Asunto(s)
Neoplasias de la Corteza Suprarrenal/inmunología , Carcinoma Corticosuprarrenal/inmunología , Síndrome de Cushing/inmunología , Linfopenia/inmunología , Neoplasias de la Corteza Suprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/diagnóstico , Adulto , Recuento de Linfocito CD4 , Síndrome de Cushing/diagnóstico , Diagnóstico Diferencial , Seronegatividad para VIH , Homosexualidad Masculina , Humanos , Linfopenia/diagnóstico , MasculinoRESUMEN
Standard and clinical strains of Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae were subjected to continuous exposure to beta-lactams and aminoglycosides during the postantibiotic effect phase induced by rifampicin or erythromycin (for S. aureus). A significant inhibition of bactericidal activity by these agents during the PAE period was observed. The degree of inhibition was dependent both on the class of antimicrobial agent (beta-lactams > aminoglycosides) and the microorganism (Gram-negative bacilli > S. aureus).
Asunto(s)
Bacterias/efectos de los fármacos , Quimioterapia Combinada/farmacología , Pruebas de Sensibilidad Microbiana , Ampicilina/farmacocinética , Ampicilina/farmacología , Fenómenos Fisiológicos Bacterianos , Cefamandol/farmacocinética , Cefamandol/farmacología , Quimioterapia Combinada/farmacocinética , Eritromicina/farmacocinética , Eritromicina/farmacología , Escherichia coli/efectos de los fármacos , Gentamicinas/farmacocinética , Gentamicinas/farmacología , Humanos , Klebsiella pneumoniae/efectos de los fármacos , Nafcilina/farmacocinética , Nafcilina/farmacología , Análisis de Regresión , Rifampin/farmacocinética , Rifampin/farmacología , Staphylococcus aureus/efectos de los fármacos , Factores de Tiempo , Tobramicina/farmacocinética , Tobramicina/farmacologíaRESUMEN
A total of ten strains of Candida spp. and Cryptococcus neoformans were examined for the presence of the postantibiotic effect (PAE) after 0.5-2 h exposure to amphotericin B, 5-fluorocytosine, miconazole and ketoconazole. Significant PAEs were observed for amphotericin B and 5-fluorocytosine, but none for the imidazoles. The duration of the PAEs of amphotericin B ranged from 0.5-10.4 h for the Candida spp. and 2.8-10.6 h for the cryptococcos, while 5-fluorocytosine induced PAEs from 0.8-7.4 h and 2.4-5.4 h, respectively. Even though no PAEs were demonstrated for the imidazoles, the growth rate was persistently reduced by continuous exposure to concentrations as low as 1/1000 of the MIC of these agents. These findings may have implications for dosing antifungal agents in systemic yeast infections.
Asunto(s)
Anfotericina B/farmacología , Candida/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Flucitosina/farmacología , Cetoconazol/farmacología , Miconazol/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
A murine thigh-infection model was used to determine the effect of certain host- and drug-related factors on the duration of the in-vivo postantibiotic effect (PAE) observed with aminoglycosides against Gram-negative bacilli. The role of neutrophils (PMNs), pharmacokinetics and variation among species and strains were studied. PAEs were quantitated after a single injection of gentamicin or amikacin. PAEs were several hours longer in normal mice than in neutropenic mice, in mice with renal impairment than in those with normal renal function, and with strains of Klebsiella pneumoniae than with strains of Escherichia coli, Serratia marcescens and Enterobacter cloacae. Among the 15 strains of Enterobacteriaceae studied, the duration of the in-vivo PAE did not correlate with MIC, duration of in-vitro PAE, and extent of in-vivo bactericidal activity. We conclude that prolonged PAEs are consistently observed in vivo with aminoglycosides against Enterobacteriaceae, and that this duration is enhanced in the presence of PMNs and by pharmacokinetic properties simulating those observed in humans.
Asunto(s)
Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Amicacina/farmacología , Animales , Enterobacter/efectos de los fármacos , Enterobacter/crecimiento & desarrollo , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Gentamicinas/farmacología , Bacterias Gramnegativas/crecimiento & desarrollo , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/crecimiento & desarrollo , Ratones , Serratia marcescens/efectos de los fármacos , Serratia marcescens/crecimiento & desarrollo , Factores de TiempoRESUMEN
Zidovudine is the only anti-retroviral drug approved by the FDA for treatment of HIV infection. We have examined the clinical and laboratory efficacy of this drug for 4 years in a cohort of HIV-infected patients from Wisconsin. Overall, we have found that individuals with AIDS will have at least 1 year of symptom reduction while on the drug. Those with asymptomatic HIV infection tolerate the drug and none have progressed to AIDS in the 4 years of study. Zidovudine is an important component in the treatment of HIV infection.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Zidovudina/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida/inmunología , Adulto , Linfocitos T CD4-Positivos , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Infecciones por VIH/inmunología , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Zidovudina/administración & dosificación , Microglobulina beta-2/análisisRESUMEN
Animal studies that compare antibiotics have used only a limited number of doses administered at intervals chosen without regard for their pharmacodynamic effects of pharmacokinetic profiles. We compared the relative efficacy and potency of three beta-lactams and two aminoglycosides in lung and thigh-infection models in neutropenic mice by defining the maximum attainable antimicrobial effect at 24 h (Emax) and the total dose required to reach 50% of maximum effect (P50) at several dosing intervals. For beta-lactams, Emaxs were similar, whereas P50s increased 10- to 50-fold with longer intervals in both models. Aminoglycosides were significantly more bactericidal in the lung than in the thigh, and dosing interval had little impact on P50s in either model. Recognizing the variable impact of dosing interval on efficacy for different classes of antibiotics is mandatory for the proper design and interpretation of comparative trials.
Asunto(s)
Antibacterianos/uso terapéutico , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/crecimiento & desarrollo , Músculos/microbiología , Neumonía/tratamiento farmacológico , Animales , Antibacterianos/administración & dosificación , Cefazolina/uso terapéutico , Ceftazidima/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Gentamicinas/uso terapéutico , Imipenem/uso terapéutico , Klebsiella pneumoniae/efectos de los fármacos , Pulmón/microbiología , Ratones , Ratones Endogámicos ICRRESUMEN
Current antimicrobial dosing regimens are designed to maintain active drug levels for most of the dosing interval and are based on 40-y-old observations. With use of numerous multiple-dosing regimens in an animal model, this study is the first to successfully minimize the interdependence between pharmacokinetic parameters and thereby determine, by stepwise multivariate regression analysis, that the time that serum levels exceeded the minimum inhibitory concentration (MIC) was the most significant parameter determining efficacy for beta-lactams and erythromycin against various pathogens, whereas the log area under the curve was the major parameter for aminoglycosides. Optimal dosing intervals were no greater than the time that serum levels exceeded the MIC plus the duration of the postantibiotic effect. Careful application of these concepts should allow other investigators to use more optimally dosed regimens than those previously used in preclinical trials and to design studies to improve on current dosing regimens for humans.
Asunto(s)
Antibacterianos/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Animales , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Cefazolina/administración & dosificación , Cefazolina/farmacocinética , Cefazolina/uso terapéutico , Eritromicina/administración & dosificación , Eritromicina/farmacocinética , Eritromicina/uso terapéutico , Escherichia coli/efectos de los fármacos , Femenino , Gentamicinas/administración & dosificación , Gentamicinas/farmacocinética , Gentamicinas/uso terapéutico , Ratones , Ratones Endogámicos ICR , Penicilinas/administración & dosificación , Penicilinas/farmacocinética , Penicilinas/uso terapéutico , Pseudomonas aeruginosa/efectos de los fármacos , Análisis de Regresión , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Ticarcilina/administración & dosificación , Ticarcilina/farmacocinética , Ticarcilina/uso terapéutico , Tobramicina/administración & dosificación , Tobramicina/farmacocinética , Tobramicina/uso terapéuticoRESUMEN
The postantibiotic effect (PAE) is the suppression of bacterial growth that persists after limited exposure of organisms to antimicrobial agents. We demonstrated and standardized the in vivo PAE in a thigh infection model in neutropenic mice. Inhibitors of protein and nucleic acid synthesis induced PAEs of 1.4-7.5 h against aerobic gram-negative bacilli, whereas beta-lactam antibiotics did not induce significant PAEs. Against aerobic gram-positive cocci, cell wall-active agents and inhibitors of protein and nucleic acid synthesis induced PAEs of 1.2-7.1 h, except for penicillins, which did not induce PAEs against streptococci. With few exceptions the in vivo PAE correlated well with the PAE reported in prior in vitro studies. Residual drug in thigh tissue did not cause the PAE. Theoretically, the presence of a PAE may allow antimicrobial agents to be given more intermittently without organism regrowth after drug levels fall below the minimal inhibitory concentration.
Asunto(s)
Agranulocitosis/complicaciones , Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Neutropenia/complicaciones , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Infecciones Bacterianas/complicaciones , Modelos Animales de Enfermedad , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Femenino , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/crecimiento & desarrollo , Ratones , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/crecimiento & desarrollo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/crecimiento & desarrollo , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/crecimiento & desarrollo , MusloRESUMEN
Cefuroxime axetil was compared with cefaclor for the therapy for lower respiratory tract infections. Sixty-one patients were randomized to receive the following drug dosages: (1) cefuroxime axetil, 250 mg orally every 12 hours (21 patients); (2) cefuroxime axetil, 500 mg orally every 12 hours (21 patients); and (3) cefaclor, 500 mg orally every eight hours (19 patients). Of these 61 patients, 80% were male, with a mean age of 59.5 years; 56% had acute pneumonia, and the remainder had an acute bronchitis. Causative pathogens included typical respiratory tract pathogens. Overall, 23 of 27 patients with bronchitis were clinically cured at the end of therapy. Thirty-one of 34 pneumonias were clinically cured or improved at the end of therapy; the three pneumonia treatment failures occurred in the lower dose cefuroxime (n = 2) and cefaclor (n = 1) treatment groups. Overall, bacteriologic cure occurred in 86% of patients treated with 500 mg of cefuroxime axetil compared with 60% of cefaclor-treated patients. Adverse clinical effects were uncommon. From this study, it was concluded that cefuroxime given every 12 hours is at least as clinically efficacious as cefaclor; it is a new oral cephalosporin with pharmacologic and bacterial spectrum advantages over many older agents.
Asunto(s)
Infecciones Bacterianas/tratamiento farmacológico , Cefaclor/uso terapéutico , Cefuroxima/análogos & derivados , Cefalexina/análogos & derivados , Cefalosporinas , Quimioterapia , Profármacos/uso terapéutico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Enfermedad Aguda , Administración Oral , Adulto , Anciano , Bronquitis/tratamiento farmacológico , Cefaclor/administración & dosificación , Cefuroxima/administración & dosificación , Cefuroxima/uso terapéutico , Ensayos Clínicos como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neumonía/tratamiento farmacológico , Profármacos/administración & dosificación , Distribución AleatoriaAsunto(s)
Antibacterianos/farmacología , Bacterias/crecimiento & desarrollo , Animales , Antibacterianos/administración & dosificación , Bacterias/efectos de los fármacos , Bacterias/metabolismo , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Sitios de Unión , Esquema de Medicación , Humanos , Factores de TiempoRESUMEN
The postantibiotic effect (PAE) in vivo of imipenem, cefoperazone and latamoxef was investigated in a neutropenic mouse thigh model. Two hours after inoculation of 10(6) cfu of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa into each thigh, the neutropenic mice were treated with single doses of 50-200 mg/kg imipenem, 40-1200 mg/kg cefoperazone and 50-100 mg/kg latamoxef. Serum levels exceeded the MIC for 1.1-2.9 h. Cefoperazone and latamoxef induced PAEs of 2.1-5.6 h for S aureus, but no significant PAEs were induced for the Gram-negative bacilli. In contrast imipenem produced PAE of 0.9-4.6 h with P. aeruginosa. However, strain variation was observed in the duration of the PAE after imipenem. These data are in concordance with the PAEs of the antimicrobials under study when these are determined in vitro. The implications of these findings for clinical use of these drugs need further evaluation.
Asunto(s)
Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Tienamicinas/uso terapéutico , Animales , Antibacterianos/metabolismo , Cefalosporinas/farmacología , Femenino , Semivida , Imipenem , Cinética , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Tienamicinas/metabolismoRESUMEN
Assessment of antimicrobial activity from standard in vitro minimum inhibitory and minimum bactericidal concentration determinations alone is incomplete. Rate of bacterial killing, effect of increasing concentration, sub-MIC effects, and degree of suppression of bacterial growth after limited exposure (post-antibiotic effect) more precisely describe the course of antimicrobial activity. Aminoglycoside antibiotics exhibit concentration-dependent bactericidal activity and a prolonged post-antibiotic effect. beta-Lactam antibiotics demonstrate more time-dependent killing and lack post-antibiotic effects, except with staphylococci. Most bacteriostatic antimicrobial agents also produce post-antibiotic suppression of growth. Studies in different animal infection models with a variety of organisms suggest that beta-lactams are more efficacious with continuous dosing, whereas the efficacy of aminoglycosides is relatively independent of dosing regimen, even when administered once daily. Knowledge of the kinetics of antimicrobial action is useful in predicting optimal dosage regimens.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Aminoglicósidos/metabolismo , Aminoglicósidos/farmacología , Animales , Antibacterianos/metabolismo , Esquema de Medicación , Humanos , Cinética , Lactamas , Pruebas de Sensibilidad Microbiana , Factores de TiempoRESUMEN
Antibiotics with high protein binding have a lower percentage of free drug available for tissue penetration than antibiotics with lower protein binding. High protein binding, however, may have a beneficial effect on drug distribution. The smaller volume of distribution and reduced glomerular filtration of highly bound agents result in higher serum levels that are sustained longer. Although intermittent and continuous dosing regimens produce similar areas under the concentration-versus-time curves for serum and tissue, intermittent dosing produces higher peak and potentially earlier effective antibiotic levels at the site of infection. The excretion of certain antibiotic agents in the bile may be related to hepatic protein binding, high molecular weight, or unique structural features. Biliary excretion is important not only for bile concentrations but also for dosage modification. Antibiotics with dual elimination by the kidney and biliary tract require minimal dosage modification unless there is concomitant hepatic and renal dysfunction. The third-generation cephalosporins provide good examples of how protein binding, tissue penetration, and excretory mechanisms can be used to alter pharmacokinetics advantageously.