RESUMO
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.
Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Lopinavir/farmacocinética , Ritonavir/farmacocinética , Carga Viral/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacologia , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , Humanos , Lopinavir/sangue , Lopinavir/farmacologia , Gravidez , Terceiro Trimestre da Gravidez , Ritonavir/sangue , Ritonavir/farmacologia , Comprimidos , Espectrometria de Massas em TandemRESUMO
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.
Assuntos
Fármacos Anti-HIV , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV , Inibidores da Protease de HIV , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Algoritmos , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Emtricitabina , Feminino , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , HIV-1/genética , Humanos , Lopinavir/efeitos adversos , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , Organofosfonatos/uso terapêutico , Pirrolidinonas/efeitos adversos , Pirrolidinonas/uso terapêutico , RNA Viral/sangue , Raltegravir Potássico , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/efeitos adversos , Ritonavir/uso terapêutico , Tenofovir , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration , Carga ViralRESUMO
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.
Assuntos
Antibacterianos/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Naftiridinas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Linfócitos B/efeitos dos fármacos , Farmacorresistência Bacteriana , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Naftiridinas/química , Naftiridinas/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Estereoisomerismo , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem , Cefalosporinas/administração & dosagem , Otite Média/tratamento farmacológico , Doença Aguda , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Cefdinir , Cefalosporinas/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Pais , Estudos Prospectivos , Resultado do TratamentoRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Proteínas de Bactérias , Eritromicina/análogos & derivados , Eritromicina/farmacologia , Cetolídeos , Macrolídeos , Antibacterianos/química , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/metabolismo , Infecções Bacterianas/microbiologia , Resistência Microbiana a Medicamentos , Eritromicina/química , Eritromicina/uso terapêutico , Humanos , Metiltransferases/metabolismo , Ribossomos/genéticaRESUMO
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.
Assuntos
Antivirais/farmacocinética , Gorduras na Dieta/administração & dosagem , Interações Alimento-Droga , Fórmulas Infantis/administração & dosagem , Ritonavir/farmacocinética , Administração Oral , Adulto , Antivirais/sangue , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Jejum , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pós , Ritonavir/sangue , Soluções , Equivalência Terapêutica , ÁguaRESUMO
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.
Assuntos
Alcinos/síntese química , Antibacterianos/síntese química , Eritromicina/farmacologia , Alcinos/química , Alcinos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Haemophilus influenzae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Staphylococcus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana/métodos , Biossíntese de Proteínas , Streptococcus pneumoniae/efeitos dos fármacos , Transcrição Gênica , Antibacterianos/efeitos adversos , Sequência de Bases , Linhagem Celular Tumoral , DNA Bacteriano , Genes Reporter , Humanos , Luciferases/genética , Dados de Sequência Molecular , Streptococcus pneumoniae/genéticaRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Oxazolidinonas/farmacologia , Acetamidas/efeitos adversos , Acetamidas/uso terapêutico , Antibacterianos/química , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Farmacorresistência Bacteriana , Humanos , Linezolida , Oxazolidinonas/efeitos adversos , Oxazolidinonas/química , Oxazolidinonas/uso terapêuticoRESUMO
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.
Assuntos
Infecções Comunitárias Adquiridas/microbiologia , Farmacorresistência Bacteriana Múltipla/genética , Resistência a Meticilina/genética , Infecções Respiratórias/microbiologia , Staphylococcus aureus/genética , Adulto , Proteínas de Bactérias/genética , DNA Girase/genética , Método Duplo-Cego , Humanos , Metiltransferases/genética , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/isolamento & purificaçãoRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Cetolídeos/farmacologia , Ribossomos/fisiologia , Eritromicina/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Haemophilus influenzae/genética , Haemophilus influenzae/isolamento & purificação , Humanos , Biossíntese de Proteínas/efeitos dos fármacos , RNA Ribossômico 23S/efeitos dos fármacos , RNA Ribossômico 23S/genética , Ribossomos/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacosRESUMO
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.
Assuntos
Dermatopatias Infecciosas/microbiologia , Staphylococcus aureus/genética , Proteínas de Bactérias/genética , Toxinas Bacterianas/metabolismo , Ensaios Clínicos como Assunto , Infecções Comunitárias Adquiridas/microbiologia , Eletroforese em Gel de Campo Pulsado , Exotoxinas/metabolismo , Humanos , Leucocidinas/metabolismo , Resistência a Meticilina/genética , Estudos Multicêntricos como Assunto , Proteínas de Ligação às Penicilinas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
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.
Assuntos
Adenosina Trifosfatases/metabolismo , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Química Farmacêutica/métodos , Haemophilus influenzae/metabolismo , Sequência de Aminoácidos , Animais , Linfócitos B/metabolismo , Desenho de Fármacos , Genoma Bacteriano , Genômica , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Dados de Sequência Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Cefalexina/uso terapêutico , Cefalosporinas/uso terapêutico , Dermatopatias Bacterianas/tratamento farmacológico , Abscesso/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cefdinir , Celulite (Flegmão)/tratamento farmacológico , Cefalexina/efeitos adversos , Cefalosporinas/efeitos adversos , Feminino , Humanos , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Infecção dos Ferimentos/tratamento farmacológicoRESUMO
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.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologiaRESUMO
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.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos , Resistência a Múltiplos Medicamentos , Propanóis/síntese química , Propanóis/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Tilosina/análogos & derivados , Tilosina/síntese química , Tilosina/farmacologia , Antibacterianos/química , Antibacterianos/farmacocinética , Disponibilidade Biológica , Meia-Vida , Testes de Sensibilidade Microbiana , Propanóis/química , Relação Estrutura-Atividade , Tilosina/químicaRESUMO
Antibacterial SAR for a series of macrolides derived from erythromycin A that are potent LHRH antagonists was developed in an attempt to eliminate the antibiotic activities of these compounds. Increasing the size of the alkyl substituents on the desosamine 3'-amine resulted in potent LHRH antagonists that were inactive against staphylococcal bacteria strains, and were significantly (>10-fold) less active against streptococcal bacteria strains. Complete elimination of antibacterial activities could be achieved by replacement of one or both methyl groups on the 3'-amine with a large alkyl substituent.
Assuntos
Antibacterianos/química , Antibacterianos/metabolismo , Eritromicina/química , Eritromicina/metabolismo , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hormônio Liberador de Gonadotropina/metabolismo , Animais , Células CHO , Cricetinae , Humanos , Testes de Sensibilidade Microbiana , Ligação Proteica/fisiologia , Staphylococcus/efeitos dos fármacos , Staphylococcus/crescimento & desenvolvimento , Streptococcus/efeitos dos fármacos , Streptococcus/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
Attempts were made to select mutants on agar media containing the new ketolide ABT-773, erythromycin or rifampicin, at concentrations above the MICs, from Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae, including erythromycin-resistant strains. ABT-773 did not select for mutants in four strains, whereas in eight strains the frequencies at 72 h were < or = 10(-9). ABT-773 MICs were 0.015-4 mg/L for mutants, except those selected from inducible Erm(A) S. aureus. Mutants selected on ABT-773 or erythromycin were cross-resistant to ABT-773, erythromycin and, sometimes, clindamycin. The susceptibility profiles indicate that different mutations were selected and that ABT-773 and erythromycin may interact with the ribosome differently.
Assuntos
Antibacterianos/farmacologia , Antibióticos Antituberculose/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Eritromicina/análogos & derivados , Eritromicina/farmacologia , Cetolídeos , Mutação/genética , Infecções Respiratórias/microbiologia , Rifampina/farmacologia , Meios de Cultura , Haemophilus influenzae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Fenótipo , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacosRESUMO
We have developed a PCR-oligonucleotide ligation assay to rapidly identify base substitutions in topoisomerase genes that are associated with quinolone resistance in clinical isolates of Streptococcus pneumoniae. Thirty-seven strains for which the ciprofloxacin MICs were >/=4 micro g/ml and 16 strains for which the MICs were =2 micro g/ml were assayed. Compared with sequence data, the assay correctly identified the DNA bases that encoded amino acids at the four positions most commonly associated with quinolone resistance (Ser79 and Asp83 of ParC and Ser81 and Glu85 of GyrA). Therefore, this procedure can rapidly distinguish single base substitutions associated with quinolone-resistant topoisomerases in S. pneumoniae.