Modulation of antimicrobial effects of beta-lactams by amino acids in vitro.

Glycine as well as 11 and 10, respectively, out of a total of 12 D-amino-acids tested increased the antimicrobial efficacy of imipenem (IMI) and of ampicillin (AMP) using the serosensitive strain E. coli ATCC 8739. D-proline was ineffective in assays with IMI as well as D-proline and D-leucine in assays with AMP. - In contrast, L-amino-acids behaved differently: In assays with IMI, 9 out of 13 isomers were ineffective whereas 3 were antagonistic (L-phenylalanine, L-serine, L-tryptophan). In combination with AMP, however, 10 L-amino acids had an antagonistic effect and 2 (L-leucine, L-methionine) were ineffective. L-alanine was an exception and showed a synergism with both antibiotics which was assumed to have been due to a racemase activity of cells. - Seroresistance of E. coli apparently reduced the synergistic effect of glycine and beta-lactams. - Glycine, alanine and tryptophan lost their typical synergistic or antagonistic effect with AMP when tested as di- or tri-amino-acid compounds. This was not the case with di-L-alanine - It is supposed that the synergistic effect of glycine or of D-amino-acids with beta-lactams can be explained mainly by an inhibition of carboxypeptidases.

[Importance of the antimicrobial mode of action of antibiotics for their combined effect with glycine in subinhibitory concentrations on microbial growth]. / Importance du mode d'action d'un antibiotique pour son effet combiné avec la glycine à concentrations sub-inhibitrices sur la croissance microbienne.

Following previous observations of an increase in microbial sensitivity to the bactericidal beta-lactams ampicillin and imipenem in the presence of glycine, the aim of the presented study was to examine if such an effect is due to the antimicrobial mode of action of an antibiotic and/or to its bactericidal or bacteriostatic capacity. Using growth curves as an experimental parameter the same synergistic glycine effect could be shown if tested concomitantly with a number of other antibiotics acting equally on bacterial cell wall formation as cefaclor, cefadroxil, or fosfomycin. This glycine effect is, therefore, associated with the antibiotic mode of action, but is independent of wether the antibiotics are beta-lactams or not (fosfomycin). In contrast, glycine had no particular effect in combination with antibiotics inhibiting protein synthesis (sisomicin, kanamycin, chloramphenicol, oxy-tetracycline) or nucleic acid polymerase activity (ciprofloxacin, cinoxacin; rifampicin being a certain exception) as well as with those acting on cytoplasmic and external membrane as polymyxin B. The synergistic effect of glycine and cell wall active antibiotics was interpreted predominantly by an action on carboxypeptidases.

[Interaction of bactericidal serum effect and antibiotics in subminimal inhibitory concentrations on E. coli strains]. / Interaction entre l'effet bactéricide du sérum et des antibiotiques à concentrations sous-inhibitrices sur les souches d'E. coli.

Imipenem (IMI) forming round cells in Gram negative rods reduces in subinhibitory concentrations (subMIC) the seroresistance of E. coli. This effect is distinctly more pronounced in a moderately seroresistant strain of E. coli than in a high seroresistant one. Conversely, human serum (HS) increases the sensitivity of E. coli strains to IMI dependent on their original seroresistance. In contrast, ampicillin (AMP), a filament inducer in E. coli, reduces equally seroresistance but only to a minimal degree and that only in a moderately seroresistant strain; the high seroresistant strain was nonreactive in this respect. It was concluded, that a synergism of antibiotics and bactericidal serum effect is predominantly produced with round cell forming antibiotics, whereas filament forming ones show only minimal effects. Moreover, the original seroresistance of strains in apparently important for the degree tho which these phenomena are expressed.

[Interpretation of the influence of immunoglobulins and glycine on bacterial sensitivity to antibiotics in vitro]. / Interprétation de l'influence des immunoglobulines et de la glycine sur la sensibilité des bactéries aux antibiotiques in vitro.

The effect of human immunoglobulins (Ig) and of glycine, often added to commercial preparations as a stabilizer, have been examined in vitro on the growth of E. coli strains in the absence or presence of antibiotics in subminimal inhibitory concentrations (subMic). The Ig's (= 7S or 5S = F(ab')2 as well as glycine had no effect by themselves on bacterial growth at concentrations up to 32 mg and 4.5 mg per ml respectively. In contrast, in the presence of ampicillin, glycine induced a concentration dependent increase of bacterial sensitivity to antibiotics. This is apparently more pronounced in serosensitive than in seroresistant E. coli strains. Such a synergism could equally be shown with cefadroxil and fosfomycin, i.e. with other antibiotics interacting with cell wall synthesis, but not with those of another mode of action, as ciprofloxacin, polymyxin B or chloramphenicol.

[Effect of fosfomycin on cellular immune reactions as affected by cyclophosphamide or corticosteroids]. / L'effet de la fosfomycine sur l'immunoréaction cellulaire sous l'influence de la cyclophosphamide ou des corticostéroïdes.

The effect of fosfomycin (FM) has been examined on the "footpad swelling reaction" (FPSR) as a model for cellular immunity and on the course of experimental infection with FM resistant E. coli using normal and immunocompromised mice. FM given the day of immunization improved FPSR response progressively up to a dose of 30 mg/kg, higher doses had no effect. If FM was injected 1 or 3 days after immunization doses of 30 mg/kg induced a considerable stimulation, whereas higher doses were inhibitory. In contrast to the high dose of 50 mg of FM per kg, 30 mg/kg increased the stimulatory effect induced by small doses of CY and reduced the inhibitory effect of high CY doses. The depressing effect of hydrocortisone (HC) was also reduced by 30 mg/kg of FM, but not by the higher one. In experimental infection with E. coli, FM in doses of 30 mg/kg was more effective than the higher ones in reducing mortality rate. Comparable results were obtained with CY pretreated animals.

Increased resistance towards two systemic experimental infections by tetrachlorodecaoxygen anion complex. Possible implications of cellular and humoral immunity.

The tetrachlorodecaoxygen anion complex (TCDO, Oxoferin) given intravenously 1 h after intravenous infection of mice with Candida albicans increased the host's resistance gradually in doses up to 3.1 mumol/kg body weight (b.w.). Above this level, the stimulatory effect decreased, turning to an inhibition at a dose of 18.6 mumol/kg b.w. TCDO. Repeated applications of the optimum single dose had no cumulative effect. In experimental infections with the strictly anaerobic Peptostreptococcus intermedius, TCDO ameliorated the course of the infection not only at a dose of 3.1 mumol/kg b.w. but also at a higher dose of 12.4 mumol/kg b.w. TCDO, which in the Candida sepsis model fell into the range of defence inhibition. A single dose of 3.1 mumol/kg b.w. TCDO also revealed to be the optimum dose to increase the humoral immune response evaluated by the number of immunoglobulin (Ig)M and IgG forming spleen cells after sensitization with sheep red blood cells (SRBC). The same results were obtained, regardless of whether TCDO had been given at the time of immunization or thereafter. The higher single dose of 18.6 mumol/kg b.w. TCDO did not show this effect but was not inhibitory either. Cellular immune reactions evaluated by the footpad swelling test and SRBC as antigen were found considerably enhanced whether TCDO was given once or repeatedly at a dose of 3.1 mumol/kg b.w., whereas single doses of 18.6 mumol/kg or repeated doses of 9.3 mumol/kg induced a certain inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of theophylline treatment on PGE2 production, PGE2 sensitivity and the distribution pattern of lymphocyte classes relative to the immune status.

In mice, theophylline reduced immune response mechanisms in case of primed cells but stimulated the reaction if priming and treatment were performed concomitantly. The reason for these bivalent reactions is unclear. We studied the effect of theophylline on prostaglandin E2 (PGE2) production by resident macrophages (M phi), on PGE2 sensitivity of thymocytes and spleen cells and on the distribution pattern of lymphocyte classes in thymus and spleen dependent on whether animals were immunized with sheep red blood cells (SRBC) or not. We found a theophylline induced decrease of PGE2 production of M phi in normal but an increase in immunized animals which was less pronounced if given concomitantly with a booster injection. The PGE2 resistance of thymocytes and spleen cells defined by the concentration of PGE2 needed for a 50% inhibition of PHA-P induced transformation was considerably increased by theophylline in normal animals. If given concomitantly with primary sensitization, theophylline equally increased PGE2 resistance but diminished it if applied together with a booster injection. This increase or decrease of PGE2 resistance ran parallel with a decrease or increase of the relative number of Lyt 2+ cells (suppressor T cells = Ts) in the thymus and in the spleen of theophylline treated animals. These results demonstrated that the bivalent effect of theophylline on immune response dependent on the immune status could predominantly be explained by its modulating effect on PGE2 sensitivity of thymocytes and spleen cells together with a corresponding shift in the number of Ts-cells, whereas the influence on PGE2 production by M phi seemed less important.

[Additive effect of an immunomodulator on the therapeutic effect of antibiotics]. / L'action additive d'un immunomodulateur sur l'effet thérapeutique des antibiotiques.

The effect of an immunomodulator, the Immunoferon (IF), on the course of experimental infections with Staphylococcus aureus and on cellular immune reactions (foot pad swelling test) was examined. The substance is a glycophosphopeptide adsorbed on sulfurized calcium phosphate. The IF improves clearly the therapeutic effect of penicillin, but has no significant effect when given alone. The substance neutralizes the negative effect of hydrocortisone on the therapeutic effectivity of penicillin. The cellular immune reaction is reduced by very small doses of IF, but is enhanced progressively by higher doses. The effect of hydrocortisone is abolished in this respect.