment-related adverse events was similar in the azithromycin and clarithromycin groups (20.9% and 26.8%, respectively), with the most common being abdominal pain (6.3% and 6.1%, respectively), diarrhea (4.4% and 5.5%, respectively), and nausea (4.4% and 3.7%, respectively). CONCLUSIONS: Three-day treatment with azithromycin 500 mg once daily is equivalent to a 10-day treatment with clarithromycin 500 mg twice daily in adult patients with AECB.

Linezolid eradicates MRSA better than vancomycin from surgical-site infections.

BACKGROUND: The purpose of this analysis was to compare the efficacy of linezolid versus vancomycin in patients with suspected or proven gram-positive methicillin-resistant Staphylococcus aureus (MRSA) surgical-site infections. METHODS: An open-label, randomized, comparator-controlled, multicenter, multinational study was conducted in hospitalized patients. Patients were randomized 1:1 to receive linezolid 600 mg (intravenous [IV] or oral) every 12 hours (n = 66) or vancomycin 1 g every 12 hours IV (n = 69) for 7 to 21 days. Patients were assessed at the test-of-cure (TOC) visit, 7 days after completing therapy. RESULTS: Clinical success at TOC was documented in similar proportions of patients treated with linezolid or vancomycin. Of those with MRSA isolated, significantly more patients who received linezolid compared with those who received vancomycin were microbiologically cured (87% vs 48%, respectively; 95% confidence interval 16.51 to 60.27; P = 0.0022). CONCLUSION: Intravenous or oral linezolid was well tolerated and superior to vancomycin in treating patients with MRSA-infected surgical-site infections.

Randomized double-blind study comparing 3- and 6-day regimens of azithromycin with a 10-day amoxicillin-clavulanate regimen for treatment of acute bacterial sinusitis.

A randomized, double-blind, multicenter study of adults with acute bacterial sinusitis (ABS) compared the efficacy and safety of two azithromycin (AZM) regimens, 500 mg/day once daily for 3 days (AZM-3) or 6 days (AZM-6) to the efficacy and safety of an amoxicillin-clavulanate (AMC) regimen of 500-125 mg three times daily for 10 days. A total of 936 subjects with clinically and radiologically documented ABS were treated (AZM-3, 312; AZM-6, 311; AMC, 313). Clinical success rates were equivalent among per-protocol subjects at the end of therapy (AZM-3, 88.8%; AZM-6, 89.3%; AMC, 84.9%) and at the end of the study (AZM-3, 71.7%; AZM-6, 73.4%; AMC, 71.3%). Subjects treated with AMC reported a higher incidence of treatment-related adverse events (AE) (51.1%) than AZM-3 (31.1%, P < 0.001) or AZM-6 (37.6%, P < 0.001). More AMC subjects discontinued the study (n = 28) than AZM-3 (n = 7) and AZM-6 (n = 11) subjects. Diarrhea was the most frequent treatment-related AE. AZM-3 and AZM-6 were each equivalent in efficacy and better tolerated than AMC for ABS.