High-dose co-trimoxazole and its penetration through uninflamed meninges.

Normal doses of co-trimoxazole (two ampoules or two tablets twice a day) gave low cerebrospinal fluid concentrations of trimethoprim and sulphamethoxazole in neurosurgical patients. For two years, four ampoules of co-trimoxazole twice a day, followed by four tablets twice a day, which were administered to neurosurgical patients and to patients admitted to hospital with skull fractures, produced no toxicity and this regimen has not been associated with postoperative meningitis. After the high-dose regimen in patients with uninflamed meninges, trimethoprim concentrations in the cerebrospinal fluid ranged from 2.6 mumol/L to 12.4 mumol/L (0.75 mg/L to 3.6 mg/L), and in the serum from 9.6 mumol/L to 42.7 mumol/L (2.8 mg/L to 12.4 mg/L). However, the bacteriostatic and bactericidal activities of the spinal fluids and sera were very variable, some with high concentrations appearing to have negligible antibacterial activity in vitro. We have treated a few patients with serious infections with dosages of 12 ampoules or 12 tablets twice a day with successful results. Studies of serum folate, 5-methyltetrahydrofolate and granulocyte dihydrofolate reductase levels showed no toxic effects from the high-dose regimen.