Neopterin, a pyrazino‐pyrimidine derivative, is synthesized in excess by human monocytes/macrophages upon stimulation with interferon‐γ, a cytokine derived from activated T‐cells. Neopterin is furthermore produced constitutively. A relatively constant ratio between neopterin and its reduced form, 7,8‐dihydroneopterin, has been described in human serum. In the study presented here we tested the ability of neopterin and its reduced form to modulate the effects of cytotoxic substances like hydrogen peroxide or hypochlorous acid and N‐chloramine derivatives. We show that 7,8‐dihydroneopterin potently reduces biological and chemical effects of these substances independently from the pH value. In contrast, at slightly alkaline pH (pH 7.5) neopterin enhances hydrogen peroxide and chloramine‐T activity. This is demonstrated by increase of signal intensity in a luminol assay and also by enhancement of toxicity towards bacteria. Thus, the macrophage derived substance neopterin is able both to enhance and to reduce cytotoxicity in dependence of pH value and its oxidation state, and it may have a pivotal role in modulation of macrophage mediated effector mechanism.

This study was designed to investigate the delay of regrowth (postantibiotic effect) in the presence of N-chlorotaurine (NCT), an endogenous active N-chlorine compound, of Staphylococcus aureus, strain Smith diffuse. The low reactivity of NCT enabled clear temporal separation of the postantibiotic and killing effect to be defined. Delay of regrowth proved to be dependent both on concentration of NCT, and incubation time. The maximum delay was 3 h. Using the model of lethal staphylococcal peritonitis in mice, in-vivo delay of regrowth of bacteria pretreated with N-chlorotaurine could be demonstrated to correlate with survival. It is concluded that the postantibiotic effect of N-chlorotaurine could be an important factor on decreasing virulence of bacteria. This effect was observed after relatively short incubation times.

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Antibiotic concentrations observed in vivo were simulated in an in vitro two compartment model with a dialyser interconnection. Kill kinetics and regrowth pattern of bacteria were investigated under these fluctuating antibiotic concentrations. There were large differences in the rate of reduction of viable organisms by various antibiotics not reflected in small differences in initial MIC values. Data suggested that the area under the concentration curve might be of importance in determining the antimicrobial activity of substances rather than the initial concentration. The inclusion of pharmacokinetic parameters in antimicrobial susceptibility testing might add a new dimension to the appreciation of the activity of antimicrobial substances.

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