Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma. METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points. RESULTS: 28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). F ENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated. CONCLUSION: Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.

Effects of prior effective therapy on the efficacy of daptomycin and ceftriaxone for the treatment of community-acquired pneumonia.

OBJECTIVE: We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-acquired pneumonia (CAP). METHODS: Two phase-3 randomized, double-blind trials that enrolled adult patients hospitalized with CAP were conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 5-14 days. Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points. RESULTS: After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95% confidence interval for the difference between cure rates, -12.4% to -0.6%). In the clinically evaluable population, the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients (87.9%; 95% confidence interval for the difference between cure rates, -13.8% to -3.2%). A posthoc analysis revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among daptomycin-treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference between cure rates, -6.1% to 11.5%). CONCLUSIONS: Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received any potentially effective therapy before enrollment.

Safety, tolerability, pharmacokinetics, and efficacy of an interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy.

We sought to determine the safety, maximum tolerated dose, optimal dose, and preliminary dose efficacy of intermittent subcutaneously (s.c.) administered BAY 50-4798 among patients with HIV infection receiving highly active antiretroviral therapy (HAART) compared with patients receiving HAART alone. A phase I/II randomized, double-blind, dose-escalation study was conducted of the safety, tolerability, pharmacokinetics, and efficacy of s.c. BAY 50-4798 administered to HIV-infected patients already receiving stable HAART. There were no unexpected safety findings in a population of HIV-infected patients receiving HAART plus SC BAY 50-4798 as adjunctive therapy. BAY 50-4798 exhibited nearly dose-proportional pharmacokinetics, and accumulation was minimal during multiple-dose treatment. Limited efficacy data indicated that treatment with BAY 50-4798 caused at least a transient increase in CD4(+) T cell counts in some recipients, particularly at the early time points. In general, this effect appeared to increase with increasing dose. Bay 50-4798 was generally well tolerated across the dose range tested, but a lack of potent, sustained immunologic activity suggests that further optimization of dose and schedule will be necessary.

Clinical characteristics and functional outcomes of West Nile Fever.

BACKGROUND: West Nile fever, considered a nonsevere manifestation of West Nile virus infection, has not been clinically well described in the United States. In 2002, Illinois had 884 documented cases of West Nile virus infection with 66 associated deaths. OBJECTIVE: To describe the symptoms and functional outcomes of West Nile fever. DESIGN: Case series. SETTING: Illinois. PATIENTS: 98 community-dwelling patients with laboratory evidence of West Nile virus infection but no history of clinical evidence of meningitis, encephalitis, or acute flaccid paralysis. INTERVENTION: Outpatient interviews. MEASUREMENTS: Presence and duration of patient-reported symptoms of infection, symptom-associated absenteeism, health care use, and impact on daily activities. RESULTS: Of 98 patients, 96% had fatigue for a median of 36 days, 81% had fever for a median of 5 days, 71% had headache for a median of 10 days, 61% had muscle weakness for a median of 28 days, and 53% had difficulty concentrating for a median of 14 days. Thirty respondents reported hospitalization, with a median stay of 5 days. At 30 days after onset, 63% of respondents continued to have symptoms. Duration did not vary significantly with increased age. Among the 72 patients who normally attended work or school, 57 (79%) could not attend because of illness (median absence, 10 days). LIMITATIONS: Recall bias could have been introduced by the delay between illness onset and interview and by self-reporting of illness information. CONCLUSIONS: West Nile fever is a more severe illness than has previously been documented. Mandatory reporting of West Nile fever cases in addition to West Nile meningoencephalitis cases could allow more accurate and timely recognition of the geographic distribution of West Nile virus infections and could inform public health interventions.

Linezolid treatment for osteomyelitis due to vancomycin-resistant Enterococcus faecium.

The incidence of nosocomial infections caused by vancomycin-resistant enterococci has risen substantially during the past 15 years. We report the use of linezolid for the successful treatment of hip prosthesis infection associated with osteomyelitis due to vancomycin-resistant Enterococcus faecium.

Comparison of a 3-day with a 1-day regimen of an extended-release formulation of ciprofloxacin as antimicrobial prophylaxis for patients undergoing transrectal needle biopsy of the prostate.

OBJECTIVE: To compare the clinical and bacteriological efficacy and the clinical safety of a 1-day with a 3-day regimen of an extended-release formulation of ciprofloxacin (ciprofloxacin XR) given as antimicrobial prophylaxis to men undergoing transrectal needle biopsy of the prostate (TRNBP). PATIENTS AND METHODS: This was a multicentre, prospective, international, double-blind study in patients who required TRNBP. Patients were randomized to receive oral ciprofloxacin XR 1000 mg as either a 1-day or a 3-day regimen. Single doses were given at 24 h before, 2-3 h before, and 24 h after TRNBP. Patients in the 1-day regimen had placebo instead of the first and third doses of ciprofloxacin. RESULTS: Of 497 patients enrolled, 247 were randomized to 1-day ciprofloxacin XR and 250 to the 3-day regimen. In the population valid for microbiological efficacy, the final assessment identified bacteriological success (primary efficacy endpoint) in more patients who had the 3-day regimen (98%) than in those who received the 1-day regimen (94.8%, 95% confidence interval, CI, - 6.1%, 0.8%), although the difference was not statistically significant. In this population, the clinical response at the final visit was 98.5% and 96.7% for patients receiving the 3-day and the 1-day regimens, respectively (95% CI - 5.2%, 0.8%). However, in the clinical efficacy population the clinical success rate was significantly greater for the 3-day (99.0%) than for the 1-day regimen (95.8%; 95% CI - 6.4%, - 0.3%). In a multivariate analysis, patients with diabetes mellitus and patients with a history of prostatitis had higher microbiological and clinical failure rates, respectively, than those without such conditions. For these patients, all failures occurred among those treated with the 1-day regimen. CONCLUSION: As defined by bacteriological success in the population assessed for microbiological efficacy, prophylaxis with one dose of ciprofloxacin XR was statistically no worse than a 3-day regimen. However, in all efficacy analyses, bacteriological and clinical success rates were consistently lower for the 1-day than for the 3-day treatment. Thus, for selected patients undergoing TRNBP, there might be a role for 3-day preventive therapy with ciprofloxacin XR.

Risk factors for a poor outcome after therapy for acute pyelonephritis.

OBJECTIVE: To define and characterize risk factors for the failure of treatment for acute uncomplicated pyelonephritis, as there are few reports available to predict which patients will respond poorly to treatment. PATIENTS AND METHODS: Retrospective univariate and multivariate logistic regression analyses were used to assess data from two prospective clinical trials designed to evaluate antibiotic regimens for urinary tract infections. Data from 522 adult patients with acute uncomplicated pyelonephritis were analysed. RESULTS: The cure rate was 442/522 (85%) for patients with acute uncomplicated pyelonephritis. Significant independent predictors for treatment failure included hospitalization at baseline (P < 0.001), the presence of a resistant infecting organism (P < 0.001), diabetes mellitus (P = 0.001), and a history of kidney stones (P = 0.004). The cure rate was 35/74 (47%) for patients with at least one of these four risk factors. Of the 80 patients assessed as treatment failures, only 39 (49%) had at least one of the four risk factors. CONCLUSION: Four risk factors for a poor outcome after therapy for acute uncomplicated pyelonephritis were identified. The strongest predictors of failure were the need for hospitalization at baseline and the presence of an organism resistant to the antimicrobial agent used for therapy. Two other factors, diabetes mellitus and a history of kidney stones, might assist clinicians at the initial evaluation to decide which patients are at risk of subsequent treatment failure.

Human herpesvirus 8 glycoprotein B (gB), gH, and gL can mediate cell fusion.

Herpesvirus entry into cells and herpesvirus-induced cell fusion are related processes in that virus penetration proceeds by fusion of the viral envelope and cell membrane. To characterize the human herpesvirus 8 (HHV-8) glycoproteins that can mediate cell fusion, a luciferase reporter gene activation assay was used. Chinese hamster ovary (CHO) cells expressing the HHV-8 glycoproteins of interest along with a luciferase reporter gene under the control of the T7 promoter were cocultivated with human cells transfected with T7 RNA polymerase. Because HHV-8 glycoprotein B (gB) expressed in CHO cells localizes to the perinuclear region, a truncated form of gB (designated gB(MUT)) that lacks putative endocytosis signals was constructed by deletion of the distal 58 amino acids of the cytoplasmic tail. HHV-8 gB(MUT) was expressed efficiently on the surface of CHO cells. HHV-8 gB, gH, and gL could mediate the fusion of CHO cells with two different human cell types, embryonic kidney cells and B lymphocytes. Substituting gB(MUT) for gB significantly enhanced the fusion of CHO cells with human embryonic kidney cells but not B lymphocytes. Thus, two human cell types known to be susceptible to HHV-8 entry were also suitable targets for cell fusion induced by HHV-8 gB, gH, and gL. For human embryonic kidney cells and B cells at least, optimal fusion was noted with the expression of all three HHV-8 glycoproteins.