RESUMO
We have synthesized new derivatives of the macrolide antibiotics erythromycin and azithromycin. Novel deoxysugar moieties were attached to these standard antibiotics by biotransformation using a heterologous host. The resulting compounds were tested against several standard laboratory and clinically isolated bacterial strains. In addition, they were also tested in vitro against standard and drug-resistant strains of human malaria parasites (Plasmodium falciparum) and the liver stages of the rodent malaria parasite (Plasmodium berghei). Antibacterial activity of modified erythromycin and azithromycin showed no improvement over the unmodified macrolides, but the modified compounds showed a 10-fold increase in effectiveness after a short-term exposure against blood stages of malaria. The new compounds also remained active against azithromycin-resistant strains of P. falciparum and inhibited growth of liver-stage parasites at concentrations similar to those used for primaquine. Our findings show that malaria parasites have two distinct responses to macrolide antibiotics, one reflecting the prokaryotic origin of the apicoplast and a second, as-yet uncharacterized response that we attribute to the eukaryotic nature of the parasite. This is the first report for macrolides that target two different functions in the Plasmodium parasites.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Azitromicina/análogos & derivados , Azitromicina/farmacologia , Cloroquina/farmacologia , Resistência a Medicamentos , Eritromicina/análogos & derivados , Eritromicina/farmacologia , Macrolídeos/síntese química , Macrolídeos/farmacologia , Malária/tratamento farmacológico , Malária/parasitologia , Testes de Sensibilidade Parasitária , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium falciparum/crescimento & desenvolvimentoRESUMO
Multiple linear regression (MLR) combined with genetic algorithm (GA) and Bayesian-regularized Genetic Neural Networks (BRGNNs) were used to model the binding affinity (pK(I)) of 38 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A for the Human Luteinizing Hormone-Releasing Hormone (LHRH) receptor using quantum chemical descriptors. A multiparametric MLR equation with good statistical quality was obtained that describes the features relevant for antagonistic activity when the substituent at the position 3 of the erythronolide core was varied. In addition, four-descriptor linear and nonlinear models were established for the whole dataset. Such models showed high statistical quality. However, the BRGNN model was better than the linear model according to the external validation process. In general, our linear and nonlinear models reveal that the binding affinity of the compounds studied for the LHRH receptor is modulated by electron-related terms.
Assuntos
Eritromicina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Modelos Químicos , Relação Quantitativa Estrutura-Atividade , Animais , Teorema de Bayes , Células CHO , Cricetinae , Cricetulus , Humanos , Modelos Lineares , Redes Neurais de Computação , Peptídeos , Teoria Quântica , SoftwareRESUMO
A total of 230 isolates were collected from clinical specimens of patients attending five health centers of the Buenos Aires, Argentina. ABT-773 was compared to erythromycin, azithromycin and clindamycin against bacterial isolates responsible for community-acquired respiratory tract infections and viridans streptococci showing different resistance patterns. Time-kill curves were also performed against selected resistant isolates. All but one of the 105 pneumococcal isolates were susceptible to ABT-773. Among the erythromycin resistant S. pyogenes isolates, all the M type and inducible isolates were susceptible to ABT-773. ABT-773 showed excellent activity against macrolide, azalide, lincosamide (MAL) inducible S. aureus producers but was inactive against constitutive producers. ABT-773 activity against viridans streptococci was also excellent.ABT-773 exerted bactericidal activity against selected isolates of S. pneumoniae, M. catarrhalis and H. influenzae, however, it was only bacteriostatic against methicillin-susceptible S. aureus.
Assuntos
Bactérias/efeitos dos fármacos , Infecções Comunitárias Adquiridas/microbiologia , Eritromicina/análogos & derivados , Eritromicina/farmacologia , Cetolídeos , Infecções Respiratórias/microbiologia , Adolescente , Adulto , Idoso , Antibacterianos/farmacologia , Bactérias/isolamento & purificação , Criança , Pré-Escolar , Farmacorresistência Bacteriana , Haemophilus influenzae/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana/métodos , Testes de Sensibilidade Microbiana/normas , Pessoa de Meia-Idade , Moraxella catarrhalis/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Streptococcus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacosRESUMO
OBJECTIVE: To compare three traditional measures of compliance with antibiotic therapy (parent report diary, preregimen and postregimen bottle-weight difference, and urine bioassay for antibiotic activity), with a deuterium oxide tracer measure of compliance. METHODS: Clinical trial in which all four compliance measures were used for subjects participating in a comparison of the efficacy of azithromycin and penicillin in treating group A beta-hemolytic streptococcal infection. Subjects were 41 children, aged 3 to 15 years (average age, 7.9 years), in a suburban pediatric private practice, who had positive rapid streptococcal antigen test results. RESULTS: Of the 41 subjects, 20 children were randomly assigned to receive azithromycin and 21 to receive penicillin. Compliance was uniformly high by all four measures. Parent diaries indicated that all doses were administered. Urine bioassays were obtained for 40 subjects, and all showed antibiotic activity. Differences in bottle weights were obtained for 27 subjects and showed that 142% of the prescribed medication was missing from the bottles at the end of the regimen. The deuterium oxide measure was obtained for 40 subjects and showed that 107% of the prescribed azithromycin and 92% of the prescribed penicillin were ingested. The correlation coefficient between measured and expected deuterium enrichment was 0.89. There was no significant correlation between the bottle-weight measure and the deuterium oxide tracer. CONCLUSIONS: The bottle-weight measure overestimates compliance; the deuterium oxide tracer is feasible for use in an office setting and produces a high correlation between the expected urinary enrichment and the measured enrichment. Increased use of this quantitative and direct measure would improve the accuracy of compliance measurement in trials of pediatric liquid medications.
Assuntos
Deutério , Embalagem de Medicamentos , Eritromicina/análogos & derivados , Pais , Cooperação do Paciente , Penicilina V/administração & dosagem , Penicilina V/urina , Água , Adolescente , Azitromicina , Criança , Pré-Escolar , Óxido de Deutério , Embalagem de Medicamentos/estatística & dados numéricos , Eritromicina/administração & dosagem , Eritromicina/urina , Feminino , Humanos , Masculino , Faringite/tratamento farmacológico , Faringite/epidemiologia , Faringite/urina , Análise de Regressão , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/epidemiologia , Infecções Estreptocócicas/urina , Streptococcus pyogenes , Tonsilite/tratamento farmacológico , Tonsilite/epidemiologia , Tonsilite/urinaRESUMO
Two children with cancer received azithromycin for Cryptosporidium-associated diarrhea that was unresponsive to supportive care. One child had choleriform diarrhea requiring daily fluid replacement of up to 65% of his total body weight; the other had protracted diarrhea and wasting. In both cases, administration of azithromycin was followed by prompt clinical improvement.
Assuntos
Criptosporidiose/tratamento farmacológico , Diarreia Infantil/tratamento farmacológico , Diarreia/tratamento farmacológico , Eritromicina/análogos & derivados , Neoplasias do Mediastino/complicações , Neuroblastoma/complicações , Infecções Oportunistas/tratamento farmacológico , Sarcoma/complicações , Administração Oral , Azitromicina , Pré-Escolar , Terapia Combinada , Criptosporidiose/etiologia , Diarreia/etiologia , Diarreia Infantil/etiologia , Avaliação de Medicamentos , Eritromicina/administração & dosagem , Hidratação , Humanos , Lactente , Masculino , Infecções Oportunistas/etiologiaRESUMO
We compared a single 1 gm dose of azithromycin with the standard 7-day course of doxycycline for the treatment of uncomplicated chlamydial genital infection in sexually active adolescents. Seventy-three adolescents (65 female) with a cervical or urethral culture positive for Chlamydia trachomatis were enrolled in the study; 46 received azithromycin and 27 received doxycycline. Follow-up evaluations were done 1, 2, and 4 weeks after treatment with azithromycin or initiation of treatment with doxycycline. There were four treatment failures (8.7%) among the patients who received azithromycin and four in the doxycycline-treated group (14.8%); all were female. Six of these girls (three treated with azithromycin and three with doxycycline) gave histories of unprotected intercourse with an untreated partner and were probably reinfected. Almost half the patients were clinically symptom free. The clinical response rate for the remaining patients with symptoms was 97.4% at 4 weeks. Nineteen percent of the azithromycin-treated patients and 33.3% of those treated with doxycycline had mild to moderate drug-related side effects, which were predominantly gastrointestinal. We conclude that treatment with a single oral dose of azithromycin appears to be as safe and efficacious as a 7-day course of doxycycline for the treatment of uncomplicated genital chlamydial infection in adolescents.
Assuntos
Infecções por Chlamydia/tratamento farmacológico , Chlamydia trachomatis , Eritromicina/análogos & derivados , Doenças Bacterianas Sexualmente Transmissíveis/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Azitromicina , Doxiciclina/administração & dosagem , Doxiciclina/efeitos adversos , Esquema de Medicação , Eritromicina/administração & dosagem , Eritromicina/efeitos adversos , Feminino , Humanos , MasculinoRESUMO
In this open study, a three-day regimen of azithromycin (single daily dose of 10 mg/kg) was compared with a ten-day regimen of amoxycillin paediatric suspension (30 mg/kg/day in three divided doses; children > 20 kg received 250 mg tid daily) in 154 children (aged 2-12 years) with a clinical diagnosis of acute otitis media (13 recurrent). Full clinical, bacteriological and laboratory safety assessments were performed during and after the study. Of the 77 azithromycin patients, 61 (79%) were considered cured, 15 (19%) improved and one (1%) failed, compared with 45 (58%) cured, 28 (36%) improved and four (5%) failed among the 77 amoxycillin patients. Excluding from analysis the 13 patients with recurrent otitis media, azithromycin was found to be significantly superior to amoxycillin (P = 0.003). The incidence of side-effects was low, with only two (3%) and three (4%) patients reporting adverse events with azithromycin and amoxycillin, respectively. These were gastrointestinal in nature and of mild or moderate severity, except for one case of severe diarrhoea in the amoxycillin group. No treatment-related abnormalities in the laboratory safety tests were observed, and no patients withdrew from therapy. A three-day regimen of azithromycin was therefore shown to be more effective than, and as well tolerated as, amoxycillin in the treatment of children with acute otitis media.
Assuntos
Amoxicilina/uso terapêutico , Eritromicina/análogos & derivados , Otite Média/tratamento farmacológico , Doença Aguda , Azitromicina , Infecções Bacterianas/complicações , Infecções Bacterianas/tratamento farmacológico , Criança , Pré-Escolar , Esquema de Medicação , Eritromicina/uso terapêutico , Feminino , Humanos , Masculino , Otite Média/complicações , Infecções Respiratórias/complicaçõesRESUMO
La azitromicina pertenece al grupo de los azálidos y tiene una mayor penetración tisular, así como una vida media más prolongada que la eritromicina. Es activa contra patógenos intracelulares debido a su captación y acumulación en células fagocíticas y fibroblastos. Ha mostrado mayor actividad in vitro contra H. influenzae, N. gonorrhoeae, M. hominis y Citrobacter diversus que la eritromicina. Se estudiaron 20 pacientes adultos ambulatorios (12 mujeres y ocho varones), con diagnóstico de infección aguda de vía respiratoria superior, quienes recibieron 500 mg de azitromicina por vía oral, en dosis única durante tres días. Se evaluaron antes del tratamiento, 48 h y siete días postratamiento. Los diagnósticos establecidos fueron: faringoamigdalitis aguda (8), sinusitis aguda (4), amigdalitis aguda (4), faringitis aguda (1), faringolaringotraqueitis aguda (1), laringitis aguda (1) y exacerbación de sinusitis crónica (1). Las bacterias encontradas en el pretratamiento fueron: S. aureus (5), M. catarrhalis (2), H. influenzae (2), estreptococo grupo D (1), estreptococo spp (1), K. oxytoca (1), Acinetobacter spp (1), E. coli (1) y Klebsiella spp (1). Todas las bacterias resultaron susceptibles a azitromicina, excepto K. oxytoca y estreptococo grupo D. Desde el punto de vista bacteriológico, la respuesta a las 48 h postratamiento se obtuvo curación en 14, mejoría en dos, y falla en cuatro, mientras que a los siete días postratamiento se obtuvo curación en 16 y falla en cuatro. Desde el punto de vista bacteriológico, la respuesta a las 48 h postratamiento fue: erradicación en 13, persistencia en cuatro y superinfección en uno, y a los siete días fue: erradicación en 13 y no evaluable en siete. Las cuatro bacterias persistentes fueron: S. aureus, estreptococo grupo D, K. oxytoca y H. influenzae, K. pneumoniae fue responsable de la superinfección. No se observaron efectos indeseables.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Antibacterianos/farmacocinética , Eritromicina/análogos & derivados , Laringite/tratamento farmacológico , Faringite/tratamento farmacológico , Sinusite/tratamento farmacológico , Tonsilite/tratamento farmacológico , Traqueíte/tratamento farmacológicoRESUMO
We prospectively studied 271 infants and children (2 months to 7 years of age) with acute otitis media (AOM) for viral and bacterial causes, outcome at the end of therapy, and frequency of recurrence within 1 month. Comprehensive virologic methods, including viral antigen detection, cell culture, and serologic studies, were used to diagnose viral infection of the respiratory tract, middle ear, or both. Evidence of viral infection was found in 46% (124/271) of patients with AOM. Sixty-six patients (24%) had virus or viral antigen in the middle ear fluid; 50 of these patients (76%) also had bacteria in middle ear fluid, and 16 (24%) had virus alone. More patients with AOM and combined bacterial and viral infection (51%) had persistent otitis (3 to 12 days after institution of antibiotic treatment), compared with those with only bacterial otitis (35%; p = 0.05) or patients with only viral infection (19%; p less than 0.01). Of patients with only viral infection, 4 of 10 with virus in middle ear fluid had persistent otitis, compared with none of 11 patients who had virus only in nasal wash specimens or whose viral infection was diagnosed only by serologic studies. Our data suggest that viruses interact with bacteria and that concurrent viral infection can significantly worsen the clinical course of bacterial AOM. The presence of virus in middle ear fluid may contribute to the pathogenesis and outcome of bacterial AOM. The mechanism of these interactions deserve further investigation.
Assuntos
Infecções Bacterianas/tratamento farmacológico , Otite Média/microbiologia , Infecções Respiratórias/epidemiologia , Viroses/epidemiologia , Amoxicilina/uso terapêutico , Combinação Amoxicilina e Clavulanato de Potássio , Infecções Bacterianas/epidemiologia , Ceftizoxima/análogos & derivados , Ceftizoxima/uso terapêutico , Claritromicina , Ácidos Clavulânicos/uso terapêutico , Quimioterapia Combinada/uso terapêutico , Eritromicina/análogos & derivados , Eritromicina/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Otite Média/tratamento farmacológico , Otite Média/epidemiologia , Resultado do Tratamento , CefpodoximaAssuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Eritromicina/análogos & derivados , HIV-1 , Síndrome da Imunodeficiência Adquirida/complicações , Claritromicina , Eritromicina/uso terapêutico , Humanos , Infecção por Mycobacterium avium-intracellulare/complicações , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecções Oportunistas/complicações , Infecções Oportunistas/tratamento farmacológicoRESUMO
Bilateral sensorineural hearing loss developed in a 64-year-old woman treated with intravenous erythromycin lactobionate for bacteremic pneumococcal pneumonia. Discontinuance of the antibiotic led to prompt correction of the hearing deficit. Reversible hearing loss is an infrequently described adverse effect attributed to high-dose erythromycin therapy. Possible risk factors, including age, gender, and hepatic and renal function, may contribute to the development of erythromycin ototoxicity.
Assuntos
Eritromicina/análogos & derivados , Perda Auditiva Bilateral/induzido quimicamente , Perda Auditiva Neurossensorial/induzido quimicamente , Eritromicina/efeitos adversos , Eritromicina/uso terapêutico , Feminino , Humanos , Injeções Intravenosas , Pessoa de Meia-Idade , Infecções Pneumocócicas/tratamento farmacológicoAssuntos
Humanos , Drogas em Investigação/uso terapêutico , Eritromicina/análogos & derivados , HIV-1 , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Eritromicina/uso terapêutico , Infecção por Mycobacterium avium-intracellulare/complicações , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecções Oportunistas/complicações , Infecções Oportunistas/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/complicaçõesRESUMO
O autor apresenta as perspectivas de progressos, no campo da terapêutica antimicrobiana, representadas pelo aparecimento de novos antibióticos macrolídicos com propriedades que os diferenciam, e muitas vezes os tornam mais atraentes, relativamente aos membros mais antigos da família. Compara esses novos antibióticos com a eritromicina, destacando as diferenças de propriedades farmacocinéticas e de espectro antimicrobiano. Por fim, apresenta as indicaçöes terapêuticas especiais que esses medicamentos poderäo vir a ter
Assuntos
Humanos , Antibacterianos/farmacocinética , Antibacterianos/química , Antibacterianos/uso terapêutico , Bactérias/metabolismo , Eritromicina/análogos & derivados , Eritromicina/química , Eritromicina/farmacocinética , Eritromicina/uso terapêutico , Miocamicina/química , Miocamicina/farmacocinética , Miocamicina/uso terapêutico , Roxitromicina/química , Roxitromicina/farmacocinética , Roxitromicina/uso terapêuticoAssuntos
Antibacterianos/farmacocinética , Antibacterianos/química , Antibacterianos/uso terapêutico , Bactérias/metabolismo , Eritromicina/análogos & derivados , Eritromicina/química , Eritromicina/farmacocinética , Eritromicina/uso terapêutico , Humanos , Miocamicina/química , Miocamicina/farmacocinética , Miocamicina/uso terapêutico , Roxitromicina/química , Roxitromicina/farmacocinética , Roxitromicina/uso terapêuticoAssuntos
Claritromicina , Eritromicina/administração & dosagem , Eritromicina/análogos & derivados , Eritromicina/uso terapêutico , Hanseníase/tratamento farmacológico , Minociclina/administração & dosagem , Minociclina/uso terapêutico , Mycobacterium leprae , Quimioterapia Combinada , Rifampina/uso terapêuticoAssuntos
Antibacterianos/uso terapêutico , Azitromicina , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos BALB C , Claritromicina , Eritromicina/análogos & derivados , Eritromicina/uso terapêutico , Hanseníase/microbiologia , Hanseníase/tratamento farmacológico , Mycobacterium leprae , Roxitromicina/uso terapêuticoRESUMO
In a previous study by our group with patients having asymptomatic teeth with pulpal necrosis and an associated periapical radiolucent lesion (PN/PL), it was shown that prophylactic administration of penicillin V or erythromycin (high-dose, 1-day regimen) resulted in a low incidence of flare-up (mean = 2.2%) and a low incidence of swelling and pain not associated with flare-up. No hypersensitivity responses occurred, and gastrointestinal side effects were found primarily with the erythromycins. To ascertain whether a single-dose administration of a long-acting 1-gm tablet of the cephalosporin antibiotic cefadroxil would result in a similar outcome, the present study was undertaken with 200 patients having quiescent PN/PL. The patients were randomly given either cefadroxil or erythromycin (base or stearate). Evaluations of flare-up were done 1 day, 1 week, and 2 months after endodontic treatment. A 2.0% flare-up incidence was found, with no statistically significant differences for cefadroxil (1.0%), stearate (2.0%), or base (4.0%). No hypersensitivity responses occurred. Gastrointestinal side effects were found primarily with the erythromycins (19.0%). The results showed that a 1-gm, single-dose regimen of cefadroxil was as effective as erythromycin and penicillin in preventing flare-ups and serious sequelae. A comparative analysis of the data from our first study (no peritreatment antibiotics) and the pooled data from our last three investigations (including the current trial) showed that peritreatment antibiotic coverage significantly reduced flare-ups and serious sequelae after endodontic treatment of asymptomatic PN/PL (p less than 0.001).
Assuntos
Cefadroxila/uso terapêutico , Necrose da Polpa Dentária/cirurgia , Eritromicina/uso terapêutico , Doenças Periapicais/cirurgia , Pré-Medicação , Doença Aguda , Adolescente , Adulto , Idoso , Distribuição de Qui-Quadrado , Criança , Necrose da Polpa Dentária/tratamento farmacológico , Edema/prevenção & controle , Eritromicina/administração & dosagem , Eritromicina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/prevenção & controle , Doenças Periapicais/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Tratamento do Canal Radicular/efeitos adversos , Inquéritos e QuestionáriosRESUMO
To evaluate the efficacy of early treatment with erythromycin on the duration of fecal excretion and of diarrhea associated with Campylobacter jejuni, 170 patients, age 3 to 60 months, were randomly assigned in a double-blind fashion to receive either erythromycin ethyl succinate or placebo immediately after being seen at Cayetano Heredia Hospital because of acute dysentery. The groups' pretreatment characteristics were comparable. Of the 30 patients with stools positive for C. jejuni, 12 were in the placebo group and 16 in the treatment group. After 2 days of treatment, none of the patients in the placebo group and 36% of those in the erythromycin group had normal stools (P less than 0.05). After 5 days of treatment, 50% of the patients in the placebo group and 93% of those in the erythromycin group had normal stools (P less than 0.02). Fecal excretion of the organism continued significantly longer in the placebo group (P less than 0.01). There were no treatment failures in the treatment group compared with five (42%) in the placebo group (P less than 0.01). Thus, early administration of erythromycin significantly reduced the duration of both diarrhea and fecal excretion of the organism in infants and children with acute dysentery associated with C. jejuni.
Assuntos
Infecções por Campylobacter/tratamento farmacológico , Disenteria/tratamento farmacológico , Eritromicina/análogos & derivados , Campylobacter fetus/isolamento & purificação , Pré-Escolar , Método Duplo-Cego , Disenteria/etiologia , Eritromicina/uso terapêutico , Etilsuccinato de Eritromicina , Fezes/microbiologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Placebos , Distribuição Aleatória , Fatores de TempoRESUMO
Foram estudados 62 casos de crianças menores de 12 anos portadoras de amigdalite aguda, presumivelmente bacteriana. Somando-se os resultados da cultura do material de amígdala e os casos com erupçäo escarlatiniforme, obteve-se uma prevalência de 30% de estreptococo beta-hemolítico. Resultados clínicos satisfatórios foram encontrados em pelo menos 87% dos casos tratados com eritromicina (30-50 mg/kg/dia) durante 10 dias. Efeitos colaterais (diarréias, vômitos e cólicas) ocorreram em 13% dos pacientes, sendo em um único caso necessária a interrupçäo do tratamento