Effects of antimicrobial agents used for therapy of CNS infections on dissociated brain cell cultures.
The prediction, measurement, and monitoring of neurologic toxicity of antibacterial agents is an exceedingly difficult matter. In this study we investigated if in vitro exposure of cultured brain cells to antibacterial drugs could predict neurotoxicity in man. Effects of antibiotics used for therapy of bacterial CNS infections on growth and differentiation in dissociated rat brain cell cultures were studied over 24 days in culture, the drugs being added from 10 to 17 days in culture, the main differentiation phase of rat CNS cells. Our results demonstrated a reversible inhibition of cerebral sulfate transferase activity (p less than 0.001 or less than 0.01) and to a lesser extent (p less than 0.001 or NS) of DNA synthesis in brain cell cultures by the highest concentrations studied of amikacin, cefuroxime, and ceftazidime which correspond to peak cerebrospinal fluid values attained by intraventricular therapy in patients. Accumulation of DNA reflects brain cell growth whereas cerebral sulfate transferase activity parallels brain cell differentiation. Our findings indicate that intraventricular therapy could be more toxic with amikacin, cefuroxime, and ceftazidime than with penicillin, chloramphenicol, or ceftriaxone. Thus, this brain cell culture model might become a supplement, complement, or even alternative technique for neurotoxicity assessment of antibiotics with proven or potential value for therapy of CNS infections.
Schaad
U B
UB
Department of Pediatrics (Inselspital), University of Berne, Switzerland.
Guenin
K
K
Steffen
C
C
Herschkowtiz
N
N
D000583:Amikacin / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002493:Central Nervous System Diseases / Q000188:drug therapy; D002511:Cephalosporins / Q000494:pharmacology; D002701:Chloramphenicol / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000494:pharmacology; D006801:Humans; D010400:Penicillin G / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013307:Streptomycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D011506:Proteins; D002701:Chloramphenicol; D000583:Amikacin; D004247:DNA; D010400:Penicillin G; D013307:Streptomycin