We have evaluated the efficacy of cefotaxime and latamoxef against a Kl Escherichia coli strain in vitro and in vivo. In vitro, the minimal inhibitory concentrations (MICs) were close to the minimal bactericidal concentrations (MBCs) for both antibiotics (≤2dilutions). However, with an inoculum of 107 CFU/ml, MIC and MBC were significantly greater than those with inocula of 103 and 105. In vivo study with an infant rat model of bacteremia and meningitis revealed that (1) both cefotaxime and latamoxef penetrated well into the cerebrospinal fluid (CSF), (2) both drugs were bactericidal in blood and CSF, (3) both were effective in prevention of the development of meningitis in bacteremic animals, and (4) the mortality rates were significantly less in the treated than in the control group (p < 0.001). However, even with cefotaxime or latamoxef treatment, the mortality was significantly greater (p < 0.001) in rats whose bacterial counts before therapy were ≥106 CFU/ml of blood. These findings suggest that the effects of cefotaxime and latamoxef may be directly correlated with the size of the bacterial population exposed to these agents and that this variable may be an important factor to influence the therapeutic outcome.
We evaluated the activity of ampicillin and chloramphenicol in vitro and in vivo against an Escherichia coli Kl strain. In vitro, the strain was relatively susceptible to both antibiotics (MIC and MBC of ampicillin, 2 and 4 ,ug/ml; MIC and MBC of chloramphenicol, 4 and 64 ,ug/ml). Checkerboard determinations of MBCs of drug combinations were consistent with antibiotic antagonism. Killing curves with concentrations of antibiotics similar to in vivo levels in blood and cerebrospinal fluid of infected rats indicated antagonism within the first 4 h and an indifferent effect of the combination at 24 h. Paradoxically, the combination was significantly more effective than ampicillin or chloramphenicol alone in vivo in infant rats. This Was shown by (i) more rapid bacterial clearance from the blood and cerebrospinal fluid, (ii) a decreased incidence of meningitis in bacteremic animals, and (iii) improved survival. These findings illustrate a divergence between the effects of ampicillin and chloramphenicol against E. coli in vitro and in vivo and suggest that this combination is an effective synergistic regimen in this experimental model of E. coli bacteremia and meningitis.
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