RESUMEN
UNLABELLED: We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. STUDY DESIGN: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization. RESULTS: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P =.034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P <.001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy. CONCLUSION: We conclude that the combination of a beta-lactam and an aminoglycoside produces a longer clinical remission than a beta-lactam alone and slightly better initial improvement.
Asunto(s)
Antibacterianos/uso terapéutico , Azlocilina/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Quimioterapia Combinada/uso terapéutico , Penicilinas/uso terapéutico , Tobramicina/uso terapéutico , Adolescente , Análisis de Varianza , Antibacterianos/efectos adversos , Azlocilina/efectos adversos , Niño , ADN Bacteriano/efectos de los fármacos , ADN Bacteriano/aislamiento & purificación , Método Doble Ciego , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Penicilinas/efectos adversos , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/aislamiento & purificación , Pruebas de Función Respiratoria , Esputo/efectos de los fármacos , Esputo/microbiología , Tobramicina/efectos adversos , Capacidad Vital/efectos de los fármacosRESUMEN
We sought to define objective indicators of the resolution of Pseudomonas aeruginosa endobronchial infection in patients with cystic fibrosis. We prospectively studied 75 patients admitted for treatment of a pulmonary exacerbation and quantitated sputum bacterial density, DNA content, and the concentration of albumin and total protein in sputum, and compared these values with clinical evaluation. Eleven of the 75 patients had systemic signs, fever, and leukocytosis, which we arbitrarily defined as due to endobronchial infection. At the end of hospitalization, these 11 patients were afebrile, had peripheral leukocyte counts in the normal range, and were judged improved. Sputum P. aeruginosa density, DNA content, and total protein content on admission were similar in the two illness groups. Hospitalization and parenteral antibiotic administration for an average of 14.6 days were associated with improved pulmonary function in all 75 subjects (P values for forced vital capacity, forced expiratory volume at 1 second, and peak expiratory flow rate were all less than 0.001). With improvement, there was a decrease in sputum P. aeruginosa density (mean of both groups decreased from 10(7.80) CFU/g on admission to 10(5.96) CFU/g; P less than 0.001), and a decreased DNA concentration (overall mean 4.73 +/- 4.75 on admission to 2.76 +/- 2.49 mg/g; P less than 0.002). The decrease in sputum total protein concentration for both groups was not significant (overall mean 60.5 +/- 48.4 to 43.9 +/- 38.2 mg/g; P = 0.06). Sputum albumin concentrations did not change in either group. We conclude that in cystic fibrosis subjects with a pulmonary exacerbation, bacterial density, sputum DNA and protein content decrease with hospitalization and parenteral antibiotic therapy. At the end of treatment, these indices of sputum infection and inflammation correlate with improved pulmonary function and clinical improvement. These changes are independent of the presence or absence of fever on admission.
Asunto(s)
Fibrosis Quística/complicaciones , Infecciones por Pseudomonas/diagnóstico , Infecciones del Sistema Respiratorio/diagnóstico , Esputo/análisis , Adolescente , Adulto , Albúminas/análisis , Antibacterianos/uso terapéutico , Niño , ADN/análisis , Hospitalización , Humanos , Proteínas/análisis , Infecciones por Pseudomonas/complicaciones , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/análisis , Pruebas de Función Respiratoria , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/tratamiento farmacológicoAsunto(s)
Fibrosis Quística/sangre , Gentamicinas/sangre , Niño , Semivida , Humanos , Cinética , Factores de TiempoRESUMEN
A pharmacokinetic approach was used for gentamicin dosing in 19 children and young adults with cystic fibrosis. A one-compartment open-model analysis of steady-state gentamicin pharmacokinetics revealed a significantly larger apparent volume of distribution and total plasma clearance for patients with CF as compared to a similar population of children without the disease. The increase in the apparent volume of distribution for patients with CF produced a larger daily gentamicin dose requirement to maintain similar steady-state levels as compared to children without the disease. Significant differences in the elimination rate constant and half-life for gentamicin were not found between these populations. Linear correlations between creatinine clearance and kel for gentamicin, and total body body weight and the apparent volume of distribution were demonstrated for children with varying degrees of stable renal function but not patients with CF. Altered gentamicin disposition peculiar to CF precludes application of currently used dosing nomograms or guidelines derived from normal populations, and emphasizes the need for individualized gentamicin therapy guided by a pharmacokinetic approach in these patients.