Clinical Evaluation Patients Research Articles

Open-Label Randomized Trial of Early Clinical Outcomes of Ceftaroline Fosamil Versus Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections at Risk of Methicillin-Resistant Staphylococcus aureus.

IntroductionAcute bacterial skin and skin structure infections (ABSSSIs) remain among the most common infectious processes seen in the clinical setting. For patients with complicated ABSSSIs deemed to require intravenous antibiotics, vancomycin remains the mainstay therapy. Ceftaroline has been shown to be non-inferior to vancomycin and may result in faster resolution of signs of infection.MethodsMulticenter, prospective, open-label, randomized trial of ceftaroline versus vancomycin for the treatment of adult patients admitted for management of ABSSSIs from April 2012 to May 2016; 166 patients in the clinically evaluable (CE) group were needed to determine a 20% difference in primary outcome of clinical response at day 2 or 3 of antibiotics. Clinical response was defined as cessation of spread of lesion and improvement in systemic signs/symptoms of infection. A secondary outcome was a ≥ 20% reduction in lesion size at day 2 or 3 of antibiotics.ResultsOne hundred seventy-four patients were enrolled in the intention-to-treat (ITT) group and 108 were CE. Among CE patients, 54 were randomized to ceftaroline and 54 to vancomycin. Baseline characteristics were similar except patients in the ceftaroline arm were older and had a non-significantly higher degree of comorbidities (median Charlson score 2 vs. 4, respectively). Cellulitis was the most common type of ABSSSI (85.2% vs. 79.6%, respectively). Rapid diagnostic testing of available cultures (n = 55) demonstrated high agreement with clinical microbiology for identification of Staphylococcus aureus (100%) and MRSA (100%). There was no significant difference in primary outcome of day 2 or 3 clinical response (50.0% vs. 51.9%).ConclusionEarly clinical response between vancomycin- and ceftaroline-treated ABSSSIs was similar. Patients with ABSSSIs rarely remained hospitalized for > 2–3 days, thus limiting our ability to critically assess clinical outcomes.Trial RegistrationClinicalTrials.gov identifier, NCT02582203.FundingAllergan plc.

A randomized phase 2 study comparing two doses of delafloxacin with tigecycline in adults with complicated skin and skin-structure infections

A randomized, double-blind, multicenter trial was done to compare two doses of delafloxacin with tigecycline in patients with various complicated skin and skin-structure infections (wound infections following surgery, trauma, burns, or animal/insect bites, abscesses, and cellulitis). Patients were randomized 1:1:1 to receive delafloxacin 300mg intravenous (IV) every 12h, delafloxacin 450mg IV every 12h, or tigecycline 100mg IV×1, followed by 50mg IV every 12h; randomization was stratified by infection type. Duration of therapy was 5-14 days. The primary efficacy analysis, performed on the clinically evaluable (CE) population at the test-of-cure (TOC) visit (14-21 days after the final dose of study drug), compared clinical response rates in the delafloxacin and tigecycline arms. Clinical response rates in the two delafloxacin arms were also compared. Among CE patients, clinical cure rates at TOC visit were similar in the delafloxacin and tigecycline arms (94.3%, 92.5%, and 91.2%, respectively in delafloxacin 300-mg, delafloxacin 450-mg, and tigecycline arms). Overall, the most frequent adverse events were nausea, vomiting, and diarrhea; the 300-mg delafloxacin arm was the best-tolerated regimen. Delafloxacin was similarly effective as tigecycline for a variety of complicated skin and skin-structure infections and was well tolerated. (Clinicaltrials.gov NCT 0719810).

Efficacy of telavancin in patients with specific types of complicated skin and skin structure infections

Telavancin is approved in the USA and Canada for the treatment of Gram-positive complicated skin and skin structure infections (cSSSIs) based on the results of the Phase 3 Assessment of TeLAvancin in complicated Skin and skin structure infections (ATLAS) trials, which demonstrated non-inferiority of telavancin to vancomycin. We conducted a post hoc analysis of the ATLAS studies (ClinicalTrials.gov identifiers NCT00091819 and NCT00107978) to explore the efficacy of telavancin in patients with various types of cSSSIs. A total of 1794 patients were included in this analysis; 1434 patients were clinically evaluable (CE) and 563 of these had methicillin-resistant Staphylococcus aureus (MRSA). Among CE patients with major abscesses (n = 619), cure rates were 91% for telavancin and 90% for vancomycin (95% CI for the difference -3.6 to 5.7). In patients with infective cellulitis (n = 519), cure was achieved in 87% and 88% of telavancin- and vancomycin-treated patients, respectively (95% CI for the difference -6.2 to 5.2). Cure rates in patients with wound infections were 85% in the telavancin group and 86% in the vancomycin group (95% CI for the difference -10.5 to 9.0). Cure rates for each type of cSSSI in patients infected with MRSA were also similar between the two treatment arms. Among CE patients infected with Panton-Valentine leucocidin (PVL)-positive MRSA (n = 447), cure rates were 93% for telavancin and 90% for vancomycin (95% CI for the difference -2.2 to 8.2). Cure rates were similar for telavancin and vancomycin in patients with different types of cSSSIs, including infections caused by MRSA and PVL-positive strains of MRSA.

Integrated Analysis of FOCUS 1 and FOCUS 2: Randomized, Doubled‐Blinded, Multicenter Phase 3 Trials of the Efficacy and Safety of Ceftaroline Fosamil versus Ceftriaxone in Patients with Community‐Acquired Pneumonia

Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin with bactericidal activity against pathogens causing community-acquired pneumonia (CAP), including Streptococcus pneumoniae. Ceftaroline was evaluated for the treatment of CAP in 2 randomized, double-blind, multicenter trials: Ceftaroline Community Acquired Pneumonia Trial versus Ceftriaxone in Hospitalized Patients (FOCUS) 1 and FOCUS 2. Patients hospitalized (but not admitted to an intensive care unit) with Pneumonia Outcomes Research Team risk class III or IV CAP requiring intravenous therapy were randomized to ceftaroline 600 mg every 12 h or ceftriaxone 1 g every 24 h for 5-7 days. Patients in FOCUS 1 received 2 doses of oral clarithromycin 500 mg every 12 h on day 1. In the individual trials, clinical cure rates in the clinically evaluable (CE) population for ceftaroline versus ceftriaxone were as follows: FOCUS 1, 86.6% vs 78.2% (difference, 8.4%; 95% confidence interval [CI], 1.4%-15.4%); FOCUS 2, 82.1% vs 77.2% (difference, 4.9%; 95% CI, -2.5% to 12.5%). In the integrated analysis, 614 patients received ceftaroline and 614 received ceftriaxone. Of the CE patients treated with ceftaroline, 84.3% achieved clinical cure, compared with 77.7% of ceftriaxone-treated patients (difference, 6.7%; 95% CI, 1.6%-11.8%). Clinical cure rates in the modified intent-to-treat efficacy population were 82.6% versus 76.6% for ceftaroline and ceftriaxone (difference, 6.0%; 95% CI, 1.4%-10.7%). Ceftaroline and ceftriaxone were well tolerated; rates of adverse events, serious adverse events, deaths, and premature discontinuations caused by an adverse event were similar in both treatment arms. Ceftaroline was noninferior to ceftriaxone in the individual trials. In this integrated analysis, clinical cure rates for the ceftaroline group were numerically higher than those for the ceftriaxone group. Ceftaroline was well tolerated, with a safety profile similar to that of ceftriaxone.

Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia

To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients.

Efficacy and safety of linezolid in methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infection (cSSTI): a meta-analysis

Objective:To evaluate the clinical and microbiological outcomes of linezolid versus vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infection (cSSTI) using a meta-analysis.Research design and methods:Clinical trials were identified using PubMed, the Cochrane Central Register of Controlled Trials, and the International Pharmaceutical s from inception to March 2009. Primary outcomes evaluated resolution of signs and symptoms of infection in clinically evaluable (CE) patients, and microbiological eradication in both the modified intent-to-treat (MITT) and MRSA evaluable (MRSA ME) patients. MITT patients had a culture-confirmed Gram-positive pathogen (S. aureus) at baseline. Secondary outcomes included mortality, adverse drug reactions (ADR), and discontinuation due to ADRs. The Mantel-Haenszel odds ratios (OR) with 95% confidence intervals (CI) were calculated using the fixed effects model based on the assumption that there was little to no heterogeneity between the studies in the primary analysis. Sensitivity analyses were performed for each outcome by removing the most weighted study.Results:Five studies with a total of 2652 patients (1361/linezolid; 1291/vancomycin) were identified. Resolution of infection in CE patients (OR = 1.41; 95% CI: 1.03, 1.95) and MITT patients (OR = 1.91; 95% CI: 1.33, 2.76) favored the use of linezolid over vancomycin, but did not remain significant after sensitivity analyses (CE: OR = 1.29; 95% CI: 0.81, 2.05; MITT: OR = 1.73; 95% CI: 0.87, 3.41). Microbiological eradication in MRSA ME patients consistently favored the use of linezolid over vancomycin (OR = 2.90; 95% CI: 1.90, 4.41). No difference in mortality was observed between the two groups (OR = 1.17; 95% CI: 0.85, 1.62). Higher proportions of linezolid patients were found to have diarrhea (119/1361 vs. 52/1291), nausea (102/1361 vs. 46/1291) and thrombocytopenia (54/1121 vs. 8/1071), whereas a higher proportion of vancomycin patients were found to have renal insufficiency compared to linezolid (16/634 vs. 4/703). Inconsistent results were seen with the incidence of anemia and rash between the base-case (anemia: OR = 1.36; 95% CI: 0.90, 2.08; rash: OR = 0.26; 95% CI: 0.10, 0.68) and sensitivity analyses (anemia: OR = 2.33; 95% CI: 1.24, 4.37; rash: OR = 0.57; 95% CI: 0.12, 2.71). Discontinuation due to ADRs was not statistically different between linezolid and vancomycin (OR = 1.06; 95% CI: 0.75, 1.51).Conclusion:Resolution of infection in CE and MITT patients were inconsistent; however, a sub-analysis revealed that linezolid was more likely to consistently achieve microbiologic eradication in MRSA ME patients. Apparent risks of thrombocytopenia, nausea, diarrhea, and possibly anemia may limit linezolid use in treating MRSA cSSTI. This study was limited due to an inability to assess for the effects of hetero-resistance and appropriate vancomycin dosing on outcomes. Moreover, the small number of studies made controlling for heterogeneity challenging.

Tigecycline Versus Levofloxacin for the Treatment of Community-Acquired Pneumonia: European Experience

Tigecycline (TGC), a first-in-class glycylcycline that has been approved for treating complicated skin and skin structure infections and complicated intra-abdominal infections, has an expanded spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, including resistant strains. The purpose of this study was to compare the efficacy and safety of TGC with levofloxacin (LEV) in adult hospitalized patients with community-acquired pneumonia (CAP) in a randomised, doubleblind, phase 3 multinational trial. This analysis evaluated TGC efficacy and safety in the European region. Hospitalised patients from 53 centres in 18 countries received 7-14 days of i.v. TGC (100-mg loading dose followed by 50 mg every 12 hours) or i.v. LEV (500 mg once or twice daily). Co-primary efficacy endpoints were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (TOC).Results indicated that 358 patients received at least 1 dose of study medication (mITT: TGC 177, LEV 181), 245 were CE (TGC 125, LEV 120). Demographics were similar in both groups and the majority of patients had a Fine Pneumonia Severity Index of II to IV (84.4% TGC, 78.2% LEV, mITT). At TOC (CE), TGC cured 112/125 patients (89.6%; 95% CI 82.9, 94.3) and LEV cured 103/120 patients (85.8%; 95% CI 78.3, 91.5), absolute difference of TGC-LEV 3.8% (95% CI -5.3, 12.8; test for noninferiority p<0.001). For those CE patients with a Fine score of <III or III/IV, TGC cured 90.0% and 88.9%, and LEV cured 88.5% and 83.6%, respectively. In c-mITT, TGC cured 146/173 patients (84.4%; 95% CI 78.1, 89.5) and LEV cured 142/173 patients (82.1%; 95% CI 75.5, 87.5), absolute difference of TGC-LEV 2.3% (95% CI 6.1, 10.8; test for noninferiority p<0.001). In c-mITT patients with a Fine score of <III or III/IV, TGC cured 86.3% and 81.9%, and LEV cured 80.7% and 83.1%, respectively. Both regimens were generally well tolerated with only a few patients being withdrawn from the study because of any adverse event (3; 1.6% TGC versus 2, 1.1% LEV). The authors concluded that TGC was safe and efficacious in patients hospitalised with CAP, achieving similar efficacy to that of the comparator.

The clinical evaluation for detecting metastatic lung cancer: A meta-analysis

The objective of this study was to assess the performance of the clinical evaluation in detecting extrathoracic metastases compared with brain and abdomen CT and radionuclide bone scans in patients with newly diagnosed bronchogenic carcinoma. The included studies were selected using the MEDLARS database from 1977 through August 1992 as well as reference lists from published articles or abstracts. Studies eligible for consideration met six criteria. The most important criterion was that results of a clinical evaluation and a CT scan of the head or abdomen or a radionuclide bone scan, obtained during the initial evaluation of a patient with primary lung cancer, must be included. Data were categorized by the type of clinical evaluation performed and whether patients had a clinical evaluation suggesting metastases (positive) or not (negative). The negative predictive value (NPV) of the clinical evaluation was calculated in all studies. The sensitivity, specificity, and the positive predictive value (PPV) were calculated in studies including positive and negative clinical evaluation patients. Twenty-five studies are included in this analysis. A total of 3,089 imaging scans were obtained in the study patients after a clinical evaluation was performed. The mean NPV of the clinical evaluation for CT of the brain, abdomen, and radionuclide bone scan is 95, 94, and 89%, respectively. When an expanded clinical evaluation was performed, the NPV was even higher. The NPV was influenced by the prevalence of metastases, but still performed well in series with high prevalence rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of the clinically significant TSH response to TRH in patients with nodular goitre.

Twenty-five patients with nodular goitre who had thyroid hormone levels within normal ranges and an absent thyrotropin (TSH) response to TSH releasing hormone (TRH) as measured by a conventional radioimmunoassay with a lower detection limit of 0.6 mU/l were studied. Based on these data, and the clinical evaluation patients were divided into a hyperthyroid group (n = 12) and a euthyroid group (n = 13). The samples from the TRH test were reanalyzed by an immunoradiometric TSH assay with a detection limit of 0.05 mU/l. Basal serum TSH showed a considerable overlap between the two groups, but values above 0.10 mU/l were always associated with euthyroidism. Using this level of discrimination 76% of the patients were correctly classified. A TSH response to TRH of 0.10 mU/l provided a better discrimination allowing a correct diagnosis in 92% of the patients. It is concluded that serum TSH as measured by a sensitive assay is suitable as a first line test in patients with nodular goitre. However, patients with basal serum TSH levels below 0.10 mU/l need further investigation with a TRH-test. A TSH response to TRH above 0.10 mU/l seems to secure euthyroidism, whereas lower responses almost always are associated with hyperthyroidism.