A Randomized, Placebo-Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome.

BACKGROUND: New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role. OBJECTIVE: The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment. METHODS: A 2-week double-blind, placebo-controlled crossover study assessed the efficacy of dipyridamole (possible up-titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Severity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response. RESULTS: Twenty-eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean ± standard deviation of 24.1 ± 3.1 at baseline to 11.1 ± 2.3 at the end of week 2, versus 23.7 ± 3.4 to 18.7 ± 3.2 under placebo (P < 0.001). Clinical Global Impression, Medical Outcomes Study Sleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 ± 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 ± 3.5 versus. 28.1 ± 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%). CONCLUSIONS: Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Development of Aspergillosis in a cohort of non-neutropenic, non-transplant patients colonised by Aspergillus spp.

BACKGROUND: A previous study explored factors discriminating colonization and true infection among non-transplant, non-neutropenic patients with repeated Aspergillus spp. isolation from lower respiratory samples. The present study explored the evolution of patients with Aspergillus colonization in that study to determine the percentage of cases progressing to aspergillosis and time to development. METHODS: Clinical records were retrospectively reviewed (for each patient from his end date in the past study) and data from all respiratory processes suffered by patients up to April 2015 were recorded. Comparisons of variables were performed between colonized patients that developed aspergillosis and those that did not. A Kaplan-Meier curve was used to describe time to development of aspergillosis in chronic obstructive pulmonary disease (COPD) patients for II-IV stages of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. RESULTS: Sixty seven colonized patients were followed, 12 of them (17.9%) developed aspergillosis. Diagnoses included six tracheobronchitis (4 invasive, 2 simple tracheobronchitis), four pulmonary disease (2 invasive pulmonary aspergillosis, 2 chronic pulmonary aspergillosis), one allergic bronchopulmonary aspergillosis and one pulmonary aspergilloma. Up to 47 (70.4%) of the study patients presented COPD. Among patients developing aspergillosis COPD was more frequent (100%) than among those that did not develop aspergillosis (35 out of 55; 63.6%) (p = 0.012), as well as GOLD IV patients were more frequent among COPD patients developing aspergillosis than among COPD patients that did not (50.0 vs. 26.1%, p = 0.046). Mean time to development of aspergillosis was 18.4 months (median: 8.5) with a wide range (1-58). Overtime, the percentage of patients developing aspergillosis was significantly higher among GOLD IV patients than among GOLD II-III patients (p = 0.032). CONCLUSIONS: The high percentage of cases progressing to aspergillosis among colonized patients, especially among those with COPD (25.5%), stresses the importance of colonization as risk factor, and creates awareness of the possible change from colonization to invasive disease in GOLD IV patients.

Risk factors for colonization by carbapenemase-producing enterobacteria at admission to a Surgical ICU: A retrospective study.

INTRODUCTION: In 2011, a hospital-wide outbreak of OXA-48 producing Klebsiella pneumoniae occurred in our hospital, an epidemiological setting of high ESBL-producing K. pneumoniae rates. This study identifies risk factors for colonization with carbapenemase-producing enterobacteria (CPE) at Surgical Intensive Care Unit (SICU) admission. METHODS: A 2-year retrospective study was performed in all patients admitted to the SICU that following routine had a rectal swab collected upon admission. RESULTS: Of 254 patients admitted, 41 (16.1%) harbored CPE (five showing two carbapenemase-producing isolates). Most frequent carbapenemase-producing isolates and carbapenemases were K. pneumoniae (39/46, 84.8%) and OXA-48 (31/46; 76.1%), respectively. Carriers significantly had higher rates of chronic renal disease, previous digestive/biliary endoscopy, hospitalization, ICU/SICU admission, intraabdominal surgery, and antibiotic intake, as well as higher median values of clinical scores (SOFA, SAPS II and APACHE II). In the multivariate analysis (R2=0.309, p<0.001), CPE carriage was associated with prior administration of 3rd-4th generation cephalosporins (OR=27.96, 95%CI=6.88, 113.58, p<0.001), ß-lactam/ß-lactamase inhibitor (OR=11.71, 95%CI=4.51, 30.43, p<0.001), abdominal surgery (OR=6.33, 95%CI=2.12, 18.89, p=0.001), and prior digestive/biliary endoscopy (OR=3.88, 95%CI=1.56, 9.67, p=0.004). CONCLUSIONS: A strong association between production of ESBLs and carriage of CPE (mainly OXA-48 producing K. pneumoniae) was found. According to the model, the co-selection of ß-lactamases by previous exposure to broad-spectrum cephalosporins and ß-lactam/ß-lactamase inhibitors (with lower relative risk), abdominal surgery and prior digestive/biliary endoscopy were factors associated with CPE carriage.

Treatment of Sleep, Motor and Sensory Symptoms with the Orexin Antagonist Suvorexant in Adults with Idiopathic Restless Legs Syndrome: A Randomized Double-Blind Crossover Proof-of-Concept Study.

BACKGROUND AND OBJECTIVES: Current treatment guidelines for restless legs syndrome (RLS) recommend treatment be initiated with non-dopaminergic drugs. Given the potential role of orexins in the pathophysiology of RLS, we performed a pilot, proof-of-concept study to investigate the therapeutic effects of suvorexant, a dual orexin receptor antagonist (DORA), on sleep and sensory/motor symptoms in individuals with idiopathic RLS. METHODS: This was a randomized, double-blind, crossover and placebo-controlled study. Inclusion criteria were diagnosis with idiopathic RLS, an International RLS Study Group Severity Rating Scale (IRLS) score > 15, and the absence of significant RLS symptoms before 9 pm. Following washout from any previous central nervous system (CNS)-active drugs, patients were randomized to receive either suvorexant or placebo for two consecutive 2-week treatment periods. Treatment was administered at 9 pm at a fixed dose of 10 mg/day during the first week, and 20 mg during the second week. Primary and coprimary endpoints were wake after sleep onset (WASO) and total sleep time (TST), respectively, while IRLS rating scale score, multiple suggested immobilization tests (m-SIT), and periodic limb movements (PLMs) were secondary endpoints. RLS severity was measured weekly using the IRLS and Clinical Global Improvement (CGI) scales. m-SIT were also performed between 8 pm and midnight at the end of each treatment phase and were followed by a sleep study. RESULTS: A total of 41 participants were randomized, 40 of whom completed the study. Compared with placebo, treatment with suvorexant significantly improved RLS symptoms (according to IRLS total score, CGI, and the m-SIT), PLM during sleep, and PLM with arousal. Improvement of RLS symptoms was greater in those who had not been exposed to dopaminergic agents in the past. Sleep architecture also improved with significant changes in TST, WASO, sleep onset latency, sleep efficiency, non rapid-eye movement stage 1 (N1) %, non rapid-eye movement stage 2 (N2) %, and rapid eye movement (REM) %. Suvorexant was well tolerated in RLS, with few and mild adverse events. CONCLUSIONS: Our results provide the first proof of evidence of the therapeutic efficacy of DORAs in improving sleep and sensory and motor symptoms in RLS. Given orexin's role in pain and sensory processing, potential mechanisms of action are discussed. CLASSIFICATION OF EVIDENCE: The study provides class II evidence supporting the therapeutic efficacy of suvorexant in patients with RLS with sleep disturbance. TRIAL REGISTRATION: EudraCT#: 2017-004580-12.

In vitro interference of tigecycline at subinhibitory concentrations on biofilm development by Enterococcus faecalis.

OBJECTIVES: Since biofilm formation is the hallmark of Enterococcus faecalis isolates, the aim of this study was to quantify biofilm formation in the presence of subinhibitory concentrations of tigecycline. METHODS: Interference of tigecycline on biofilm formation was spectrophotometrically quantified using 20 biofilm-producing E. faecalis isolates with tigecycline MICs of 0.12 (8 strains) or 0.25 mg/L (12 strains). Biofilm production was measured in antibiotic-free tryptic soy broth supplemented with 1% glucose and compared with biofilm production in the same medium with tigecycline at subinhibitory concentrations (0.25× or 0.5× MIC, similar to trough concentrations in serum or concentrations in the colon after a standard dose) by reading the optical density at 450 nm (OD(450)) after staining with Crystal Violet. RESULTS: In the presence of subinhibitory tigecycline concentrations, pooled OD(450) values for the 20 strains [median (IQR)] were significantly lower than those for controls: 0.468 (0.379-0.516) for antibiotic-free controls versus 0.295 (0.200-0.395) for 0.25× MIC tigecycline (P < 0.001) and 0.287 (0.245-0.479) for 0.5× MIC tigecycline (P < 0.001), with significant differences between pooled OD(450) values obtained with each concentration of tigecycline (P = 0.022). In 17 out of 20 (85%) strains the OD(450) obtained with 0.25× MIC tigecycline was significantly (P < 0.05) lower than the basal OD(450), while this occurred in 12 out of 20 (60%) strains with 0.5× MIC. CONCLUSIONS: In vitro tigecycline subinhibitory concentrations were able to interfere with biofilm formation by E. faecalis.

Repeated Aspergillus isolation in respiratory samples from non-immunocompromised patients not selected based on clinical diagnoses: colonisation or infection?

BACKGROUND: Isolation of Aspergillus from lower respiratory samples is associated with colonisation in high percentage of cases, making it of unclear significance. This study explored factors associated with diagnosis (infection vs. colonisation), treatment (administration or not of antifungals) and prognosis (mortality) in non-transplant/non-neutropenic patients showing repeated isolation of Aspergillus from lower respiratory samples. METHODS: Records of adult patients (29 Spanish hospitals) presenting ≥ 2 respiratory cultures yielding Aspergillus were retrospectively reviewed and categorised as proven (histopathological confirmation) or probable aspergillosis (new respiratory signs/symptoms with suggestive chest imaging) or colonisation (symptoms not attributable to Aspergillus without dyspnoea exacerbation, bronchospasm or new infiltrates). Logistic regression models (step-wise) were performed using Aspergillosis (probable + proven), antifungal treatment and mortality as dependent variables. Significant (p < 0.001) models showing the highest R2 were considered. RESULTS: A total of 245 patients were identified, 139 (56.7%) with Aspergillosis. Aspergillosis was associated (R2 = 0.291) with ICU admission (OR = 2.82), congestive heart failure (OR = 2.39) and steroids pre-admission (OR = 2.19) as well as with cavitations in X-ray/CT scan (OR = 10.68), radiological worsening (OR = 5.22) and COPD exacerbations/need for O2 interaction (OR = 3.52). Antifungals were administered to 79.1% patients with Aspergillosis (100% proven, 76.8% probable) and 29.2% colonised, with 69.5% patients receiving voriconazole alone or in combination. In colonised patients, administration of antifungals was associated with ICU admission at hospitalisation (OR = 12.38). In Aspergillosis patients its administration was positively associated (R(2) = 0.312) with bronchospasm (OR = 9.21) and days in ICU (OR = 1.82) and negatively with Gold III + IV (OR = 0.26), stroke (OR = 0.024) and quinolone treatment (OR = 0.29). Mortality was 78.6% in proven, 41.6% in probable and 12.3% in colonised patients, and was positively associated in Aspergillosis patients (R2 = 0.290) with radiological worsening (OR = 3.04), APACHE-II (OR = 1.09) and number of antibiotics for treatment (OR = 1.51) and negatively with species other than A. fumigatus (OR = 0.14) and aspergillar tracheobronchitis (OR = 0.27). CONCLUSIONS: Administration of antifungals was not always closely linked to the diagnostic categorisation (colonisation vs. Aspergillosis), being negatively associated with severe COPD (GOLD III + IV) and concomitant treatment with quinolones in patients with Aspergillosis, probably due to the similarity of signs/symptoms between this entity and pulmonary bacterial infections.

Correlation between clinical parameters characterising peri-implant and periodontal health: a practice-based research in Spain in a series of patients with implants installed 4-5 years ago.

OBJECTIVES: To explore peri-implant health (and relation with periodontal status) 4-5 years after implant insertion. STUDY DESIGN: A practice-based dental research network multicentre study was performed in 11 Spanish centres. The first patient/month with implant insertion in 2004 was considered. Per patient four teeth (one per quadrant) showing the highest bone loss in the 2004 panoramic X-ray were selected for periodontal status assessment. Bone losses in implants were calculated as the differences between 2004 and 2009 bone levels in radiographs. RESULTS: A total of 117 patients were included. Of the 408 teeth considered, 73 (17.9%) were lost in 2009 (losing risk: >50% for bone losses ≥7 mm). A total of 295 implants were reviewed. Eight of 117 (6.8%) patients had lost implants (13 of 295 implants installed; 4.4%). Implant loss rate (quadrant status) was 1.4% (edentulous), 3.6% (preserved teeth), and 11.1% (lost teeth) (p=0.037). The percentage of implant loss significantly (p<0.001) increased when the medial/distal bone loss was ≥3 mm. The highest (p≤0.001) pocket depths were found in teeth with ≥5 mm and implants with ≥3 mm bone losses, with similar mean values (≥4 mm), associated with higher rates of plaque index and bleeding by probing. CONCLUSIONS: The significant bi-directional relation between plaque and bone loss, and between each of these two parameters/signs and pocket depths or bleeding (both in teeth and implants, and between them) together with the higher percentage of implants lost when the bone loss of the associated teeth was ≥3 mm suggest that the patient's periodontal status is a critical issue in predicting implant health/lesion.

Evolution of clonal and susceptibility profiles of serotype 19A Streptococcus pneumoniae among invasive isolates from children in Spain, 1990 to 2008.

The genetic structure and antibiotic nonsusceptibility of all serotype 19A Streptococcus pneumoniae pediatric pneumococcal isolates received at the Spanish Pneumococcal Reference Laboratory (1990 to 2008) were analyzed. Of them, 410 (79.8%) isolates belonged to 14 sequence types (STs) with >10 isolates each, and 104 to 73 STs (with 21 new STs, ST5141 to ST5161, with one isolate each). Time trends in 2000 to 2008 (n=471) were explored by lineal regression. Serotype 19A increased from 5.7% in 2000 to 16.8% in 2008 (R2=0.872; P=0.001). Decreasing trends (P<0.03) were found for ST202 (R2=0.774) and ST81 (R2=0.559), and increasing trends (P<0.03) for ST878 (R2=0.544) and ST320 (R2=0.530), both belonging to the clonal complex (CC) Denmark(14)-32 and first detected in 2003 and 2007, respectively, and ST2013 (R2=0.704) and ST4461 (R2=0.707), both appearing in 2004. Penicillin nonsusceptibility was clustered in ST81, ST276, ST320, ST878, ST2013, and ST4461 (>90% nonsusceptibility), and amoxicillin and cefotaxime nonsusceptibility in ST320: 87% amoxicillin (MIC50/MIC90=8/8 µg/ml) and 43.5% cefotaxime (MIC50/MIC90=1/2 µg/ml) nonsusceptibility. No trends were found for erythromycin nonsusceptibility (ranging from 38.5% to 66.7%) and cefotaxime nonsusceptibility (ranging from 0.0% to 7.8%), but increasing trends (P<0.02) were found for oral penicillin (from 16.7% in 2000 to 56.3% in 2008; R2=0.628) and amoxicillin (from 0.0% before 2007 to 13.8% in 2008; R2=0.628) nonsusceptibility. This study warns about the emergence of serotype 19A STs associated with high-level antibiotic nonsusceptibility, with a role for ST320 and ST878 occupying the niche left by some pneumococcal 7-valent conjugate vaccine (PCV7)-related resistant STs. The rapid expansion of serotype 19A and STs related to antibiotic resistance indicates that vaccines covering serotype 19A present advantages in countering invasive disease.

Increase in serotype 19A prevalence and amoxicillin non-susceptibility among paediatric Streptococcus pneumoniae isolates from middle ear fluid in a passive laboratory-based surveillance in Spain, 1997-2009.

BACKGROUND: Conjugate vaccines, such as the 7-valent conjugate vaccine (PCV7), alter serotype nasopharyngeal carriage, potentially increasing cases of otitis media by non-vaccine serotypes. METHODS: All paediatric middle ear fluid (MEF) isolates received in the Spanish Reference Laboratory for Pneumococci through a passive, laboratory-based surveillance system from January 1997 to June 2009 were analysed. Data from 1997 to 2000 were pooled as pre-vaccination period. Trends over time were explored by linear regression analysis. RESULTS: A total of 2,077 isolates were analysed: 855 belonging to PCV7 serotypes, 466 to serotype 19A, 215 to serotype 3, 89 to serotype 6A and 452 to other serotypes (< 40 isolates each). Over time, there has been a decreasing trend for PCV7 serotypes (R(2) = 0.944; p < 0.001, with significant decreasing trends for serotypes 19F, 14, 23F and 9V), and increasing trends for serotype 19A (R(2) = 0.901; p < 0.001), serotype 3 (R(2) = 0.463; p = 0.030) and other non-PCV7 serotypes (R(2) = 0.877; p < 0.001), but not for serotype 6A (R(2) = 0.311; p = 0.094). Considering all isolates, amoxicillin non-susceptibility showed an increasing trend (R(2) = 0.528; p = 0.017). Regarding serotype 19A, increasing trends in non-susceptibility to penicillin (R(2) = 0.726; p = 0.001), amoxicillin (R(2) = 0.804; p < 0.001), cefotaxime (R(2) = 0.546; p = 0.005) and erythromycin (R(2) = 0.546; p = 0.009) were found, with amoxicillin non-susceptibility firstly detected in 2003 (7.4%) and increasing up to 38.0% in 2009. In PCV7 serotypes (which prevalence decreased from 70.7% during 1997-2000 to 10.6% in 2009) amoxicillin non-susceptibility rates showed an increasing trend (R(2) = 0.702; p = 0.002). However, overall, amoxicillin non-susceptibility (≈25% in 2008-9) could be mainly attributed to serotype 19A (> 35% isolates) since PCV7 strains represented < 11% of total clinical isolates. CONCLUSIONS: In contrast to reports on invasive pneumococcal strains, in MEF isolates the reduction in the prevalence of PCV7 serotypes was not associated with decreases in penicillin/erythromycin non-susceptibility. The high prevalence of serotype 19A among paediatric MEF isolates and the amoxicillin non-susceptibility found in this serotype are worrisome since amoxicillin is the most common antibiotic used in the treatment of acute otitis media. These data suggest that non-PCV7 serotypes (mainly serotype 19A followed by serotypes 3 and 6A) are important etiological agents of acute otitis media and support the added value of the broader coverage of the new 13-valent conjugate vaccine.

A safe protocol to identify low-risk patients with COVID-19 pneumonia for outpatient management.

The coronavirus disease 2019 (COVID-19) outbreak has made it necessary to rationalize health-care resources, but there is little published data at this moment regarding ambulatory management of patients with COVID-19 pneumonia. The objective of the study is to evaluate the performance of a protocol for ambulatory management of patients with COVID-19 pneumonia regarding readmissions, admission into the Intensive Care Unit (ICU) and deaths. Also, to identify unfavorable prognostic factors that increase the risk of readmission. This is a prospective cohort study of patients with COVID-19 pneumonia discharged from the emergency ward of Infanta Cristina Hospital (Madrid, Spain) that met the criteria of the hospital protocol for outpatient management. We describe outcomes of those patients and compare those who needed readmission versus those who did not. We use logistic regression to explore factors associated with readmissions. A total of 314 patients were included, of which 20 (6.4%) needed readmission, and none needed ICU admission nor died. At least one comorbidity was present in 29.9% of patients. Hypertension, leukopenia, lymphocytopenia, increased lactate dehydrogenase (LDH) and increased aminotransferases were all associated with a higher risk of readmission. A clinical course of 10 days or longer, and an absolute eosinophil count over 200/µL were associated with a lower risk. After the multivariate analysis, only hypertension (OR 4.99, CI 1.54-16.02), temperature over 38 °C in the emergency ward (OR 9.03, CI 1.89-45.77), leukopenia (OR 4.92, CI 1.42-17.11) and increased LDH (OR 6.62, CI 2.82-19.26) remained significantly associated with readmission. Outpatient management of patients with low-risk COVID-19 pneumonia is safe, if adequately selected. The protocol presented here has allowed avoiding 30% of the admissions for COVID-19 pneumonia in our hospital, with a very low readmission rate and no mortality.

Susceptibility of recently collected Spanish pneumococci nonsusceptible to oral penicillin from serotypes not included in the 7-valent conjugate vaccine.

The susceptibilities of pneumococci recently collected (up to June 2009) in Spain (500 isolates nonsusceptible to oral penicillin and 150 susceptible isolates) from serotypes not included in the conjugate vaccine were determined. Most nonsusceptible isolates (53.6%) belonged to serotype 19A. Susceptibility rates in serotype 19A penicillin-intermediate (n = 201)/penicillin-resistant (n = 67) isolates were <33%/< or =6.0% (erythromycin and oral cephalosporins with defined breakpoints), 85.1%/11.9% (amoxicillin), and 96.0%/52.2% (cefotaxime), respectively. Low susceptibility to common oral beta-lactams was also found in serotypes 11A (95.5% susceptibility to cefotaxime and erythromycin) and 35B.

Predictive model of short-term amputation during hospitalization of patients due to acute diabetic foot infections.

INTRODUCTION: Factors predicting short-term amputation during hospital treatment of patients admitted for acute diabetic foot infections are of interest for clinicians managing the acute episode. METHODS: A retrospective clinical records analysis of 78 consecutive patients hospitalized for acute diabetic foot infections was performed to identify predictive factors for short-term amputation by comparing the data of patients who ultimately required amputation and those who did not. Clinical/epidemiological, laboratory, imaging, and treatment variables were comparatively analyzed. A logistic regression model was performed, with amputation as the dependent variable and factors showing significant differences in the bivariate analysis as independent variables. A prediction score was calculated (and validated by ROC curve analysis) using beta coefficients for significant variables in the regression analysis to predict amputation. RESULTS: Of the 78 patients (70.5% with peripheral vasculopathy) included, 26 ultimately required amputation. In the bivariate analysis, white blood cell count, previous homolateral lesions, odor, lesion depth, sedimentation rate, Wagner ulcer grade, and arterial obstruction on Doppler study were significantly higher in patients ending in amputation. In the multivariate analysis, the risk of amputation was increased only by Wagner grade 4 or 5 (20-fold higher), obstruction (12.5-fold higher), and elevated sedimentation rate (6% higher per unit). Logistic regression predicted outcome in 76.9% of patients who underwent amputation and 92.3% of those who did not. CONCLUSION: The score calculated using beta coefficients for significant variables in the regression model (Wagner grades 4 and 5, obstruction on Doppler, and elevated sedimentation rate for the clinical, imaging, and laboratory data, respectively) correctly predicted amputation during hospital management of acute diabetic foot infections.

Quantitative transcranial sonography of the substantia nigra as a predictor of therapeutic response to intravenous iron therapy in restless legs syndrome.

OBJECTIVE: To analyze changes in substantia nigra (SN) iron deposits, assessed by quantitative transcranial sonography (TCS), to obtain and compare substantia nigra echogenicity indices (SNEI) at baseline and after intravenous (IV) iron therapy in patients with restless legs syndrome (RLS)/Willis-Ekbom disease (WED). METHODS: A total of 30 consecutive subjects diagnosed with RLS/WED were recruited and underwent IV iron treatment. The SNEI, total daily dose of dopamine equivalents, and International Restless Legs Syndrome Rating Scale (IRLS) scores were obtained at baseline and following IV iron administration. Comparative statistics were performed by means of nonparametric testing. RESULTS: The sample was stratified into two groups according to the median baseline SNEI and the grade of SN hypoechogenicity: severely hypoechogenic (HE) (n = 13) and moderately HE (n = 17). Following IV iron, the increase in SNEI among severely HE subjects was 19% (0.038 ± 0.046 cm2; P < 0.01), whereas in moderately HE subjects it was 10% (0.021 ± 0.069 cm2; P = 0.28). Among severely HE subjects, the average reduction in IRLS following IV iron was 10 ± 7.12 points (P < 0.01), in contrast to 1.85 ± 9.85 (not significant) among moderately HE subjects. Finally, we quantified the percentage of patients in each group who were able to reduce by ≥30% their total daily dopaminergic requirements (TDR) after IV iron, with a 57.14% reduction in the severely HE group vs 25% in the moderately HE group (P = 0.1). Three of 30 subjects (17%) were able to completely cease all dopaminergic treatment. CONCLUSION: Intravenous iron caused changes in SNEI in both groups of patients, reflecting an increase in brain iron stores. However, the increase in SNEI was greater in patients previously defined as severely HE. Furthermore, RLS/WED symptoms also improved more in severely HE subjects, and there was a greater reduction in TDR. This study highlights the role of TCS in quantifying brain iron deposits and in predicting which patients will likely benefit from IV iron.

Reduced response to gabapentin enacarbil in restless legs syndrome following long-term dopaminergic treatment.

OBJECTIVES: To determine whether long-term treatment with dopaminergic agents (DAs) might dampen the response to a non-dopaminergic agent, such as gabapentin enacarbil. METHODS: We performed a two-week randomized, double-blind, crossover, and placebo-controlled study in a single, referral center in dopamine treatment-naive patients and non-augmented patients continuously treated with dopaminergics for the last five consecutive years. Following washout from any previous CNS-active drugs, patients were randomized into one of two groups for two consecutive two-week treatment periods with gabapentin enacarbil (GBPen) and placebo. Treatment was administered at 7 PM at a fixed dose of 600 mg/day. RLS severity was measured weekly using the International RLS Scale (IRLS) and Clinical Global Improvement (CGI). An M-SIT was also performed between 6 pm and midnight at the end of each treatment condition. RESULTS: There were no significant differences between groups in age, sex, duration of disease, ferritin levels, RLS severity at baseline, or existing concomitant conditions. Both groups improved more during treatment with GBPen than during placebo on the IRLS scale, CGI and mSIT. However, improvements were greater in the DA-naïve group than in long-term treatment with DAs group on the IRLS (p < 0.05), CGI (p < 0.01), and mSIT (p < 0.01). CONCLUSIONS: Previous long-term treatment with DAs reduces future response to GBPen in RLS patients. Potential pathiophysiological explanations are discussed. Our finding has strong implications for the initial choice of treatment in RLS and supports the notion that initial treatment should not be started with DAs. CLASSIFICATION OF EVIDENCE: The study provides class II evidence supporting reduced effects of gabapentin enacarbil in RLS patients previously exposed to long-term treatment with dopamine agonists.

Levofloxacin plus rifampicin conservative treatment of 25 early staphylococcal infections of osteosynthetic devices for rigid internal fixation.

Therapeutic conclusions for staphylococcal implant infections treated with debridement and implant retention can only be drawn from a small series. To this aim, data from patients with implant staphylococcal infections (1998-2006) treated with debridement and implant retention were retrospectively reviewed. Infections were defined by staphylococci isolation (two or more consecutive debridement or three sinus tract discharge samples) along with clinical criteria. Patients received oral levofloxacin plus rifampicin for >or=6 weeks after the resolution of signs/symptoms and C-reactive protein normalisation. Failure was defined as lack of response or recurrence of signs/symptoms and/or sinus tract bacterial isolation during therapy or follow-up and/or implant removal. Twenty-five patients (53.2+/-20.8 years; 48% males) were included, 12 with spinal infections and 13 with limb implant infections. Diagnosis was performed from debridement material (72%) and sinus tract discharge (28%) (11 Staphylococcus aureus and 14 coagulase-negative staphylococci (CoNS)). Time from surgery to symptom onset was higher in CoNS infections compared with S. aureus infections (21.6+/-9.3 days vs. 12.6+/-5.2 days; P=0.007). Seven patients (28%) were failures, with no differences between cured patients with respect to age, sex, infection site, time from surgery to symptom onset, sinus tract diagnosis and aetiology. Longer symptom duration prior to attendance was observed in failures (5.7+/-6.2 months vs. 1.4+/-0.6 months; P=0.04). Levofloxacin plus rifampicin showed efficacy in implant infections, which was higher for short duration of symptoms.

Revisiting cefditoren for the treatment of community-acquired infections caused by human-adapted respiratory pathogens in adults.

Fifteen years after its licensure, this revision assesses the role of cefditoren facing the current pharmacoepidemiology of resistances in respiratory human-adapted pathogens (Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae and Moraxella catarrhalis). In the era of post- pneumococcal conjugate vaccines and in an environment of increasing diffusion of the ftsI gene among H. influenzae isolates, published studies on the cefditoren in vitro microbiological activity, pharmacokinetic/pharmcodynamic (PK/PD) activity and clinical efficacy are reviewed. Based on published data, an overall analysis is performed for PK/PD susceptibility interpretation. Further translation of PK/PD data into clinical/microbiological outcomes obtained in clinical trials carried out in the respiratory indications approved for cefditoren in adults (tonsillitis, sinusitis, acute exacerbation of chronic bronchitis and community-acquired pneumonia) is commented. Finally, the role of cefditoren within the current antibiotic armamentarium for the treatment of community respiratory tract infections in adults is discussed based on the revised information on its intrinsic activity, pharmacodynamic adequacy and clinical/bacteriological efficacy. Cefditoren remains an option to be taken into account when selecting an oral antibiotic for the empirical treatment of respiratory infections in the community caused by human-adapted pathogens, even when considering changes in the pharmacoepidemiology of resistances over the last two decades.

Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis.

OBJECTIVES: Recent animal models of restless legs syndrome (RLS) suggest that brain iron deficiency is associated with a hypoadenosinergic state, with downregulation of adenosine A1 receptors (A1R) in the striatum and cortex. We hypothesized that an increase in extracellular adenosine induced by inhibitors of adenosine transporters, such as the non-selective ENT1/ENT2 inhibitor dipyridamole, would result in an improvement in RLS symptoms. METHODS: In a prospective two-month open-label, non-placebo controlled clinical trial, 15 untreated idiopathic RLS patients began treatment with 100 mg dipyridamole (with uptitration to 400 mg if necessary). Multiple Suggested Immobilization Tests and polysomnography were performed at baseline and at eight weeks. Severity was assessed at four and eight weeks using the IRLS, and the CGI scales. The primary endpoint was therapeutic response (50% improvement in IRLS total score). RESULTS: Thirteen patients completed the study. IRLS score improved from a mean (±S.D.) of 23.4 ± 4.6 at baseline to 10.7 ± 4.5 at eight weeks. Six out of 13 patients were full responders and four were partial responders. The mean (±S.D.) effective dose of dipyridamole at eight weeks was 281.8 ± 57.5 mg/day. Sleep variables also improved, and the mean (±S.D.) periodic leg movement index decreased from 26.7 ± 7.2 to 4.3 ± 1.9. Dipyridamole was generally well tolerated. Main side effects were abdominal cramps, diarrhea, dizziness, and flushing. CONCLUSIONS: These preliminary results suggest that dipyridamole has significant therapeutic effects on both sensory and motor symptoms, as well as sleep. In addition, it provides evidence that hypoadenosinergic mechanisms play a central role in RLS. CLASSIFICATION OF EVIDENCE: The study provides class III evidence supporting the therapeutic effects of dipyridamole in RLS.

Treatment of restless legs syndrome with the selective AMPA receptor antagonist perampanel.

OBJECTIVES: Perampanel is a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) antagonist that has been approved for the treatment of partial seizures. Here we report on the first open study evaluating its efficacy in idiopathic restless legs syndrome (RLS). METHODS: The study was designed as a prospective two-month open trial. Twenty-two previously untreated patients diagnosed with idiopathic RLS began treatment with 2 mg perampanel, which was increased to 4 mg at week four if clinically necessary. Multiple Suggested Immobilization Tests (mSITs) followed by polysomnography were performed at baseline and at week eight. Severity ratings were performed every two weeks by means of the IRLS scale, and Clinical Global Index (CGI) subscale. The main endpoint was therapeutic response, defined as a 50% improvement in IRLS total score. RESULTS: Twenty patients completed the study. During the 8-week treatment period, the IRLS score improved from a mean (±standard deviation (SD)) 23.7 ± 4.2 to 11.5 ± 5.3. Twelve of 20 patients were full responders (improvement 50% in IRLS total score), and four responded partially. The mean effective dose of perampanel at the end of treatment was 3.8 mg/day. Treatment with perampanel also resulted in an improvement in the mean (±SD) periodic leg movement index from 27.8 ± 6.9 to 4.36 ± 2.0. Perampanel was well tolerated. The main side effects were dizziness, somnolence, headache, and irritability. CONCLUSION: These preliminary results suggest that perampanel has significant therapeutic effects on both sensory and motor symptoms. If confirmed by future controlled studies, perampanel might become a promising alternative to existing dopaminergic treatments due to its glutamatergic mechanism of action. The study provides class IV evidence supporting the therapeutic effects of perampanel in RLS/WED.

The efficacy of cefditoren pivoxil in the treatment of lower respiratory tract infections, with a focus on the per-pathogen bacteriologic response in infections caused by Streptococcus pneumoniae and Haemophilus influenzae: a pooled analysis of seven clinical trials.

BACKGROUND: Community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB) are frequently caused by Streptococcus pneumoniae, Haemopbilus influenzae, and Moraxella catarrbalis; thus, these are the target pathogens for antibiotic treatment. OBJECTIVES: This pooled analysis was performed to evaluate the efficacy of cefditoren pivoxil (CDN) in patients with lower respiratory tract infections (CAP or AECB). A particular focus was the per-pathogen bacteriologic response rate among the most common causative pathogens, S pneumoniae, H influenzae, and M catarrbalis. METHODS: The final reports of all clinical trials of CDN in the treatment of community-acquired lower respiratory tract infection were reviewed. Microbiologic outcome data for CDN 200 and 400 mg and comparator treatments were pooled from 4 CAP studies (3 randomized and 1 noncomparative) and 3 AECB studies. The comparators were the standard oral treatments clarithromycin 500 mg BID, cefuroxime 250 mg BID, cefpodoxime 200 mg BID, and amoxicillin/clavulanate 500/125 mg TID or 875/125 mg BID. Microbiologic response was defined as eradication of the initial pathogen or presumed eradication (absence of sputum for culture in a patient with a clinical response). RESULTS: The bacteriologically evaluable population contained 654 patients in the CDN 200-mg group, 592 in the CDN 400-mg group, and 664 in the comparator group. A total of 1223 target pathogens were isolated before treatment: 406 isolates of S pneumoniae (including 56 penicillin-nonsusceptible [intermediate + resistant] strains), 595 isolates of H influenzae, and 222 isolates of M catarrbalis. The microbiologic response ranged from 84.1% to 88.8% in the CAP studies and from 75.1% to 77.1% in the AECB studies, with no differences between the CDN 200-mg, CDN 400-mg, and comparator groups. In the analysis of per-pathogen bacteriologic response, similar response rates were found for S pneumoniae (range, 88.5%-92.0%), H influenzae (range, 82.7%-86.6%), and M catarrbalis (range, 84.1%-95.2%), with no significant differences between groups. Focusing on penicillin-nonsusceptible (MIC >or=0.12 microg/mL) strains of S pneumoniae, CDN (both doses pooled) was associated with a response rate of 92.3% (36/39 isolates); all nonresponders were in the CDN 200-mg group. When only penicillin-resistant (MIC >or=2 microg/mL) strains were considered, there was only 1 nonresponder, again in the CDN 200-mg group. Thus, the overall response rate to CDN (both doses pooled) was 94.4% (17/18 isolates). CONCLUSIONS: In this pooled analysis, CDN was associated with high rates of per-pathogen bacteriologic response among the main causative pathogens in lower respiratory tract infection. The rates of response were approximately 85% against H influenzae and approximately 90% against S pneumoniae, including penicillin-intermediate and penicillin-resistant strains.