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1.
Cochrane Database Syst Rev ; 2: CD003610, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33704780

RESUMO

BACKGROUND: Coronary heart disease is the leading cause of mortality worldwide with approximately 7.4 million deaths each year. People with established coronary heart disease have a high risk of subsequent cardiovascular events including myocardial infarction, stroke, and cardiovascular death. Antibiotics might prevent such outcomes due to their antibacterial, antiinflammatory, and antioxidative effects. However, a randomised clinical trial and several observational studies have suggested that antibiotics may increase the risk of cardiovascular events and mortality. Furthermore, several non-Cochrane Reviews, that are now outdated, have assessed the effects of antibiotics for coronary heart disease and have shown conflicting results. No previous systematic review using Cochrane methodology has assessed the effects of antibiotics for coronary heart disease. OBJECTIVES: We assessed the benefits and harms of antibiotics compared with placebo or no intervention for the secondary prevention of coronary heart disease. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-EXPANDED, and BIOSIS in December 2019 in order to identify relevant trials. Additionally, we searched TRIP, Google Scholar, and nine trial registries in December 2019. We also contacted 11 pharmaceutical companies and searched the reference lists of included trials, previous systematic reviews, and other types of reviews. SELECTION CRITERIA: Randomised clinical trials assessing the effects of antibiotics versus placebo or no intervention for secondary prevention of coronary heart disease in adult participants (≥18 years). Trials were included irrespective of setting, blinding, publication status, publication year, language, and reporting of our outcomes. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data. Our primary outcomes were all-cause mortality, serious adverse event according to the International Conference on Harmonization - Good Clinical Practice (ICH-GCP), and quality of life. Our secondary outcomes were cardiovascular mortality, myocardial infarction, stroke, and sudden cardiac death. Our primary time point of interest was at maximum follow-up. Additionally, we extracted outcome data at 24±6 months follow-up. We assessed the risks of systematic errors using Cochrane 'Rosk of bias' tool. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes. We calculated absolute risk reduction (ARR) or increase (ARI) and number needed to treat for an additional beneficial outcome (NNTB) or for an additional harmful outcome (NNTH) if the outcome result showed a beneficial or harmful effect, respectively. The certainty of the body of evidence was assessed by GRADE. MAIN RESULTS: We included 38 trials randomising a total of 26,638 participants (mean age 61.6 years), with 23/38 trials reporting data on 26,078 participants that could be meta-analysed. Three trials were at low risk of bias and the 35 remaining trials were at high risk of bias. Trials assessing the effects of macrolides (28 trials; 22,059 participants) and quinolones (two trials; 4162 participants) contributed with the vast majority of the data. Meta-analyses at maximum follow-up showed that antibiotics versus placebo or no intervention seemed to increase the risk of all-cause mortality (RR 1.06; 95% CI 0.99 to 1.13; P = 0.07; I2 = 0%; ARI 0.48%; NNTH 208; 25,774 participants; 20 trials; high certainty of evidence), stroke (RR 1.14; 95% CI 1.00 to 1.29; P = 0.04; I2 = 0%; ARI 0.73%; NNTH 138; 14,774 participants; 9 trials; high certainty of evidence), and probably also cardiovascular mortality (RR 1.11; 95% CI 0.98 to 1.25; P = 0.11; I2= 0%; 4674 participants; 2 trials; moderate certainty of evidence). Little to no difference was observed when assessing the risk of myocardial infarction (RR 0.95; 95% CI 0.88 to 1.03; P = 0.23; I2 = 0%; 25,523 participants; 17 trials; high certainty of evidence). No evidence of a difference was observed when assessing sudden cardiac death (RR 1.08; 95% CI 0.90 to 1.31; P = 0.41; I2 = 0%; 4520 participants; 2 trials; moderate certainty of evidence). Meta-analyses at 24±6 months follow-up showed that antibiotics versus placebo or no intervention increased the risk of all-cause mortality (RR 1.25; 95% CI 1.06 to 1.48; P = 0.007; I2 = 0%; ARI 1.26%; NNTH 79 (95% CI 335 to 42); 9517 participants; 6 trials; high certainty of evidence), cardiovascular mortality (RR 1.50; 95% CI 1.17 to 1.91; P = 0.001; I2 = 0%; ARI 1.12%; NNTH 89 (95% CI 261 to 49); 9044 participants; 5 trials; high certainty of evidence), and probably also sudden cardiac death (RR 1.77; 95% CI 1.28 to 2.44; P = 0.0005; I2 = 0%; ARI 1.9%; NNTH 53 (95% CI 145 to 28); 4520 participants; 2 trials; moderate certainty of evidence). No evidence of a difference was observed when assessing the risk of myocardial infarction (RR 0.95; 95% CI 0.82 to 1.11; P = 0.53; I2 = 43%; 9457 participants; 5 trials; moderate certainty of evidence) and stroke (RR 1.17; 95% CI 0.90 to 1.52; P = 0.24; I2 = 0%; 9457 participants; 5 trials; high certainty of evidence). Meta-analyses of trials at low risk of bias differed from the overall analyses when assessing cardiovascular mortality at maximum follow-up. For all other outcomes, meta-analyses of trials at low risk of bias did not differ from the overall analyses. None of the trials specifically assessed serious adverse event according to ICH-GCP. No data were found on quality of life. AUTHORS' CONCLUSIONS: Our present review indicates that antibiotics (macrolides or quinolones) for secondary prevention of coronary heart disease seem harmful when assessing the risk of all-cause mortality, cardiovascular mortality, and stroke at maximum follow-up and all-cause mortality, cardiovascular mortality, and sudden cardiac death at 24±6 months follow-up. Current evidence does, therefore, not support the clinical use of macrolides and quinolones for the secondary prevention of coronary heart disease. Future trials on the safety of macrolides or quinolones for the secondary prevention in patients with coronary heart disease do not seem ethical. In general, randomised clinical trials assessing the effects of antibiotics, especially macrolides and quinolones, need longer follow-up so that late-occurring adverse events can also be assessed.


Assuntos
Antibacterianos/efeitos adversos , Doença das Coronárias/prevenção & controle , Prevenção Secundária/métodos , Antibacterianos/uso terapêutico , Doenças Cardiovasculares/mortalidade , Causas de Morte , Doença das Coronárias/mortalidade , Morte Súbita Cardíaca/epidemiologia , Humanos , Macrolídeos/efeitos adversos , Macrolídeos/uso terapêutico , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/epidemiologia
2.
Cochrane Database Syst Rev ; 3: CD004406, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33728634

RESUMO

BACKGROUND: Antibiotics provide only modest benefit in treating sore throat, although their effectiveness increases in people with positive throat swabs for group A beta-haemolytic streptococci (GABHS). It is unclear which antibiotic is the best choice if antibiotics are indicated. This is an update of a review first published in 2010, and updated in 2013, 2016, and 2020. OBJECTIVES: To assess the comparative efficacy of different antibiotics in: (a) alleviating symptoms (pain, fever); (b) shortening the duration of the illness; (c) preventing clinical relapse (i.e. recurrence of symptoms after initial resolution); and (d) preventing complications (suppurative complications, acute rheumatic fever, post-streptococcal glomerulonephritis). To assess the evidence on the comparative incidence of adverse effects and the risk-benefit of antibiotic treatment for streptococcal pharyngitis. SEARCH METHODS: We searched the following databases up to 3 September 2020: CENTRAL (2020, Issue 8), MEDLINE Ovid (from 1946), Embase Elsevier (from 1974), and Web of Science Thomson Reuters (from 2010). We also searched clinical trial registers on 3 September 2020. SELECTION CRITERIA: Randomised, double-blind trials comparing different antibiotics, and reporting at least one of the following: clinical cure, clinical relapse, or complications and/or adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened trials for inclusion and extracted data using standard methodological procedures as recommended by Cochrane. We assessed the risk of bias of included studies according to the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions, and used the GRADE approach to assess the overall certainty of the evidence for the outcomes. We have reported the intention-to-treat analysis, and also performed an analysis of evaluable participants to explore the robustness of the intention-to-treat results. MAIN RESULTS: We included 19 trials reported in 18 publications (5839 randomised participants): six trials compared penicillin with cephalosporins; six compared penicillin with macrolides; three compared penicillin with carbacephem; one compared penicillin with sulphonamides; one compared clindamycin with ampicillin; and one compared azithromycin with amoxicillin in children. All participants had confirmed acute GABHS tonsillopharyngitis, and ages ranged from one month to 80 years. Nine trials included only, or predominantly, children. Most trials were conducted in an outpatient setting. Reporting of randomisation, allocation concealment, and blinding was poor in all trials. We downgraded the certainty of the evidence mainly due to lack of (or poor reporting of) randomisation or blinding, or both; heterogeneity; and wide confidence intervals. Cephalosporins versus penicillin We are uncertain if there is a difference in symptom resolution (at 2 to 15 days) for cephalosporins versus penicillin (odds ratio (OR) for absence of symptom resolution 0.79, 95% confidence interval (CI) 0.55 to 1.12; 5 trials; 2018 participants; low-certainty evidence). Results of the sensitivity analysis of evaluable participants differed (OR 0.51, 95% CI 0.27 to 0.97; 5 trials; 1660 participants; very low-certainty evidence). We are uncertain if clinical relapse may be lower for cephalosporins compared with penicillin (OR 0.55, 95% CI 0.30 to 0.99; number needed to treat for an additional beneficial outcome (NNTB) 50; 4 trials; 1386 participants; low-certainty evidence). Very low-certainty evidence showed no difference in reported adverse events. Macrolides versus penicillin We are uncertain if there is a difference between macrolides and penicillin for resolution of symptoms (OR 1.11, 95% CI 0.92 to 1.35; 6 trials; 1728 participants; low-certainty evidence). Sensitivity analysis of evaluable participants resulted in an OR of 0.79, 95% CI 0.57 to 1.09; 6 trials; 1159 participants). We are uncertain if clinical relapse may be different (OR 1.21, 95% CI 0.48 to 3.03; 6 trials; 802 participants; low-certainty evidence).  Azithromycin versus amoxicillin Based on one unpublished trial in children, we are uncertain if resolution of symptoms is better with azithromycin in a single dose versus amoxicillin for 10 days (OR 0.76, 95% CI 0.55 to 1.05; 1 trial; 673 participants; very low-certainty evidence). Sensitivity analysis for per-protocol analysis resulted in an OR of 0.29, 95% CI 0.11 to 0.73; 1 trial; 482 participants; very low-certainty evidence). We are also uncertain if there was a difference in relapse between groups (OR 0.88, 95% CI 0.43 to 1.82; 1 trial; 422 participants; very low-certainty evidence). Adverse events were more common with azithromycin compared to amoxicillin (OR 2.67, 95% CI 1.78 to 3.99; 1 trial; 673 participants; very low-certainty evidence). Carbacephem versus penicillin There is low-certainty evidence that compared with penicillin, carbacephem may provide better symptom resolution post-treatment in adults and children (OR 0.70, 95% CI 0.49 to 0.99; NNTB 14.3; 3 trials; 795 participants). Studies did not report on long-term complications, so it was unclear if any class of antibiotics was better in preventing serious but rare complications.  AUTHORS' CONCLUSIONS: We are uncertain if there are clinically relevant differences in symptom resolution when comparing cephalosporins and macrolides with penicillin in the treatment of GABHS tonsillopharyngitis. Low-certainty evidence in children suggests that carbacephem may be more effective than penicillin for symptom resolution. There is insufficient evidence to draw conclusions regarding the other comparisons in this review. Data on complications were too scarce to draw conclusions. These results do not demonstrate that other antibiotics are more effective than penicillin in the treatment of GABHS pharyngitis. All studies were conducted in high-income countries with a low risk of streptococcal complications, so there is a need for trials in low-income countries and Aboriginal communities, where the risk of complications remains high.


Assuntos
Antibacterianos/uso terapêutico , Faringite/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus pyogenes , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amoxicilina/efeitos adversos , Amoxicilina/uso terapêutico , Ampicilina/efeitos adversos , Ampicilina/uso terapêutico , Antibacterianos/efeitos adversos , Azitromicina/efeitos adversos , Azitromicina/uso terapêutico , Cefalosporinas/efeitos adversos , Cefalosporinas/uso terapêutico , Criança , Pré-Escolar , Clindamicina/efeitos adversos , Clindamicina/uso terapêutico , Humanos , Lactente , Macrolídeos/efeitos adversos , Macrolídeos/uso terapêutico , Pessoa de Meia-Idade , Penicilinas/efeitos adversos , Penicilinas/uso terapêutico , Faringite/microbiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecções Estreptocócicas/microbiologia , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Adulto Jovem
3.
Reprod Toxicol ; 100: 101-108, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33454317

RESUMO

This study investigated the risk of congenital heart defects (CHD) and other congenital anomalies (CA) associated with first trimester use of macrolide antibiotics (mainly erythromycin, spiramycin, clarithromycin and azithromycin) and lincosamides (clindamycin) using a case-malformed control design. Data included 145,936 babies with a CA diagnosis (livebirths, stillbirths and terminations of pregnancy for CA) from 15 population-based EUROCAT registries in 13 European countries, covering 9 million births 1995-2012. Cases were babies with CHD, anencephaly, orofacial clefts, genital and limb reduction anomalies associated with antibiotic exposure in the literature. Controls were babies with other CA or genetic conditions. Main outcomes were odds ratios adjusted (AOR) for maternal age and registry, with 95 % Confidence Intervals (95 %CI). Macrolide and lincosamide exposure was recorded for 307 and 28 cases, 72 and 4 non-genetic controls, 57 and 7 genetic controls, respectively. AOR for CHD was not significantly raised (AOR 0.94, 95 %CI: 0.70-1.26 vs non-genetic controls; AOR 1.01, 95 %CI: 0.73-1.41 vs genetic controls), nor significantly raised for any specific macrolide. The risk of atrioventricular septal defect was significantly raised with exposure to any macrolide (AOR 2.98; 95 %CI: 1.48-6.01), erythromycin (AOR 3.68, 95 %CI: 1.28-10.61), and azithromycin (AOR 4.50, 95 %CI: 1.30-15.58). Erythromycin, clarithromycin, azithromycin, and clindamycin were associated with an increased risk of at least one other CA. Further research is needed on the risk of specific CA associated with macrolide and lincosamide use in the first trimester, particularly relevant for the potential use of azithromycin in the treatment of COVID-19.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Antibacterianos/efeitos adversos , Lincosamidas/efeitos adversos , Macrolídeos/efeitos adversos , /tratamento farmacológico , Estudos de Casos e Controles , Feminino , Cardiopatias Congênitas/induzido quimicamente , Humanos , Gravidez , Primeiro Trimestre da Gravidez
4.
Cochrane Database Syst Rev ; 1: CD013198, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33448349

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterised by persistent respiratory symptoms and airflow limitation. Acute exacerbations punctuate the natural history of COPD and are associated with increased morbidity and mortality and disease progression. Chronic airflow limitation is caused by a combination of small airways (bronchitis) and parenchymal destruction (emphysema), which can impact day-to-day activities and overall quality of life. In carefully selected patients with COPD, long-term, prophylactic use of antibiotics may reduce bacterial load, inflammation of the airways, and the frequency of exacerbations. OBJECTIVES: To assess effects of different prophylactic antibiotics on exacerbations, quality of life, and serious adverse events in people with COPD in three separate network meta-analyses (NMAs), and to provide rankings of identified antibiotics. SEARCH METHODS: To identify eligible randomised controlled trials (RCTs), we searched the Cochrane Airways Group Specialised Register of trials and clinical trials registries. We conducted the most recent search on 22 January 2020. SELECTION CRITERIA: We included RCTs with a parallel design of at least 12 weeks' duration evaluating long-term administration of antibiotics prophylactically compared with other antibiotics, or placebo, for patients with COPD. DATA COLLECTION AND ANALYSIS: This Cochrane Review collected and updated pair-wise data from two previous Cochrane Reviews. Searches were updated and additional studies included. We conducted three separate network meta-analyses (NMAs) within a Bayesian framework to assess three outcomes: exacerbations, quality of life, and serious adverse events. For quality of life, we collected data from St George's Respiratory Questionnaire (SGRQ). Using previously validated methods, we selected the simplest model that could adequately fit the data for every analysis. We used threshold analysis to indicate which results were robust to potential biases, taking into account each study's contributions to the overall results and network structure. Probability ranking was performed for each antibiotic class for exacerbations, quality of life, and serious adverse events. MAIN RESULTS: Characteristics of studies and participants Eight trials were conducted at multiple sites that included hospital clinics or academic health centres. Seven were single-centre trials conducted in hospital clinics. Two trials did not report settings. Trials durations ranged from 12 to 52 weeks. Most participants had moderate to severe disease. Mean age ranged from 64 years to 73 years, and more males were recruited (51% to 100%). Forced expiratory volume in one second (FEV1) ranged from 0.935 to 1.36 L. Most participants had previous exacerbations. Data from 12 studies were included in the NMAs (3405 participants; 16 treatment arms including placebo). Prophylactic antibiotics evaluated were macrolides (azithromycin and erythromycin), tetracyclines (doxycyclines), quinolones (moxifloxacin) and macrolides plus tetracyclines (roxithromycin plus doxycycline). Risk of bias and threshold analysis Most studies were at low risk across domains, except detection bias, for which only seven studies were judged at low risk. In the threshold analysis for exacerbations, all comparisons in which one antibiotic was compared with another were robust to sampling variation, especially macrolide comparisons. Comparisons of classes with placebo were sensitive to potential bias, especially macrolide versus placebo, therefore, any bias in the comparison was likely to favour the active class, so any adjustment would bring the estimated relative effect closer to the null value, thus quinolone may become the best class to prevent exacerbations. Exacerbations Nine studies were included (2732 participants) in this NMA (exacerbations analysed as time to first exacerbation or people with one or more exacerbations). Macrolides and quinolones reduced exacerbations. Macrolides had a greater effect in reducing exacerbations compared with placebo (macrolides: hazard ratio (HR) 0.67, 95% credible interval (CrI) 0.60 to 0.75; quinolones: HR 0.89, 95% CrI 0.75 to 1.04), resulting in 127 fewer people per 1000 experiencing exacerbations on macrolides. The difference in exacerbations between tetracyclines and placebo was uncertain (HR 1.29, 95% CrI 0.66 to 2.41). Macrolides ranked first (95% CrI first to second), with quinolones ranked second (95% CrI second to third). Tetracyclines ranked fourth, which was lower than placebo (ranked third). Contributing studies were considered as low risk of bias in a threshold analysis. Quality of life (SGRQ) Seven studies were included (2237 participants) in this NMA. SGRQ scores improved with macrolide treatment compared with placebo (fixed effect-fixed class effect: mean difference (MD) -2.30, 95% CrI -3.61 to -0.99), but the mean difference did not reach the minimally clinical important difference (MCID) of 4 points. Tetracyclines and quinolones did not improve quality of life any more than placebo, and we did not detect a difference between antibiotic classes. Serious adverse events Nine studies were included (3180 participants) in the NMA. Macrolides reduced the odds of a serious adverse event compared with placebo (fixed effect-fixed class effect: odds ratio (OR) 0.76, 95% CrI 0.62 to 0.93). There was probably little to no difference in the effect of quinolone compared with placebo or tetracycline plus macrolide compared with placebo. There was probably little to no difference in serious adverse events between quinolones or tetracycline plus macrolide. With macrolide treatment 49 fewer people per 1000 experienced a serious adverse event compared with those given placebo. Macrolides ranked first, followed by quinolones. Tetracycline did not rank better than placebo. Drug resistance Ten studies reported drug resistance. Results were not combined due to variation in outcome measures. All studies concluded that prophylactic antibiotic administration was associated with the development of antimicrobial resistance. AUTHORS' CONCLUSIONS: This NMA evaluated the safety and efficacy of different antibiotics used prophylactically for COPD patients. Compared to placebo, prolonged administration of macrolides (ranked first) appeared beneficial in prolonging the time to next exacerbation, improving quality of life, and reducing serious adverse events. No clear benefits were associated with use of quinolones or tetracyclines. In addition, antibiotic resistance was a concern and could not be thoroughly assessed in this review. Given the trade-off between effectiveness, safety, and risk of antibiotic resistance, prophylactic administration of antibiotics may be best reserved for selected patients, such as those experiencing frequent exacerbations. However, none of the eligible studies excluded patients with previously isolated non-tuberculous mycobacteria, which would contraindicate prophylactic administration of antibiotics, due to the risk of developing resistant non-tuberculous mycobacteria.


Assuntos
Antibacterianos/uso terapêutico , Antibioticoprofilaxia/métodos , Carga Bacteriana/efeitos dos fármacos , Progressão da Doença , Metanálise em Rede , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Adulto , Idoso , Antibacterianos/efeitos adversos , Antibioticoprofilaxia/efeitos adversos , Teorema de Bayes , Viés , Feminino , Volume Expiratório Forçado , Humanos , Macrolídeos/efeitos adversos , Macrolídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/microbiologia , Qualidade de Vida , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Tetraciclinas/efeitos adversos , Tetraciclinas/uso terapêutico , Resultado do Tratamento
5.
Medicine (Baltimore) ; 99(51): e23747, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33371133

RESUMO

BACKGROUND: Mycoplasma pneumoniae pneumonia (MPP) is a common respiratory disease in children. Its incidence rate is increasing year by year. The drug resistance rate of macrolide antibiotics and other conventional treatment methods is higher, and there are limitations in clinical application. Traditional Chinese patent medicine (TCPM) is a powerful weapon to treat this disease. At present, there is no comparison of the safety and effectiveness of multiple TCPMs in the treatment of MPP in children. Therefore, we take the method of network meta-analysis to systematically compare the efficacy of various TCPMs in the treatment of this disease. METHODS: We will conduct comprehensive searches of Cochrane Library, PubMed, Web of Science, Clinical Trials, China National Knowledge Infrastructure, Chinese Scientific Journals Database, Chinese BioMedical Literature, Wanfang Database, and other electronic databases. The time frame is set from the establishment of the database to October 2020. All randomized controlled trials that meet the inclusion criteria will be included in this study. The 2 researchers will independently screen the literature according to the inclusion criteria, extract the data, and assess the bias risk of the included study. We will evaluate all the obtained data and evidence through Bayesian network meta-analysis, and use Stata 15.0 to process and analyze the data. RESULTS: Through this study, we will evaluate the efficacy and safety of a variety of TCPMs for the treatment of MPP in children. CONCLUSION: The purpose of this study is to provide a strong reference for clinical application of TCPMs in the treatment of MPP in children, and to provide an important basis for clinicians to make correct judgments and put forward accurate treatment plans. ETHICS AND DISSEMINATION: This review does not involve any human or animal experiments and therefore does not require ethical approval. INPLASY REGISTRATION NUMBER: INPLASY 2020100108.


Assuntos
Antibacterianos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Macrolídeos/uso terapêutico , Pneumonia por Mycoplasma/tratamento farmacológico , Adolescente , Antibacterianos/efeitos adversos , Criança , Pré-Escolar , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Humanos , Lactente , Macrolídeos/efeitos adversos , Masculino , Mycoplasma pneumoniae , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
6.
Ann Intern Med ; 172(12): JC70, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32539502

RESUMO

SOURCE CITATION: Fan H, Gilbert R, O'Callaghan F, Li L. Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study. BMJ. 2020;368:m331. 32075790.


Assuntos
Macrolídeos , Penicilinas , Antibacterianos/efeitos adversos , Criança , Estudos de Coortes , Feminino , Humanos , Macrolídeos/efeitos adversos , Penicilinas/efeitos adversos , Gravidez , Reino Unido/epidemiologia
7.
BMC Infect Dis ; 20(1): 365, 2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32448204

RESUMO

BACKGROUND: Mycobacterium fortuitum complex is a group of rapidly growing nontuberculous mycobacteria (NTM) associated with skin and soft-tissue infections after surgery or trauma. Treatment of NTM is challenging, due to resistance to multiple antimycobacterial agents. Bedaquiline is a diarylquinoline that inhibits mycobacterial ATP-synthase. The drug has recently been approved for the treatment of multidrug-resistant tuberculosis and evidence of its in vitro efficacy against NTM, including Mycobacterium fortuitum complex, has been published. CASE PRESENTATION: A 20-year-old Caucasian woman with chronic skin and soft tissue infection in the lower leg following a traffic accident in Vietnam underwent a tedious journey of healthcare visits, hospital admissions, empiric antimicrobial treatments, surgical debridement and plastic reconstruction before definite diagnosis of Mycobacterium fortuitum complex-infection was established by culture from a tissue biopsy and targeted antimycobacterial therapy was administered. Histopathological examination revealed granulomatous purulent inflammation, which strongly supported the diagnosis. Genotypic identification was performed and broth microdilution for susceptibility testing showed macrolide resistance. Five weeks of induction treatment with intravenous amikacin, imipenem / cilastin, and oral levofloxacin was administered, followed by all-oral treatment with bedaquiline combined with levofloxacin for four months, which was well-tolerated and led to persistent healing with scars but without signs of residual infection. CONCLUSIONS: Bedaquiline is a promising novel agent for NTM treatment, although clinical data are limited and trials evaluating efficacy, safety, and resistance of bedaquiline are required. To our knowledge, this is the first reported case of successful in vivo use of bedaquiline for a skin and soft tissue infection caused by Mycobacterium fortuitum complex.


Assuntos
Antituberculosos/uso terapêutico , Diarilquinolinas/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium fortuitum/efeitos dos fármacos , Dermatopatias Bacterianas/tratamento farmacológico , Pele/lesões , Infecções dos Tecidos Moles/tratamento farmacológico , Amicacina/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , Feminino , Humanos , Imipenem/uso terapêutico , Levofloxacino/uso terapêutico , Macrolídeos/efeitos adversos , Macrolídeos/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium fortuitum/genética , Lesões dos Tecidos Moles/microbiologia , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Vietnã , Adulto Jovem
9.
Thorax ; 75(5): 405-406, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32303622

RESUMO

The British Thoracic Society (BTS) guideline on the use of long-term macrolides in adults with respiratory disease has been published. It indicates where there is evidence to support the use of long-term low-dose macrolides and where there is not. It discusses the potential benefits of such therapy for patients and also describes the potential risks to individuals and wider populations. It seeks to provide a pragmatic approach for clinicians considering long-term macrolide therapy for their patients. This guideline has also acted as a learning exercise for the BTS in introducing the Grading of Recommendations Assessment, Development and Evaluation approach to guideline development, which will be used going forwards.


Assuntos
Antibacterianos/uso terapêutico , Macrolídeos/uso terapêutico , Doenças Respiratórias/tratamento farmacológico , Administração Oral , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Humanos , Macrolídeos/administração & dosagem , Macrolídeos/efeitos adversos , Guias de Prática Clínica como Assunto , Fatores de Tempo
10.
Neurology ; 94(22): 959-969, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32284362

RESUMO

The coronavirus 2019 (COVID-19) pandemic has potential to disproportionately and severely affect patients with neuromuscular disorders. In a short period of time, it has already caused reorganization of neuromuscular clinical care delivery and education, which will likely have lasting effects on the field. This article reviews (1) potential neuromuscular complications of COVID-19, (2) assessment and mitigation of COVID-19-related risk for patients with preexisting neuromuscular disease, (3) guidance for management of immunosuppressive and immunomodulatory therapies, (4) practical guidance regarding neuromuscular care delivery, telemedicine, and education, and (5) effect on neuromuscular research. We outline key unanswered clinical questions and highlight the need for team-based and interspecialty collaboration. Primary goals of clinical research during this time are to develop evidence-based best practices and to minimize morbidity and mortality related to COVID-19 for patients with neuromuscular disorders.


Assuntos
Infecções por Coronavirus/terapia , Imunossupressores/efeitos adversos , Doenças Neuromusculares/terapia , Pneumonia Viral/terapia , Antivirais/efeitos adversos , Cloroquina/efeitos adversos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/prevenção & controle , Assistência à Saúde , Desprescrições , Progressão da Doença , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/efeitos adversos , Síndrome de Guillain-Barré/etiologia , Visita Domiciliar , Humanos , Hidroxicloroquina/efeitos adversos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Infusões Subcutâneas , Macrolídeos/efeitos adversos , Doenças Musculares/etiologia , Miastenia Gravis/induzido quimicamente , Neurologia/educação , Doenças Neuromusculares/complicações , Pandemias/prevenção & controle , Pneumonia Viral/complicações , Pneumonia Viral/prevenção & controle , Guias de Prática Clínica como Assunto , Pesquisa , Comportamento de Redução do Risco , Autoadministração , Telemedicina , Vacinas Virais/uso terapêutico
11.
BMJ ; 368: m331, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075790

RESUMO

OBJECTIVE: To assess the association between macrolide antibiotics prescribing during pregnancy and major malformations, cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder in children. DESIGN: Population based cohort study. SETTING: The UK Clinical Practice Research Datalink. PARTICIPANTS: The study cohort included 104 605 children born from 1990 to 2016 whose mothers were prescribed one macrolide monotherapy (erythromycin, clarithromycin, or azithromycin) or one penicillin monotherapy from the fourth gestational week to delivery. Two negative control cohorts consisted of 82 314 children whose mothers were prescribed macrolides or penicillins before conception, and 53 735 children who were siblings of the children in the study cohort. MAIN OUTCOME MEASURES: Risks of any major malformations and system specific major malformations (nervous, cardiovascular, gastrointestinal, genital, and urinary) after macrolide or penicillin prescribing during the first trimester (four to 13 gestational weeks), second to third trimester (14 gestational weeks to birth), or any trimester of pregnancy. Additionally, risks of cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder. RESULTS: Major malformations were recorded in 186 of 8632 children (21.55 per 1000) whose mothers were prescribed macrolides and 1666 of 95 973 children (17.36 per 1000) whose mothers were prescribed penicillins during pregnancy. Macrolide prescribing during the first trimester was associated with an increased risk of any major malformation compared with penicillin (27.65 v 17.65 per 1000, adjusted risk ratio 1.55, 95% confidence interval 1.19 to 2.03) and specifically cardiovascular malformations (10.60 v 6.61 per 1000, 1.62, 1.05 to 2.51). Macrolide prescribing in any trimester was associated with an increased risk of genital malformations (4.75 v 3.07 per 1000, 1.58, 1.14 to 2.19, mainly hypospadias). Erythromycin in the first trimester was associated with an increased risk of any major malformation (27.39 v 17.65 per 1000, 1.50, 1.13 to 1.99). No statistically significant associations were found for other system specific malformations or for neurodevelopmental disorders. Findings were robust to sensitivity analyses. CONCLUSIONS: Prescribing macrolide antibiotics during the first trimester of pregnancy was associated with an increased risk of any major malformation and specifically cardiovascular malformations compared with penicillin antibiotics. Macrolide prescribing in any trimester was associated with an increased risk of genital malformations. These findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available. TRIAL REGISTRATION: ClinicalTrials.gov NCT03948620.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Antibacterianos/efeitos adversos , Macrolídeos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Anormalidades Induzidas por Medicamentos/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/epidemiologia , Anormalidades Cardiovasculares/induzido quimicamente , Anormalidades Cardiovasculares/epidemiologia , Paralisia Cerebral/induzido quimicamente , Paralisia Cerebral/epidemiologia , Estudos de Coortes , Bases de Dados Factuais , Prescrições de Medicamentos/estatística & dados numéricos , Epilepsia/induzido quimicamente , Epilepsia/epidemiologia , Feminino , Humanos , Recém-Nascido , Gravidez , Primeiro Trimestre da Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Reino Unido/epidemiologia
12.
J Biol Chem ; 295(7): 2057-2067, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31915244

RESUMO

Macrolide antibiotics, such as erythromycin and josamycin, are natural polyketide products harboring 14- to 16-membered macrocyclic lactone rings to which various sugars are attached. These antibiotics are used extensively in the clinic because of their ability to inhibit bacterial protein synthesis. More recently, some macrolides have been shown to also possess anti-inflammatory and other therapeutic activities in mammalian cells. To better understand the targets and effects of this drug class in mammalian cells, we used a genome-wide shRNA screen in K562 cancer cells to identify genes that modulate cellular sensitivity to josamycin. Among the most sensitizing hits were proteins involved in mitochondrial translation and the mitochondrial unfolded protein response, glycolysis, and the mitogen-activated protein kinase signaling cascade. Further analysis revealed that cells treated with josamycin or other antibacterial agents exhibited impaired oxidative phosphorylation and metabolic shifts to glycolysis. Interestingly, we observed that knockdown of the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene, which contributes to p38 mitogen-activated protein kinase signaling, sensitized cells only to josamycin but not to other antibacterial agents. There is a growing interest in better characterizing the therapeutic effects and toxicities of antibiotics in mammalian cells to guide new applications in both cellular and clinical studies. To our knowledge, this is the first report of an unbiased genome-wide screen to investigate the effects of a clinically used antibiotic on human cells.


Assuntos
Antibacterianos/farmacologia , MAP Quinase Quinase Quinase 4/genética , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Antibacterianos/efeitos adversos , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Eritromicina/efeitos adversos , Eritromicina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Josamicina/efeitos adversos , Josamicina/farmacologia , Células K562 , MAP Quinase Quinase Quinase 4/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrolídeos/efeitos adversos , Macrolídeos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/genética , Fosforilação Oxidativa/efeitos dos fármacos , Inibidores da Síntese de Proteínas/efeitos adversos , Inibidores da Síntese de Proteínas/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
13.
Sci Rep ; 10(1): 911, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969575

RESUMO

The practice of prophylactic administration of a macrolide antimicrobial with rifampin (MaR) to apparently healthy foals with pulmonary lesions identified by thoracic ultrasonography (i.e., subclinically pneumonic foals) is common in the United States. The practice has been associated epidemiologically with emergence of R. equi resistant to MaR. Here, we report direct evidence of multi-drug resistance among foals treated with MaR. In silico and in vitro analysis of the fecal microbiome and resistome of 38 subclinically pneumonic foals treated with either MaR (n = 19) or gallium maltolate (GaM; n = 19) and 19 untreated controls was performed. Treatment with MaR, but not GaM, significantly decreased fecal microbiota abundance and diversity, and expanded the abundance and diversity of antimicrobial resistance genes in feces. Soil plots experimentally infected with Rhodococcus equi (R. equi) and treated with MaR selected for MaR-resistant R. equi, whereas MaR-susceptible R. equi out-competed resistant isolates in GaM-treated or untreated plots. Our results indicate that MaR use promotes multi-drug resistance in R. equi and commensals that are shed into their environment where they can persist and potentially infect or colonize horses and other animals.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Antibioticoprofilaxia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Doenças dos Cavalos/prevenção & controle , Macrolídeos/efeitos adversos , Macrolídeos/uso terapêutico , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/uso terapêutico , Pneumonia Bacteriana/prevenção & controle , Pneumonia Bacteriana/veterinária , Pironas/efeitos adversos , Pironas/uso terapêutico , Rhodococcus equi/efeitos dos fármacos , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Animais , Antibacterianos/uso terapêutico , Fezes/microbiologia , Cavalos , Macrolídeos/farmacologia , Testes de Sensibilidade Microbiana , Compostos Organometálicos/farmacologia , Pneumonia Bacteriana/microbiologia , Pironas/farmacologia , Rhodococcus equi/genética , Rifampina/farmacologia
14.
Drug Saf ; 43(3): 211-221, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31721138

RESUMO

INTRODUCTION: Macrolides are widely used during pregnancy; however, their fetal safety remains uncertain. We performed a meta-analysis to assess the relation between prenatal exposure to macrolides and occurrence of congenital malformations. METHODS: We searched MEDLINE, EMBASE, and other databases until June 12, 2019. We assessed the quality of the studies and checked for heterogeneity and publication bias. We performed three different analyses and compared the effect of macrolides with each of the following unexposed populations: Group 1: babies unexposed to any medicine before birth, Group 2: babies exposed to non-macrolide antibiotics/non-teratogens, and Group 3: mixed population of the first and second comparators. RESULTS: A weak association between macrolides and congenital malformation of any type was observed when macrolides were compared with the mixed population (ORgroup 3 1.06 [95% CI 1.01-1.10]). Subgroup analysis showed that this weak association is restricted to fetus exposure in the first trimester of pregnancy (OR 1.06 [95% CI 1.01-1.11]) and to cohort studies (OR 1.07 [95% CI 1.02-1.13]). Digestive system malformations were found to be slightly associated with prenatal exposure to macrolides (ORgroup 3 1.14 [95% CI 1.02-1.26]). The musculoskeletal system was also found to be potentially affected (ORgroup 2 1.21 [95% CI 1.08-1.35] and ORgroup 3 1.15 [95% CI 1.05-1.26]). European studies showed a slightly stronger association than American studies in these two comparisons. CONCLUSIONS: Our study suggests a weak association between prenatal use of macrolides and congenital malformations, limited to exposure in early pregnancy, and musculoskeletal and digestive systems. In addition to studies with a larger control of confounding, risk-benefit research is needed to determine the usefulness of macrolides during pregnancy.


Assuntos
Anormalidades Induzidas por Medicamentos , Antibacterianos/efeitos adversos , Macrolídeos/efeitos adversos , Complicações Infecciosas na Gravidez/tratamento farmacológico , Antibacterianos/uso terapêutico , Feminino , Humanos , Macrolídeos/uso terapêutico , Gravidez , Fatores de Risco
15.
J Med Chem ; 63(12): 6462-6473, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31644280

RESUMO

This is a review of the macrolide and ketolide field focusing on differentiating the pharmacodynamics and especially the toxicology of the macrolides and ketolides. We emphasize the diversity in pharmacodynamics and toxicity of the macrolides and ketolides, resulting from even small structural changes, which makes it important to consider the various different compounds separately, not necessarily as a class. The ketolide, telithromycin, was developed because of rising bacterial macrolide resistance but was withdrawn postapproval after visual disturbances, syncope, myasthenia gravis, and hepatotoxicity were noted. These diverse adverse effects could be attributed to inhibition of nicotinic acetylcholine receptors. Solithromycin, a later generation ketolide, was effective in treating bacterial pneumonia, but it was not approved by the U.S. Food and Drug Administration owing, in part, to its structural similarity to telithromycin. This Miniperspective describes that structurally similar macrolides/ketolides have clearly mechanistically distinct effects. Understanding these effects could help in developing and securing regulatory approval of a new macrolide/ketolide that is active against macrolide-resistant pathogenic bacteria.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Cetolídeos/farmacologia , Macrolídeos/farmacologia , Animais , Bactérias/crescimento & desenvolvimento , Infecções Bacterianas/microbiologia , Farmacorresistência Bacteriana , Humanos , Cetolídeos/efeitos adversos , Macrolídeos/efeitos adversos
16.
Pediatrics ; 145(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31796504

RESUMO

OBJECTIVES: Antibiotics are among the most common prescriptions in children, and non-ß-lactam antibiotics (NBLAs) account for almost half of those prescribed in Australian pediatric hospitals. Despite this, data on NBLA hypersensitivity in children are limited. This study describes reported hypersensitivity reactions to NBLAs in children and the results of allergy evaluation. METHODS: Children with a suspected NBLA allergy who had skin testing and/or an intravenous or oral challenge test (OCT) between May 2011 and June 2018 were included. Patients were excluded if they were >18 years old or did not complete the allergy evaluation for any reason other than allergic reaction. RESULTS: Over the 7-year study period, 141 children had 150 allergy evaluations of 15 different NBLAs. The median time from the initial reported reaction to allergy evaluation was 1.9 (range 0.1-14.9) years. Overall, 27 of the 150 (18.0%) challenge tests to NBLAs had positive results, with the rate of positive OCT results being highest for trimethoprim-sulfamethoxazole (15 of 46; 32.6%) and macrolides (8 of 77; 10.4%). Although 4 children reported initial anaphylactic reactions, no patients had severe symptoms on rechallenge or required adrenaline. Of the challenges that had positive results, the majority of children (23 of 27; 85.2%) had symptoms on repeat challenge similar to those that were initially reported. CONCLUSIONS: Overall, 8 of 10 children with NBLA allergy could be delabeled. On average, patients waited 1.9 years to be rechallenged. Timely access to allergy evaluation to delabel these patients is needed to preserve first-line antibiotics.


Assuntos
Antibacterianos/efeitos adversos , Hipersensibilidade a Drogas/diagnóstico , Adolescente , Criança , Pré-Escolar , Hipersensibilidade a Drogas/epidemiologia , Feminino , Hospitais Pediátricos , Humanos , Lactente , Macrolídeos/efeitos adversos , Masculino , Estudos Retrospectivos , Testes Cutâneos , Combinação Trimetoprima e Sulfametoxazol/efeitos adversos , Vitória/epidemiologia
17.
Respir Res ; 20(1): 286, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852452

RESUMO

BACKGROUND: Macrolide is a key drug in the treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). Macrolide-resistant MAC is gaining importance, but there are little data in clinical characteristics and treatment outcomes of macrolide-resistant MAC-PD (MR-MAC-PD). METHODS: We performed a systematic review and meta-analysis of published studies reporting clinical characteristics and treatment outcomes of patients with MR-MAC-PD. Risk of bias was assessed using the modified Newcastle-Ottawa Scale. RESULTS: Nine studies (seven retrospective and two prospective) comprising 319 patients were identified through a database search. Around 73% were women, and 52% had the fibrocavitary form. Pooled sputum culture conversion rate after combined multiple antibiotics or surgical resection was 21% (95% confidence interval [CI], 14-30%), and the one-year all-cause mortality was 10% (95% CI, 5-20%). There was no significant difference in treatment outcomes between nodular bronchiectatic and fibrocavitary types. CONCLUSIONS: Even combination therapy with fluoroquinolone, aminoglycoside, and surgical resection, the treatment outcomes of MR-MAC-PD were poor. The investigation of new treatment modalities is urgent.


Assuntos
Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana , Macrolídeos/uso terapêutico , Complexo Mycobacterium avium/efeitos dos fármacos , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Idoso , Antibacterianos/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Macrolídeos/efeitos adversos , Masculino , Complexo Mycobacterium avium/crescimento & desenvolvimento , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Pneumonectomia , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/microbiologia , Fatores de Risco , Resultado do Tratamento
18.
Top Companion Anim Med ; 37: 100366, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31837760

RESUMO

Drug-associated adverse events cause approximately 30 billion dollars a year of added health care expense, along with negative health outcomes including patient death. This constitutes a major public health concern. The US Food and Drug Administration (FDA) requires drug labeling to include potential adverse effects for each newly developed drug product. With the advancement in incidence of adverse drug events (ADEs) and potential adverse drug events, published studies have mainly concluded potential ADEs from labeling documents obtained from the FDA's preapproval clinical trials, and very few analyzed their research work based on reported ADEs after widespread use of a drug to animal subjects. The aforesaid procedure of deriving practice based on information from preapproval labeling may misrepresent or deprecate the incidence and prevalence of specific ADEs. In this study, we make the most of the recently disseminated ADE data by the FDA for animal drugs and devices used in animals to address this public and welfare concern. For this purpose, we implemented 5 different methods (Pearson distance, Spearman distance, cosine distance, Yule distance, and Euclidean distance) to determine the most efficient and robust approach to properly discover highly associated ADEs from the reported data and accurately exclude noise-induced reported events, while maintaining a high level of correlation precision. Our comparative analysis of ADEs based on an artificial intelligence (AI) approach for the 5 robust similarity methods revealed high ADE associations for 2 drugs used in dogs and cats. In addition, the described distance methods systematically analyzed and compared ADEs from the drug labeling sections with a specific emphasis on analyzing serious ADEs. Our finding showed that the cosine method significantly outperformed all the other methods by correctly detecting and validating ADEs based on the comparative similarity association analysis compared with ADEs reported by preapproval clinical trials, premarket testing, or postapproval complication experience of FDA-approved animal drugs.


Assuntos
Inteligência Artificial , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/veterinária , Aprendizado de Máquina , Farmacovigilância , Algoritmos , Animais , Gatos , Cães , Combinação de Medicamentos , Ivermectina/efeitos adversos , Ivermectina/análogos & derivados , Macrolídeos/efeitos adversos
19.
Clin Ther ; 41(12): 2540-2548, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31676040

RESUMO

PURPOSE: Current data suggest potential benefits with ß-lactam plus macrolide combination therapy for empiric treatment of intensive care unit (ICU) patients with severe community-acquired pneumonia (CAP). However, it is unclear whether deescalation to ß-lactam monotherapy in the absence of positive results on diagnostic tests, such as the BioFire FilmArray Respiratory Panel 2 (BioFire polymerase chain reaction [PCR]), affects clinical outcomes. The purpose of this study was to compare outcomes between patients with negative BioFire PCR results deescalated to ß-lactam monotherapy with those not deescalated. METHODS: This single-center, retrospective cohort study assessed the in-hospital mortality rates of critically ill adults with CAP treated for ≥48 h with combination ß-lactam and azithromycin therapy. Additional end points included hospital length of stay (LOS), ICU LOS, duration of mechanical ventilatory support, 30-day readmission, and incidence of azithromycin-related adverse effects. FINDINGS: A total of 94 patients were included: 53 in the deescalation group and 41 in the nondeescalation group. No difference was observed with respect to in-hospital mortality (2.4% vs 11.3%, P = 0.312), although patients in the deescalated group experienced shorter ICU (1.9 vs 3.4 days, P = 0.029) and hospital LOS (6 vs 7 days, P = 0.025). No differences were found between groups with respect to additional secondary end points. Simple logistic regression confirmed that deescalation was not associated with hospital mortality (odds ratio = 0.17, 95% CI, 0.02-1.70). IMPLICATIONS: In this study of ICU patients with severe CAP and a negative BioFire PCR result, deescalation from combination ß-lactam and macrolide therapy to ß-lactam monotherapy was not associated with increased in-hospital mortality but was associated with decreased hospital and ICU LOS. Larger prospective studies are warranted to verify these findings.


Assuntos
Antibacterianos , Infecções Comunitárias Adquiridas/tratamento farmacológico , Prescrição Inadequada , Macrolídeos , Pneumonia Bacteriana/tratamento farmacológico , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Infecções Comunitárias Adquiridas/mortalidade , Estado Terminal , Humanos , Prescrição Inadequada/prevenção & controle , Prescrição Inadequada/estatística & dados numéricos , Macrolídeos/administração & dosagem , Macrolídeos/efeitos adversos , Macrolídeos/uso terapêutico , Pneumonia Bacteriana/mortalidade , Estudos Retrospectivos
20.
Parasit Vectors ; 12(1): 433, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492168

RESUMO

BACKGROUND: The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies. The recommended dose is 0.5 mg/kg subcutaneously once yearly. METHODS: Study 1: safety margin was evaluated as 3 treatments of PH 12 (0× (control); 1× (recommended dose); 3× (3 times recommended dose) and 5× (5 times recommended dose) in 12 months via clinical observations, body weights, food consumption, injection site observations, physical examinations, moxidectin tissue assay, pharmacokinetics, and clinical and anatomic pathology. Study 2: safety in breeding-age males was demonstrated by semen testing at 14-day intervals from Day 7 to Day 91 post-treatment (0× or 3×). Study 3: reproductive safety in females was demonstrated by monitoring dams and litters following treatments (0× or 3×) administered during breeding, gestation, or lactation. Study 4: safety in dogs surgically implanted with adult heartworms was evaluated by clinical and laboratory monitoring following treatment with 0× or 3× administered 61 days post-implantation. Study 5: safety in ivermectin-sensitive dogs (120 µg/kg SC) was by clinical monitoring for 1 week after administering 1×, 3× or 5×. RESULTS: Study 1: slight swelling clinically detectable at some 3× and 5× injection sites was characterized microscopically as granulomatous inflammation, like tissue responses to medical implants, interpreted as non-adverse. Pharmacokinetics were dose-proportional and there was little or no systemic accumulation. Residual moxidectin mean (range) at 1× injection sites after 1 year was 16.0% (0.045-37.6%) of the administered mass. Studies 2 and 3: no effects were identified in reproductive indices (females) or semen quality characteristics (males). Study 4: PH 12 produced marked reductions in circulating microfilariae and lower numbers of adult heartworms, but no adverse clinical signs were identified. Study 5: there were no abnormal clinical signs at 1×, 3× or 5× overdoses of PH 12 in ivermectin-sensitive dogs. CONCLUSIONS: PH 12 has a > 5× safety margin in both normal and ivermectin-sensitive dogs, has no effects on canine reproduction, and is well tolerated in heartworm-positive dogs. The only treatment-related finding was non-adverse, granulomatous inflammation at the injection site.


Assuntos
Antinematódeos/efeitos adversos , Preparações de Ação Retardada/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Injeções/efeitos adversos , Macrolídeos/efeitos adversos , Suspensões/efeitos adversos , Animais , Antinematódeos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Doenças do Cão/tratamento farmacológico , Cães , Hidropericárdio/tratamento farmacológico , Macrolídeos/administração & dosagem , Suspensões/administração & dosagem , Resultado do Tratamento
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