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1.
Open Forum Infect Dis ; 7(3): ofaa054, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32154325

RESUMO

BACKGROUND: In the randomized controlled RESTORE-IMI 1 clinical trial (NCT02452047), imipenem/cilastatin (IMI) with relebactam (IMI/REL) was as effective as colistin plus IMI for the treatment of imipenem-nonsusceptible gram-negative infections. Differences in nephrotoxicity were observed between treatment arms. As there is no standard definition of nephrotoxicity used in clinical trials, we conducted analyses to further understand the renal safety profile of both treatments. METHODS: Nephrotoxicity was retrospectively evaluated using 2 acute kidney injury assessment criteria (Kidney Disease Improving Global Outcomes [KDIGO] and Risk, Injury, Failure, Loss, and End-stage Kidney Disease [RIFLE]). Additional outcomes included time to onset of protocol-defined nephrotoxicity and incidence of renal adverse events. RESULTS: Of 47 participants receiving treatment, 45 had sufficient data to assess nephrotoxicity (IMI/REL, n = 29; colistin plus IMI, n = 16). By KDIGO criteria, no participants in the IMI/REL but 31.3% in the colistin plus IMI group experienced stage 3 acute kidney injury. No IMI/REL-treated participants experienced renal failure by RIFLE criteria, vs 25.0% for colistin plus IMI. Overall, the time to onset of nephrotoxicity varied considerably (2-22 days). Fewer renal adverse events (12.9% vs 37.5%), including discontinuations due to drug-related renal adverse events (0% vs 12.5%), were observed in the IMI/REL group compared with the colistin plus IMI group, respectively. CONCLUSIONS: Our analyses confirm the findings of a preplanned end point and provide further evidence that IMI/REL had a more favorable renal safety profile than colistin-based therapy in patients with serious, imipenem-nonsusceptible gram-negative bacterial infections. CLINICALTRIALSGOV IDENTIFIER: NCT02452047.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32094127

RESUMO

The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (n = 41) and MITT (n = 31) populations had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI-REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI-REL and 40.0% for colistin plus IMI in the mMITT population, whereas they were 75.0% for IMI-REL and 53.8% for colistin plus IMI in the SmMITT population. Day 28 all-cause mortality rates were 9.5% for IMI-REL and 30.0% for colistin plus IMI in the mMITT population, whereas they were 10.7% for IMI-REL and 23.1% for colistin plus IMI in the SmMITT population. The outcomes in the SmMITT population were generally consistent with those in the mMITT population, suggesting that outcomes may be applicable to the real-world use of IMI-REL for treating infections caused by imipenem-nonsusceptible Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02452047.).


Assuntos
Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Combinação Imipenem e Cilastatina/uso terapêutico , Colistina/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Imipenem/uso terapêutico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Determinação de Ponto Final , Feminino , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/mortalidade , Humanos , Imipenem/farmacologia , Rim/fisiopatologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Fatores Sexuais , Resultado do Tratamento , Adulto Jovem , Inibidores de beta-Lactamases/farmacologia
3.
Clin Infect Dis ; 70(9): 1799-1808, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31400759

RESUMO

BACKGROUND: The ß-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. METHODS: Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5-21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment. RESULTS: Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, -27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, -46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drug-related deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively. CONCLUSIONS: Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections. CLINICAL TRIALS REGISTRATION: NCT02452047.


Assuntos
Infecções Bacterianas , Imipenem , Antibacterianos/efeitos adversos , Compostos Azabicíclicos/efeitos adversos , Infecções Bacterianas/tratamento farmacológico , Colistina/efeitos adversos , Humanos , Imipenem/efeitos adversos , Testes de Sensibilidade Microbiana
4.
Am J Epidemiol ; 186(8): 899-907, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28549073

RESUMO

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.


Assuntos
Determinação da Pressão Arterial , Doenças Cardiovasculares/epidemiologia , Colesterol/sangue , Medição de Risco/métodos , Adulto , Idoso , Pressão Sanguínea , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco
5.
JAMA ; 307(23): 2499-506, 2012 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-22797450

RESUMO

CONTEXT: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. OBJECTIVE: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. DESIGN, SETTING, AND PARTICIPANTS: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). MAIN OUTCOME MEASURES: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk. RESULTS: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. CONCLUSION: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.


Assuntos
Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Lipoproteínas/sangue , Idoso , HDL-Colesterol/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco
6.
Am J Cardiol ; 95(8): 983-5, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15820170

RESUMO

Lovastatin (Mevacor) 20 mg is being considered for nonprescription availability. Because the most severe untoward consequence of therapy with any statin is rhabdomyolysis, the clinical data for lovastatin pertaining to this adverse event were reviewed. Evidence to date, based on almost 2 decades of experience, points to an extremely low risk for myopathy and rhabdomyolysis associated with lovastatin.


Assuntos
Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/uso terapêutico , Lovastatina/efeitos adversos , Lovastatina/uso terapêutico , Rabdomiólise/induzido quimicamente , Ensaios Clínicos como Assunto , Humanos , Estudos Retrospectivos , Fatores de Risco
7.
Am J Cardiol ; 94(10): 1243-8, 2004 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-15541238

RESUMO

The Consumer Use Study of OTC Mevacor evaluated the ability of subjects to self-manage high levels of low-density lipoprotein (LDL) cholesterol by using a multifaceted cholesterol self-management program (the Mevacor Over-the-Counter Self-Management System; MOTC-SMS). This 26-week all-comers multicenter observational study was conducted in naturalistic storefront settings that used the fully functional MOTC-SMS to guide subjects' behavior. Of 3,316 subjects who evaluated the product (evaluators), 1,061 took >or=1 20-mg tablet of Mevacor OTC (users). Eighty-four percent of evaluators made appropriate initial use decisions. Most users demonstrated acceptable ongoing use behavior regarding treatment to goal, compliance/persistence, changes in health status, dietary patterns, and exercise habits. Throughout the study, 23 users (2%) demonstrated behavior that created the potential for suboptimal safety. After 26 weeks, median levels of LDL cholesterol were reduced by 25% among users who fasted. Of the 878 users who completed the study lipid test, 548 (62%) achieved the LDL cholesterol target goal (<130 mg/dl). Physician interactions were common. Mevacor OTC was well tolerated, with no observable adverse experiences from drug interactions or reports of myopathy. This actual use study demonstrates that the MOTC-SMS can effectively guide consumers to interact with health care professionals and to make appropriate initial and ongoing use decisions to manage their elevated levels of LDL cholesterol, with minimal potential or actual safety risk.


Assuntos
Anticolesterolemiantes/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Lovastatina/uso terapêutico , Medicamentos sem Prescrição/uso terapêutico , Autocuidado , LDL-Colesterol/sangue , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Hiperlipidemias/sangue , Masculino , Pessoa de Meia-Idade , Autoadministração
8.
J Biopharm Stat ; 13(2): 327-36, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12729398

RESUMO

The effect of within-household reinfestation on design sensitivity is investigated through statistical modeling of the reinfestation process. When reinfestation is present, household randomization tends to magnify treatment differences when compared with individual randomization or a randomized blocking design in the simple setting of two patients per household. The effect of reinfestation under more general household randomization settings is investigated by determining the relationship between the treatment effect and the number of patients per household. In an actual clinical study of treatment for head lice infestation, household randomization with proper stratification was adopted. The results from the study were consistent with theoretical expectations. This seeming contradiction to the blocking principle demonstrates the need to check whether all conditions are met before applying standard design principles.


Assuntos
Infestações por Piolhos , Pediculus , Distribuição Aleatória , Animais , Humanos , Infestações por Piolhos/tratamento farmacológico
9.
J Biopharm Stat ; 12(2): 179-92, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12413239

RESUMO

Total cholesterol (TC) measurements are subject to errors primarily because of temporal variations in cholesterol levels within each individual. These errors make it difficult to estimate the proportion of study subjects with true (error-free) TC in a specific range, an extremely important parameter to policy makers in health care management. To properly address this issue, it is key to accurately estimate the distribution function of the true TC, which typically deviates from the normal distribution. To better approximate the distribution function of the true TC, we propose a constrained maximum likelihood estimator based on a mixture-of-normals model. A simulation study illustrates that the proposed estimator performs better than an estimator based on the normality assumption that is frequently used in the literature to address the same issue. Finally, the proposed estimator is applied to data from a study, and its performance is once again compared with that of an estimator based on the normality assumption.


Assuntos
Colesterol/sangue , Algoritmos , Simulação por Computador , Feminino , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Estatísticas não Paramétricas
10.
J Pediatr ; 141(5): 665-70, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12410195

RESUMO

OBJECTIVES: To determine if NIX (Warner Lambert Healthcare, Morris Plains, NJ) 1% Permethrin Creme Rinse Lice Treatment (1% PLT) without combing will effectively treat >/=95% of patients on day 2 or on day 15; to determine whether combing influences efficacy. STUDY DESIGN: A randomized, observer-blinded study enrolled 95 infested adults and children. All patients were treated with 1% PLT on day 1 and, if still infested, on day 8. One third of households were randomized to the combing group and two thirds to the no-combing group. Efficacy was assessed by: (1) visual inspection on days 1, 2, 8, 9, and 15 and, (2) shampooing/straining on days 2, 9, and 15. The target efficacy was 95%. RESULTS: In the no-combing group, the lice-free rate was 83.1% on day 2 (95% CI, 71.0-91.6), 45.8% on day 8 (before second treatment) (95% CI, 32.7-59.2), 77.6% on day 9 (95% CI, 64.7-87.5), and 78.3% on day 15 (95% CI, 65.8-87.9). Adjunctive combing did not improve efficacy on any day. CONCLUSIONS: In this population, 1% PLT was significantly less than 95% effective and suggests resistance to 1% PLT. The failure of nit removal combing by nonprofessional caregivers to improve efficacy demonstrates the unreliability of combing as adjunctive treatment in this setting.


Assuntos
Higiene , Inseticidas/administração & dosagem , Infestações por Piolhos/tratamento farmacológico , Pediculus , Permetrina/administração & dosagem , Dermatoses do Couro Cabeludo/tratamento farmacológico , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Humanos , Infestações por Piolhos/terapia , Masculino , Método Simples-Cego , Falha de Tratamento
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