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1.
Antibiotics (Basel) ; 11(4)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35453240

RESUMO

Despite its use for decades, pharmacokinetic (PK) and safety studies on colistin are limited. We conducted a phase l, open-label trial to evaluate the safety and PK of multiple doses of intravenous (IV) and aerosolized colistimethate sodium (CMS) administered separately and in combination. In total, 31 healthy adults were enrolled into three cohorts of 9, 10, and 12 participants, respectively. Each cohort received increasing doses of CMS over three dosing periods as follows: Period 1 (IV only), 2.5 mg/kg every 12 h (q12h) to 3.3 mg/kg every 8 h (q8h); Period 2 (aerosolized only), 75 mg 2-4 doses, and Period 3 (combined IV aerosolized), in which was Periods 1 and 2 combined. Safety assessments, serum and lung concentrations of colistin analytes (colistin A, colistin B, CMS A, and CMS B), and kidney biomarkers were measured at specified time points. Increasing the CMS dose from 2.5 mg/kg q12h to q8h resulted in a 33% increase in serum colistin A concentrations from 3.9 µg/mL to 5.3 µg/mL-well above the accepted target of 2 µg/mL for 6 h after dosing, without evidence of nephrotoxicity. However, there was an increase in neurotoxicity, primarily perioral and lingual paresthesias, and self-limited ataxia. IV administration did not increase the lung concentrations of colistin.

2.
J Pharm Biomed Anal ; 176: 112775, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31446299

RESUMO

This article describes the simultaneous determination of bedaquiline fumarate (TMC-207) and rifabutin in human plasma by stable isotope dilution tandem mass spectrometry. The methodology was developed for an investigation of potential drug-drug interactions of the two anti-tuberculosis drugs when given together to healthy human volunteers. Use of the two drugs in combination to treat disease caused by Mycobacterium tuberculosis is contemplated as the bacterium becomes resistant to many currently available drugs.


Assuntos
Antituberculosos/sangue , Diarilquinolinas/sangue , Monitoramento de Medicamentos/métodos , Rifabutina/sangue , Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Diarilquinolinas/administração & dosagem , Diarilquinolinas/farmacocinética , Interações Medicamentosas , Quimioterapia Combinada , Humanos , Rifabutina/administração & dosagem , Rifabutina/farmacocinética , Espectrometria de Massas em Tandem/métodos , Tuberculose/tratamento farmacológico
3.
Clin Pharmacol Drug Dev ; 8(4): 436-442, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30500116

RESUMO

There is an urgent need to identify safe and effective combination treatments for multidrug-resistant (MDR) Mycobacterium tuberculosis infection (TB). Bedaquiline, a new diarylquinoline, is approved for the treatment of MDR pulmonary TB in combination with other drugs, which could include rifabutin, which is also used to treat drug-resistant TB. Both rifabutin and bedaquiline are metabolized via cytochrome P450 3A4, and rifabutin is an inducer of this enzyme. Bedaquiline is metabolized into its primary N-monodesmethyl metabolite, M2, and further desmethylated into an N-didesmethyl metabolite, M3. Both metabolites are cytotoxic and induce phospholipidosis. The effect of rifabutin on the generation and disposition of the 2 metabolites was investigated in healthy adult volunteers coadministered bedaquiline and either rifabutin or rifampin. Subjects received single oral doses (400 mg) of bedaquiline on days 1 and 29. Oral rifabutin (300 mg) or rifampin (600 mg) were given daily on days 20-41. In the rifabutin group maximum M2 concentrations (Cmax ) increased significantly (P < .001) from 47.59 to 79.53 ng/mL, and clearance slowed slightly (P = .01). This resulted in significantly (P < .001) increased overall exposure (area under the concentration-time curve [AUC0-τ ]). Peak concentrations of M3 increased approximately 3-fold with little decline thereafter. In rifampin recipients M2 Cmax doubled (48.44 to 101.52 ng/mL), but M2 clearance and time to Cmax significantly (P < .001) increased, and AUC0-∞ and mean residence time significantly decreased (P < .001). Peak M3 concentrations increased 4-fold and rapidly declined. Although both rifamycins accelerate desmethylation of bedaquiline and M2, differences in clearance resulted in sustained elevations of both metabolites during rifabutin, but not rifampin, treatment.


Assuntos
Diarilquinolinas/administração & dosagem , Rifabutina/administração & dosagem , Rifampina/administração & dosagem , Administração Oral , Área Sob a Curva , Diarilquinolinas/farmacocinética , Esquema de Medicação , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Masculino , Estudos Prospectivos , Rifabutina/farmacocinética , Rifampina/farmacocinética , Adulto Jovem
4.
PLoS One ; 13(5): e0196756, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29718967

RESUMO

BACKGROUND: Bedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture. METHODS: Subjects were randomly assigned to receive two single 400 mg doses of bedaquiline, alone, and, after a 4 week washout period, in combination with steady-state daily dosing of either rifabutin 300 mg or rifampin 600 mg. Blood samples were collected prior to dosing and at multiple time points subsequently, to measure plasma drug concentrations and bactericidal activity in ex vivo M tuberculosis-infected whole blood cultures (WBA). RESULTS: Single oral doses of bedaquiline produced readily detectable WBA ex vivo, reaching a maximal effect of -0.28 log/day, with negative values indicating bacterial killing. Plasma concentrations of 355 ng/ml were sufficient for intracellular mycobacteriostasis. Combined dosing with rifampin or rifabutin produced maximal effects of -0.91 and -0.79 log/d, respectively. However, the activity of the rifabutin combination was sustained throughout the dosing interval, thereby producing a greater cumulative or total effect. At low drug concentrations, rifabutin plus bedaquiline yielded greater mycobactericidal activity than the sum of their separate effects. Neither drug metabolites nor cellular drug accumulation could account for this observation. CONCLUSIONS: The combination of rifabutin plus bedaquiline produces sustained intracellular mycobactericidal activity that is greater than the sum of their individual effects. Further studies of the treatment-shortening potential of this combination are warranted.


Assuntos
Antituberculosos/farmacologia , Diarilquinolinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Rifabutina/farmacologia , Rifampina/farmacologia , Adulto , Antituberculosos/administração & dosagem , Diarilquinolinas/administração & dosagem , Quimioterapia Combinada , Humanos , Rifabutina/administração & dosagem , Rifampina/administração & dosagem
5.
Sex Transm Dis ; 45(10): 677-683, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29624558

RESUMO

BACKGROUND: There are no fully oral recommended treatment regimens for gonorrhea. Inadequately treated pharyngeal gonococcal infections are a likely reservoir for transmission and development of antimicrobial resistance. We sought to determine an oral cefixime dosing regimen that would theoretically treat pharyngeal infections by gonococci with minimum inhibitory concentrations 0.5 µg/mL. METHODS: We conducted an open-label, nonrandomized, phase I pharmacokinetic and safety study of cefixime in 25 healthy male and female volunteers divided into 4 dosing cohorts (cohort A, 400 mg; cohort B, 800 mg; cohort C, 1200 mg; and cohort D, 800 mg every 8 hours × 3 doses [total dose 2400 mg]) with a target serum concentration of at least 2.0 µg/mL for more than 20 hours. Cefixime concentrations from serum and pharyngeal fluid were determined with use of a validated liquid chromatography-tandem mass spectrometry assay. Safety measures included laboratories, physical examinations, and symptom diaries. RESULTS: None of the single-dose regimens attained the target concentration; however, 50% of subjects in cohort D attained the target concentration. Variation in absorption and protein binding contributed to differences in concentrations. Pharyngeal fluid concentrations were negligible. The single-dose regimens were well tolerated; the multidose regimen resulted in mild to moderate gastrointestinal symptoms in 43% of subjects. CONCLUSIONS: None of the dosing regimens achieved the target concentration. However, the proposed theoretical target was extrapolated from penicillin data; there are no empirically derived pharmacokinetic/pharmacodynamic criteria for pharyngeal gonorrhea. Under alternative cephalosporin-specific therapeutic goals, the multidose regimen may be effective, although the absence of cefixime in pharyngeal fluid is concerning. A clinical trial evaluating efficacy and defining pharmacokinetic/pharmacodynamic outcomes may be warranted.


Assuntos
Cefixima/farmacocinética , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana , Gonorreia/tratamento farmacológico , Neisseria gonorrhoeae/efeitos dos fármacos , Faringe/microbiologia , Administração Oral , Adolescente , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Cefixima/administração & dosagem , Estudos de Coortes , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Adulto Jovem
6.
Artigo em Inglês | MEDLINE | ID: mdl-29061739

RESUMO

Bedaquiline is a diarylquinoline that specifically inhibits mycobacterial ATP synthase. Bedaquiline has been used to effectively treat tuberculosis (TB) caused by drug-susceptible and drug-resistant Mycobacterium tuberculosis Rifamycins are a cornerstone of combination drug regimens for the treatment of TB. This phase 1, open-label, randomized, controlled trial evaluated the effect of steady-state dosing of rifabutin or rifampin on the safety, tolerability, and pharmacokinetics of bedaquiline given as a single dose. Thirty-three healthy subjects were enrolled to receive a 400-mg single oral dose of bedaquiline at two time points, on study days 1 and 29. Subjects were randomly assigned to once daily oral doses of rifabutin (300 mg/day, n = 17) or rifampin (600 mg/day, n = 16) during period 2 from days 20 to 41. Serial blood sampling for bedaquiline measurement occurred on days 1 and 29 through 336 h after bedaquiline administration. The day 29 bedaquiline pharmacokinetic parameter estimates were compared to the corresponding day 1 estimates for each rifamycin group. Steady-state rifampin reduced bedaquiline AUC0-336 approximately 45%, from 47.69 h·µg/ml in period 1 to 26.33 h·µg/ml in period 2. Bedaquiline apparent clearance accelerated 24% in rifampin-treated subjects from 6.59 liters/h in period 1 to 8.19 liters/h in period 2. Steady-state rifabutin resulted in little quantitative impact on bedaquiline exposure but was associated with grade 3 and 4 adverse events before and after the day 29 bedaquiline dose. Dosage adjustments may therefore be necessary to ensure that bedaquiline plasma concentrations reach therapeutic levels safely when combining bedaquiline and rifamycins in TB treatment regimens. (This single-site, randomized, open-label, prospective study in healthy adult volunteers was registered at Clinicaltrials.gov under registration no. NCT01341184.).


Assuntos
Antituberculosos/farmacocinética , Diarilquinolinas/efeitos adversos , Diarilquinolinas/farmacocinética , Rifabutina/farmacologia , Rifampina/farmacologia , Adulto , Antituberculosos/efeitos adversos , Área Sob a Curva , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Masculino
7.
Pediatrics ; 140(5)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29051331

RESUMO

BACKGROUND: Children with severe influenza infection may require parenteral therapy if oral or inhaled therapies are ineffective or cannot be administered. Results from a study investigating intravenous (IV) zanamivir for the treatment of hospitalized infants and children with influenza are presented. METHODS: This phase II, open-label, multicenter, single-arm study assessed the safety of investigational IV zanamivir in hospitalized children with influenza. Safety outcomes included treatment-emergent adverse events (TEAEs), clinical laboratory measurements, and vital signs. Clinical outcomes, pharmacokinetics, and virologic efficacy data were collected as key secondary outcomes. RESULTS: In total, 71 children received treatment with investigational IV zanamivir (exposure comparable to 600 mg twice daily in adults). TEAEs and serious TEAEs (STEAEs) were reported in 51 (72%) and 15 (21%) patients, respectively. The mortality rate was 7%, and median durations of hospital and ICU stays were 6 and 7.5 days, respectively. No STEAEs or deaths were considered related to IV zanamivir treatment, and no patterns of TEAEs, laboratory abnormalities, or vital signs were observed. The mean zanamivir exposures from 34 patients with normal renal function who received 12 mg/kg, 14 mg/kg, or 600 mg of IV zanamivir ranged from 64.5 to 110 hour·µg/mL. The median change from baseline in the viral load was -1.81 log10 copies per mL after 2 days of treatment. CONCLUSIONS: The safety profile of IV zanamivir was favorable, with no drug-related STEAEs reported. The majority of children experienced virologic response and clinical improvement during the treatment course. Systemic zanamivir exposures in children were consistent with adults.


Assuntos
Antivirais/administração & dosagem , Hospitalização/tendências , Influenza Humana/diagnóstico , Influenza Humana/tratamento farmacológico , Zanamivir/administração & dosagem , Adolescente , Antivirais/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Influenza Humana/epidemiologia , Infusões Intravenosas , Masculino , Neutropenia/induzido quimicamente , Carga Viral/efeitos dos fármacos , Carga Viral/fisiologia , Zanamivir/efeitos adversos
8.
Pediatr Infect Dis J ; 35(7): 760-6, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27078119

RESUMO

BACKGROUND: The broad-spectrum cephalosporin ceftaroline, a metabolite of the prodrug ceftaroline fosamil, has shown in vitro activity against clinical isolates from pediatric patients. METHODS: This multicenter, randomized, observer-blinded, active-controlled study (NCT01669980) assessed the safety and effectiveness of ceftaroline fosamil compared with ceftriaxone plus vancomycin in patients between 2 months and 17 years of age with complicated community-acquired bacterial pneumonia. Patients were randomized 3:1 (stratified by age cohort) to receive either ceftaroline fosamil or ceftriaxone plus vancomycin (comparator) as intravenous therapy for ≥3 days. Patients who met specific study criteria on or after Study Day 4 were permitted to switch to an oral study drug. Safety assessments were treatment-emergent adverse events, and the effectiveness of treatment was assessed by clinical and microbiologic outcomes. RESULTS: The median duration of intravenous treatment was 9.0 (range, 3.0-19.0) days in the ceftaroline fosamil group (N=30) and 7.5 (5.0-13.0) days in the comparator group (N=10). At least one treatment-emergent adverse event was experienced by 12/30 patients (40%) in the ceftaroline fosamil group and 8/10 (80%) in the comparator group; most treatment-emergent adverse events in both groups were mild to moderate in intensity. Clinical response rates in the modified intent-to-treat population were 52% (15/29 patients) in the ceftaroline fosamil group and 67% in the comparator group (6/9); clinical stability at Study Day 4 was 21% (6/29) and 22% (2/9), respectively. CONCLUSIONS: Ceftaroline fosamil was well tolerated and showed similar clinical response rates to ceftriaxone plus vancomycin in pediatric patients with complicated community-acquired bacterial pneumonia.


Assuntos
Antibacterianos/administração & dosagem , Ceftriaxona/administração & dosagem , Cefalosporinas/administração & dosagem , Infecções Comunitárias Adquiridas/tratamento farmacológico , Pneumonia Bacteriana/tratamento farmacológico , Vancomicina/administração & dosagem , Adolescente , Antibacterianos/efeitos adversos , Ceftriaxona/efeitos adversos , Cefalosporinas/efeitos adversos , Criança , Pré-Escolar , Infecções Comunitárias Adquiridas/complicações , Feminino , Humanos , Lactente , Infusões Intravenosas , Masculino , Pneumonia Bacteriana/complicações , Resultado do Tratamento , Vancomicina/efeitos adversos , Ceftarolina
9.
Blood Press Monit ; 20(5): 295-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26529437

RESUMO

BACKGROUND: Ambulatory blood pressure monitoring techniques provide unique advantages for diagnosing hypertension, although few devices have been independently validated in the pediatric population. METHODS: We sought to validate the accuracy of ambulatory blood pressure monitoring with the Spacelabs 90217 monitor in children using a modified British Hypertension Society protocol. RESULTS: A total of 112 children, aged between 6 and 17 years, completed the study at one of the three participating centers. Overall, the monitor earned an 'A' for systolic blood pressure and 'B' for diastolic blood pressure. It performed slightly better among 6-12 year olds (A/A) compared with 13-17 year olds (A/B). CONCLUSIONS: We conclude that the Spacelabs 90217 monitor is an appropriate monitor for use in children who are 6 years of age or older.


Assuntos
Monitorização Ambulatorial da Pressão Arterial/instrumentação , Monitores de Pressão Arterial , Adolescente , Fatores Etários , Antropometria , Braço , Criança , Protocolos Clínicos , Diástole , Feminino , Humanos , Hipertensão/diagnóstico , Masculino , Variações Dependentes do Observador , Oscilometria , Reprodutibilidade dos Testes , Método Simples-Cego , Sístole
10.
Antimicrob Agents Chemother ; 59(7): 4173-80, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25941220

RESUMO

Despite over 40 years of worldwide usage, relatively few data have been published on the pharmacokinetics of cefazolin in pediatric surgical patients. The primary objectives of this study were to examine the pharmacokinetics and safety of cefazolin in children 10 to 12 years of age (inclusive) receiving 1 or 2 g of cefazolin, based on body weight. This multiple-center, open-label study enrolled pediatric patients electively scheduled for surgical procedures who required cefazolin as part of their routine clinical management. Patients weighing ≥25 to <50 kg received a 1-g dose, and patients weighing ≥50 to ≤85 kg received a 2-g dose. Postdose pharmacokinetic and safety assessments were conducted following drug administration. Cefazolin concentration-time data were analyzed by using both noncompartmental and population pharmacokinetics methods. Monte Carlo simulations were performed to identify appropriate weight-based cutoffs for the dosing of children aged 10 to 17 years of age. Twelve patients were enrolled in this study and provided the requisite pharmacokinetic data. In general, cefazolin was well tolerated. The mean cefazolin terminal elimination half-life, clearance, and area under the concentration-time curve from time zero to infinity in this population were 1.95 h, 0.804 ml/min/kg, and 607 mg · h/liter, respectively. Patients weighing 50 to 60 kg exhibited elevated cefazolin exposures. Observed pharmacokinetic parameters and simulation results indicated that a weight-based cutoff of 60 kg is predicted to provide cefazolin exposure consistent with that observed in normal, healthy adults at recommended doses for surgical prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01904357.).


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibioticoprofilaxia/métodos , Cefazolina/administração & dosagem , Cefazolina/farmacocinética , Adolescente , Antibacterianos/uso terapêutico , Área Sob a Curva , Peso Corporal , Cefazolina/uso terapêutico , Criança , Pré-Escolar , Simulação por Computador , Feminino , Meia-Vida , Humanos , Masculino , Modelos Biológicos , Método de Monte Carlo , Padrões de Referência
11.
Pediatr Infect Dis J ; 34(7): 748-52, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25551831

RESUMO

BACKGROUND: Dalbavancin is a lipoglycopeptide antibiotic with Gram-positive activity and novel pharmacokinetic (PK) properties that result in a prolonged terminal half-life of 15.5 days in adults. Once weekly dosing in adults in phase 3 studies of complicated skin and skin structure infections documented dalbavancin exposures associated with clinical and microbiologic efficacy. PK properties have not been examined in children. The primary objective of this open-label, multicenter single-dose phase 1 study was to characterize the PK of dalbavancin in hospitalized pediatric subjects 12-17 years of age. METHODS: A single dose of 1000 mg of dalbavancin (the standard adult dose) was administered as a 30-minute intravenous infusion to subjects weighing 60 kg or greater and 15 mg/kg for subjects weighing <60 kg. A noncompartmental PK analysis was performed. RESULTS: The apparent terminal t1/2 was approximately 9 days and was similar for dalbavancin dosages of 1000 mg and 15 mg/kg. Median dalbavancin plasma exposures (Cmax and AUCinf) when administered as 1000 mg to subjects weighing 60 kg or greater were similar to those when dalbavancin was administered at 15 mg/kg to subjects weighing <60 kg and slightly lower than exposures in adults given 1000 mg in prior PK and treatment studies. Single dose dalbavancin was well tolerated. CONCLUSIONS: Given dalbavancin exposures documented in children 12-17 years of age, and recognized dose proportionality, appropriate dosing can be modeled for pediatric phase 3 trials in acute bacterial skin and skin structure infections, to achieve the same exposure that is reported to be safe and effective in adults.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Teicoplanina/análogos & derivados , Adolescente , Antibacterianos/administração & dosagem , Criança , Feminino , Humanos , Infusões Intravenosas , Pacientes Internados , Masculino , Teicoplanina/administração & dosagem , Teicoplanina/efeitos adversos , Teicoplanina/farmacocinética
12.
Pediatrics ; 134(4): e1095-103, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25266438

RESUMO

OBJECTIVE: To evaluate efficacy and safety of eszopiclone compared with placebo in children and adolescents with insomnia associated with attention-deficit/hyperactivity disorder (ADHD). METHODS: A 12-week, randomized, double-blind, placebo-controlled trial evaluated efficacy and safety of high- or low-dose eszopiclone (1 or 2 mg in children aged 6-11 years, 2 or 3 mg in children ages 12-17 years), given every evening, in 486 patients with ADHD-related insomnia. The primary efficacy variable was change in latency to persistent sleep from baseline to week 12, based on polysomnography. Key secondary measures were polysomnography-measured wake time after sleep onset, Clinical Global Impression Parent/Caregiver and Child scales, and the Conners' ADHD rating scales. The safety of eszopiclone was further studied over 1 year of open-label treatment in 55 patients who completed the double-blind study, and 249 patients with no previous eszopiclone exposure. RESULTS: Neither low-dose nor high-dose eszopiclone significantly reduced latency to persistent sleep compared with placebo after 12 weeks of treatment. Secondary outcomes were considered nonsignificant based on the hierarchical statistical analysis plan. The most frequent treatment-emergent adverse events over 12 weeks with eszopiclone were headache, dysgeusia, and dizziness. The study results demonstrated that eszopiclone was well tolerated over 1 year of treatment, with 11.2% of patients discontinuing open-label treatment because of an adverse event. CONCLUSIONS: Eszopiclone (up to 3 mg) failed to reduce latency to persistent sleep on polysomnography after 12 weeks in children aged 6 to 17 years with ADHD-related insomnia. Eszopiclone was well tolerated in the 1-year study.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Compostos Azabicíclicos/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Piperazinas/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/etiologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Zopiclona , Feminino , Seguimentos , Humanos , Masculino , Polissonografia/métodos , Método Simples-Cego , Distúrbios do Início e da Manutenção do Sono/diagnóstico
13.
Antimicrob Agents Chemother ; 58(11): 6735-41, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25182635

RESUMO

Serum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group A Streptococcus pyogenes (GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.


Assuntos
Antibacterianos/farmacocinética , Penicilina G Benzatina/farmacocinética , Streptococcus pyogenes/efeitos dos fármacos , Adolescente , Adulto , Antibacterianos/sangue , Antibacterianos/metabolismo , Humanos , Masculino , Testes de Sensibilidade Microbiana , Penicilina G Benzatina/sangue , Penicilina G Benzatina/metabolismo , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Cardiopatia Reumática/microbiologia , Cardiopatia Reumática/prevenção & controle , Sífilis/tratamento farmacológico , Sífilis/microbiologia , Adulto Jovem
14.
PLoS One ; 6(10): e25308, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21991307

RESUMO

When introduced in the 1950s, benzathine penicillin G (BPG) was shown to be effective in eradicating group A beta-hemolytic streptococcus (GAS) for at least 3 weeks after administration. Several studies since the 1990s suggest that at 3-4 weeks serum penicillin G levels are less than adequate (below MIC(90) of 0.016 µg/ml). We studied these levels for 4 weeks after the recommended dose of BPG in military recruits, for whom it is used as prophylaxis against GAS. The 329 subjects (mean age 20 years) each received 1.2 million units BPG IM and gave sera 1 day post injection and twice more at staggered time points over 4 weeks. Serum penicillin G levels were measured by liquid chromatography/tandem mass spectometry. The half-life of serum penicillin G was 4.1 days. By day 11, mean levels were <0.02 µg/ml, and by day 15<0.01 µg/ml. Levels in more than 50% of the subjects were below 0.02 µg/ml on day 9, and <.01 µg/ml on day 16. There was no demonstrable effect of subject body-surface area nor of the four different lots of BPG used. These data indicate that in healthy young adults serum penicillin G levels become less than protective <2½ weeks after injection of 1.2 million units of BPG. The findings require serious consideration in future medical and public health recommendations for treatment and prophylaxis of GAS upper respiratory tract infections.


Assuntos
Penicilina G/administração & dosagem , Penicilina G/sangue , Adolescente , Adulto , Intervalos de Confiança , Demografia , Relação Dose-Resposta a Droga , Humanos , Injeções Intramusculares , Masculino , Adulto Jovem
15.
Respir Res ; 11: 137, 2010 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-20925941

RESUMO

BACKGROUND: Cystic Fibrosis (CF) is a life-shortening genetic disease in which ~80% of deaths result from loss of lung function linked to inflammation due to chronic bacterial infection (principally Pseudomonas aeruginosa). Pulmonary exacerbations (intermittent episodes during which symptoms of lung infection increase and lung function decreases) can cause substantial resource utilization, morbidity, and irreversible loss of lung function. Intravenous antibiotic treatment to reduce exacerbation symptoms is standard management practice. However, no prospective studies have identified an optimal antibiotic treatment duration and this lack of objective data has been identified as an area of concern and interest. METHODS: We have retrospectively analyzed pulmonary function response data (as forced expiratory volume in one second; FEV1) from a previous blinded controlled CF exacerbation management study of intravenous ceftazidime/tobramycin and meropenem/tobramycin in which spirometry was conducted daily to assess the time course of pulmonary function response. RESULTS: Ninety-five patients in the study received antibiotics for at least 4 days and were included in our analyses. Patients received antibiotics for an average of 12.6 days (median = 13, SD = 3.2 days), with a range of 4 to 27 days. No significant differences were observed in mean or median treatment durations as functions of either treatment group or baseline lung disease stage. Average time from initiation of antibiotic treatment to highest observed FEV1 was 8.7 days (median = 10, SD = 4.0 days), with a range of zero to 19 days. Patients were treated an average of 3.9 days beyond the day of peak FEV1 (median = 3, SD = 3.8 days), with 89 patients (93.7%) experiencing their peak FEV1 improvement within 13 days. There were no differences in mean or median times to peak FEV1 as a function of treatment group, although the magnitude of FEV1 improvement differed between groups. CONCLUSIONS: Our results suggest that antibiotic response to exacerbation as assessed by pulmonary function is essentially complete within 2 weeks of treatment initiation and relatively independent of the magnitude of pulmonary function response observed.


Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística/tratamento farmacológico , Progressão da Doença , Volume Expiratório Forçado/fisiologia , Testes de Função Respiratória , Doença Aguda , Antibacterianos/farmacologia , Fibrose Cística/fisiopatologia , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
16.
Pediatr Infect Dis J ; 29(12): 1072-6, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20571461

RESUMO

BACKGROUND: Ertapenem is a carbapenem antibiotic with broad spectrum activity and a pharmacokinetic profile that favors once-daily administration in adults. OBJECTIVES: This investigation was designed to evaluate the dose-exposure profile of ertapenem in children from infancy through adolescence. METHODS: Eighty-four children (3 months-16 years) requiring antibiotic therapy were enrolled in this multicenter trial. Children received a single intravenous dose of ertapenem at 15, 20, or 40 mg/kg followed by repeated blood sampling for 24 hours. Free and total plasma ertapenem concentrations were quantitated by high-performance liquid chromatography, and the pharmacokinetics were determined using a model-independent approach. RESULTS: Ertapenem exposure increased proportionally with increasing dose; however, achievable concentrations were influenced by age. Children older than 12 years attained higher dose-normalized concentrations at the end of the infusion (concentration at the end of the infusion [Ceoi]: 8.7 ± 1.9 mg/L per mg/kg dose) and total body exposure (area under the curve area under the plasma concentration-time curve [AUC]0-∞: 34.7 ± 14.7 mg hr/L per mg/kg dose) as compared with children 2 to 12 years (Ceoi: 6.9 ± 2.4 mg/L per mg/kg dose, AUC0-∞: 18.4 ± 8.0 mg hr/L per mg/kg dose) and children younger than 2 years (Ceoi: 6.1 ± 2.2 mg/L per mg/kg dose, AUC0-∞: 17.0 ± 5.4 mg hr/L per mg/kg dose). These findings were accounted for by age-dependent changes in ertapenem clearance and distribution volume. In 3 children adverse events (nausea, n = 2; injection site reaction, n = 1) were considered related to study drug administration. CONCLUSIONS: Children younger than 12 years require dosing more frequently than once daily to achieve optimal efficacy when treating organisms with a minimum inhibitory concentration near the susceptibility breakpoint.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , beta-Lactamas/efeitos adversos , beta-Lactamas/farmacocinética , Adolescente , Antibacterianos/administração & dosagem , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Ertapenem , Feminino , Humanos , Lactente , Masculino , Plasma/química , beta-Lactamas/administração & dosagem
17.
Clin Pediatr (Phila) ; 49(3): 280-6, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19487765

RESUMO

OBJECTIVES: To describe (a) the predictive value of symptoms for diagnosis of tinea capitis and (b) the rate and timing of cure with high-dose griseofulvin treatment. METHODS: This prospective open-label study enrolled children aged 1 to 12 years with clinical tinea capitis. Participants with a positive dermatophyte culture received oral griseofulvin (20-25 mg/kg/day) and topical selenium sulfide shampoo for 6 weeks. Main outcome measures. The rate of symptoms of tinea capitis, and rates of mycologic and clinical cure. RESULTS: The positive predictive values of any 1, 2, 3, or 4 symptoms for a positive culture were 88%, 82%, 78%, and 77%, respectively. The observed rates of mycologic, clinical, and complete cure were 89%, 66%, and 49%, respectively. conclusion: In a high-risk population it is reasonable to diagnose tinea capitis using one or more cardinal symptoms. Oral griseofulvin at 20 to 25 mg/ kg/day with adjunctive shampooing for 6 weeks is moderately successful as treatment.


Assuntos
Antifúngicos/uso terapêutico , Griseofulvina/uso terapêutico , Tinha do Couro Cabeludo/tratamento farmacológico , Administração Cutânea , Administração Oral , Antifúngicos/administração & dosagem , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Griseofulvina/administração & dosagem , Preparações para Cabelo/farmacologia , Humanos , Lactente , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Compostos de Selênio/administração & dosagem , Compostos de Selênio/uso terapêutico , Fatores de Tempo , Tinha do Couro Cabeludo/microbiologia , Resultado do Tratamento , Trichophyton/efeitos dos fármacos , Trichophyton/isolamento & purificação
18.
Pediatrics ; 123(5): e770-6, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19403468

RESUMO

OBJECTIVE: The goal was to evaluate the hypnotic efficacy of zolpidem at 0.25 mg/kg per day (maximum of 10 mg/day), compared with placebo, in children 6 through 17 years of age who were experiencing insomnia associated with attention-deficit/hyperactivity disorder. METHODS: An 8-week, North American, multicenter, double-blind, placebo-controlled, parallel-group study was conducted. Patients underwent stratification according to age (6-11 years [N = 111] or 12-17 years [N = 90]) and were assigned randomly to receive treatment with the study drug or placebo (in a 2:1 ratio). The primary efficacy variable was latency to persistent sleep between weeks 3 and 6. Secondary efficacy variables also were assessed, and behavioral and cognitive components of attention-deficit/hyperactivity disorder were monitored. Safety was assessed on the basis of reports of adverse events, abnormal laboratory data, vital signs, and physical examination findings. The potential for next-day residual effects also was assessed. RESULTS: The baseline-adjusted mean change in latency to persistent sleep at week 4 did not differ significantly between the zolpidem and placebo groups (-20.28 vs -21.27 minutes). However, differences favoring zolpidem were observed for the older age group in Clinical Global Impression scores at weeks 4 and 8. No next-day residual effects of treatment were associated with zolpidem, and no rebound phenomena occurred after treatment discontinuation. Central nervous system and psychiatric disorders were the most-frequent treatment-emergent adverse events (>5%) that were observed more frequently with zolpidem than with placebo; these included dizziness, headache, and hallucinations. Ten (7.4%) patients discontinued zolpidem treatment because of adverse events. CONCLUSION: Zolpidem at a dose of 0.25 mg/kg per day to a maximum of 10 mg failed to reduce the latency to persistent sleep on polysomnographic recordings after 4 weeks of treatment in children and adolescents 6 through 17 years of age who had attention-deficit/hyperactivity disorder-associated insomnia.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/complicações , Hipnóticos e Sedativos/administração & dosagem , Piridinas/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Adolescente , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Polissonografia , Distúrbios do Início e da Manutenção do Sono/etiologia , Resultado do Tratamento , Zolpidem
19.
Int J Antimicrob Agents ; 34(1): 67-71, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19307106

RESUMO

This study compared the pharmacokinetics of azithromycin (AZI) following administration of extended-release (ER) and immediate-release (IR) formulations in plasma and sinus mucosa in patients with chronic rhinosinusitis. Patients (n=71) were randomised 1:1 to receive a single dose of AZI-ER 2g or up to three doses of AZI-IR 500 mg daily. Paired plasma and sinus tissue samples were taken during endoscopic sinus surgery at 2-168 h (four patients per time point) after the first dose. Samples were measured by a validated liquid chromatography/mass spectrometry assay. Pharmacokinetics were determined using composite concentration-time profiles. Comparison between formulations showed that within the first 24 h, the AZI area under the plasma concentration-time curve (AUC(24)) for ER was 5.2- and 7.0-fold higher than IR in plasma and sinus tissue, respectively. Comparison between matrices showed that the AUC(24) and AUC(168) in sinus tissue were 28.2- and 62.2-fold higher than in plasma for the ER formulation, whilst the AUC(24) in sinus tissue was 21.1-fold higher than in plasma for IR formulation. These results indicated that AZI has good penetration into sinus tissue regardless of formulation; however, dosing of AZI-ER (2 g) increased AZI exposure within the first 24 h compared with the Day 1 dose of 500 mg IR regimen.


Assuntos
Antibacterianos/farmacocinética , Azitromicina/farmacocinética , Mucosa Olfatória/química , Plasma/química , Sinusite/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Cromatografia Líquida , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Adulto Jovem
20.
Pediatr Infect Dis J ; 27(6): 483-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18449063

RESUMO

BACKGROUND: The need for alternative antimicrobial therapy for recurrent and persistent acute otitis media (AOM) in children has raised interest in assessing the efficacy and safety of fluoroquinolones for treatment of these infections. METHODS: In an evaluator-blinded, active-comparator, noninferiority, multicenter study, children (6 months to <5 years) were randomized 1:1 to receive levofloxacin (10 mg/kg twice daily) or amoxicillin/clavulanate (14:1; amoxicillin 45 mg/kg twice daily) for 10 days, with evaluations 4-6 days of therapy (visit 2), 2-5 days after completing therapy (visit 3), and 10-17 days after last dose (visit 4). Primary outcome was clinical cure at visit 3 based on resolution of clinical signs and symptoms of AOM. RESULTS: A total of 1650 children were randomized and 1305 were clinically evaluable at visit 3 (630 levofloxacin, 675 comparator). Clinical cure rates were 72.4% (456 of 630) in levofloxacin-treated and 69.9% (472 of 675) in amoxicillin/clavulanate-treated children. Cure rates were also similar for levofloxacin and comparator for each age group (< or =24 months: 68.9% versus 66.2%; >24 months: 76.9% versus 75.1%; respectively). Cure rates at visit 4 were 74.9% and 73.8% in levofloxacin and amoxicillin/clavulanate groups, respectively. The upper limits of the confidence intervals were less than the noninferiority margin of 10% indicating that levofloxacin treatment is noninferior to comparator treatment overall and in both infants (6 months to 2 years) and children 2-5 years. No differences between treatment groups regarding the frequency or type of adverse events were apparent. CONCLUSIONS: Levofloxacin was not inferior to amoxicillin/clavulanate for the treatment of recurrent and/or persistent AOM in infants and children.


Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Antibacterianos/uso terapêutico , Levofloxacino , Ofloxacino/uso terapêutico , Otite Média/tratamento farmacológico , Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Ofloxacino/administração & dosagem , Ofloxacino/efeitos adversos , Resultado do Tratamento
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