We examined the influence of several pharmacokinetic parameters on cure rates in rabbits with experimental pneumococcal meningitis. When the duration of treatment was kept constant, cure rates improved as the individual dose of ampicillin was increased. On the other hand, when four doses of ampicillin at 60 mg/kg of body weight, producing peak concentrations in cerebrospinal fluid (CSF) of approximately 40 times the MBC, were administered at intervals of 24 instead of 4 h and the duration of therapy was thus prolonged from 12 to 72 h, cure rates also increased (85 versus 25%; P < 0.01). These high cure rates were achieved even though bacterial titers in CSF 24 h after the first dose had reached levels similar to those present at the beginning of therapy. Cure in these animals was explained by the fact that the second ampicillin dose reduced bacterial titers in CSF significantly more than did the first dose (5.2 versus 2.5 loglo CFU/ml; P < 0.02). The clinical relevance of these observations remains to be determined.Since the introduction of penicillin in the therapy of bacterial diseases 40 years ago, mortality of bacterial meningitis has not been significantly reduced (25), despite the development of many new antibiotics. A recent study found a mortality rate for pneumococcal meningitis of 26% (19), a figure almost identical to those found in studies performed several decades earlier (9, 22).The pharmacodynamic parameters that determine efficacy in the therapy of bacterial meningitis have not been completely elucidated. In earlier studies using a model of experimental pneumococcal meningitis, we defined some of the factors that influence the therapeutic response to ampicillin (16,23,26). First, we found that only antibiotic doses that produce concentrations in cerebrospinal fluid (CSF) 10-to 100-fold above the in vitro MBC show a maximal bactericidal activity in CSF (23). Second, our studies showed that with such high doses, antibiotic concentrations in CSF may fall below the MIC for several hours without loss of efficacy (16,26). A persistent inhibitory effect of low residual amounts of the antibiotic in CSF seems responsible for this apparent in vivo postantibiotic effect, since the injection of penicillinase into the subarachnoid space in these animals was followed by immediate regrowth of the bacteria (26).In this study, we examined more closely the influences of the amount of the single dose, the dosing interval, and the duration of therapy on the outcome of experimental pneumococcal meningitis in rabbits. Three different doses of ampicillin, producing peak concentrations in CSF approximately 1, 10, and 40 times the MBC, were administered as bolus injections. Ten treatment groups treated with one of the three doses, given at various dosing intervals for four or eight doses, were examined. The longest treatment regimens (4 days) with high single doses produced the highest cure rates in these experiments. A detailed analysis of bacterial * Corresponding author. growth characteristics showed that the second a...