Influence of antibiotic dose, dosing interval, and duration of therapy on outcome in experimental pneumococcal meningitis in rabbits

Abstract

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...

Pharmacodynamics of Vancomycin for the Treatment of Experimental Penicillin- and Cephalosporin-Resistant Pneumococcal Meningitis

“…For ␤-lactam agents, peak concentrations in CSF at least 10-fold greater than the MBC are required for therapeutic effectiveness (24,25). In the present study, the rate of bacterial clearance was similar for the two treatment regimens, and peak CSF vancomycin concentrations that were four-to eightfold greater than the MBC were adequate for bactericidal activity.…”

“…Prior experimental meningitis studies suggested that, for ␤-lactam antibiotics, peak concentrations in CSF correlate with bactericidal activity and that concentrations in CSF at least 10-fold greater than the minimum bactericidal concentration (MBC) for the pathogen are required for optimal bacterial killing (24,25). For vancomycin, the range of concentrations in CSF considered therapeutic and the pharmacodynamic index that best predicts outcome are not known.…”

Meropenem Administered as a Prolonged Infusion to Treat Serious Gram‐Negative Central Nervous System Infections

“…Experts in CNS infection advocate that effective bactericidal activity of ␤-lactams in the CSF is quantified most appropriately through measurement of the T>MBC. 16 Unfortunately, the MBC of the pathogens in both cases was not reported by the clinical microbiology laboratory, which is consistent with the standard of care used in the hospital setting. The T>MBC associated with the use of meropenem as a prolonged infusion in our two patients was not known, and confirmation of bactericidal activity was not available.…”

“…Animal infection models have substantiated that for the ␤-lactams in the CSF, the component of time of exposure, as opposed to concentration, is most highly correlated with bacterial killing activity. [16][17][18] However, the parameter of time in these experiments was indexed to microbiologic activity of the drug through the MBC and not the MIC. Experts in CNS infection advocate that effective bactericidal activity of ␤-lactams in the CSF is quantified most appropriately through measurement of the T>MBC.…”

Timing of penicillin treatment influences the course of Streptococcus pneumoniae-induced middle ear inflammation

“…Antimicrobial treatment is essential for reducing the number of viable bacteria in invasive pneumococcal infection. Beta-lactam treatment timing with regard to the kinetics of bacterial growth inhibition was reported by Tauber et al for the rabbit meningitis model (13). Cure rates were improved as the dose of penicillin was increased and the interval between doses was increased.…”