Interference of antimicrobial agents in some reactions of host-defense system.
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Biomedical subjects
Publications and source records attributed to A Fietta.
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The in vitro and in vivo effects of ceftriaxone, a newly developed cephalosporin, on phagocytes and T-cell subsets were studied. Ceftriaxone in vitro did not interfere with phagocytosis, phagocytosis-dependent metabolic activation, and microbicidal activity (against Staphylococcus aureus and Candida albicans) of human neutrophils at doses ranging from 10 to 320 micrograms/ml. In vitro chemotaxis was markedly inhibited both in the presence of and after 30 minutes of exposure to 40 micrograms/ml of ceftriaxone. Six normal adult volunteers were given 2 g of antibiotic intravenously every 24 hours for six days. The in vivo effects of ceftriaxone on neutrophil functions and T-cell subsets were investigated before and 30 minutes after injection on the first and third days. No change in any phagocyte function (chemotaxis, phagocytosis, phagocytosis-dependent metabolic activation, and microbicidal activity) or in the distribution of T-cell subpopulations was observed.
The effect of beta-lactam antibiotics upon some functions of human phagocytes was examined. Penicillins (carbenicillin and piperacillin), thienamycin, and cephalosporins (cefotetan, ceftazidime, and moxalactam) had no effect on either the random or directional migration or on the bactericidal activity of neutrophils and monocytes against Staphylococcus aureus. On the contrary, cefoperazone at therapeutic levels was shown to inhibit neutrophil chemotaxis.
The in vitro activity of teichomycin has been evaluated against 189 clinical isolates of Staphylococcus aureus, Staphylococcus epidermidis and group D streptococci. Teichomycin was as active as vancomycin, a chemically related antibiotic, on staphylococci and inhibited the in vitro growth of methicillin-resistant strains at the same concentration necessary to inhibit the sensitive ones. Against group D streptococci teichomycin was about three times more active than vancomycin (MIC50 = 0.125 mg/l, MIC90 = 0.4 mg/l). MBC:MIC ratios of both drugs against staphylococci were comparable, but teichomycin had higher bactericidal activity against group D streptococci, as shown also by killing curves. The activity of teichomycin was not significantly affected by variation of pH, even if the maximum activity was achieved at neutral pH, or by different methods of MIC evaluation. The antibiotic seemed more active when tested with a low inoculum (10(3)-10(5)/ml): a two- to threefold increase in MIC was observed at an inoculum of 10(7)/ml. A reduction of the in vitro activity could be shown when Penassay broth was used as culture medium.
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This review summarizes the experience gained on interactions between antimicrobial agents and some reactions of the host defense system (adherence, chemotaxis, phagocytosis, microbicidal activity of leukocytes, complement system, antibody production, cell-mediated immunity) and attempts a critical evaluation. The data collected from the literature are often conflicting and there seem to be differences of behavior among derivatives belonging to the same family of antibiotics. Therefore it is quite difficult to draw a correct conclusion from these data. So far it has not been possible to understand the impact that the interference of antibiotics in natural and immunologic reactions of the host defense has on the outcome of chemotherapy, mainly in patients with some degree of immunodepression. In this instance, in fact, the interference with certain immunologic reactions could influence the therapeutic activity of specific antibiotics that are endowed with inhibitory activity. However, so far no controlled study or clear demonstration has shown that antibiotics with different activity on the immunologic reactions can have different efficacy in immunodepressed patients.
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The inhibitory effect of neutrophil chemotaxis of gentamicin, tobramycin, and sisomicin was shown. The combined effect of aminoglycosides and histamine was not additive.
The bactericidal reactions of normal human serum and of ethylene glycol-bis(beta-aminoethyl ether)-N,N-tetraacetic acid (trisodium salt)-Mg2+-treated human serum differ in a number of aspects. The latter reaction was shown (i) to require the integrity of the alternative pathway of complement, (ii) to display two levels of efficiency depending on the concentration of target bacteria, and (iii) to be modulated by the addition of thermostable serum fractions with inhibitory and stimulatory activities. The inhibitory activities were characterized to a certain extent; they comprised several glycoprotein species of molecular weights between 60,000 and 20,000. The stimulatory activities could be measured only after depletion of the inhibitors by concanavalin A-Sepharose or heat-killed bacteria and could be fractionated into several peaks by gel filtration.
Atopic sera were shown to be defective in serum bactericidal activity by a reaction dependent upon the integrity of the alternative pathway of complement activation. In normal human sera, the efficiency of such a reaction could be modulated by the addition of thermostable serum fractions with inhibitory and stimulatory activity, as demonstrated on two different assay systems. Atopic sera contained the inhibitory activities, but no stimulatory activity. The bactericidal defect of atopic sera was shown to be familial, but its hereditary mechanism could not be unambiguously interpreted.
Eight plasmids out of 26 tested confer partial serum resistance to Escherichia coli K-12 strains (Bhs character). Four Bhs+ plasmids were tested in a rough Salmonella typhimurium host, and three conferred partial serum resistance to this host as well. Plasmids representative of 19 different incompatibility groups were examined; the Bhs+ property was found in some (but not all) representatives of groups N, O, S, T, W, and F'lac (FI), and there was no apparent association between other plasmid markers and Bhs. It is likely that more than one mechanism can promote the Bhs+ phenotype and that Bhs genes are responsible for modifications of the surface structures involved in serum sensitivity.
Subinhibitory doses of rifampin cured F(+)Escherichia coli cells from the episome. The target of the drug was transcription because E. coli mutants with a ribonucleic acid polymerase resistant to rifampin were not cured. The experimental conditions required for optimal curing with rifampin very closely resembled those required for curing with acridine orange. Mutants were found which are more resistant to curing by both acridine orange and rifampin. Probably the two drugs affect a common metabolic step, or alternatively they may inhibit the synthesis of a factor which is necessary for the replication of the episome.
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An apparently healthy boy was suffering from recurrent Aspergillus infections. No classical conditions of immunodeficiency were found. Studies on the patient's phagocytic system revealed neutrophils and monocytes to function normally except in Aspergillus killing (microbicidal activity for bacteria and Candida was normal). Aspergillus killing mechanisms may be complex and peculiarly selective, possibly involving both oxygen-dependent and independent mechanisms.
Some measures of systemic host defences, i.e. white cell counts, lymphocyte subsets, delayed-type hypersensitivity and polymorphonuclear leucocyte functions, were evaluated in 42 patients suffering from cutaneous superficial mycoses and in 35 healthy volunteers. Patients were divided according to the extent of their lesions into two groups: group A (30 patients) with skin involvement > or = 30% and group B (12 patients) with skin involvement < or = 1%. No significant abnormalities in systemic defence mechanisms were observed in group B patients, whereas multiple alterations of polymorphonuclear phagocyte activities, i.e. chemotaxis, phagocytosis, mitogen-induced superoxide anion production, were observed in patients with extensive lesions. The values of these phagocytic functions remained significantly reduced (P < 0.01) in these patients after recovery and during a 6-month follow-up period.
The in vitro effects of cefixime and cefdinir (CI 983), two so-called third-generation oral cephalosporin derivatives, on human polymorphonuclear and mononuclear phagocyte functions (random migration and chemotaxis, specific and nonspecific phagocytosis, nitroblue tetrazolium reduction, superoxide production, microbicidal activity) were studied. Neither antibiotic, in the range of its attainable therapeutic concentration, exhibited any toxic effect on random migration, chemotaxis, metabolic activation and microbicidal mechanisms of phagocytic cells. Cefixime did not interfere in phagocytosis while cefdinir enhanced both phagocytosis frequency and index. The modulating effect on phagocytosis exerted by cefdinir was achieved at very low antibiotic concentrations (0.06 mg/l for polymorphonuclear leukocytes and 0.03 mg/l for monocytes) when non-opsonized zymosan particles were used as phagocytic challenge. Moreover, the effect was demonstrated both in the presence of cefdinir and after pretreatment of cells with the antibiotic and its removal by washings. As for specific phagocytosis, parameters were slightly increased by cefdinir but only the phagocytosis index was significantly improved in the presence of 2 mg/l of antibiotic.
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