Antibiotic-host defence interactions in vitro and in vivo

A markedly depressed chemotaxis was detected with an agarose gel technique when human leucocytes were incubated with fusidic acid and rifampicin in clinically obtainable concentrations. At high concentrations of newer well absorbed tetracyclines there was a definite depression and a less pronounced inhibition was detected for classical tetracycline. The incorporation of 14C-leucine into a trichloroacetic-acid insoluble form by human neutrophils was markedly depressed by the same antibiotics and it is suggested that some antibiotics acting by inhibition of protein synthesis also affect chemotaxis of human neutrophils. At therapeutic concentrations fusidic acid and rifampicin had a pronounced inhibiting effect on the incorporation of 3H-thymidine by human T-lymphocytes stimulated by PHA and B-lymphocytes by S. aurens, Cowan I. At concentrations above the therapeutic level inhibition was detected for doxycycline, erythromycin, clindamycin and nitrofurantoin. No apparent inhibition of neither chemotaxis by human neutrophils nor thymidine incorporation by lymphocytes could be detected for penicillins, cephalosporins, nalidixic acid, sulfamethoxazole and trimethoprim. Due to high albumin binding for some of the tested antibiotics and other factors involved, experiments were performed to test whether depression also takes place in vivo. The cellular immunity in mice was registered by monitoring the survival of transplanted heart grafts and the humoral immunity by quantitating plaque-forming cells and by titration of antibodies after immunization with sheep erythrocytes. Fusidic acid (500 mg/kg/day) and rifampicin (20 mg/kg/day, human therapeutic dose) had a highly significant effect (P less than 0.001) on the rejection of heart grafts and plaque-forming cells while the effect o serum antibodies was of low significance (P less than 0.02--P less than 0.01). The effect of doxycycline (2.5 mg/kg/day) and fusidic acid (25 mg/kg/day) at human therapeutic dose on immunity in mice was slight but significant (P less than 0.02). The relevance of experiments in mice to the situation in man is discussed. The migration of neutrophils into a skin chamber was shown to be dramatically reduced in eight healthy volunteers during a standard regimen of doxycycline.