RESUMEN
This study was designed to investigate the penetration across the blood-brain barrier of three doses of levofloxacin using a microdialysis probe implanted into the cerebrospinal fluid (CSF) of a rabbit pneumococcal meningitis model. The microdialysis guide cannula was implanted into rabbit subarachnoid space using a stereotaxic frame. After 3 days, 10(4) cfu Streptococcus pneumoniae serotype 3 in 0.3 mL saline was injected via intracisternal puncture and animals were allowed to incubate the organisms for 16-18 h. Groups of animals (n = 5) then received 7, 10.5 or 14 mg/kg iv of the drug over 10 min. Plasma samples were obtained via an ear vein 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 h after the antibiotic infusion. CSF microdialysis effluent samples were collected every 0.5 h for the entire experiment. Plasma and microdialysis effluent samples were analysed by HPLC. AUC(0-8) in plasma and CSF were computed using the trapezoid rule. The elimination half-life in plasma and CSF was calculated using non-linear regression analysis. The unbound peak plasma concentrations for the three doses studied were 3.9, 6.4 and 10.3 mg/L, respectively. There was a significant increase in the plasma AUC(0-8) [29.7 +/- 6.3, 49.1 +/- 19.1 and 67.6 +/- 8.9 mg x h/L (P < 0.005)]. The unbound peak CSF concentrations were 3.8, 5.7 and 8.6 mg/L and occurred at 0-0.5 h after the administration of the dose. The AUC(CSF(0-8)) was significantly higher as the dose was increased (7 mg/kg, 15.8 +/- 6.6; 10.5 mg/kg, 37.3 +/- 7.8; and 14 mg/kg, 46.4 +/- 20.9 mg x h/L; P < 0.03). The penetration of levofloxacin averaged 53% for the 7 mg/kg dosage group, 76% for the 10.5 mg/kg group and 68% for the 14 mg/kg group. Our results demonstrate that levofloxacin penetration into the CSF averages 66% for the doses that would be used in clinical practice.
Asunto(s)
Antiinfecciosos/líquido cefalorraquídeo , Levofloxacino , Meningitis Neumocócica/líquido cefalorraquídeo , Ofloxacino/líquido cefalorraquídeo , Animales , Antiinfecciosos/farmacocinética , Área Bajo la Curva , Modelos Animales de Enfermedad , Meningitis Neumocócica/metabolismo , Ofloxacino/farmacocinética , Conejos , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
Streptococcus pneumoniae is a common cause of meningitis. Nitric oxide (NO) has been implicated in causing cerebral edema. Modulating NO production in cerebrospinal fluid (CSF) may have a role in the treatment of bacterial meningitis. Experimental S. pneumoniae meningitis was induced in a rabbit model to determine CSF parameters and NO concentrations. An electrochemical probe in the CSF throughout the 7-hour experiment monitored NO concentrations. The animals had S. pneumoniae (10(5)) injected intracisternally and incubated for 1 hour. Cerebrospinal fluid 200-300 microl was obtained by intracisternal puncture at zero, 2, 4, and 7 hours after drug administration to measure glucose, protein, and lactic acid by standard chemical methods. White blood cell count was measured by hemocytometry. Three groups of five animals were used-control (C), ceftriaxone (CTX), and ceftriaxone plus dexamethasone (CTX+D). Ceftriaxone concentrations in CSF were obtained by microdialysis and analyzed by high-performance liquid chromatography. Mean (+/- SEM) CSF white blood cell count was significantly higher at 2 hours in the C group than in the other two groups (C 7307 +/- 1302, CTX 605 +/- 345, CTX+D 730 +/- 43/mm3, p<0.002). Ceftriaxone induced a significant rise in protein at 4 hours compared with the other groups (C 364 +/- 107, CTX 1158 +/- 797, CTX+D 365 +/- 100 mg/dl, p<0.02). Cerebrospinal fluid lactic acid was significantly different at 4 and 7 hours between C and CTX+D groups (4-hr C 8.0 +/- 2.2, CTX+D 2.0 +/- 0.4 mmol/L, p<0.05; 7-hr C 10.2 +/- 2.4, CTX+D 2.8 +/- 0.8 mmol/L, p<0.01). Median NO concentrations were significantly elevated in the control group compared with the other two groups (C 11.7, CTX 6.8, CTX+D 6.5 micro, p<0.02 C vs CTX, p<0.01 C vs CTX+D). Average (+/- SEM) NO concentrations were significantly higher in the C group at 4 hours (18.1 +/- 0.4, CTX 5.8 +/- 1.8 microM, p<0.05; CTX+D 11.5 +/- 4.0 microM, p>0.05), whereas they did not rise significantly until 7 hours in the CTX group (CTX 18.7 +/- 0.7, C 8.9 +/- 0.4 microM, p=0.055; CTX+D 8.1 +/- 2.2 microM, p<0.05). These results indicate that ceftriaxone with or without dexamethasone significantly decreases lactic acid concentrations and white cell penetration into the CSF in an experimental model of S. pneumoniae meningitis. In addition, ceftriaxone induced a significant elevation in CSF protein. Median NO production in the CSF was significantly attenuated by ceftriaxone.
Asunto(s)
Meningitis Neumocócica/líquido cefalorraquídeo , Óxido Nítrico/líquido cefalorraquídeo , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Ceftriaxona/farmacocinética , Ceftriaxona/farmacología , Recuento de Células , Cefalosporinas/farmacocinética , Cefalosporinas/farmacología , Proteínas del Líquido Cefalorraquídeo/análisis , Dexametasona/farmacocinética , Dexametasona/farmacología , Interacciones Farmacológicas , Glucosa/líquido cefalorraquídeo , Ácido Láctico/líquido cefalorraquídeo , Leucocitos/microbiología , Leucocitos/patología , Meningitis Neumocócica/tratamiento farmacológico , Meningitis Neumocócica/patología , Microdiálisis , Conejos , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of azithromycin against reference strains of Streptococcus pneumoniae ATCC 49619, Neisseria meningitidis ATCC 13090, and Haemophilus influenzae ATCC 49247 were determined by the macrodilution broth method with and without 10% bovine cerebrospinal fluid (CSF) supplementation. The MICs and MBCs were within one to two dilutions for N. meningitidis and S. pneumoniae, and no difference was observed for H. influenzae. Time-kill curves demonstrated enhanced killing by azithromycin when 10% bovine CSF was added to media for N. meningitidis. The minimum azithromycin concentration for a greater than 3 log10 reduction in inoculum with bovine CSF was 0.03 microg/ml and without CSF was 0.12 microg/ml, a 3-fold difference. Killing was not significantly different for either H. influenzae nor S. pneumoniae.
Asunto(s)
Antibacterianos/farmacología , Azitromicina/farmacología , Líquido Cefalorraquídeo/microbiología , Haemophilus influenzae/efectos de los fármacos , Neisseria meningitidis/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Animales , Bovinos , Cinética , Pruebas de Sensibilidad MicrobianaRESUMEN
Using microdialysis in a rabbit model of Streptococcus pneumoniae meningitis, the pharmacokinetics and pharmacodynamics of a new fluoroquinolone, A-80556, were determined. A-80556 (10 mg/kg iv) was administered to four rabbits. Saline was given to four separate control animals. A microdialysis probe perfused the CSF (2 microL/min) and effluent was collected at 0-0.25, 0.25-1, 1-2, 2-4, and 4-6 h after injection of A-80556. Seven blood samples were collected and analyzed by HPLC. At 0, 2, 4 and 6 h 300 microL of CSF was withdrawn for pharmacodynamic measurements. Plasma A-80556 concentrations demonstrated AUC0-infinity 2.40 +/- 0.272 micrograms.h/mL; T1/2 beta 1.07 +/- 0.011 h; Vd 6.35 +/- 0.50 L/kg; and Cl1 4.23 +/- 0.48 L/h.kg. Penetration into the CSF was 18.21%. Pharmacodynamics using time-kill curves showed a 3-log reduction in bacterial counts in CSF at 2 h after administration continuing for the remaining four hours of the experiment. These results demonstrate that microdialysis can be used for determination of drug penetration and efficacy in experimental S. pneumoniae meningitis.
Asunto(s)
Antiinfecciosos/farmacología , Antiinfecciosos/farmacocinética , Fluoroquinolonas , Meningitis Bacterianas/tratamiento farmacológico , Meningitis Bacterianas/metabolismo , Infecciones Neumocócicas , Quinolonas/farmacología , Quinolonas/farmacocinética , Streptococcus pneumoniae , Animales , Modelos Animales de Enfermedad , Meningitis Bacterianas/líquido cefalorraquídeo , Pruebas de Sensibilidad Microbiana , Microdiálisis , Conejos , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
The bactericidal activity of aminoglycosides alone and in combination with various beta-lactams was studied by the time-kill technique against ten Pseudomonas aeruginosa isolates with an unusual antibiogram (amikacin-resistant, gentamicin-resistant, tobramycin-susceptible [ArGrTs]). Previous studies have indicated that ArGrTs isolates are moderately resistant to all aminoglycosides and many are multiply resistant to beta-lactams. Aminoglycoside-beta-lactam combinations showed infrequent synergistic (16%) or enhanced killing (12%) against the ArGrTs isolates. Synergistic activity, when present, was more likely to occur with tobramycin and amikacin than with gentamicin, even though these differences were not statistically significant. Antibiotic resistance patterns were not predictive of synergy or enhanced killing. Systemic infections produced by ArGrTs isolates that are multiply resistant to the beta-lactams may not respond to combination therapy with an aminoglycoside and beta-lactam. Alternative treatment with polymyxin B or a quinolone may be required for these infections.
Asunto(s)
Antibacterianos/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Aminoglicósidos , Recuento de Colonia Microbiana , Farmacorresistencia Microbiana , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Pruebas de Sensibilidad Microbiana , beta-LactamasRESUMEN
In recent years, a number of clinical microbiology laboratories have isolated Pseudomonas aeruginosa with the unusual aminoglycoside disk diffusion result of resistance to both amikacin and gentamicin but susceptibility to tobramycin (ArGrTs). A total of 39 isolates of P. aeruginosa reported to have this resistance pattern were retested by the standard National Committee for Clinical Laboratory Standards disk diffusion procedure; 30 strains (77%) were confirmed to be ArGrTs. These 30 isolates were further examined for susceptibility to those aminoglycosides by agar dilution and broth micro- and macrodilution methods. Only 27, 27, and 23% of the isolates appeared to be ArGrTs by agar, broth microdilution, and broth macrodilution testing, respectively. Most of the remaining isolates were resistant to all three aminoglycosides when tested by broth dilution and resistant only to gentamicin when tested by agar dilution. The percentages of strains resistant to any particular aminoglycoside by agar dilution, broth microdilution, and broth macrodilution, respectively, were 43, 80, and 70 for amikacin, 97, 93, and 100 for gentamicin, 100, 100, and 100 for netilmicin, 30, 87, and 93 for sisomicin, and 13, 57, and 50 for tobramycin. These results indicate that strains showing the unusual aminoglycoside antibiogram are less susceptible to aminoglycosides in general and should probably be considered borderline resistant to all aminoglycosides. The efficacy of aminoglycosides in the treatment of infections produced by these strains is unknown.