Nitric oxide concentrations and cerebrospinal fluid parameters in an experimental animal model of Streptococcus pneumoniae meningitis.
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.
Destache
C J
CJ
Department of Pharmacy Practice, Creighton University School of Pharmacy and Allied Health Professions, Omaha, Nebraska 68178, USA.
Pakiz
C B
CB
Dash
A K
AK
Larsen
C
C
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002443:Ceftriaxone / Q000493:pharmacokinetics / Q000494:pharmacology; D002452:Cell Count; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology; D002556:Cerebrospinal Fluid Proteins / Q000032:analysis; D003907:Dexamethasone / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D005947:Glucose / Q000134:cerebrospinal fluid; D019344:Lactic Acid / Q000134:cerebrospinal fluid; D007962:Leukocytes / Q000382:microbiology / Q000473:pathology; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000473:pathology; D017551:Microdialysis; D009569:Nitric Oxide / Q000134:cerebrospinal fluid*; D011817:Rabbits; D013296:Streptococcus pneumoniae / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D002511:Cephalosporins; D002556:Cerebrospinal Fluid Proteins; D009569:Nitric Oxide; D019344:Lactic Acid; D002443:Ceftriaxone; D003907:Dexamethasone; D005947:Glucose