RESUMEN
The purpose of this study was to investigate the relationship between efficacy and percentage of time above the MIC (%T>MIC) in the cerebrospinal fluid (CSF) for different dosing regimens of meropenem against an experimental lethal meningitis model in guinea pigs with type b ß-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (Hib BLNAR). Guinea pigs were intrathecally inoculated with 10(8) CFU/head of Hib BLNAR 8 h before the start of therapy. A single dose of 20, 40, or 80 mg/kg meropenem or multiple doses of 40 mg/kg meropenem were subcutaneously administered. Numbers of bacteria in CSF were counted 8 h after the start of therapy. Meropenem concentration in serum and CSF were determined in infected guinea pigs receiving a single dose of 40 mg/kg. In the single-dose regimen, 40 and 80 mg/kg meropenem significantly reduced the number of bacteria in CSF compared with the control, but 20 mg/kg meropenem did not. The %T>MIC for an 8-h period of 20, 40, and 80 mg/kg meropenem were 41, 52, and 62, respectively. Two and four doses of 40 mg/kg meropenem, for both of which %T>MIC was calculated as 100, had similar efficacy and were significantly superior to a single-dose of 40 mg/kg. In conclusion, meropenem had high efficacy when %T>MIC in the CSF was increased because of the high dose level and shortening of the dosing interval in a guinea pig meningitis model caused by Hib BLNAR, suggesting that high and frequent doses of meropenem are useful for treatment of meningitis with Hib BLNAR.
Asunto(s)
Antibacterianos/farmacología , Haemophilus influenzae tipo b/efectos de los fármacos , Meningitis por Haemophilus/tratamiento farmacológico , Tienamicinas/farmacología , Animales , Antibacterianos/farmacocinética , Ceftriaxona/farmacocinética , Ceftriaxona/farmacología , Modelos Animales de Enfermedad , Cobayas , Masculino , Meningitis por Haemophilus/metabolismo , Meningitis por Haemophilus/microbiología , Meropenem , Pruebas de Sensibilidad Microbiana , Tienamicinas/farmacocinética , Resistencia betalactámicaRESUMEN
Intraperitoneal inoculation of Haemophilus influenzae type b (Hib) to 3-week-old Sprague-Dawley rats resulted in nonlethal meningitis with high levels of leukocytes in the cerebrospinal fluid (CSF) and positive bacterial culture. Using in situ hybridization, levels of cytokine mRNA-expressing cells were determined in the brain, CSF, and spleen from Hib-inoculated and uninfected control rats. IFN-gamma, IL-1 beta, IL-4, IL-6, IL-10, IL-12, and TNF-alpha mRNA levels were elevated at 12 hr postinoculation (pi) in spleen and CSF. At this time point, strong expression of IL-6 and TGF-beta was detected in the brain, and also of IL-10 at 48 hr while IFN-gamma and IL-12 were expressed at very low levels throughout the observation time. Delayed cytokine induction occurred in CSF compared to spleen and brain. TGF-beta was high in CSF at 48 hr, and some elevation of IL-1 beta, IL-6, IL-10, TNF-alpha, IFN-gamma, and IL-12 was evident at 72 hr pi. This may suggest measures that promote production of TGF-beta and/or IL-10 should be evaluated in treatment of bacterial meningitis.
Asunto(s)
Citocinas/metabolismo , Meningitis por Haemophilus/metabolismo , ARN Mensajero/metabolismo , Animales , Encéfalo/metabolismo , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Citocinas/genética , Masculino , Meningitis por Haemophilus/sangre , Meningitis por Haemophilus/líquido cefalorraquídeo , Meningitis por Haemophilus/genética , Ratas , Ratas Sprague-Dawley , Bazo/metabolismoRESUMEN
Using in situ hybridization with radiolabelled oligonucleotide probes, we studied the mRNA expression of IL-1beta, IL-4, IL-6, IL-10, IL-12, tumour necrosis factor-alpha (TNF-alpha), TNF-beta, interferon-gamma (IFN-gamma), and transforming growth factor-beta (TGF-beta) in the brain during the lethal course of experimental meningitis in a rat model inoculated intracisternally with Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae and in uninfected control rats inoculated with the same volume of PBS. The production of IL-1beta, IL-4, IL-6 and IFN-gamma was also evaluated by immunohistochemistry. In the brain of Hib-inoculated rats, there was marked mRNA expression of IL-1beta, IL-6, TNF-alpha, IL-12 and IFN-gamma. IL-1beta, IL-6 and TNF-alpha were up-regulated throughout the observation period at 2, 8 and 18 h post-inoculation (p.i.), with similar patterns of induction. The Th1 cytokines IFN-gamma and TNF-beta were up-regulated within 8 h p.i. IL-10 and TGF-beta were down-regulated at 18 h p.i., while IL-4 was not detected. In contrast, the brain of S. pneumoniae-inoculated rats showed lower levels of IL-1beta, IL-6 and TNF-alpha, but higher levels of TNF-beta and detectable mRNA expression of IL-4 when compared with Hib-inoculated rats. IL-12, IFN-gamma, IL-10 and TGF-beta exhibited similar patterns of induction in the brains of Hib- and S. pneumoniae-inoculated rats. At 18 h p.i., immunohistochemistry showed similar patterns of IL-1beta, IL-4, IL-6 and IFN-gamma as mRNA expression in the brains of Hib- and S. pneumoniae-inoculated rats. The differences of cytokine profiles induced by the two bacterial strains may imply that different immunomodulating approaches should be considered, depending on etiology.
Asunto(s)
Encéfalo/metabolismo , Citocinas/metabolismo , Haemophilus influenzae/fisiología , Meningitis por Haemophilus/metabolismo , Meningitis Neumocócica/metabolismo , ARN Mensajero/metabolismo , Streptococcus pneumoniae/fisiología , Animales , Citocinas/genética , Sondas de ADN , Técnicas para Inmunoenzimas , Hibridación in Situ , Masculino , Meningitis por Haemophilus/inmunología , Meningitis por Haemophilus/patología , Meningitis Neumocócica/inmunología , Meningitis Neumocócica/patología , Ratas , Ratas Sprague-Dawley , Regulación hacia ArribaRESUMEN
Bacterial meningitis is a major cause of childhood morbidity and mortality in South Africa. However, comprehensive regional or national epidemiological data, essential for rational public health interventions, are lacking. The purpose of this 1-year prospective study, from 1 August 1991 to 31 July 1992, was to define the magnitude of the problem of childhood bacterial meningitis in Cape Town. The study group consisted of all children, aged > 1 month to < 14 years, who presented with proven bacterial meningitis at all the hospitals in the Cape Town metropolitan area. During the year 201 cases were identified: 101 (50.2%) were due to Neisseria meningitidis, 74 (36.8%) were due to Haemophilus influenzae and 26 (12.9%) were due to Streptococcus pneumoniae. The overall incidence rate (95% confidence interval) for children less than 14 years, 5 years and 1 year was 34 (30-40), 76 (65-88) and 257 (213-309) per 100,000 children, respectively. The rate was highest in black infants, 416 (316-545)/100,000. This was 2 times greater than the rate in coloured infants and about 4.5 times greater than the rate in white infants. The median age of all the children was 10 months. The ages of children with haemophilus and pneumococcal meningitis were similar, 9 and 7.5 months respectively (P = 0.43), while children with meningococcal meningitis were significantly older (22 months) than the others (P < 0.01). The overall case fatality rate was 5%, and 12.9% of survivors had significant neurological sequelae (disability) on discharge.
Asunto(s)
Meningitis Bacterianas/epidemiología , Adolescente , Distribución por Edad , Niño , Preescolar , Femenino , Haemophilus influenzae , Humanos , Incidencia , Lactante , Tiempo de Internación , Masculino , Meningitis Bacterianas/complicaciones , Meningitis Bacterianas/metabolismo , Meningitis por Haemophilus/complicaciones , Meningitis por Haemophilus/epidemiología , Meningitis por Haemophilus/metabolismo , Meningitis Meningocócica/complicaciones , Meningitis Meningocócica/epidemiología , Meningitis Meningocócica/metabolismo , Meningitis Neumocócica/complicaciones , Meningitis Neumocócica/epidemiología , Meningitis Neumocócica/metabolismo , Estado Nutricional , Estudios Prospectivos , Estaciones del Año , Distribución por Sexo , Sudáfrica/epidemiologíaRESUMEN
The effect of experimental meningitis on regional cerebral blood flow (rCBF), cerebral metabolic rate for oxygen (CMRO2), and cerebrovascular responsiveness to CO2 was determined in pentobarbital-anesthetized rabbits. The animals were inoculated intracisternally with saline (control) or log-phase Haemophilus influenzae type b (Hib). Eighteen hours later rCBF was determined with radiolabeled microspheres at normocapnia, hypocapnia, and hypercapnia. Cerebrovascular responses to hypocapnia and hypercapnia were assessed by calculating the change in cerebrovascular resistance per millimeter mercury change in PaCO2. At all CO2 levels, meningitis (M) was associated with elevated CBF compared with control (C: 47.5 +/- 3.0, M: 60.9 +/- 4.5 ml.100 g-1.min-1 at normocapnia, P < 0.01). Regional differences were present. In forebrain, the hyperemia in meningitis was confined to the superficial cortical grey matter. When compared with control, meningitis was not associated with altered vasoreactivity during hypocapnia (C: -0.026 +/- 0.006, M: -0.026 +/- 0.008 mmHg.ml-1 x 100 g-1.min-1.mmHg PaCO2(-1)) or hypercapnia (C: -0.037 +/- 0.004, M: -0.026 +/- 0.008 mmHg.ml-1 x 100 g.min.mmHg PaCO2(-1)). CMRO2 in meningitis was not significantly different from control (C: 3.53 +/- 0.29, M: 3.51 +/- 0.22 ml O2.100 g-1.min-1). These findings indicate that cerebrovascular responsiveness to CO2 is preserved in experimental Hib meningitis. Furthermore, enhanced CBF together with unchanged CMRO2 indicates that "luxury" cerebral perfusion is present in this model of bacterial meningitis.
Asunto(s)
Dióxido de Carbono/farmacología , Circulación Cerebrovascular/fisiología , Haemophilus influenzae , Meningitis por Haemophilus/fisiopatología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dióxido de Carbono/sangre , Circulación Cerebrovascular/efectos de los fármacos , Masculino , Meningitis por Haemophilus/metabolismo , Especificidad de Órganos , Consumo de Oxígeno/efectos de los fármacos , Consumo de Oxígeno/fisiología , Conejos , Valores de Referencia , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiologíaRESUMEN
Limited data are available about cefixime pharmacokinetics and cerebrospinal fluid (CSF) penetration in infants and young children. Ten patients with bacterial meningitis and 8 undergoing CSF shunt placement, aged 2-22 months (mean 9.5 +/- 6.5 months), were given a single dose of cefixime suspension, 8 mg/kg, before undergoing a routine lumbar puncture. Patients were fasted for 2 h before and 2 h after drug administration. Blood samples were collected just before drug administration (0 h) and at 1, 2, 3, 4, 6, 8 h; CSF was obtained at 1-8.8 h after drug administration. Cefixime was measured by a high-performance liquid chromatographic method. The peak serum concentration of cefixime ranged from 0.85 to 6.2 (mean 3.1) micrograms/ml and occurred at 2-8 h (mean 4.5). The area under the serum concentration-time curve ranged from 5.3 to 28.4 micrograms h/ml, and the elimination half-life ranged from 2.6 to 5.6 h. CSF concentrations ranged from 0.02 to 0.57 micrograms/ml. The mean CSF concentration of cefixime was 0.22 micrograms/ml in patients with meningitis and 0.10 microgram/ml in those undergoing shunt placement (p < 0.02). The mean CSF concentration/serum concentration ratio was 11.7 in patients with meningitis compared with 5.4 in those undergoing shunt procedures (p < 0.02). These data indicate that cefixime can be considered as an alternative to other antimicrobials for infants and children with respiratory and urinary tract infections, since the observed peak serum concentration exceeded the minimum inhibitory concentrations of the common pathogens by severalfold.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antiinfecciosos/líquido cefalorraquídeo , Antiinfecciosos/farmacocinética , Cefotaxima/análogos & derivados , Cefixima , Cefotaxima/líquido cefalorraquídeo , Cefotaxima/farmacocinética , Derivaciones del Líquido Cefalorraquídeo , Cromatografía Líquida de Alta Presión , Semivida , Humanos , Lactante , Meningitis por Haemophilus/líquido cefalorraquídeo , Meningitis por Haemophilus/metabolismo , Punción EspinalRESUMEN
To further examine the effects of purified Haemophilus influenzae type b lipopolysaccharide (LPS) on blood-brain barrier permeability, we have developed an in vitro model of the BBB. Microvascular endothelial cells were isolated from rat cerebral cortices by enzymatic digestion, dextran centrifugation, and separation on percoll gradients. The cells were determined to be endothelial in origin by positive fluorescent staining for Factor VIII-related antigen and the ability to take up acetylated low density lipoproteins, and their cerebral origin by the formation of junctional complexes in vitro. Cells were seeded onto semipermeable polycarbonate filters and permeability assessed by measuring traversal of radioactive albumin across the monolayer. Treatment of the cells with LPS at concentrations of 1.0 microgram/ml and 0.1 microgram/ml for 4 h led to statistically significant increases in albumin permeability of 4.6% (P = 0.001) and 5.6% (P less than 0.001), respectively, without evidence of cell death as assessed by release of lactate dehydrogenase into the media. These results indicate that LPS significantly increases albumin permeability across a monolayer of cerebral microvascular endothelial cells in the absence of host inflammatory cells. Future studies on the effects of LPS on intracellular regulation will determine the mechanisms responsible for these alterations.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Glicosaminoglicanos/farmacología , Meningitis por Haemophilus/fisiopatología , Albúminas/farmacocinética , Animales , Barrera Hematoencefálica/fisiología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/fisiología , Separación Celular/métodos , Supervivencia Celular/fisiología , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Femenino , Glicosaminoglicanos/metabolismo , Haemophilus influenzae/metabolismo , Haemophilus influenzae/fisiología , L-Lactato Deshidrogenasa/metabolismo , Meningitis por Haemophilus/metabolismo , Microcirculación/efectos de los fármacos , Microcirculación/fisiología , Ratas , Ratas EndogámicasRESUMEN
Interleukin-1 (IL-1) is the key initiator of host responses to infection. We describe here the lipopolysaccharide-(LPS) (20 micrograms/ml) stimulated IL-1 production of peripheral blood monocytes in 2 children with Haemophilus influenzae meningitis. We found a depressed IL-1 production at the acute stage of the infection when the meningitis was most active with return to normal coinciding with clinical recovery. These results show an inverse correlation with acute phase reactants and IL-1 production. Normalization of IL-1 production seems to be a good prognostic sign in bacterial meningitis.
Asunto(s)
Interleucina-1/biosíntesis , Leucocitos Mononucleares/metabolismo , Meningitis por Haemophilus/metabolismo , Niño , Preescolar , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Lipopolisacáridos/farmacología , Masculino , Meningitis por Haemophilus/patología , Valor Predictivo de las Pruebas , Pronóstico , Estimulación QuímicaRESUMEN
Tumor necrosis factor (TNF) could possibly be instrumental in mediating injury to the CNS during bacterial meningitis. In CSF of rabbits with meningitis induced with Haemophilus influenzae type b (Hib) lipooligosaccharide (LOS), TNF activity was first detected 45 min after intracisternal (IC) injection of 20 ng Hib LOS and white blood cells (WBC) first appeared 75 min later. The peak TNF activity (45 ng/ml) was observed at 120 min after IC and persisted for 5 h. When 1-2 X 10(7) CFU of Hib was used to induce meningitis, peak CSF TNF activity was comparable with that after 20 ng Hib LOS, but the activity persisted for 14 h. Dexamethasone (DXM) (1 mg/kg per i.v.) given 1 h before or simultaneously with IC Hib LOS reduced significantly TNF activity and meningeal inflammation. Goat anti-human TNF alpha antibodies given IC with 20 ng Hib LOS or 2 X 10(6) CFU of Hib resulted in a significant reduction in CSF TNF concentrations, which was also associated with reduced meningeal inflammation in Hib LOS-inoculated animals. We conclude that TNF participates in mediating meningeal inflammation associated with Hib experimental meningitis, and that DXM, when given before or with Hib LOS, inhibits CSF TNF production and modulates the meningeal inflammatory response.
Asunto(s)
Meningitis por Haemophilus/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/uso terapéutico , Animales , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Glucosa/líquido cefalorraquídeo , Haemophilus influenzae/aislamiento & purificación , Lactatos/líquido cefalorraquídeo , Lipopolisacáridos/toxicidad , Masculino , Meningitis por Haemophilus/inducido químicamente , Meningitis por Haemophilus/metabolismo , Proteínas/análisis , Conejos , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
One hundred patients (71 males and 29 females) with bacterial meningitis were randomly assigned into two therapeutic regimens. Patients in group I were intravenously given ceftriaxone (CRO: Rocephin) to adults and intramuscularly to children once daily in a dose of 100 mg/kg/day. Patients in group II received ampicillin 160 mg/kg/day and chloramphenicol (AMCL) 100 mg/kg/day (i.v. to adults and i.m. to children) every 6 h. No significant difference was observed between the two therapeutic regimens with regard to mortality, time taken to become afebrile, fully alert and sequelae. Seven patients in the CRO group died compared to 10 in the AMCL group. The mean number of days taken to become afebrile were 3.4 and 3.5, and to become fully alert 3.9 and 3.5 for groups I and II, respectively. CRO administered in a single daily dose appears to be as effective as a combination of ampicillin and chloramphenicol given every 6 h in the treatment of acute bacterial meningitis. However, the once daily dose is more appropriate for use especially in areas where nursing care is limited.
Asunto(s)
Ampicilina/administración & dosificación , Ceftriaxona/administración & dosificación , Cloranfenicol/administración & dosificación , Meningitis por Haemophilus/tratamiento farmacológico , Meningitis Meningocócica/tratamiento farmacológico , Meningitis Neumocócica/tratamiento farmacológico , Adolescente , Adulto , Ampicilina/uso terapéutico , Ceftriaxona/uso terapéutico , Niño , Preescolar , Cloranfenicol/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Lactante , Inyecciones Intramusculares , Inyecciones Intravenosas , Masculino , Meningitis por Haemophilus/metabolismo , Meningitis Meningocócica/metabolismo , Meningitis Neumocócica/metabolismo , Distribución AleatoriaRESUMEN
Hemophilus influenzae is the most common cause of bacterial meningitis in children, and a high percentage of survivors are at risk for long-term sequelae. To explore the mechanisms responsible for these sequelae, a neonatal rat model was used to define the behavioral, electrophysiological, and biochemical changes following meningitis. Three days after inoculation of 6-day-old rats with a minimum of 1 X 10(7) colony-forming units of a virulent Hemophilus influenzae, type b, cerebrospinal fluid and blood were cultured to confirm the presence of meningitis and bacteremia, respectively. At this time, forebrain norepinephrine and dopamine levels were significantly elevated in meningitic rats when standardized on a wet-weight basis. No changes in brain serotonin or heart norepinephrine levels could be found in the 9-day-old rats. No residual changes were found in steady-state concentrations of norepinephrine or dopamine in surviving adult rats. However, survivors that had had meningitis as neonates showed significant impairment in active and passive avoidance learning tasks and demonstrated a significantly higher level of activity during a habituation period in circular photocell activity cages. No change in the flinch-jump threshold was detected. Brainstem auditory evoked potentials showed delays of various waves in 3 of 10 Hemophilus influenzae type b-treated adult rats tested. These rats also exhibited markedly augmented locomotory responses to d-amphetamine (1 mg/kg), suggesting a long-lasting perturbation of central monoamine neuronal transmission.
Asunto(s)
Conducta Animal/fisiología , Encéfalo/metabolismo , Potenciales Evocados Auditivos , Meningitis por Haemophilus/fisiopatología , Factores de Edad , Animales , Reacción de Prevención , Conducta Animal/efectos de los fármacos , Encéfalo/fisiopatología , Dextroanfetamina/farmacología , Dopamina/metabolismo , Meningitis por Haemophilus/metabolismo , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Dolor/fisiopatología , Ratas , Ratas EndogámicasRESUMEN
298 cerebrospinal fluid (CSF) samples obtained from 116 children with ongoing Haemophilus influenzae meningitis were analyzed in order to determine the kinetics of the white blood cell (WBC) count and the glucose and protein concentrations--parameters for which there are no "reference values" available for the convalescence period of meningitis. The values determined during the first 10 days of treatment are presented as percentile distribution graphs. CSF WBC counts increased slightly for the first 24 h but declined thereafter without reaching, however, the normal value (less than or equal to 5/microliter) within 10 days in the majority of cases. Low CSF glucose concentrations usually increased to a normal or almost normal level within 48 h. CSF protein concentrations declined steadily throughout the treatment. Extremely high CSF WBC or low CSF glucose concentrations suggested neurological complications or treatment failure. The value of sequentially determined CSF WBC, glucose and protein in monitoring recovery from H. influenzae meningitis is, however, so vague that routine spinal taps do not seem indicated after CSF has become sterilized.
Asunto(s)
Proteínas del Líquido Cefalorraquídeo/aislamiento & purificación , Glucosa/líquido cefalorraquídeo , Linfocitos , Meningitis por Haemophilus/líquido cefalorraquídeo , Ampicilina/uso terapéutico , Niño , Preescolar , Cloranfenicol/uso terapéutico , Trastornos de la Audición/etiología , Humanos , Lactante , Recién Nacido , Cinética , Meningitis por Haemophilus/complicaciones , Meningitis por Haemophilus/tratamiento farmacológico , Meningitis por Haemophilus/metabolismoRESUMEN
Aztreonam (SQ 26,776), a new monocyclic beta-lactam agent, was compared with several frequently used antibiotics in therapy for three types of experimental meningitis in rabbits and for experimental Escherichia coli cerebritis in rats. Aztreonam was highly active against common gram-negative meningeal pathogens in vitro (all minimal bactericidal concentrations less than or equal to 0.125 microgram/ml), including ampicillin-sensitive and ampicillin-resistant strains of Haemophilus influenzae, E. coli, and meningococci. In both rabbits and rats, serum concentrations of all antibiotics evaluated closely approximated concentrations found in humans receiving standard parenteral regimens. The percent penetration of aztreonam into purulent rabbit cerebrospinal fluid was 23%. In experimental meningitis, aztreonam was more rapidly bactericidal than ampicillin in meningitis due to ampicillin-sensitive H. influenzae, than ampicillin or chloramphenicol in meningitis due to ampicillin-resistant H. influenzae, and than gentamicin in meningitis due to E. coli. Aztreonam also reduced concentrations of E. coli in rat brain as rapidly as did gentamicin during therapy for experimental cerebritis, the early stage of brain abscess formation.
Asunto(s)
Aztreonam/uso terapéutico , Encefalitis/tratamiento farmacológico , Meningitis/tratamiento farmacológico , Ampicilina/uso terapéutico , Animales , Aztreonam/metabolismo , Encéfalo/metabolismo , Absceso Encefálico/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Encefalitis/metabolismo , Infecciones por Escherichia coli/tratamiento farmacológico , Femenino , Gentamicinas/uso terapéutico , Meningitis/metabolismo , Meningitis por Haemophilus/tratamiento farmacológico , Meningitis por Haemophilus/metabolismo , Resistencia a las Penicilinas , Conejos , Ratas , Ratas EndogámicasRESUMEN
The single dose pharmacokinetics and cerebrospinal fluid (CSF) penetration of ceftazidime were determined in 10 children with bacterial meningitis. Serum ceftazidime pharmacokinetics showed a distinct age dependence in which the clearance in children less than 1 month of age was markedly reduced. Ceftazidime concentrations in CSF, which ranged from 1.4-8.5 micrograms/ml, exceeded the minimum bactericidal concentrations for infecting pathogens throughout the 8-hour sampling period. These concentrations were found to be independent of CSF cell count, protein concentration or the day of therapy on which the study was performed. The ratio of CSF to serum ceftazidime concentration increased with time, suggesting that ceftazidime was cleared more slowly from CSF than from peripheral blood. Our data support the initiation of a study comparing the efficacy of ceftazidime to conventional therapy in children with bacterial meningitis.
Asunto(s)
Ceftazidima/metabolismo , Meningitis/metabolismo , Factores de Edad , Ceftazidima/administración & dosificación , Ceftazidima/líquido cefalorraquídeo , Femenino , Humanos , Lactante , Recién Nacido , Cinética , Masculino , Meningitis/líquido cefalorraquídeo , Meningitis/tratamiento farmacológico , Meningitis por Haemophilus/líquido cefalorraquídeo , Meningitis por Haemophilus/tratamiento farmacológico , Meningitis por Haemophilus/metabolismo , Meningitis Meningocócica/líquido cefalorraquídeo , Meningitis Meningocócica/tratamiento farmacológico , Meningitis Meningocócica/metabolismo , Infecciones Estreptocócicas/líquido cefalorraquídeo , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/metabolismoRESUMEN
A model of human Hemophilus influenzae type b meningitis was developed in infant rabbits infected intranasally. The pathogenesis and course resembled that in human beings; bacteremia was followed by meningitis with a high mortality. Pretreatment of the nasopharyngeal mucosa with 0.5% trypsin or normal saline significantly increased the rate of bacteremia. Death was age related. Intranasal challenge with type f and nontypeable H influenzae was associated with transient bacteremia. Our results suggest that factors on the respiratory tract epithelial cell surface influence colonization and infection with H influenzae type b and confirm the importance of other host and parasite factors. Intravenous aztreonam resulted in a peak CSF concentration that was 6% to 7% of the serum concentration in infected meninges but only 2% to 3% in normal meninges. Aztreonam reduced mortality in established H influenzae type b meningitis from 88% in untreated animals to 9%.
Asunto(s)
Antibacterianos/uso terapéutico , Meningitis por Haemophilus/microbiología , Animales , Antibacterianos/sangre , Aztreonam , Modelos Animales de Enfermedad , Infecciones por Haemophilus , Semivida , Meningitis por Haemophilus/tratamiento farmacológico , Meningitis por Haemophilus/metabolismo , Mucosa Nasal/microbiología , Conejos , Sepsis/microbiologíaRESUMEN
The level of C-reactive protein (CRP) was determined in the cerebrospinal fluid (CSF) by particle counting immunoassay. In non-neurological patients (N = 24), CRP was detectable only in 10 samples at concentrations ranging from 1.5 to 37 micrograms/l. The multiple sclerosis group did not differ from the controls. The highest CRP levels were found in viral and bacterial, including tuberculous, infections of the nervous system, with overlapping results for the various types of infections. However, in serum, the levels of CRP were much higher in pyogenic than in viral meningitis. We compared the CSF CRP/serum CRP ratio to the same ratio for albumin and found a significant correlation between the two ratios in viral, but not in bacterial, infections. These results suggest a local consumption of CRP during bacterial meningitis.
Asunto(s)
Infecciones Bacterianas/metabolismo , Proteína C-Reactiva/metabolismo , Meningitis/metabolismo , Adulto , Anciano , Barrera Hematoencefálica , Humanos , Lactante , Meningitis por Haemophilus/metabolismo , Meningitis Neumocócica/metabolismo , Meningitis Viral/metabolismo , Persona de Mediana Edad , Albúmina Sérica/metabolismo , Infecciones Estafilocócicas/metabolismo , Tuberculosis Meníngea/metabolismoRESUMEN
We studied the pharmacokinetics of N-formimidoyl thienamycin with and without a renal dipeptidase inhibitor in plasma and cerebrospinal fluid (CSF) of rabbits. Thienamycin reached a maximal concentration of 0.6 +/- 0.06 mg/l in the CSF of normal rabbits. When the meninges were inflamed, the mean CSF concentration of N-formimidoyl thienamycin was 3.2 +/- 1.5 mg/l, five times higher than in normal rabbits. This concentration would kill most bacteria that cause meningitis. The renal dipeptidase inhibitor alone had no detectable antibacterial activity. When administered with N-formimidoyl thienamycin, it exerted only minor effects on the pharmacokinetics in either plasma or CSF of normal or infected rabbits.
Asunto(s)
Antibacterianos/metabolismo , Dipeptidasas/antagonistas & inhibidores , Riñón/enzimología , Meningitis por Haemophilus/metabolismo , Tienamicinas/metabolismo , Animales , Imipenem , Cinética , ConejosRESUMEN
The pharmacokinetics of ceftriaxone were studied in five infants (7 to 15 months old) and five young children (24 to 70 months old). Both groups received a single 50-mg/kg dose in an intravenous infusion over 5 min. No major pharmacokinetic differences were observed between the two populations. The total (bound plus unbound) plasma concentration-versus-time data could be described in each case by a biexponential equation. Changes in renal clearance indicated time- and dose- dependent pharmacokinetic behavior. The fraction excreted unchanged in the urine (fu) and the biological half-life (t 1/2 (beta)) were, however, dose independent. The average values were 47% for fu (0 to 12 h) and 6.5 for T 1/2 (beta). Weight-corrected total systemic clearance was C1TS = 0.71 ml/min per kg; volume of distribution was VD (beta) = 394 mg/kg. The data support intravenous administration of 50 mg of ceftriaxone per kg of body weight every 12 h in assessing its activity against Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis in postneonatal-stage pediatric patients.
Asunto(s)
Cefotaxima/análogos & derivados , Meningitis/metabolismo , Cefotaxima/administración & dosificación , Cefotaxima/metabolismo , Ceftriaxona , Preescolar , Femenino , Semivida , Humanos , Lactante , Infusiones Parenterales , Cinética , Masculino , Meningitis por Haemophilus/metabolismo , Meningitis Meningocócica/metabolismo , Meningitis Neumocócica/metabolismo , Unión Proteica , Albúmina Sérica/metabolismoRESUMEN
The pharmacokinetics and bacteriological efficacy of cefoperazone, cefuroxime, ceftriaxone, and moxalactam were evaluated in the experimental rabbit meningitis model of Haemophilus influenzae type b or Streptococcus pneumoniae infection. The cerebrospinal fluid penetration of these beta-lactam antibiotics was from 3 to 14% and was greater in Haemophilus-infected that in pneumococcus-infected animals. With the exception of moxalactam, the antibacterial activity in cerebrospinal fluid and change in concentration of bacteria during therapy with the test drugs were comparable to those of penicillin G in pneumococcal infection. In animals infected with H. influenzae, cefoperazone, moxalactam, and ceftriaxone were as effective as chloramphenicol in reducing the bacterial counts in cerebrospinal fluid. Moxalactam and ceftriaxone produced the largest cerebrospinal fluid bactericidal titers against this beta-lactamase-producing strain of Haemophilus. On the basis of these data, it was concluded that ceftriaxone and cefoperazone were effective against both pathogens in this meningitis model, whereas moxalactam was effective against only Haemophilus, and cefuroxime was effective against only S. pneumoniae.