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High-dose co-trimoxazole and its penetration through uninflamed meninges
Abstract:
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.
Insights
High-dose co-trimoxazole in neurosurgical patients achieved therapeutic cerebrospinal fluid concentrations without toxicity. This regimen shows promise for treating serious infections, warranting further investigation into its antibacterial efficacy.
Area of Science:
- Pharmacology
- Neurosurgery
- Infectious Diseases
Background:
- Normal co-trimoxazole doses yield low cerebrospinal fluid (CSF) levels in neurosurgical patients.
- High-dose co-trimoxazole has not been linked to postoperative meningitis in neurosurgical patients.
Purpose of the Study:
- To evaluate the efficacy and safety of high-dose co-trimoxazole in neurosurgical patients.
- To determine CSF and serum concentrations of trimethoprim and sulfamethoxazole with high-dose regimens.
Main Methods:
- Administered high-dose co-trimoxazole (four ampoules/tablets twice daily) to neurosurgical patients and those with skull fractures for two years.
- Measured trimethoprim concentrations in CSF and serum.
- Assessed in vitro antibacterial activity of CSF and serum.
- Monitored folate and granulocyte dihydrofolate reductase levels.
Main Results:
- High-dose co-trimoxazole produced no toxicity and was not associated with postoperative meningitis.
- CSF trimethoprim concentrations ranged from 2.6 to 12.4 µmol/L; serum concentrations ranged from 9.6 to 42.7 µmol/L.
- Antibacterial activity of CSF and serum was variable, even with high drug concentrations.
- Very high doses (12 ampoules/tablets twice daily) were successfully used for serious infections.
- No toxic effects on folate or dihydrofolate reductase levels were observed.
Conclusions:
- High-dose co-trimoxazole is safe and achieves therapeutic CSF concentrations in neurosurgical patients.
- The variable in vitro antibacterial activity suggests further research is needed.
- High-dose co-trimoxazole is a potential treatment for serious infections in this patient population.