European Medical Centers Research Articles

Characteristics of a large sample of candidates for permanent ventricular pacing included in the Biventricular Pacing for Atrio-ventricular Block to Prevent Cardiac Desynchronization Study (BioPace)

The general clinical profile of European pacemaker recipients who require predominant ventricular pacing (VP) is scarcely known. We examined the demographic and clinical characteristics of the 1808 participants (out of 1833 randomized patients) of the ongoing Biventricular Pacing for Atrio-ventricular Block to Prevent Cardiac Desynchronization (BioPace) study. BioPace recruited patients between May 2003 and September 2007 predominantly in European medical centres. We analysed demographic data and described clinical characteristics and electrophysiological parameters prior to device implantation in 1808 enrolled patients. The mean age ± standard deviation (SD) of the 1808 patients was 73.5 ± 9.2 years, 1235 (68%) were men, 654 (36%) presented without structural heart disease, 547 (30%) had ischemic, 355 (20%) hypertensive, 146 (8%) valvular, and 102 (6%) non-ischemic dilated cardiomyopathy. Mean left ventricular ejection fraction was 55.4 ± 12.3%. The main pacing indications were (a) permanent and intermittent atrioventricular (AV) block in 973 (54%), (b) atrial fibrillation with slow ventricular rate in 313 (17%), and (c) miscellaneous bradyarrhythmias in 522 (29%) patients. Mean QRS duration was 118.5 ± 30.5 ms, left bundle branch block was present in 316 (17%), and atrial tachyarrhythmias in 426 (24%) patients. To the best of our knowledge, this sample is a representative source of description of the general profile of European pacemaker recipients who require predominant VP. Patients' characteristics included advanced age, predominantly male gender, preserved left ventricular systolic function, high-grade AV block, narrow QRS complex, and atrial tachyarrhythmias, the latter being present in nearly one-fourth of the cohort.

Long-term testosterone supplementation is useful for ED with testosterone deficiency

Long-term testosterone supplementation is useful for ED with testosterone deficiency

Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study

Siponimod is an oral selective modulator of sphingosine 1-phosphate receptor types 1 and type 5, with an elimination half-life leading to washout in 7 days. We aimed to determine the dose-response relation of siponimod in terms of its effects on brain MRI lesion activity and characterise safety and tolerability in patients with relapsing-remitting multiple sclerosis. In this double-blind, adaptive dose-ranging phase 2 study, we enrolled adults (aged 18-55 years) with relapsing-remitting multiple sclerosis at 73 medical centres in Europe and North America. We tested two patient cohorts sequentially, separated by an interim analysis at 3 months. We randomly allocated patients in cohort 1 (1:1:1:1) to receive once-daily siponimod 10 mg, 2 mg, or 0·5 mg, or placebo for 6 months. We randomly allocated patients in cohort 2 (4:4:1) to siponimod 1·25 mg, siponimod 0·25 mg, or placebo once-daily for 3 months. Randomisation was done with a central, automated system and patients and investigators were masked to treatment assignment. The primary endpoint was dose-response, assessed by percentage reduction in monthly number of combined unique active lesions at 3 months for siponimod versus placebo; this endpoint was analysed by a multiple comparison procedure with modelling techniques in all patients with at least one MRI scan up to 3 months. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00879658. Between March 30, 2009, and Oct 22, 2010, we recruited 188 patients into cohort 1 and 109 patients into cohort 2. We showed a dose-response relation (p=0·0001) across the five doses of siponimod, with reductions in combined unique active lesions at 3 months compared with placebo of 35% (95% CI 17-57) for siponimod 0·25 mg (51 patients included in the primary endpoint analysis), 50% (29-69) for siponimod 0·5 mg (43 patients), 66% (48-80) for siponimod 1·25 mg (42 patients), 72% (57-84) for siponimod 2 mg (45 patients), and 82% (70-90) for siponimod 10 mg (44 patients). In patients treated for 6 months, 37 (86%) of 43 patients who received siponimod 0·5 mg had adverse events (eight serious), as did 48 (98%) of 49 patients who received siponimod 2 mg (four serious), 48 (96%) of 50 patients who received siponimod 10 mg (three serious), and 36 (80%) of 45 controls (none serious). For individuals treated to 3 months, 38 (74%) of 51 patients who received siponimod 0·25 mg had adverse events (none serious), as did 29 (69%) of 42 patients who received siponimod 1·25 mg (two serious) and 13 (81%) of 16 controls (none serious). Therapeutic effects of siponimod on MRI lesion activity in model-based analyses and its tolerability in relapsing-remitting multiple sclerosis warrant investigation in a phase 3 trial. Novartis Pharma AG.

Low-dose acetyl salicylic acid versus oral anticoagulation after bioprosthetic aortic valve replacement. Final report of the ACTION registry

The administration of antiplatelet agents versus anticoagulation after bioprosthetic aortic valve replacement (AVR) remains controversial. This study examined the safety and efficacy of anticoagulation with a vitamin-K antagonist (VKA) versus low-dose acetyl salicylic acid (ASA), up to 6 months after bioprosthetic AVR. The ACTION Registry prospectively collected data at 47 medical centers in Europe, Canada and India. The investigators were free to prescribe the postoperative antithrombotic regimen of their choice. Between January 2006 and June 2009, 1118 patients underwent AVR alone or combined with coronary artery bypass graft (CABG), of whom 500 received a VKA and 618 received ASA. Patients who received VKA had a higher prevalence of peripheral vascular disease, chronic renal insufficiency and coronary artery disease. At 180 days, 14 anticoagulated patients (2.8%) suffered a thromboembolism (TE) versus 9 patients (1.5%) treated with ASA (P=0.12) and 18 anticoagulated patients (3.6%) suffered major bleeding (MB) versus 8 patients (1.3%) in the ASA group (P=0.01). MB or TE occurred in 31 patients (6%) treated with VKA versus 17 patients (2.8%) treated with ASA (P=0.003). By multiple variable analysis, preoperative cerebrovascular accident and peripheral vascular disease were strong predictors of postoperative TE, MB or both, in patients treated with VKA, though not in patients treated with ASA. Compared with ASA, treatment with VKA was associated with higher morbidity within 6 months after bioprosthetic AVR, suggesting that, particularly after concomitant CABG surgery, recipients of bioprosthetic AVR should receive prophylactic ASA instead of VKA.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial

No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. AstraZeneca.

Comparison of Radiologist Performance with Photon-Counting Full-Field Digital Mammography to Conventional Full-Field Digital Mammography

The purpose of this study was to assess the performance of a MicroDose photon-counting full-field digital mammography (PCM) system in comparison to full-field digital mammography (FFDM) for area under the receiver-operating characteristic (ROC) curve (AUC), sensitivity, specificity, and feature analysis of standard-view mammography for women presenting for screening mammography, diagnostic mammography, or breast biopsy. A total of 133 women were enrolled in this study at two European medical centers, with 67 women who had a pre-existing 10-36 months FFDM enrolled prospectively into the study and 66 women who underwent breast biopsy and had screening PCM and diagnostic FFDM, including standard craniocaudal and mediolateral oblique views of the breast with the lesion, enrolled retrospectively. The case mix consisted of 49 cancers, 17 biopsy-benign cases, and 67 normal cases. Sixteen radiologists participated in the reader study and interpreted all 133 cases in both conditions, separated by washout period of ≥4 weeks. ROC curve and free-response ROC curve analyses were performed for noninferiority of PCM compared to FFDM using a noninferiority margin Δ value of 0.10. Feature analysis of the 66 cases with lesions was conducted with all 16 readers at the conclusion of the blinded reads. Mean glandular dose was recorded for all cases. The AUC for PCM was 0.947 (95% confidence interval [CI], 0.920-0.974) and for FFDM was 0.931 (95% CI, 0.898-0.964). Sensitivity per case for PCM was 0.936 (95% CI, 0.897-0.976) and for FFDM was 0.908 (95% CI, 0.856-0.960). Specificity per case for PCM was 0.764 (95% CI, 0.688-0.841) and for FFDM was 0.749 (95% CI, 0.668-0.830). Free-response ROC curve figures of merit were 0.920 (95% CI, 0.881-0.959) and 0.903 (95% CI, 0.858-0.948) for PCM and FFDM, respectively. Sensitivity per lesion was 0.903 (95% CI, 0.846-0.960) and 0.883 (95% CI, 0.823-0.944) for PCM and FFDM, respectively. The average false-positive marks per image of noncancer cases were 0.265 (95% CI, 0.171-0.359) and 0.281 (95% CI, 0.188-0.374) for PCM and FFDM, respectively. Noninferiority P values for AUC, sensitivity (per case and per lesion), specificity, and average false-positive marks per image were all statistically significant (P < .001). The noninferiority P value for free-response ROC was <.025, from the 95% CI for the difference. Feature analysis resulted in PCM being preferred to FFDM by the readers for ≥70% of the cases. The average mean glandular dose for PCM was 0.74 mGy (95% CI, 0.722-0.759 mGy) and for FFDM was 1.23 mGy (95% CI, 1.199-1.262 mGy). In this study, radiologist performance with PCM was not inferior to that with conventional FFDM at an average 40% lower mean glandular dose.

What Disturbs Our Blood: A Son’s Quest to Redeem the Past (review)

Reviewed by: What Disturbs Our Blood: A Son’s Quest to Redeem the Past J.T.H. Connor What Disturbs Our Blood: A Son’s Quest to Redeem the Past. James Fitzgerald. Toronto: Random House Canada, 2010. Pp. 497, $34.95 When classifying What Disturbs Our Blood, one needs to address at least the following keywords: autobiography; biography; pathography; mental institutions, mental health and therapies; medical innovation and discovery; medical education; along with insecurity; infidelity; sex, drugs, rock ’n’ roll, and jazz! Prestigious medical and educational institutions such as Johns Hopkins, Cambridge, Queen’s, the Rockefeller Foundation, Connaught Laboratories, and the University of Toronto figure prominently in FitzGerald’s personal story; so too, such luminaries as Fred Banting, Charlie Best, and Clarence ‘C.B.’ Farrar. Duke Ellington makes an appearance too, as he knew the author’s father and, after his Toronto shows, would visit the FitzGerald home to tickle the ivories while filling the air with the pungent smoke of reefers – who knew such bohemianism existed in upscale Toronto during the 1950s? But FitzGerald’s main goal in writing this book is to see through this purple haze and uncover the many secrets that shrouded his and his family’s rollercoaster history. In attempting to redeem this past, FitzGerald had to delve deep into his own, his father’s, and his grandfather’s lives to reveal their painful struggles with mental illness that too often resulted in attempted or fulfilled suicide. On this journey, [End Page 732] the author discovers that his grandfather, Dr John Gerald ‘Gerry’ Fitz-Gerald, was a truly significant figure in the history of Canadian medicine. Gerry FitzGerald graduated in medicine from the University of Toronto in 1903 and would embark on a career of neurology and psychiatry in an effort to understand the links between body and mind. After postgraduate training with the eminent Dr Adolf Meyer at the Buffalo State Asylum for the Insane (the man who ‘invented’ the term depression), Gerry travelled to Baltimore’s Johns Hopkins Medical School, where he met C.B. Farrar, who appointed him a clinical assistant in the Sheppard and Enoch Pratt Hospital, a private institution for the treatment of nervous diseases. In 1906 he returned to Toronto as pathologist at the asylum at 999 Queen Street West. FitzGerald continued to take extensive trips to the United States as well as key medical centres in Europe, where he was to learn from different research institutes and their functioning. Inspired by these models, FitzGerald created a medical farm ‘factory’ following a rabies outbreak in 1913; this initially modest enterprise would evolve into the University of Toronto Connaught Laboratories, which produced millions of doses of vaccine and antitoxins (against rabies, smallpox, typhoid, diphtheria, tetanus, and meningitis) for Ontario. In the following decade, Connaught would be pivotal in the early production, purification, and standardization of insulin. By 1927, FitzGerald was also heading up the university’s pioneering public health unit known as the School of Hygiene; five years later, he was appointed dean of medicine in the University of Toronto. Then, in 1938, suddenly, FitzGerald ‘went off the deep end’ when he suffered a complete mental breakdown. Two years later, he committed suicide in the Toronto General Hospital, following a previously unsuccessful attempt and after incarceration in a tony American mental hospital where he endured insulin shock therapy – excruciating details of which were preserved in a series of letters between him and C.B. Farrar, who had since become a Toronto colleague and physician-confidante to FitzGerald. Such archival documents well illustrate the author’s research skills. The biography of Gerry’s son, ‘Jack,’ is disturbingly similar to that of his father. Educated first at McGill and Cambridge, Jack FitzGerald then graduated in medicine from the University of Toronto in 1942; he would also undertake postgraduate study at Johns Hopkins. A successful allergist at Toronto Western Hospital who also had a medical entrepreneurial bent, his life was plagued by strained marriages along with his own personal mental health issues. During his life he was a patient at 999 Queen, Clarke Institute of Psychiatry, Donwoods Institute, and Homewood; he was also subjected to insulin sub coma treatment, [End Page 733] electroconvulsive...

Safety of Screening Procedures With Hand-Held Metal Detectors Among Patients With Implanted Cardiac Rhythm Devices

Case reports suggest that the hand-held metal detectors used for security screening generate electromagnetic fields that may interfere with pacemaker and implantable cardioverter-defibrillator (ICD) function. To assess changes in function of pacemakers and ICDs after exposure to hand-held metal detectors. Cross-sectional study. Two medical centers in Europe. 388 patients (209 with pacemakers and 179 with ICDs) presenting for routine follow-up of device function between September 2009 and December 2010. Abnormalities on electrocardiography suggestive of rhythm device malfunction (pacing inhibition, loss of capture, inappropriate mode switch, ventricular oversensing, and spontaneous reprogramming) after 30 seconds of exposure to 2 widely used hand-held metal detectors with a maximal electromagnetic flux density of 6.3 µT. No change in device function, including pacing or sensing abnormalities or device reprogramming, was observed in any patient. The study included a convenience sample of patients, and the number of different device models tested was small. Testing was conducted in 2 clinic settings. Hand-held metal detectors did not affect the function of pacemakers or ICDs in this sample. The use of hand-held metal detectors for security screening is probably safe for patients with pacemakers and ICDs, but these findings require confirmation. None.

Efficacy of an Artificial Neural Network–Based Approach to Endoscopic Ultrasound Elastography in Diagnosis of Focal Pancreatic Masses

By using strain assessment, real-time endoscopic ultrasound (EUS) elastography provides additional information about a lesion's characteristics in the pancreas. We assessed the accuracy of real-time EUS elastography in focal pancreatic lesions using computer-aided diagnosis by artificial neural network analysis. We performed a prospective, blinded, multicentric study at of 258 patients (774 recordings from EUS elastography) who were diagnosed with chronic pancreatitis (n = 47) or pancreatic adenocarcinoma (n = 211) from 13 tertiary academic medical centers in Europe (the European EUS Elastography Multicentric Study Group). We used postprocessing software analysis to compute individual frames of elastography movies recorded by retrieving hue histogram data from a dynamic sequence of EUS elastography into a numeric matrix. The data then were analyzed in an extended neural network analysis, to automatically differentiate benign from malignant patterns. The neural computing approach had 91.14% training accuracy (95% confidence interval [CI], 89.87%-92.42%) and 84.27% testing accuracy (95% CI, 83.09%-85.44%). These results were obtained using the 10-fold cross-validation technique. The statistical analysis of the classification process showed a sensitivity of 87.59%, a specificity of 82.94%, a positive predictive value of 96.25%, and a negative predictive value of 57.22%. Moreover, the corresponding area under the receiver operating characteristic curve was 0.94 (95% CI, 0.91%-0.97%), which was significantly higher than the values obtained by simple mean hue histogram analysis, for which the area under the receiver operating characteristic was 0.85. Use of the artificial intelligence methodology via artificial neural networks supports the medical decision process, providing fast and accurate diagnoses.

Direct hemoperfusion with polymyxin B immobilized fiber for abdominal sepsis in Europe

Since direct hemoperfusion with polymyxin B immobilized fiber (PMX-DHP) received its product certification for use in Europe in 1998, several prospective randomized controlled trials (RCTs) have been conducted in European countries. The first RCT, performed in six European academic medical centers in 2005, concluded that PMX-DHP is associated with improved hemodynamic status and cardiac function. Subsequently, a meta-analysis of PMX-DHP was presented in Italy in 2007. This systematic review found positive effects of PMX-DHP on mean arterial pressure and dopamine/ dobutamine use, PaO2/FiO2 ratio, endotoxin removal, and mortality. However, like most trials on extracorporeal therapies, none of the studies was double-blinded. The EUPHAS study, a multicenter RCT performed in ten Italian intensive care units in 2009, found that PMX-DHP improved 28-day survival, blood pressure, vasopressor requirement, and degree of organ failure. However, investigators in Belgium and Canada pointed out that there was no statistical difference in 28-day survival. Two more RCTs, the ABDO-MIX and EUPHRATES studies, the primary end points of which are 28-day mortality, were started in Europe and the United States at the end of 2010. We are hoping that these RCTs will resolve this issue.

Eight-year (2002-2009) Summary of the Linezolid (Zyvox® Annual Appraisal of potency and Spectrum; ZAAPS) Program in European Countries

The linezolid surveillance network (ZAAPS program) has been monitoring linezolid activity and susceptibility rates for eight years (2002-2009) in European medical centers. Samples from 12-24 sites annually in 11 countries were monitored by a central laboratory design using reference MIC methods with international and regional interpretations (EUCAST). A total of 13,404 Gram-positive pathogens were tested from 6 pathogen groups. Linezolid remained without documented resistance from 2002 through 2005, but beginning in 2006 resistant strains emerged at very low rates among Staphylococcus aureus (G2576T mutant in ireland, 2007), coagulase-negative staphylococci (CoNS; usually Staphylococcus epidermidis, France and italy in 2006-2009) and enterococci (Enterococcus faecium in Germany [2006, 2008, 2009] and E. faecalis in Sweden [2008], United Kingdom [2008] and Germany [2009]); all but one strain having a target mutation. A mobile cfr was detected in an italian CoNS strain (2008 and 2009), and clonal spread was noted for linezolid-resistant strains (pfGe results). Overall the linezolid susceptibility rates were >99.9, 99.7 and 99.6% for S. aureus, CoNS and enterococci, respectively; and all streptococcal strains were susceptible (MIC90, 1 mg/L). In conclusion, the ZAAPS program surveillance confirmed high, sustained levels of linezolid activity from 2002-2009 and without evidence of MIC creep or escalating resistance in Gram-positive pathogens across monitored European nations.

Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial

No treatments are presently available to increase survival in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy. We aimed to assess efficacy and safety of zalutumumab, a human IgG1 monoclonal antibody targeting the epidermal growth factor receptor, for overall survival in such patients. In our open-label, parallel-group, phase 3, randomised trial, we randomly allocated patients with squamous-cell carcinoma of the head and neck who were regarded as incurable with standard therapy, a WHO performance status of 0-2, and progressive disease within 6 months of platinum-based therapy in a 2:1 ratio to receive zalutumumab plus best supportive care (zalutumumab group) or best supportive care with optional methotrexate (control group) at medical centres in Europe, Brazil, and Canada. Randomisation was done via a centralised interactive voice-response system, stratified by performance status. Data were analysed when the randomisation code was broken, after the completion of the accrual and cleaning of the relevant data. An independent review committee, masked to treatment assignment, assessed tumour response and disease progression according to response evaluation criteria in solid tumours. Zalutumumab was given weekly by individual dose titration on the basis of skin rash. After a prespecified 231 deaths, we included all randomised patients in the survival analyses and all patients receiving at least one session of therapy in the safety analysis. The primary endpoint was overall survival, although progression-free survival was also assessed. This trial is registered with ClinicalTrials.gov, NCT00382031. We randomly allocated 191 (67%) of 286 eligible patients to the zalutumumab group and 95 (33%) to the control group. Median overall survival was 6.7 months (95% CI 5.8-7.0) in the zalutumumab group and 5.2 months (4.1-6.4) in the control group (hazard ratio [HR] for death, stratified by WHO performance status, was 0.77, 97.06% CI 0.57-1.05; unadjusted p=0.0648). Progression-free survival was longer in the zalutumumab group than in the control group (HR for progression or death, stratified by WHO performance status, was 0.63, 95% CI 0.47-0.84; p=0.0012). 189 patients given zalutumumab and 94 controls were included in the safety analysis. The most common grade 3-4 adverse events were rash (39 [21%] patients in the zalutumumab group vs none in the control group), anaemia (11 [6%] vs five [5%]), and pneumonia (nine [5%] vs two [2%]). 28 (15%) patients in the zalutumumab group had grade 3/4 infections compared with eight (9%) in the control group. The most common serious adverse events were tumour haemorrhage (28 [15%] patients given zalutumumab vs 13 [14%] controls), pneumonia (13 [7%] vs three [3%]), and dysphagia (11 [6%] vs two [2%]). Although zalutumumab did not increase overall survival, progression-free survival was extended in patients with recurrent squamous-cell carcinoma of the head and neck who had failed platinum-based chemotherapy. Zalutumumab dose titration on the basis of rash is safe. Genmab.

Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity

Ceftaroline fosamil is a novel cephalosporin with broad-spectrum activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae, and common Gram-negative organisms. The activity of ceftaroline against MRSA is attributed to its ability to bind to penicillin-binding protein (PBP) 2a with high affinity and inhibit the biochemical activity of PBP 2a more efficiently than other presently available β-lactams. The activity of ceftaroline against MRSA and the β-haemolytic streptococci makes it an attractive monotherapy agent for the treatment of complicated skin and skin structure infections (cSSSIs). Recent profiling and surveillance studies have shown that ceftaroline is active against contemporary skin pathogens collected from US and European medical centres in 2008. The mean free drug %T > MIC (percentage of time the drug concentration remains above the MIC) needed for stasis ranged from 26% for S. aureus to 39% for S. pneumoniae in the murine thigh infection model. Pharmacokinetic and pharmacodynamic target attainment predictions for 600 mg of ceftaroline fosamil every 12 h showed that the mean %T > MICs for which plasma free-drug concentrations exceeded an MIC of 1 and 2 mg/L were 71% and 51% of the dosing interval, respectively. For a 40% T > MIC target, the predicted attainments for infections due to pathogens for which ceftaroline MICs were 1 or 2 mg/L were 100% and 90%, respectively. Clinical and microbiological successes of ceftaroline fosamil in treating cSSSIs were demonstrated in two Phase III clinical studies, in which 96.8% of all baseline cSSSI isolates from the microbiologically evaluable population were inhibited by ceftaroline at ≤ 2 mg/L. Ceftaroline fosamil is a promising broad-spectrum agent for the treatment of cSSSIs.

Update on Fusidic Acid (CEM-102) Tested against Neisseria gonorrhoeae and Chlamydia trachomatis

Sexually transmitted diseases (STDs), including urethritis caused by gonococcus and Chlamydia trachomatis, are of increasing public health importance (1, 3, 6, 7, 9). The common occurrence of coinfections and the emergence of antimicrobial resistance of both pathogens emphasize the need for a single broadly active drug for management of these STDs (2, 3, 7, 9, 11-13). Penicillins and other beta-lactam agents effective against susceptible gonococci are ineffective against chlamydia. However, fluoroquinolones and macrolides provide broad coverage for both pathogens, but the emergence of gonococcal resistance within these classes limits their utility (2, 3, 9, 11-13). Early descriptions of the in vitro spectrum of activity of fusidic acid indicated the susceptibility of a limited number of Neisseria gonorrhoeae isolates (MIC range of 0.40 to 0.89 μg/ml) (8). This report examines the in vitro susceptibility of recent isolates of N. gonorrhoeae and C. trachomatis to fusidic acid (CEM-102; sodium fusidate), a potential alternative therapy for use in this clinical setting. Thirty-five clinical isolates of N. gonorrhoeae collected in the United States, Asia, and European medical centers since 2005 were tested using reference agar dilution methods per the Clinical and Laboratory Standards Institute (CLSI) M07-A8 (4) and M100-S20 (5) documents. Five strains were penicillinase positive, and all gonococci were identified to the species level by at least two laboratories, including a reference, central laboratory (JMI Laboratories, North Liberty, IA). Resistance phenotypes were determined by agar dilution test results, followed by the use of confirmatory techniques as required by CLSI M100-S20 criteria (5). The quality control (QC) ranges and interpretive criteria for comparator compounds were as published by the CLSI (5). The tested QC strains included Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, and N. gonorrhoeae ATCC 49226, with all results being within established limits. The activities of fusidic acid and five comparators tested against N. gonorrhoeae are shown in Table ​Table1.1. The resistance rates for this organism collection were as follows (each pair of values represents the CLSI and EUCAST criteria, respectively): for penicillin, 45.7 and 45.7%; for tetracycline, 34.3 and 34.3%; for ciprofloxacin, 20.0 and 48.6%; for ceftriaxone, no criteria and 0.0%; and for azithromycin, no criteria and 5.7%. The MIC90 of fusidic acid against these N. gonorrhoeae isolates was only 1 μg/ml. According to the MIC50 (0.5-μg/ml) results, fusidic acid was 2-fold more active than penicillin and tetracycline (MIC50, 1 μg/ml) but slightly less potent than azithromycin (MIC50, 0.25 μg/ml). Fusidic acid was active against all strains of N. gonorrhoeae tested at ≤2 μg/ml. TABLE 1. Activity of fusidic acid and five comparator agents tested against a comprehensive resistant challenge collection of 35 contemporary N. gonorrhoeae isolates Ten isolates of C. trachomatis, including standard isolates from the ATCC (E-BOUR, F-IC-CAL3, C-HAR32, J-UW-36, L2434, D-UW-57kx, and B-HAR-36) and recent clinical isolates N18 (cervical), N19 (cervical), and 7015 (infant eye), were selected for study. Susceptibility testing was performed with cell culture by use of HEp-2 cells (13) at State University of New York, Downstate Medical Center (Brooklyn, NY). The activity of fusidic acid against C. trachomatis was compared with those of azithromycin, clarithromycin, telithromycin, and doxycycline (Table ​(Table2).2). The MIC range of fusidic acid against C. trachomatis was 0.12 to 0.5 μg/ml, with identical fusidic acid MBC90 and MIC90 values for this organism of 0.5 μg/ml. The MIC90 values for azithromycin, clarithromycin, telithromycin, and doxycycline were 0.12, 0.06, 0.06, and 0.06 μg/ml, respectively, each 2- to 4-fold lower than that for fusidic acid. TABLE 2. Activity of fusidic acid and four comparator agents tested against 10 C. trachomatis strains These in vitro testing data suggest that fusidic acid may be considered an alternative treatment for multidrug-resistant N. gonorrhoeae strains and could provide an advantage for treatment of STD as a single agent targeting both gonococcus and C. trachomatis (1, 3, 7, 9). The pharmacokinetics of fusidic acid has recently been modeled to define safe high-dose regimens designed to attenuate selection of resistance that was reported for doses originally approved for clinical use in Europe and Australia as well as to maximize potency versus cutaneous infection pathogens such as Staphylococcus aureus (10, 14). These modified dosing schedules achieve fusidic acid trough plasma levels of ca. 80 μg/ml, representing 40- to 160-fold-greater concentrations than the highest N. gonorrhoeae or C. trachomatis MIC result found in this report (8, 10, 14). However, fusidic acid urinary tract concentrations are limited. Further investigations of fusidic acid are needed to determine its potential role for STDs caused by these two pathogens.

Activity of telavancin and comparator antimicrobial agents tested against Staphylococcus spp. isolated from hospitalised patients in Europe (2007–2008)

The activity of telavancin was evaluated against Staphylococcus spp. collected from European hospitals as part of an international surveillance study (2007–2008). A total of 7534 staphylococcal clinical isolates [5726 Staphylococcus aureus and 1808 coagulase-negative staphylococci (CoNS)] were included. Isolates were tested for susceptibility according to reference methods and minimum inhibitory concentration (MIC) values were interpreted based on Clinical and Laboratory Standards Institute (CLSI) 2010 and European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2009 criteria. Telavancin breakpoints approved by the US Food and Drug Administration (FDA) were applied. Telavancin activity was evaluated against meticillin-resistant S. aureus (MRSA) displaying several antibiogram resistance patterns, including multidrug-resistant isolates. Telavancin was active against S. aureus [MIC 50/90 values (MICs for 50% and 90% of the isolates, respectively) = 0.12/0.25 mg/L; 100.0% susceptible] and CoNS (MIC 50/90 = 0.12/0.25 mg/L), inhibiting all isolates at ≤0.5 mg/L. Similar results were observed when S. aureus were stratified by year or country of origin (MIC 50/90 = 0.12/0.25 mg/L). When MRSA isolates were clustered according to 48 different resistance patterns, telavancin showed consistent MIC 90 values (0.25 mg/L) regardless of multidrug resistance. Amongst CoNS, telavancin was slightly more active against Staphylococcus capitis, Staphylococcus epidermidis, Staphylococcus hominis, Staphylococcus lugdunensis and Staphylococcus xylosus (MIC 50 = 0.12 mg/L) compared with Staphylococcus haemolyticus, Staphylococcus saprophyticus and Staphylococcus warneri (MIC 50 = 0.25 mg/L). Overall, telavancin exhibited MIC 90 results two- to eight-fold lower than comparators (daptomycin, quinupristin/dalfopristin, vancomycin and linezolid). Based upon MIC 90 values, telavancin demonstrated potent in vitro activity against a contemporary (2007–2008) collection of Staphylococcus spp. recovered from nearly 30 European medical centres.

Multicenter Study of 19 Aortopulmonary Window Parathyroid Tumors: The Challenge of Embryologic Origin

Ectopic abnormal parathyroid glands are relatively common in the superior mediastinum but are rarely situated in the aortopulmonary window (APW). The embryological origin of these abnormal parathyroid glands is controversial. The purpose of this investigation was to investigate the embryological origin and the surgical management of abnormal parathyroid glands situated in the APW. The databases of patients operated on for primary, secondary, and tertiary hyperparathyroidism at eight European medical centers with a special interest in endocrine surgery were reviewed to identify those with APW adenomas. Demographic features, localization procedures, and perioperative and pathology findings were documented. The embryological origin was determined based on the number and position of identified parathyroid glands. Nineteen (0.24%) APW parathyroid tumors were identified in 7,869 patients who underwent an operation for hyperparathyroidism (HPT) and 181 patients (2.3%) with mediastinal abnormal parathyroid glands. Ten patients had primary, eight had secondary, and one had tertiary HPT. Sixteen patients had undergone previous unsuccessful cervical exploration. In three patients, an APW adenoma was suspected by preoperative localization studies and was cured at the initial operation. Sixteen patients had persistent HPT of whom 15 were reoperated, resulting in 6 failures. Evaluation of 17 patients who had bilateral neck exploration allowed us to determine the most probable origin of the APW parathyroid tumors: 12 were supernumerary, 4 appeared to originate from a superior, and 1 from an inferior gland. Abnormal parathyroid glands situated in the APW are rare and usually identified after an unsuccessful cervical exploration. Preoperative imaging of the mediastinum and neck are essential. The origin of these ectopically situated tumors is probably, as suggested by our data, from a supernumerary fifth parathyroid gland or from abnormal migration of a superior parathyroid gland during the embryologic development.

Fractional Flow Reserve Versus Angiography for Guiding Percutaneous Coronary Intervention in Patients With Multivessel Coronary Artery Disease: 2-Year Follow-Up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) Study

The purpose of this study was to investigate the 2-year outcome of percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) in patients with multivessel coronary artery disease (CAD). In patients with multivessel CAD undergoing PCI, coronary angiography is the standard method for guiding stent placement. The FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study showed that routine FFR in addition to angiography improves outcomes of PCI at 1 year. It is unknown if these favorable results are maintained at 2 years of follow-up. At 20 U.S. and European medical centers, 1,005 patients with multivessel CAD were randomly assigned to PCI with drug-eluting stents guided by angiography alone or guided by FFR measurements. Before randomization, lesions requiring PCI were identified based on their angiographic appearance. Patients randomized to angiography-guided PCI underwent stenting of all indicated lesions, whereas those randomized to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was ≤0.80. The number of indicated lesions was 2.7 ± 0.9 in the angiography-guided group and 2.8 ± 1.0 in the FFR-guided group (p = 0.34). The number of stents used was 2.7 ± 1.2 and 1.9 ± 1.3, respectively (p < 0.001). The 2-year rates of mortality or myocardial infarction were 12.9% in the angiography-guided group and 8.4% in the FFR-guided group (p = 0.02). Rates of PCI or coronary artery bypass surgery were 12.7% and 10.6%, respectively (p = 0.30). Combined rates of death, nonfatal myocardial infarction, and revascularization were 22.4% and 17.9%, respectively (p = 0.08). For lesions deferred on the basis of FFR >0.80, the rate of myocardial infarction was 0.2 % and the rate of revascularization was 3.2 % after 2 years. Routine measurement of FFR in patients with multivessel CAD undergoing PCI with drug-eluting stents significantly reduces mortality and myocardial infarction at 2 years when compared with standard angiography-guided PCI. (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation [FAME]; NCT00267774 )

Antimicrobial susceptibility of Gram-positive cocci isolated from skin and skin-structure infections in European medical centres

Skin and skin-structure infections (SSSIs) usually involve Gram-positive organisms. Prompt initiation of appropriate antimicrobial treatment is essential for achieving a favourable outcome in severe cases. Empirical antibacterial therapy should be based on several considerations, including patient risk factors, expected pathogens and local/regional susceptibility profiles, among others. In the present study, we evaluated the antimicrobial susceptibility patterns of Gram-positive bacteria isolated from patients with SSSIs hospitalised in European medical centres. A total of 3573 bacterial isolates were collected from 33 medical centres located in 13 European countries as well as Israel over a 6-year period (2003–2008) and were tested for susceptibility to daptomycin and other comparator agents by reference broth microdilution methods in a central laboratory. The most frequently isolated organisms were Staphylococcus aureus (71.1%), β-haemolytic streptococci (10.5%) and enterococci (9.3%). Overall, rates of meticillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE) were 22.5% and 5.1%, respectively, but with great intercountry variation. The overall MRSA rate varied slightly during the study period, but with no overall tendency toward increase or decrease, whilst the overall VRE rate consistently increased from 1.5% in 2003 to 11.0% in 2008. Daptomycin and linezolid were the most active agents tested overall. All isolates monitored were considered susceptible to daptomycin, and only one isolate ( Enterococcus faecium) was categorised as non-susceptible to linezolid. In conclusion, the results of this contemporary surveillance study indicate that daptomycin and linezolid retain sustained in vitro activity against Gram-positive cocci isolated from patients hospitalised with SSSI in numerous European medical centres.

Update on the In Vitro Activity of Daptomycin Tested against 17,193 Gram-positive Bacteria Isolated From European Medical Centers (2005-2007)

The antimicrobial susceptibility patterns of 17,193 Gram-positive isolates consecutively collected from 28 medical centers in 12 countries in Europe and Israel in 2005-2007 were evaluated by Clinical and laboratory Standards institute (CLSI) broth microdilution methods supplemented with calcium to 50 mg/L for testing daptomycin. Overall, the rate of methicillin-re-sistant Staphylococcus aureus(MRSA) was 28.3%, varying from 32.3% in 2005 to 27.1% in 2006 and 28.5% in 2007. Vancomycin resistance rates were 0.8% and 21.5% among Enterococcus faecalis and E. faecium, respectively. Among E. faecium, vancomycin resistance increased from 17.9% in 2005 to 26.3% in 2007, and varied from 0.0% in Spain, Sweden and Switzerland to as high as 54.6% in ireland for 2007. All isolates tested, except for seven CoNS(0.2%; 3,234 tested) were considered susceptible to daptomycin using breakpoints establishedby the United States food and Drug Administration, the CLSI and the EUCAST. Daptomycin wasvery active against all Gram-positive species with the highest minimum inhibitory concentration(MIC) results being 1, 4, 2 and 4 mg/L for S. aureus, coagulase-negative staphylococci, E. faecalis and E. faecium, respectively. Daptomycin activity was not adversely influenced by resistanceto oxacillin among staphylococci or to vancomycin among enterococci.

Efficacy of Radiofrequency Ablation Combined With Endoscopic Resection for Barrett's Esophagus With Early Neoplasia

Radiofrequency ablation (RFA) is safe and effective for eradicating intestinal metaplasia and neoplasia in patients with Barrett's esophagus. We sought to assess the safety and efficacy of RFA in conjunction with baseline endoscopic resection for high-grade intraepithelial neoplasia (HGIN) and early cancer. This multicenter, prospective cohort study included 24 patients (mean age, 65 years; median Barrett's esophagus, 8 cm), with Barrett's esophagus of < or =12 cm containing HGIN or early cancer, from 3 European tertiary-care medical centers. Visible lesions were endoscopically resected, followed by serial RFA. Focal escape endoscopic resection was used if Barrett tissue persisted despite RFA. Complete response, defined as all biopsies negative for intestinal metaplasia and neoplasia, was assessed during endoscopy with 4-quadrant biopsies taken every 1 cm of the original Barrett's segment 2 months after the patient was last treated. Twenty-three patients underwent pre-RFA endoscopic resection for visible lesions; 16 patients had early cancer and 7 patients had HGIN. The worst residual histology results, pre-RFA (after any endoscopic resection) were: HGIN (10 patients), low-grade intraepithelial neoplasia (11 patients), and intestinal metaplasia (3 patients). Neoplasia and intestinal metaplasia were eradicated in 95% and 88% of patients, respectively; after escape endoscopic resection in 2 patients, rates improved to 100% and 96%, respectively. Complications after RFA included melena (n = 1) and dysphagia (n = 1). After additional follow-up (median, 22 months; interquartile range, 17.2-23.8 months) no neoplasia recurred. This European multicenter study to show that early neoplasia in Barrett's esophagus can be effectively and safely treated with RFA, in combination with prior endoscopic resection of visible lesions.