RESUMEN
Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0-12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0-12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Lopinavir/farmacocinética , Ritonavir/farmacocinética , Carga Viral/efectos de los fármacos , Adulto , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacología , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Esquema de Medicación , Quimioterapia Combinada , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , Humanos , Lopinavir/sangre , Lopinavir/farmacología , Embarazo , Tercer Trimestre del Embarazo , Ritonavir/sangre , Ritonavir/farmacología , Comprimidos , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: There is growing interest in studying age-related diseases, such as coronary artery disease (CAD) and resulting myocardial infarction (MI) in HIV-infected patients. While some cohort studies indicate that several antiretrovirals (ARVs), including the protease inhibitor lopinavir/ ritonavir (LPV/r), are associated with an increased relative risk (RR) of MI, other studies show a reduction of MI and CAD in subjects taking ARVs when compared with HIV+ patients not taking ARV therapy. This manuscript reviews data from Abbott-sponsored clinical trials and pharmacovigilance reporting system. METHODS: A systematic search was performed to retrieve cases of MI and CAD in Abbott's clinical trial and pharmacovigilance safety databases. The rates of MI and CAD, and risk factors for the events were reviewed in detail. RESULTS: The rate of MI and CAD per 1,000 patient treatment years (PTY) was 1.24 (95% CI = 0.40 - 2.90) and 2.74 (95% CI = 1.37 - 4.90), respectively, for subjects taking LPV/r during clinical trials. The frequency of pharmacovigilance reports of MI and CAD were 2.9 per 100,000 PTY and 3.6 per 100,000 PTY, respectively. Most subjects who had MI and CAD events had multiple baseline risk factors. CONCLUSIONS: Relatively few subjects experienced MI or CAD during Abbott-sponsored clinical trials of LPV/r. Analysis of clinical trial and pharmacovigilance data did not indicate an increased risk of MI or CAD associated with LPV/r compared with the general population. In general, the subjects that experienced MI or CAD had known traditional risk factors suggesting that addressing modifiable risk factors could decrease the risk of MI or CAD. ARVs have not been thoroughly studied in subjects at high risk for MI and CAD, and further studies of this population could identify whether starting ARVs affects the incidences of cardic events in subjects with many traditional risk factors
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Fármacos Anti-VIH/efectos adversos , Enfermedad de la Arteria Coronaria/epidemiología , Infecciones por VIH/tratamiento farmacológico , Lopinavir/efectos adversos , Infarto del Miocardio/epidemiología , Farmacovigilancia , Ritonavir/efectos adversos , Adulto , Ensayos Clínicos como Asunto , Enfermedad de la Arteria Coronaria/etiología , Femenino , Humanos , Masculino , Infarto del Miocardio/etiología , Factores de RiesgoRESUMEN
PURPOSE: Current antiretroviral regimens recommended for treatment-naïve patients include 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). The purpose of this study is to evaluate whether a new NRTI-sparing regimen may provide an alternative for persons for whom traditional regimens may not be the best option. METHODS: PROGRESS is a 96-week, randomized, open-label, multicenter trial comparing the efficacy and safety of a boosted protease inhibitor (PI) and an integrase inhibitor (lopi-navir/ritonavir [LPV/r] + raltegravir [RAL]) to a boosted PI and 2 NRTIs (LPV/r + tenofovir/ emtricitabine [TDF/FTC]) in antiretroviral (ARV)-naïve HIV-1-infected adults. RESULTS: A total of 206 subjects were randomized to receive LPV/r + RAL (n=101) or LPV/r + TDF/FTC (n=105) and analyzed for ARV efficacy using the US Food and Drug Administration time to loss of virologic response (FDA-TLOVR) algorithm. The percentage of subjects with plasma HIV-1 RNA <40 copies/mL at week 48 was 83.2% in the LPV/r + RAL group and 84.8% in the LPV/r + TDF/FTC group (P = .850; difference -1.6%; exact 95% CI, -12.0% to 8.8%). As the lower limit of the exact 95% CI for the difference between regimens was at or above the protocol-defined threshold of -20% (as well as the more stringent threshold of -12%), LPV/r + RAL was noninferior to LPV/r + TDF/FTC. The occurrence of treatment-related, moderate/severe adverse events was similar between treatment groups through 48 weeks of treatment. CONCLUSIONS: The HIV treatment regimen of LPV/r + RAL resulted in noninferior efficacy and comparable safety and tolerability compared with a traditional NRTI-containing regimen through 48 weeks of treatment. These results support further evaluation of the LPV/r + RAL regimen.
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Fármacos Anti-VIH , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH , Inhibidores de la Proteasa del VIH , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa , Adenina/efectos adversos , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Algoritmos , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/efectos adversos , Terapia Antirretroviral Altamente Activa/métodos , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Esquema de Medicación , Quimioterapia Combinada , Emtricitabina , Femenino , Infecciones por VIH/virología , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/genética , Humanos , Lopinavir/efectos adversos , Lopinavir/uso terapéutico , Masculino , Persona de Mediana Edad , Organofosfonatos/efectos adversos , Organofosfonatos/uso terapéutico , Pirrolidinonas/efectos adversos , Pirrolidinonas/uso terapéutico , ARN Viral/sangre , Raltegravir Potásico , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/uso terapéutico , Tenofovir , Resultado del Tratamiento , Estados Unidos , United States Food and Drug Administration , Carga ViralRESUMEN
We describe the synthesis and antibacterial activity of a series of tetracyclic naphthyridones. The members of this series act primarily via inhibition of bacterial translation and belong to the class of novel ribosome inhibitors (NRIs). In this paper we explore the structure-activity relationships (SAR) of these compounds to measure their ability both to inhibit bacterial translation and also to inhibit the growth of bacterial cells in culture. The most active of these compounds inhibit Streptococcus pneumoniae translation at concentrations of <5 microM and have minimum inhibitory concentrations (MICs) of <8 microg/mL against clinically relevant strains of bacteria.
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Antibacterianos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Naftiridinas/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Linfocitos B/efectos de los fármacos , Farmacorresistencia Bacteriana , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Naftiridinas/química , Naftiridinas/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Estereoisomerismo , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
OBJECTIVES: To compare efficacy, tolerability, and parental satisfaction of cefdinir and high-dose amoxicillin/clavulanate oral suspensions given to young children with non-refractory acute otitis media (AOM) based on clinical endpoints and outcomes measures. RESEARCH DESIGN AND METHODS: This was an investigator-blinded, multicenter study in which 318 children 6 months through 6 years of age with a clinical diagnosis of AOM were randomized to receive 10 days of either cefdinir (14 mg/kg divided BID) or high-dose amoxicillin/clavulanate (90/6.4 mg/kg divided BID). MAIN OUTCOME MEASURES: Investigators evaluated clinical response at an end-of-therapy (EOT) office visit conducted on day 12-15. Outcomes of satisfaction, tolerability, and adherence were also assessed at that visit using an Otitis Parent Questionnaire. RESULTS: The treatment groups were similar at baseline with respect to patient demographics. At the EOT visit, for cefdinir and amoxicillin/clavulanate, respectively, intent-to-treat (ITT) clinical cure rates were 82% (129/158) and 85% (134/158) (p = 0.547; 95% confidence interval [CI] -11.7 to 5.4) and per-protocol cure rates were 82% (123/150) and 90% (129/143) (p = 0.045; 95% CI -16.4 to 0.0). This difference was driven primarily by reduced cefdinir response in patients with recurrent AOM (p = 0.010) and those younger than 24 months (p = 0.039). Comparing cefdinir with amoxicillin/clavulanate, parents more often reported significantly better ease of use (89% vs. 57%; p < 0.0001), better taste (85% vs. 39%; p < 0.0001), and better adherence (at least 95% of doses) (82% vs. 61%; p < 0.0001). Diarrhea/loose stools were more common in the amoxicillin/clavulanate group than in the cefdinir group (28% vs. 18%, respectively; p = 0.0341). One patient in the cefdinir group and eight patients in the amoxicillin/clavulanate group withdrew from the study prematurely due to at least one adverse event (p = 0.0364). Study limitations included assessment of clinical recurrence by telephone call rather than office visit, exclusion of children with refractory AOM, and no assessment of middle ear microbiology. CONCLUSIONS: Among young children with non-refractory AOM, cefdinir was as efficacious as high-dose amoxicillin/clavulanate in the ITT group, but somewhat less effective in per-protocol analysis. From the parental perspective, cefdinir was easier to administer, had a better taste, caused less diarrhea, and resulted in higher treatment adherence than high-dose amoxicillin clavulanate.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Cefalosporinas/administración & dosificación , Otitis Media/tratamiento farmacológico , Enfermedad Aguda , Combinación Amoxicilina-Clavulanato de Potasio/efectos adversos , Cefdinir , Cefalosporinas/efectos adversos , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Masculino , Padres , Estudios Prospectivos , Resultado del TratamientoRESUMEN
The prevalence of antibiotic resistance in bacterial pathogens associated with community-acquired respiratory tract infections is increasing. Ketolides, semi-synthetic derivatives of erythromycin, overcome the macrolide resistance mechanisms found in Streptococcus pneumoniae and Streptococcus pyogenes, two key pathogens. They also have improved potency and longer post-antibiotic effects, while maintaining the antibacterial spectrum of the macrolide class. The new ketolides cethromycin (ABT-773) and telithromycin have overall antibacterial properties that suggest they will be clinically useful new antibiotics and are undergoing clinical development and regulatory review.
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Antibacterianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Proteínas Bacterianas , Eritromicina/análogos & derivados , Eritromicina/farmacología , Cetólidos , Macrólidos , Antibacterianos/química , Antibacterianos/uso terapéutico , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/metabolismo , Infecciones Bacterianas/microbiología , Farmacorresistencia Microbiana , Eritromicina/química , Eritromicina/uso terapéutico , Humanos , Metiltransferasas/metabolismo , Ribosomas/genéticaRESUMEN
BACKGROUND: A novel ritonavir oral powder formulation has been developed to eliminate the alcohol and propylene glycol contents in the current ritonavir oral solution for paediatric use. Two clinical studies were conducted to assess the bioequivalence of the powder formulation to the marketed oral solution and to evaluate the effect of food and vehicles on bioavailability. METHODS: Study 1 was a randomized, partial-crossover, 4-period study in 48 subjects. Regimens included: oral solution under moderate-fat conditions, powder formulation in water under fasting, moderate-fat or high-fat conditions, and powder formulation in chocolate milk or pudding under moderate-fat conditions. Study 2 was a randomized, crossover, 4-period study in 24 subjects. Subjects were randomized to a sequence of the oral solution and powder formulation in water, infant formula and apple sauce, all under moderate-fat conditions. Bioavailability comparisons were assessed by the 90% CIs for the geometric least-squares mean ratios. RESULTS: Ritonavir powder formulation in water was found to be bioequivalent to the marketed oral solution. Ritonavir powder formulation administered in chocolate milk, pudding, infant formula or apple sauce was bioequivalent to the powder formulation administered in water. Compared with fasting conditions, moderate-fat and high-fat meals were associated with approximately 25-40% and 35-50% reduction in ritonavir concentrations, respectively. CONCLUSIONS: The novel ritonavir powder formulation is bioequivalent to marketed ritonavir oral solution under moderate-fat conditions with a similar effect of meals. None of the vehicles tested negatively affected the bioavailability, which suggests the potential for use of a broad range of vehicles for dose preparation.
Asunto(s)
Antivirales/farmacocinética , Grasas de la Dieta/administración & dosificación , Interacciones Alimento-Droga , Fórmulas Infantiles/administración & dosificación , Ritonavir/farmacocinética , Administración Oral , Adulto , Antivirales/sangre , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Ayuno , Femenino , Semivida , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Polvos , Ritonavir/sangre , Soluciones , Equivalencia Terapéutica , AguaRESUMEN
A series of novel 6-O-substituted homopropargyl ketolides was synthesized and evaluated against various erythromycin-resistant pathogens. Promising in vitro antibacterial activity was demonstrated for compounds bearing this structural motif.
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Alquinos/síntesis química , Antibacterianos/síntesis química , Eritromicina/farmacología , Alquinos/química , Alquinos/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Haemophilus influenzae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Staphylococcus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The authors report the development of a high-throughput screen for inhibitors of Streptococcus pneumoniae transcription and translation (TT) using a luciferase reporter, and the secondary assays used to determine the biochemical spectrum of activity and bacterial specificity. More than 220,000 compounds were screened in mixtures of 10 compounds per well, with 10,000 picks selected for further study. False-positive hits from inhibition of luciferase activity were an extremely common artifact. After filtering luciferase inhibitors and several known classes of antibiotics, approximately 50 hits remained. These compounds were examined for their ability to inhibit Escherichia coli TT, uncoupled S. pneumoniae translation or transcription, rabbit reticulocyte translation, and in vitro toxicity in human and bacterial cells. One of these compounds had the desired profile of broad-spectrum biochemical activity in bacteria and selectivity versus mammalian biochemical and whole-cell assays.
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Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana/métodos , Biosíntesis de Proteínas , Streptococcus pneumoniae/efectos de los fármacos , Transcripción Genética , Antibacterianos/efectos adversos , Secuencia de Bases , Línea Celular Tumoral , ADN Bacteriano , Genes Reporteros , Humanos , Luciferasas/genética , Datos de Secuencia Molecular , Streptococcus pneumoniae/genéticaRESUMEN
Linezolid was the first antibacterial oxazolidinone to be approved for clinical use. Oxazolidinones meet a growing medical need to treat multidrug-resistant, methicillin-resistant staphylococci, vancomycin-resistant enterococci, and penicillin-non-susceptible pneumococci in hospitalized patients. They also offer a treatment option for patients who are intolerant of vancomycin and other antibacterial agents, or who have infections that are refractory or resistant to other therapies. Two main concerns, however, have arisen as linezolid use has increased. The first is the incidence of myelosuppression, in particular thrombocytopenia, which appears to be greater than that seen during clinical trials. Secondly, linezolid-resistant Staphylococcus aureus and enterococci have emerged during linezolid treatment, which can be transmitted from patient-to-patient. This review will discuss the mechanism of action, the mechanism of resistance, and the antibacterial spectrum and potency of the oxazolidinones. In addition, the efficacy and safety of linezolid derived from clinical experience will be presented.
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Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Oxazolidinonas/farmacología , Acetamidas/efectos adversos , Acetamidas/uso terapéutico , Antibacterianos/química , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Farmacorresistencia Bacteriana , Humanos , Linezolid , Oxazolidinonas/efectos adversos , Oxazolidinonas/química , Oxazolidinonas/uso terapéuticoRESUMEN
Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections are increasing. Since most published data are on nosocomial MRSA, our goal was to identify the antimicrobial susceptibility profile and resistance mechanisms of pretreatment MRSA isolates obtained from adult subjects participating in recent clinical treatment trials of community respiratory infections. Out of 465 S. aureus isolates, 43 were identified as MRSA. Antimicrobial susceptibility testing indicated susceptibility rates to: vancomycin (100%), gentamicin (86%), clindamycin (39%), quinolones (49%), and erythromycin (12%). Among our MRSA isolates, the MLS constitutive phenotype and ermA were more prevalent than the MLS inducible phenotype and ermC. No isolates had ermB or msrA. All ciprofloxacin resistant isolates had an amino acid change in GyrA and GrlA. The relatedness of our MRSA strains was assessed by ribotyping. Our results indicate that MRSA from adult subjects with community respiratory infections have similar antimicrobial susceptibility profiles and resistance mechanisms as nosocomial MRSA, and represent a genetically diverse group.
Asunto(s)
Infecciones Comunitarias Adquiridas/microbiología , Farmacorresistencia Bacteriana Múltiple/genética , Resistencia a la Meticilina/genética , Infecciones del Sistema Respiratorio/microbiología , Staphylococcus aureus/genética , Adulto , Proteínas Bacterianas/genética , Girasa de ADN/genética , Método Doble Ciego , Humanos , Metiltransferasas/genética , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
Cethromycin (ABT-773) is a new ketolide currently in clinical trials, for treatment of community acquired respiratory tract infections. The drug is active in vitro and in vivo against Haemophilus influenzae. In this study, the mechanism of action of cethromycin was investigated in H. influenzae. The drug effect was studied using in vitro transcription-translation and whole cell amino acid incorporation. Both cethromycin and erythromycin inhibit protein synthesis with similar potencies; cethromycin, however, had a prolonged molecular postantibiotic effect (PAE) compared with erythromycin which was consistent with previously reported microbiological data. Ribosome binding assay using ribosomes isolated from H. influenzae NP200 revealed that the ribosome binding affinity of cethromycin was more than 20-fold tighter than that of erythromycin. Studies of binding kinetics showed that the tight binding of cethromycin mainly contributed to the 20-fold slower dissociation from cells. Further studies showed cethromycin had a four-fold faster drug accumulation rate than erythromycin. Therefore, the tight binding of cethromycin with ribosomes likely contributed to the faster drug accumulation, slower dissociation from cells and prolonged molecular PAE of cethromycin for H. influenzae.
Asunto(s)
Antibacterianos/farmacología , Haemophilus influenzae/efectos de los fármacos , Cetólidos/farmacología , Ribosomas/fisiología , Eritromicina/farmacología , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Haemophilus influenzae/genética , Haemophilus influenzae/aislamiento & purificación , Humanos , Biosíntesis de Proteínas/efectos de los fármacos , ARN Ribosómico 23S/efectos de los fármacos , ARN Ribosómico 23S/genética , Ribosomas/efectos de los fármacos , Transcripción Genética/efectos de los fármacosRESUMEN
The co-formulated, ritonavir-boosted protease inhibitor lopinavir is a frequently used component of HAART for treatment of HIV-infected women during pregnancy and prevention of mother-to-child transmission. We performed a systematic review to assess the effects of lopinavir/ritonavir on maternal and infant clinical and safety outcomes in HIV-infected pregnant women. PubMed, EMBASE, and select congresses were searched for studies published through May 31, 2012. Studies were selected that included HIV-infected pregnant mothers treated with a lopinavir/ritonavir-based regimen and described relevant maternal and infant outcomes. Ten articles or presentations describing nine studies were identified, comprising 2,675 lopinavir/ritonavir-treated women. In studies reporting HIV-1 RNA at delivery, HIV-1 RNA < 200 to < 1,000 copies/ml was achieved in 64-97% of subjects. Preterm delivery (< 37 weeks gestation) rates ranged from 8.3 to 25%; low birth weight (< 2,500 g) rates ranged from 11 to 20.3%. In one study, preterm delivery rates and low birth weight were similar between women who received standard or increased doses of lopinavir/ritonavir. In five studies reporting stillbirths and live births, 38 stillbirths occurred versus 2,058 live births (1.8%) among women receiving lopinavir/ritonavir. In eight studies reporting mother-to-child transmission at different time points, rates ranged from 0 to 3.3% and appeared to be similar in the one study comparing pregnant women who received standard or higher doses of lopinavir/ritonavir. The results from this systematic review suggest no unique safety or efficacy concerns with use of standard dose lopinavir/ritonavir as part of HAART in pregnant women.
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Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Lopinavir/administración & dosificación , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Ritonavir/administración & dosificación , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Esquema de Medicación , Quimioterapia Combinada , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , Humanos , Recién Nacido , Guías de Práctica Clínica como Asunto , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/prevención & control , ARN Viral , Resultado del Tratamiento , Carga ViralRESUMEN
Alternative combinations of antiretrovirals (ARVs) are desired to increase treatment options for HIV-infected patients. PROGRESS was a randomized, open-label, 96-week pilot study comparing a regimen of lopinavir/ritonavir (LPV/r) 400/100 mg twice daily in combination with either raltegravir (RAL) 400 mg twice daily or tenofovir/emtricitabine (TDF/FTC) 300/200 mg once daily in ARV-naive adults. A total of 206 subjects were randomized and treated (LPV/r+RAL, N=101; LPV/r+TDF/FTC, N=105). Demographics and baseline characteristics were similar across treatment groups. At 96 weeks, 66.3% of subjects receiving LPV/r+RAL and 68.6% of subjects receiving LPV/r+TDF/FTC were responders (plasma HIV-1 RNA levels<40 copies/ml) by the FDA time to loss of virologic response (FDA-TLOVR) algorithm (p=0.767). Mean CD4(+) T cell increases through 96 weeks were similar between treatment groups (LPV/r+RAL=281 cells/mm(3), LPV/r+TDF/FTC=296 cells/mm(3), p=0.598). Safety and tolerability were generally similar between groups. The LPV/r+RAL regimen resulted in greater increases in peripheral fat, but not trunk fat, compared with LPV/r+TDF/FTC. There was a statistically significantly greater mean reduction in estimated glomerular filtration rate from baseline to week 96 in the LPV/r+TDF/FTC group compared with the LPV/r+RAL group (-7.33 ml/min vs. -1.43 ml/min; p=0.035). The LPV/r+TDF/FTC group had a statistically significant (p<0.001) mean percent decrease from baseline to week 96 in bone mineral density, which was significantly different from the mean percent change in the LPV/r+RAL group (-2.48% vs. +0.68%, p<0.001). These efficacy and safety observations support further evaluation of the LPV/r+RAL regimen.
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Antirretrovirales/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Carga Viral , Adulto , Antirretrovirales/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Recuento de Linfocito CD4 , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Plasma/virología , ARN Viral/sangre , Resultado del TratamientoRESUMEN
A clinical trial of uncomplicated skin and skin structure infections (39 locations in 19 states) observed that community-associated or community-onset methicillin-resistant Staphylococcus aureus (CO-MRSA) represented 23% of all pathogens at baseline culture and 53% of 190 S. aureus isolates. CO-MRSA strains typically were Panton-Valentine leukocidin (PVL) positive (95%), contained staphylococcal cassette chromosome mec type IVa (99%), were USA300 or USA400 clones (92%), and exhibited minimal coresistances (macrolides and/or fluoroquinolones). Clinical results remained identical (89% cures) regardless of the antimicrobial used or CO-MRSA molecular patterns, PVL production, or antimicrobial susceptibility profiles.
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Enfermedades Cutáneas Infecciosas/microbiología , Staphylococcus aureus/genética , Proteínas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Ensayos Clínicos como Asunto , Infecciones Comunitarias Adquiridas/microbiología , Electroforesis en Gel de Campo Pulsado , Exotoxinas/metabolismo , Humanos , Leucocidinas/metabolismo , Resistencia a la Meticilina/genética , Estudios Multicéntricos como Asunto , Proteínas de Unión a las Penicilinas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacosRESUMEN
As part of a fully integrated and comprehensive strategy to discover novel antibacterial agents, NMR- and mass spectrometry-based affinity selection screens were performed to identify compounds that bind to protein targets uniquely found in bacteria and encoded by genes essential for microbial viability. A biphenyl acid lead series emerged from an NMR-based screen with the Haemophilus influenzae protein HI0065, a member of a family of probable ATP-binding proteins found exclusively in eubacteria. The structure-activity relationships developed around the NMR-derived biphenyl acid lead were consistent with on-target antibacterial activity as the Staphylococcus aureus antibacterial activity of the series correlated extremely well with binding affinity to HI0065, while the correlation of binding affinity with B-cell cytotoxicity was relatively poor. Although further studies are needed to conclusively establish the mode of action of the biphenyl series, these compounds represent novel leads that can serve as the basis for the development of novel antibacterial agents that appear to work via an unprecedented mechanism of action. Overall, these results support the genomics-driven hypothesis that targeting bacterial essential gene products that are not present in eukaryotic cells can identify novel antibacterial agents.
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Adenosina Trifosfatasas/metabolismo , Antibacterianos/química , Proteínas Bacterianas/metabolismo , Química Farmacéutica/métodos , Haemophilus influenzae/metabolismo , Secuencia de Aminoácidos , Animales , Linfocitos B/metabolismo , Diseño de Fármacos , Genoma Bacteriano , Genómica , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Datos de Secuencia Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
OBJECTIVES: To compare the efficacy and safety of cefdinir to that of cephalexin in adolescents and adults with mild to moderate uncomplicated skin and skin structure infections (USSSI). RESEARCH DESIGN AND METHODS: This was an investigator-blinded, multicenter study in which patients at least 13 years of age with USSSI were randomized to receive 10 days of cefdinir 300 mg twice daily (BID) or cephalexin 250 mg four times daily (QID). Patients were evaluated at baseline, by telephone on Days 3-5, and during office visits on Days 12-14 (end-of-therapy [EOT] visit) and Days 17-24 (test-of-cure [TOC] visit). MAIN OUTCOME MEASURES: Clinical response was evaluated at the TOC visit. Patient reported outcomes, including a usefulness questionnaire, were also assessed. RESULTS: Three hundred and ninety-one patients were treated. The treatment groups were well matched with regard to demographic characteristics and types of infection. Abscess(es) (26%), wound infection (24%), and cellulitis (21%) were the most common infections. At the TOC visit, the clinical cure rate for both treatment groups was 89% (151/170 for cefdinir and 154/174 for cephalexin) in clinically evaluable patients (95% CI for difference in cure rates [-6.7 to 7.3]). In the intent-to-treat analysis, cure rates were 83% for cefdinir vs. 82% for cephalexin. Clinical cure rates for infections caused by methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus were 93% (37/40) and 92% (35/38) for cefdinir vs. 91% (29/32) and 90% (37/41) for cephalexin (p > 0.999 comparing treatment groups for MSSA; p > 0.999 for MRSA). The usefulness questionnaire demonstrated that cefdinir was more highly rated in the mean composite score (87.4 vs. 83.6, p = 0.04), with the difference primarily due to the respondents' preference for the convenience of taking the study medication (mean score 93.5 vs. 74.1 for cephalexin, p < 0.001). The study had the following limitations: the requirement for culture at baseline likely skewed the enrollment of patients towards those with abscesses; the results of culture in patients with USSSIs are often nonspecific; in some patients entering the study with a diagnosis of cellulitis, the cellulitis was associated with an abscess; and, incision and drainage (I&D), spontaneous drainage, and needle aspiration are likely to have contributed to clinical response for purulent infections, and in particular MRSA-associated infections. Both study drugs were well tolerated. The most common treatment-related adverse events were diarrhea (10% cefdinir, 4% cephalexin, p = 0.017), nausea (3% and 6%, respectively, p = 0.203), and vaginal mycosis (3% and 6% of females, respectively, p = 0.500). CONCLUSIONS: This study demonstrated that empiric coverage of USSSIs with cephalosporin therapy remains an appropriate clinical strategy. MRSA infections responded well in both arms of the study, suggesting that the choice of a cephalosporin did not adversely affect patient outcome. However, cephalosporins do not have accepted, clinically relevant in vitro activity against MRSA. Hence, the clinical response rates seen in this study against MRSA infections must be interpreted with caution. Cefdinir was more highly rated than cephalexin in a composite usefulness assessment.
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Cefalexina/uso terapéutico , Cefalosporinas/uso terapéutico , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Absceso/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cefdinir , Celulitis (Flemón)/tratamiento farmacológico , Cefalexina/efectos adversos , Cefalosporinas/efectos adversos , Femenino , Humanos , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Staphylococcus aureus/efectos de los fármacos , Staphylococcus epidermidis/efectos de los fármacos , Infección de Heridas/tratamiento farmacológicoRESUMEN
A series of 5-methoxy- and 5-hydroxy-6-fluoro-1,8-naphthyridone-3-carboxylic acid derivatives were prepared and evaluated for cell-free bacterial protein synthesis inhibition and whole cell antibacterial activity. When compared to the analogous 5-hydrogen compounds, the presence of the 5-OH group negatively affects biochemical potency. However, a tolerance of the 5-methoxy group is indicated. Only moderate whole cell antibacterial activity is seen, but this could be due to poor cellular penetration. Because only a few 7-position variants were made for this study, further investigation into this novel series combining a broader range of 7-amino derivatives with these 5-position modifications is warranted.
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Antibacterianos/síntesis química , Antibacterianos/farmacología , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacologíaRESUMEN
A novel series of 6-O-arylpropargyl diazalides was synthesized and evaluated for their antibacterial activity. Members of this series exhibited potent activity against erythromycin-resistant respiratory tract pathogens.