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BACKGROUND: This study aimed to evaluate the gap between guidelines and local clinical practice for diagnosis and treatment of uncomplicated and severe malaria, the patient characteristics, diagnostic approach, treatment, and compliance to standard guideline recommendations. METHODS: This was a multicentre, observational study conducted between October 2020 and March 2021 in which patients of all ages with symptoms suggestive of malaria and who visited a healthcare facility were prospectively enrolled in six countries in sub-Saharan Africa (The Democratic Republic of the Congo, Mozambique, Nigeria, Rwanda, The United Republic of Tanzania, and Zambia). RESULTS: Of 1001 enrolled patients, 735 (73.4%) patients had confirmed malaria (based on overall judgment by investigator) at baseline (uncomplicated malaria: 598 [81.4%] and severe malaria: 137 [18.6%]). Of the confirmed malaria patients, 533 (72.5%) were administered a malaria rapid diagnostic test. The median age of patients was 11 years (range: 2 weeks-91 years) with more patients coming from rural (44.9%) than urban (30.6%) or suburban areas (24.5%). At the community level, 57.8% of patients sought advice or received treatment for malaria and 56.9% of patients took one or more drugs for their illness before coming to the study site. In terms of early access to care, 44.1% of patients came to the study site for initial visit ≥ 48 h after symptom onset. In patients with uncomplicated malaria, the most prescribed treatments were artemisinin-based combination therapy (ACT; n = 564 [94.3%]), primarily using artemether-lumefantrine (82.3%), in line with the World Health Organization (WHO) treatment guidelines. In addition, these patients received antipyretics (85.6%) and antibiotics (42.0%). However, in those with severe malaria, only 66 (48.2%) patients received parenteral treatment followed by oral ACT as per WHO guidelines, whereas 62 (45.3%) received parenteral treatment only. After receiving ambulatory care, 88.6% of patients with uncomplicated malaria were discharged and 83.2% of patients with severe malaria were discharged after hospitalization. One patient with uncomplicated malaria having multiple co-morbidities and three patients with severe malaria died. CONCLUSIONS: The findings of this study suggest that the prescribed treatment in most patients with uncomplicated malaria, but not of those with severe malaria, was in alignment with the WHO recommended guidelines.
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Antimaláricos , Malaria Falciparum , Malaria , Humanos , Recién Nacido , Combinación Arteméter y Lumefantrina/uso terapéutico , Estudios Prospectivos , Arteméter/uso terapéutico , Malaria/diagnóstico , Malaria/tratamiento farmacológico , Prescripciones , Organización Mundial de la Salud , Tanzanía , Malaria Falciparum/tratamiento farmacológico , Combinación de MedicamentosRESUMEN
BACKGROUND: Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria. METHODS: This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (>1000 and <150â000 parasites per µL). Part A identified the optimal dose regimens in adults and adolescents (aged ≥12 years) and in part B, the selected doses were assessed in children (≥2 years and <12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to <6 years and 6 to <12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020-003284-25) and ClinicalTrials.gov (NCT03167242). FINDINGS: Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81-98] with 1 day, 47 of 48 [98%, 89-100] with 2 days, and 42 of 43 [98%, 88-100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83-99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93-100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92-100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86-100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83-99] vs 21 of 22 [96%, 77-100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study. INTERPRETATION: Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633). FUNDING: Novartis and Medicines for Malaria Venture.
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Antimaláricos , Artemisininas , Malaria Falciparum , Malaria , Adulto , Adolescente , Niño , Humanos , Lumefantrina/farmacología , Lumefantrina/uso terapéutico , Fluorenos/uso terapéutico , Fluorenos/farmacología , Etanolaminas/uso terapéutico , Etanolaminas/farmacología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Arteméter/farmacología , Arteméter/uso terapéutico , Malaria/tratamiento farmacológico , Combinación de Medicamentos , Plasmodium falciparum , Resultado del TratamientoRESUMEN
OBJECTIVE: The purpose of this study was to evaluate if the cognitive benefit of rivastigmine is affected by the presence of orthostatic hypotension (OH) in patients with Parkinson's disease dementia (PDD). METHODS: We conducted a post hoc analysis on 1,047 patients with PDD from 2 randomized controlled trials comparing rivastigmine versus placebo at week 24 (n = 501) and rivastigmine patch versus capsule at week 76 (n = 546). A drop ≥ 20 mm Hg in systolic blood pressure (SBP) or ≥ 10 in diastolic blood pressure (DBP) upon standing classified subjects as OH positive (OH+); otherwise, OH negative (OH-). The primary end point was the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) at week 24 and the Mattis Dementia Rating Scale (MDRS) at week 76, using intention-to-treat with retrieved dropout at week 24 and observed cases at week 76, consistent with the original analyses. RESULTS: Overall safety was comparable between OH+ (n = 288, 27.5%) and OH- (n = 730, 69.7%), except for higher frequency of syncope (9.2%) in the OH+ placebo arm. The placebo-adjusted effect of rivastigmine on ADAS-Cog at week 24 was 5.6 ± 1.2 for OH+ and 1.9 ± 0.9 in OH- (p = 0.0165). Among subjects with OH, the MDRS change from baseline at week 76 was higher for rivastigmine capsules versus patch (10.6 ± 2.9 vs -1.5 ± 3.0, p = 0.031). The overall prevalence of OH was lower for rivastigmine than placebo at week 24 (28.3% vs 44.6%, p = 0.0476). INTERPRETATION: The cognitive benefit from rivastigmine is larger in patients with PDD with OH, possibly mediated by a direct antihypotensive effect. ANN NEUROL 2021;89:91-98.
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Enfermedad de Alzheimer/tratamiento farmacológico , Hipotensión/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Rivastigmina/uso terapéutico , Anciano , Inhibidores de la Colinesterasa/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fármacos Neuroprotectores/uso terapéutico , Pruebas NeuropsicológicasRESUMEN
The study aimed to determine the efficacy of a safe and well-tolerated dose and regimen of tobramycin inhalation powder (TIP) on Pseudomonas aeruginosa sputum density in patients with bronchiectasis.This is a phase II, double-blind, randomised study in bronchiectasis patients aged ≥18â years with chronic P. aeruginosa infection. Patients were randomised 1:1:1 to either cohort A: three capsules of TIP once daily (84â mg); cohort B: five capsules once daily (140â mg) or cohort C: four capsules twice daily (224â mg). Within each cohort, patients were further randomised 2:2:1 either to TIP continuously, TIP cyclically (alternating 28â days of TIP and placebo) or placebo for 16â weeks, respectively and were followed up for 8â weeks.Overall, 107 patients were randomised to cohorts A (n=34), B (n=36) and C (n=37). All three TIP doses significantly reduced the P. aeruginosa sputum density from baseline to day 29 versus placebo in a dose-dependent manner (p≤0.0001, each). A smaller proportion of patients in the continuous-TIP (34.1%) and cyclical-TIP (35.7%) groups experienced pulmonary exacerbations versus placebo (47.6%) and also required fewer anti-pseudomonal antibiotics (38.6% on continuous TIP and 42.9% on cyclical TIP) versus placebo (57.1%) although not statistically significant. Pulmonary exacerbation of bronchiectasis was the most frequent (37.4%) adverse event. Overall, TIP was well tolerated, however, 23.4% of the patients discontinued the study drug due to adverse events.Continuous- and cyclical-TIP regimens with all three doses were safe and effective in reducing the P. aeruginosa sputum density in patients with bronchiectasis and chronic P. aeruginosa infection.
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Bronquiectasia , Infecciones por Pseudomonas , Administración por Inhalación , Adolescente , Adulto , Bronquiectasia/complicaciones , Bronquiectasia/tratamiento farmacológico , Humanos , Infecciones por Pseudomonas/complicaciones , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa , Tobramicina/uso terapéuticoRESUMEN
BACKGROUND: Secukinumab, a human monoclonal antibody that selectively targets interleukin-17A, is highly efficacious in the treatment of moderate-to-severe psoriasis, starting at early time points, with a sustained effect and a favorable safety profile. METHODS: Patients with moderate-to-severe plaque psoriasis were randomized to secukinumab 300 mg, secukinumab 150 mg, or placebo self-administered by prefilled syringe at baseline, weeks 1, 2, and 3, and then every four weeks from week 4 to 48. Efficacy responses (≥ 75/90/100% improvement in Psoriasis Area and Severity Index [PASI 75/90/100] and clear/almost clear skin by Investigator's Global Assessment 2011 modified version [IGA mod 2011 0/1]) were measured to week 52. Patient-reported usability of the prefilled syringe was evaluated by the Self-Injection Assessment Questionnaire to week 48. RESULTS: The efficacy of secukinumab increased to week 16 and was maintained to week 52. With secukinumab 300 mg at week 52, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 83.5%/68.0%/47.5% and 71.5% of patients when analyzed by multiple imputation, respectively, and by 75.9%/62.1%/43.1% and 63.8% of patients when analyzed by nonresponder imputation, respectively. With secukinumab 150 mg at week 52, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 63.5%/50.3%/31.1% and 43.6% of patients when analyzed by multiple imputation, respectively, and by 61.0%/49.2%/30.5% and 42.4% of patients when analyzed by nonresponder imputation, respectively. Self-reported acceptability of the prefilled syringe was high throughout the study. The incidence of adverse events (AE) was well balanced between groups, with AEs reported in 74.4% of patients receiving secukinumab 300 mg and 77.3% of patients receiving secukinumab 150 mg. Nasopharyngitis was the most common AE across both secukinumab groups. CONCLUSION: Self-administration of secukinumab by prefilled syringe was associated with robust and sustained efficacy and a favorable safety profile up to week 52.
J Drugs Dermatol. 2016;15(10):1226-1234.
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Anticuerpos Monoclonales/administración & dosificación , Psoriasis/diagnóstico , Psoriasis/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Jeringas , Adulto , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Femenino , Humanos , Inyecciones , Interleucina-17/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Autoadministración , Encuestas y Cuestionarios , Jeringas/estadística & datos numéricos , Resultado del TratamientoRESUMEN
BACKGROUND: Pooled data from two large registries, Cubicin(®) Outcomes Registry and Experience (CORE; USA) and European Cubicin(®) Outcomes Registry and Experience (EU-CORE; Europe, Latin America, and Asia), were analyzed to determine the characteristics and clinical outcomes of daptomycin therapy in patients with Gram-positive infections across wide geographical regions. METHODS: Patients receiving at least one dose of daptomycin between 2004 and 2012 for the treatment of Gram-positive infections were included. Clinical success was defined as an outcome of 'cured' or 'improved'. Post-treatment follow-up data were collected for a subset of patients (CORE: osteomyelitis and orthopedic foreign body device infection; EU-CORE: endocarditis, intracardiac/intravascular device infection, osteomyelitis, and orthopedic device infection). Safety was assessed for up to 30 days after daptomycin treatment. RESULTS: In 11,557 patients (CORE, 5482; EU-CORE, 6075) treated with daptomycin (median age, 62 [range, 1-103] years), the most frequent underlying conditions were cardiovascular disease (54.7 %) and diabetes mellitus (28.0 %). The most commonly treated primary infections were complicated skin and soft tissue infection (cSSTI; 31.2 %) and bacteremia (21.8 %). The overall clinical success rate was 77.2 % (uncomplicated SSTI, 88.3 %; cSSTI, 81.0 %; osteomyelitis, 77.7 %; foreign body/prosthetic infection (FBPI), 75.9 %; endocarditis, 75.4 %; and bacteremia, 69.5 %). The clinical success rate was 79.1 % in patients with Staphylococcus aureus infections (MRSA, 78.1 %). An increasing trend of high-dose daptomycin (>6 mg/kg/day) prescribing pattern was observed over time. Clinical success rates were higher with high-dose daptomycin treatment for endocarditis and FBPI. Adverse events (AEs) and serious AEs possibly related to daptomycin therapy were reported in 628 (5.4 %) and 133 (1.2 %) patients, respectively. CONCLUSIONS: The real-world data showed that daptomycin was effective and safe in the treatment of various Gram-positive infections, including those caused by resistant pathogens, across wide geographical regions.
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Antibacterianos/uso terapéutico , Daptomicina/uso terapéutico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Asia , Niño , Preescolar , Europa (Continente) , Femenino , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/fisiología , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Lactante , Recién Nacido , América Latina , Masculino , Persona de Mediana Edad , Sistema de Registros , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: This subgroup analysis of the European Cubicin Outcomes Registry Experience evaluated the safety and effectiveness of daptomycin in children and adolescent patients (<18 years). METHODS: Clinical outcomes at the end of therapy were assessed as success (cured or improved), failure or nonevaluable. Safety was assessed for up to 30 days post treatment. RESULTS: Eighty-one children and adolescent patients were included in this study. The most common primary infections were bacteremia (19.8%), complicated skin and soft-tissue infection (18.5%), osteomyelitis (13.6%), endocarditis (12.3%), foreign body/prosthetic infection (12.3%), uncomplicated skin and soft-tissue infection (9.9%) and other (13.6%). Daptomycin doses ranged from 4 to >10 mg/kg/day. Median duration of therapy was 12.5 (interquartile range, 7-25; mean, 16.7; standard deviation, 12.8) days. Staphylococcus aureus (46.7%) was the most commonly isolated pathogen (23.8% methicillin-resistant S. aureus). Forty-nine (60.5%) patients completed daptomycin therapy without further antibiotics, 27 (33.3%) switched to another antibiotic, 4 (4.9%) discontinued because of adverse events (AEs) and 1 (1.2%) discontinued because of other reason. Overall, 75 (92.6%; 95% confidence interval: 95.2-100.0%) patients achieved clinical success; 39 of 41 (95.1%) patients receiving daptomycin monotherapy and 36 of 40 (90.0%) patients receiving concomitant antibiotics. Six (7.4%) patients reported AEs, including 1 patient with increased blood creatine phosphokinase. Three (3.7%) patients had serious AEs; 1 (1.2%) had a serious AE possibly related to daptomycin. CONCLUSION: Daptomycin, alone or combined with other antibiotics and/or surgery, demonstrated high clinical success rates against a wide variety of infections and was well tolerated in children and adolescents.
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Antibacterianos/uso terapéutico , Daptomicina/uso terapéutico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Adolescente , Antibacterianos/efectos adversos , Niño , Preescolar , Daptomicina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Resultado del TratamientoRESUMEN
INTRODUCTION: Daptomycin, a rapid concentration-dependent bactericidal antibiotic, is approved at a dose of 4 mg/kg/day for the treatment of complicated skin and soft tissue infections (cSSTI) and at a dose of 6 mg/kg/day for the treatment of Staphylococcus aureus right-sided infective endocarditis (RIE) and bacteremia associated with cSSTI and RIE. Studies have reported the successful use of high-dose daptomycin (>6 mg/kg/day) in patients with difficult-to-treat infections. The present analysis evaluated the effectiveness and safety of high doses (>6 mg/kg/day) of daptomycin for the treatment of different Gram-positive infections. METHODS: European Cubicin(®) Outcomes Registry and Experience (EU-CORE) is a non-interventional, multicenter, retrospective, patient registry designed to collect real-world data from patients treated with daptomycin between 2006 and 2012. Clinical outcomes were assessed at the end of daptomycin treatment for three dose groups: ≤6, >6 to <8, and ≥8 mg/kg/day. Safety was assessed for up to 30 days post-daptomycin treatment. RESULTS: Of the 6075 patients enrolled in EU-CORE, 4892 patients received daptomycin doses ≤6 mg/kg/day, while 1097 patients received high doses (>6 mg/kg/day). The primary infections with the largest proportion of patients treated with a high dose (>6 mg/kg/day) were osteomyelitis (37.1%), foreign body/prosthetic infection (31.6%), and endocarditis (27.6%). S. aureus was identified in 42.9% of patients with positive cultures treated with either ≤6 or >6 mg/kg/day. The overall clinical success rate was 82.0% (899/1097) with high doses (>6 mg/kg/day) and 80.3% (3928/4890) with doses ≤6 mg/kg/day. Numerically higher clinical success rate was observed for endocarditis and foreign body/prosthetic infection, as well as for coagulase-negative staphylococcal and enterococcal infections, with high-dose daptomycin treatment. There were no new or unexpected safety findings at doses >6 mg/kg/day. CONCLUSION: These results suggested that daptomycin at doses >6 mg/kg/day was effective and well tolerated. High-dose daptomycin is a potential therapeutic option in patients with difficult-to-treat Gram-positive infections. FUNDING: This study was funded by Novartis Pharma AG.
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Antibacterianos/uso terapéutico , Daptomicina/uso terapéutico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Adulto , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Daptomicina/administración & dosificación , Daptomicina/efectos adversos , Relación Dosis-Respuesta a Droga , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
INTRODUCTION: The aim of this analysis was to describe in real-world settings the clinical outcomes and safety associated with daptomycin treatment in patients with neutropenia and Gram-positive infections. METHODS: Patients with an absolute neutrophil count (ANC) ≤1000 cells/mm(3) who received at least one dose of daptomycin between 2006 and 2012 were selected from a non-interventional, multicenter, retrospective registry (European Cubicin(®) Outcome Registry and Experience; EU-CORE(SM)). RESULTS: Of the 6075 patients enrolled in EU-CORE, 446 (7.3%) had an ANC ≤ 1000 cells/mm(3) at baseline or during daptomycin therapy; they were all included in efficacy and safety populations. Half of the patients had severe neutropenia (ANC ≤ 100 cells/mm(3)). Most patients had hematologic malignancy (60.5%), an immunosuppressed state (39.7%) or had undergone a transplant (27.8%). The most common primary infections were bacteremia (42.2%) and complicated skin and soft tissue infection (13.9%). Cultures were positive for 68.6% (254/370) of patients with available culture results; coagulase-negative staphylococci (43.7%; 111/254) and Staphylococcus aureus (18.9%; 48/254) were the most commonly isolated primary pathogens. Median duration of daptomycin therapy was 10.0 (range 1-98) days. Most patients (82.8%) received antibiotics concomitantly with daptomycin; the most common were carbapenems (51.2%), penicillins (42.1%), and aminoglycosides (19.9%). The overall clinical success rate (cured or improved) associated with daptomycin was 77.1%. Adverse events possibly related to daptomycin treatment were reported in seven (1.6%) patients and led to drug discontinuation in 27 (6.1%) patients. CONCLUSION: The study results suggest that daptomycin is an effective therapeutic option for the treatment of a broad range of Gram-positive infections in patients with neutropenia, and has a good safety profile. FUNDING: This study was funded by Novartis Pharma AG.
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Daptomicina , Neoplasias Hematológicas/complicaciones , Terapia de Inmunosupresión/efectos adversos , Neutropenia , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Daptomicina/administración & dosificación , Daptomicina/efectos adversos , Femenino , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/aislamiento & purificación , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/etiología , Humanos , Recuento de Leucocitos/métodos , Masculino , Persona de Mediana Edad , Neutropenia/sangre , Neutropenia/diagnóstico , Neutropenia/tratamiento farmacológico , Neutropenia/etiología , Sistema de Registros , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
INTRODUCTION: The objective of this analysis was to describe in real-life settings the clinical outcomes and safety associated with daptomycin treatment in a cohort of patients with complicated skin and soft tissues infection (cSSTI). METHODS: All patients with cSSTI who had received at least one dose of daptomycin between January 2006 and April 2012 were identified from a non-interventional, multicenter, retrospective registry (European Cubicin(®) Outcome Registry and Experience; EU-CORE(SM)). RESULTS: Of the 6075 patients included in the EU-CORE registry, 1927 (31.7%) were diagnosed with cSSTI (male, 63.8%; median age, 63 years). The most frequent underlying diseases were cardiovascular disease (58.1%) and diabetes mellitus (40.7%). The most frequent cSSTIs included surgical site infections (34.9%), wound infections (20.2%) and diabetic foot infections (19.9%). The most frequently prescribed doses of daptomycin were 4 mg/kg/day (38.9%) and 6 mg/kg/day (35.2%). A total of 1126 (58.4%) patients received antibiotics prior to daptomycin treatment; treatment failure (53.7%) was the most common reason for switching to daptomycin. The majority of hospitalized patients (61.8%) were treated with concomitant antibiotics. Among patients with positive cultures, Staphylococcus aureus (51.9%; 673/1297) was the most common pathogen. The overall clinical success rate was 84.6%; for infections caused by S. aureus, the success rate was 87.2% (methicillin susceptible, 87.8%; methicillin resistant, 87.0%). Adverse events possibly related to daptomycin treatment were reported in 2.4% of patients and adverse events led to drug discontinuation in 2.4% of patients. CONCLUSION: Daptomycin treatment resulted in high clinical success rates in patients with different cSSTI subtypes, the majority of whom having failed previous antibiotic therapy. Daptomycin was well tolerated and there were no new or unexpected safety findings.
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INTRODUCTION: The European Cubicin(®) Outcomes Registry and Experience (EU-CORE(SM)) was a retrospective, non-interventional, multicenter study which evaluated the safety and effectiveness of daptomycin therapy in patients with Gram-positive infections including infective endocarditis (IE). METHODS: Data from the EU-CORE registry were collected for patients with IE who had received at least one dose of daptomycin between January 2006 and April 2012, across 18 countries in Europe (12), Latin America (5) and Asia (1). Clinical outcomes were assessed as success (cured or improved), failure or non-evaluable. Adverse events (AEs) were recorded during treatment and for up to 30 days post-treatment; follow-up data were collected for 2 years. RESULTS: Of 6075 patients included in the EU-CORE registry, 610 were diagnosed with IE as primary infection; 149 (24.4%) right-sided IE (RIE), 414 (67.9%) left-sided IE (LIE), and 47 (7.7%) with both right- and left-sided IE (BRLIE). Overall clinical success was achieved in 80.0% of patients (RIE 88.6%, LIE 76.6% and BRLIE 82.9%). Success rates for methicillin-resistant Staphylococcus aureus (MRSA) infections were 90.9%, 71.7% and 66.6% in patients with RIE, LIE and BRLIE, respectively. The overall sustained clinical success rate in patients followed for up to 2 years was 86.7% (RIE 93.5%, LIE 88.3% and BRLIE 77.8%). AEs deemed possibly related to daptomycin in the investigator's opinion were reported in 2 (1.3%) RIE, 18 (4.3%) LIE and 1 (2.1%) BRLIE patients. There were 11 (1.8%) patients (2 with RIE, 8 with LIE and 1 with BRLIE) with AEs of creatine phosphokinase elevation reported as possibly related to daptomycin. CONCLUSION: Data from this real-world clinical setting showed that daptomycin was well tolerated and effective for the treatment of LIE and BRLIE in addition to RIE caused by Gram-positive bacteria, including MRSA. Two-year follow-up data showed that a high proportion of patients had a sustained response.
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INTRODUCTION: The aim of this study was to evaluate the clinical outcomes and safety of daptomycin therapy in patients with serious Gram-positive infections. METHODS: Patients were enrolled in the European Cubicin(®) Outcomes Registry and Experience (EU-CORE(SM)), a non-interventional, multicenter, observational registry. The real-world data were collected across 18 countries (Europe, Latin America, and Asia) for patients who had received at least one dose of daptomycin between January 2006 and April 2012. Two-year follow-up data were collected until 2014 for patients with endocarditis, intracardiac/intravascular device infection, osteomyelitis, or orthopedic device infection. RESULTS: A total of 6075 patients were enrolled. The most common primary infections were complicated skin and soft tissue infection (31.7%) and bacteremia (20.7%). Staphylococcus aureus was the most frequently reported pathogen (42.9%; methicillin-resistant S. aureus [MRSA], 23.2%), followed by Staphylococcus epidermidis and other coagulase-negative staphylococci (CoNS, 28.5%). The most commonly prescribed dose of daptomycin was 6 mg/kg/day (43.6%), and the median duration of therapy was 11 (range 1-300) days. Overall clinical success rate was 80.5%, and was similar whether daptomycin was used as first-line (82.9%) or second-line (79.2%) therapy. Clinical success rates were high in patients with S. aureus (83.9%; MRSA 83.0%) and CoNS (including S. epidermidis, 82.5%) infections. The majority of patients with endocarditis or intracardiac/intravascular device infection (86.7%) or osteomyelitis/orthopedic device infection (85.9%) had a sustained response during the 2-year follow-up period. There were no new or unexpected safety findings. CONCLUSION: Results from real-world clinical experience showed that daptomycin is a valuable therapeutic option in the management of various difficult-to-treat Gram-positive infections. FUNDING: This study was funded by Novartis Pharma AG.
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Antibacterianos/uso terapéutico , Daptomicina/uso terapéutico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antibacterianos/administración & dosificación , Asia , Bacteriemia/tratamiento farmacológico , Daptomicina/administración & dosificación , Europa (Continente) , Femenino , Infecciones por Bacterias Grampositivas/microbiología , Humanos , América Latina , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Adulto JovenRESUMEN
BACKGROUND: Daptomycin has proven efficacy in patients with Gram-positive complicated skin and soft tissue infections (cSSTIs), including those caused by Staphylococcus aureus, regardless of methicillin susceptibility. OBJECTIVE: This study was undertaken to evaluate the efficacy and safety of daptomycin in elderly patients. STUDY DESIGN: This was an open-label, multicentre, randomized phase IIIb study conducted in hospitalized patients PATIENTS: Patients aged ≥65 years with a diagnosis of Gram-positive cSSTIs with or without bacteraemia were included. In addition, infections were required to be of sufficient severity to require inpatient hospitalization and treatment with parenteral antibiotics for at least 96 h. The main exclusion criterion was the presence of a non-complicated SSTI that could heal by itself or be cured by surgical removal of the site of infection. INTERVENTION: Patients were randomized (2:1) to intravenous daptomycin or pooled intravenous standard therapies (semi-synthetic penicillin or vancomycin, referred to as the 'comparator'). Duration of treatment was between 5 and 14 days for cSSTIs without bacteraemia and between 10 and 28 days for cSSTIs with bacteraemia. MAIN OUTCOME MEASURE: The primary objective was descriptive comparison of clinical success in clinically evaluable patients at test of cure, 7-14 days post treatment. Secondary objectives were microbiological outcome, duration of treatment and safety. RESULTS: In total, 120 patients were randomized (81 to daptomycin; 39 to the comparator) and 102 patients completed the study. Baseline characteristics were similar between the two groups. Common infections included cellulitis, ulcers and abscesses; six patients had bacteraemia [five documented (daptomycin, n = 3; comparator, n = 2); and one suspected (daptomycin, n = 1)]. Test-of-cure clinical success rates were numerically higher for daptomycin than for the comparator [89.0 % (65/73) vs. 83.3 % (25/30); odds ratio 1.65 (95 % confidence interval 0.49-5.54)]. For patients with S. aureus infections, cure rates were 89.7 % (35/39) versus 69.2 % (9/13), respectively; percentage points difference, 20.5 (95 % confidence interval -12.2 to 50.9)]. Rates of adverse events (AEs) and serious AEs were similar in both treatment arms; however, discontinuation rates for AEs/serious AEs were lower for daptomycin than for the comparator (3.8 % vs. 10.0 %). Three serious AEs were considered to be related to the study drug: one case each of pancytopenia (semi-synthetic penicillin), renal failure (vancomycin) and asymptomatic increase in creatine phosphokinase concentrations (daptomycin). CONCLUSION: In elderly patients, for whom data were previously limited, the efficacy and safety of daptomycin have been confirmed, including for infections caused by S. aureus, regardless of methicillin susceptibility.
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Daptomicina/efectos adversos , Daptomicina/uso terapéutico , Seguridad del Paciente , Enfermedades de la Piel/complicaciones , Enfermedades de la Piel/tratamiento farmacológico , Infecciones de los Tejidos Blandos/complicaciones , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Anciano , Daptomicina/farmacología , Femenino , Humanos , Masculino , Infecciones Estafilocócicas/complicaciones , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Osteomyelitis is a complex and heterogeneous group of infections that require surgical and antimicrobial interventions. Because treatment failure or intolerance is common, new treatment options are needed. Daptomycin has broad Gram-positive activity, penetrates bone effectively and has bactericidal activity within biofilms. This is the first report on clinical outcomes in patients with osteomyelitis from the multicentre, retrospective, non-interventional European Cubicin(®) Outcomes Registry and Experience (EU-CORE(SM)), a large database on real-world daptomycin use. PATIENTS AND METHODS: In total, 220 patients were treated for osteomyelitis; the population was predominantly elderly, with predisposing baseline conditions such as diabetes and chronic renal/cardiac diseases. RESULTS: Most patients (76%) received prior antibiotic treatment, and first-line treatment failure was the most frequent reason to start daptomycin. Common sites of infection were the knee (22%) or hip (21%), and the most frequently isolated pathogens were Staphylococcus aureus (33%) and coagulase-negative staphylococci (32%). Overall, 52% of patients had surgery, 55% received concomitant antibiotics and 29% received a proportion of daptomycin therapy as outpatients. Clinical success was achieved in 75% of patients. Among patients with prosthetic device-related osteomyelitis, there was a trend towards higher success rates if the device was removed. Daptomycin was generally well tolerated. CONCLUSIONS: This analysis suggests that daptomycin is an effective and well-tolerated treatment option for osteomyelitis and highlights the importance of optimal surgical intervention and appropriate microbiological diagnosis for clinical outcomes.
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Antibacterianos/uso terapéutico , Daptomicina/uso terapéutico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Osteomielitis/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Bacterias Grampositivas/aislamiento & purificación , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Masculino , Persona de Mediana Edad , Osteomielitis/microbiología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: The Roadmap concept is a therapeutic framework in chronic hepatitis B for the intensification of nucleoside analogue monotherapy based on early virologic response. The efficacy and safety of this approach applied to telbivudine treatment has not been investigated. METHODS: A multinational, phase IV, single-arm open-label study (ClinicalTrials.gov ID NCT00651209) was undertaken in HBeAg-positive, nucleoside-naive adult patients with chronic hepatitis B. Patients received telbivudine (600 mg once-daily) for 24 weeks, after which those with undetectable serum HBV DNA (<300 copies/mL) continued to receive telbivudine alone while those with detectable DNA received telbivudine plus tenofovir (300 mg once-daily). Outcomes were assessed at Week 52. RESULTS: 105 patients commenced telbivudine monotherapy, of whom 100 were included in the efficacy analysis. Fifty-five (55%) had undetectable HBV DNA at Week 24 and continued telbivudine monotherapy; 45 (45%) received tenofovir intensification. At Week 52, the overall proportion of undetectable HBV DNA was 93% (93/100) by last-observation-carried-forward analysis (100% monotherapy group, 84% intensification group) and no virologic breakthroughs had occurred. ALT normalization occurred in 77% (87% monotherapy, 64% intensification), HBeAg clearance in 43% (65% monotherapy, 16% intensification), and HBeAg seroconversion in 39% (62% monotherapy, 11% intensification). Six patients had HBsAg clearance. Myalgia was more common in the monotherapy group (19% versus 7%). No decrease in the mean glomerular filtration rate occurred in either treatment group at Week 52. CONCLUSIONS: Telbivudine therapy with tenofovir intensification at Week 24, where indicated by the Roadmap strategy, appears effective and well tolerated for the treatment of chronic hepatitis B.
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Adenina/análogos & derivados , Antivirales/uso terapéutico , ADN Viral/sangre , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Organofosfonatos/uso terapéutico , Timidina/análogos & derivados , Adenina/farmacología , Adenina/uso terapéutico , Adulto , Alanina Transaminasa/sangre , Antivirales/farmacología , Esquema de Medicación , Quimioterapia Combinada , Femenino , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/sangre , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Organofosfonatos/farmacología , Telbivudina , Tenofovir , Timidina/farmacología , Timidina/uso terapéutico , Resultado del Tratamiento , Replicación Viral/efectos de los fármacosRESUMEN
OBJECTIVES: Infective endocarditis (IE) is a complex infection associated with high mortality. Daptomycin, a cyclic lipopeptide antibiotic highly active against Gram-positive bacteria, has recently been incorporated into IE treatment guidelines. This retrospective analysis provides insights into the use of daptomycin in IE in the European Cubicin(®) Outcomes Registry Experience (EU-CORE(SM)) between 2006 and 2010. PATIENTS AND METHODS: Three hundred and seventy-eight (10%) of 3621 enrolled patients received daptomycin for treatment of IE. Two hundred and fifty-nine (69%) had left-sided IE (LIE) and 182 patients (48%) underwent concomitant surgery. RESULTS: Staphylococcus aureus was the most frequently identified pathogen (n=92; methicillin susceptible, n=50) and daptomycin was used empirically in 134 patients. Among cases of second-line therapy (n=312), the most common reason for switching to daptomycin was failure of the previous regimen (including glycopeptides and penicillins). Daptomycin was administered at 6 mg/kg in 224 patients and at ≥ 8 mg/kg in 72 patients. Clinical success rates were 80% overall, 91% for right-sided IE (RIE) and 76% for LIE, with similar rates seen for infections caused by methicillin-susceptible S. aureus (84%) and methicillin-resistant S. aureus (81%). The clinical success rate in patients treated with ≥ 8 mg/kg daptomycin was 90% [n=72 (RIE, 91%; LIE, 89%)]. No new safety signals were observed. CONCLUSIONS: In patients with IE registered in EU-CORE, daptomycin was most frequently used as second-line treatment after treatment failure. The majority of patients had LIE and most commonly received daptomycin for the treatment of staphylococcal infections. Clinical success was high in this difficult-to-treat population. The role of doses ≥ 8 mg/kg per day in the empirical treatment of IE deserves further investigation.