[Management and choice of antibiotics for patients with an allergy to penicillin].
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Anti-Bacterial Agents↗
Biomedical subjects
B J Kullberg
Publications and source records attributed to B J Kullberg.
Soluble murine IL-1 receptor type I induces release of constitutive IL-1 alpha.
IL-1 alpha and IL-1 beta are proinflammatory cytokines involved in the pathogenesis of many infectious and noninfectious inflammatory diseases. To reduce IL-1 toxicity, extracellular domains of the soluble (s) IL-1R are shed from cell membranes and prevent triggering of cell-bound receptors. We investigated to what extent murine sIL-1RI can neutralize the IL-1 produced by LPS-stimulated macrophages. When mouse peritoneal macrophages were incubated with LPS, addition of sIL-1RI significantly inhibited the bioactivity of IL-1. Stimulation of cells with sIL-1RI alone induced no bioactive IL-1. When immunoreactive cytokine concentrations were measured with specific radioimmunoassays, sIL-1RI alone appeared to induce a significant release of IL-1 alpha in a concentration-dependent manner. This effect was independent of new protein synthesis. The production of IL-1 beta or TNF-alpha was not influenced by sIL-1RI. There was no interference of sIL-1RI with the IL-1 alpha radioimmunoassay. In mice, an i.v. injection of sIL-RI alone induced a rapid release of IL-1 alpha, but not of TNF-alpha or IL-1 beta. Treatment of mice with sIL-1RI improved the survival during a lethal infection with Candida albicans. In conclusion, sIL-1RI induces a rapid release of IL-1 alpha from cells, as well as into the systemic circulation. Although this IL-1 alpha may be inactivated in circulation by the same sIL-1RI, this phenomenon probably has immunostimulatory effects at local levels where the sIL-1RI-induced IL-1 alpha acts in a paracrine or autocrine manner.
Animals↗
Disease-specific ex vivo stimulation of whole blood for cytokine production: applications in the study of tuberculosis.
As a simple method for field studies to assess the cytokine-status of patients with tuberculosis (TB), the use of whole blood instead of isolated cells has advantages, especially since the risk of contamination is minimal. Therefore, cytokine production in whole blood cultures was determined using non-specific and disease-specific stimuli. Heparinized blood from healthy volunteers was either incubated in closed vacutainer tubes or in tissue culture wells after dilution in culture medium. Dose-response and kinetics were investigated for the production of TNFalpha, IL-1beta, IL-1ra, IL-10 and IFNgamma. Patients with TB and healthy individuals were examined for IFN-gamma production in whole blood. In the absence of a stimulus, the production of cytokines is negligible in whole blood cultures. LPS induces the production of TNFalpha, IL-1beta, IL-1ra and IL-10; PHA induces the production of IFNgamma and IL-10. Live BCG induces the production of proinflammatory cytokines, irrespective of tuberculin skin status. In contrast, PPD and MTB-culture filtrate induce production of IFNgamma in skin-test positive and not in skin-test negative healthy subjects. Five out of 13 patients with TB had a low antigen-specific IFNgamma production, suggestive of a minimal or absent specific T-cell response. For most purposes, cultures in closed vacutainer tubes are optimal. If one wishes to focus on T-cell cytokines or if only small volumes of blood are available, dilution of whole blood in culture medium before incubation in tissue culture wells may be preferable.
Blood Cell Count↗
Immunomodulation by n-3 polyunsaturated fatty acids.
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Adjuvants, Immunologic↗
Therapy of invasive fungal infections.
During the past decades, the incidence and severity of invasive fungal infections has been increasing. These events have lead to the development of new antifungal agents, and amphotericin B no longer is the standard therapy for a variety of invasive mycoses. Fluconazole has become the drug of choice for treatment of C. albicans infections in non-neutropenic as well as neutropenic patients. For treatment of cryptococcal meningitis, amphotericin B with flucytosine, followed by fluconazole consolidation therapy is used. For therapy of invasive aspergillosis, the lipid formulations of amphotericin B may be associated with reduced toxicity and allow for larger doses, although the efficacy of each of the formulations still has to be established in randomized trials. Finally, treatment modalities aimed at improving host defense mechanisms, including adjunctive therapy with rG-CSF for disseminated candidiasis and rG-CSF-elicited granulocyte transfusions, are under way.
Amphotericin B↗
Do only circulating pyrogenic cytokines act as mediators in the febrile response? A hypothesis.
The classical model of the pathogenesis of fever suggests that pyrogenic cytokines, produced by leucocytes in the bloodstream in response to exogenous pyrogens, represent the distal mediators of the febrile response. They are recognized at the level of the organum vasculosum of the lamina terminalis in the central nervous system, where they induce synthesis of prostaglandins representing the central mediators of the coordinated responses leading to fever. This classical model is challenged by studies showing inconsistencies between the febrile response and the cytokine pattern, as well as by data demonstrating paradoxical hyperfebrile reactions in knock-out mice lacking cytokines or cytokine receptors. Moreover, no measurable cytokine concentrations are to be found in a variety of specific patients groups with febrile conditions. There are recent data in the literature suggesting that alternative pathways may be involved in the induction of fever, ranging from the use of vagal fibres to transmit the signals leading to fever, to local production of cytokines at the level of the hypothalamus, or the use of membrane-bound cytokines as mediators. A multipathway mechanism for the induction of fever is suggested.
Animals↗
Increased susceptibility to systemic candidiasis in interleukin-6 deficient mice.
Interleukin-6 (IL-6) is a multifunctional cytokine that regulates multiple aspects of the innate immune response. It has been recently shown that endogenous IL-6 is crucial for an efficient defence against severe infections with Gram-negative and Gram-positive bacteria. The aim of the present study was to investigate the role of endogenous IL-6 in the defence against infection with the yeast Candida albicans. During experimental candidemia, IL-6 deficient mice (IL-6-/-) had a decreased survival and an increased fungal load in their organs when compared with IL-6+/+ controls, despite increased plasma concentrations of tumour necrosis factor-alpha (TNF), interleukin-1 alpha (IL-1 alpha) and IL-1 beta, IL-6-/- mice were not able to mount an efficient neutrophil response during the infection. When mice were rendered neutropenic by cyclophosphamide, neutropenic IL-6-/- mice were equally susceptible to C. albicans when compared to neutropenic IL-6+/+ mice, implying that neutrophils mediate the beneficial effect of endogenous IL-6. In conclusion, IL-6-/- mice are more susceptible to disseminated candidiasis, and the effect of IL-6 is most likely mediated by neutrophils.
Animals↗
Modulation of the pro- and antiinflammatory cytokines by amphotericin B.
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Amphotericin B↗
Fas-FasL interactions modulate host defense against systemic Candida albicans infection.
Fas-FasL costimulation modulates the production of proinflammatory cytokines, and MRL/lpr mice, which lack a functional Fas molecule, produce more proinflammatory cytokines. This study found that Fas-FasL interactions are involved in host defense against lethal infection with Candida albicans. Macrophages of MRL/lpr mice produced significantly more tumor necrosis factor and interleukin-1 after stimulation with C. albicans than did control MRL+/+ macrophages. Mortality of Fas-deficient mice with disseminated candidiasis was significantly lower than control animals' because of decreased fungal load and inhibition of the formation of invasive hyphae in their organs. Increased recruitment of neutrophils at the infection site appeared to be responsible for these effects. In contrast, phagocytosis and killing of C. albicans by neutrophils of MRL/lpr and MRL+/+ mice was similar. Absence of Fas-FasL interactions leads to increased cytokine production after C. albicans stimulation, protecting mice against disseminated candidiasis.
Animals↗
Infusion of lipoproteins into volunteers enhances the growth of Candida albicans.
Infusion of reconstituted high-density lipoproteins (rHDL) is being studied in clinical trials as an adjunctive therapy for gram-negative sepsis. Since no data are available on its possible effects in systemic candidiasis, we investigated the effect of rHDL infusion into volunteers on the growth of Candida albicans. C. albicans growth was 10- to 100-fold higher in the plasma of volunteers infused with 80 or 100 mg/kg rHDL than in plasma collected before infusion; administration of 60 mg/kg rHDL had marginal effects. In vitro, the isolated lipoprotein subfractions had a growth-promoting effect on C. albicans. These data suggest potential adverse effects of rHDL if infused into patients with systemic candidiasis. Thus, rHDL infusion into patients with sepsis caused by an unknown microorganism may be contraindicated.
Animals↗
Modulation of neutrophil function in host defense against disseminated Candida albicans infection in mice.
Neutrophils (PMNs) constitute the main mechanism of host defense against acute invasive and disseminated candidiasis. Recent studies have demonstrated that tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF) play an important role in the recruitment of PMNs at the site of invasive Candida infection. In the absence of either TNFalpha or IL-6, the course of experimental disseminated candidiasis is more severe, due to defective PMN recruitment. Treatment of mice with recombinant G-CSF (rG-CSF) leads to a significantly reduced mortality during disseminated candidiasis. The outgrowth of Candida albicans from the organs of rG-CSF-treated mice is significantly decreased. Treatment with the combination of rG-CSF and fluconazole has an additive effect on the reduction of fungal load in the organs. In subacute or chronic disseminated Candida infection, rG-CSF is less effective, indicating that neutrophil recruitment and activation are crucial in acute, life-threatening candidiasis, whereas other host defense mechanisms control the outcome of less overwhelming invasive Candida infection.
Animals↗
Aspergillus meningitis: diagnosis by non-culture-based microbiological methods and management.
The performance of antibody detection, antigen detection, and Aspergillus genus-specific PCR for diagnosing Aspergillus meningitis was investigated with 26 cerebrospinal fluid (CSF) samples obtained from a single patient with proven infection caused by Aspergillus fumigatus. Immunoglobulin G antibodies directed against Aspergillus were not detected by enzyme-linked immunosorbent assay in CSF or serum. The antigen galactomannan was detected in the CSF 45 days before a culture became positive, and Aspergillus DNA was detected 4 days prior to culture. Decline of the galactomannan antigen titer in the CSF during treatment with intravenous and intraventricular amphotericin B and intravenous voriconazole corresponded with the clinical response to treatment.
Aged↗
Treatment of fungal infections in surgical patients using conventional antifungals.
In surgical and intensive care units an alarming increase in the number of invasive fungal infections has been observed. This is partly due to temporal transferral of patients from hemato-oncological units or transplant units and partly to the enhanced use of corticosteroids and other immunosuppressants. Candida species have now become a common isolate in ill patients. Amphotericin B with or without flucytosine constituted the standard therapy for candidosis but similar response rates with less toxicity may be obtained with lipid and with fluconazole. Data on an improved outcome of candidemia if a central venous catheter is removed promptly are conflicting. Amphotericin B remains the standard therapy for other invasive mycoses; it is seldom possible to administer adequate doses and therefore the options and limitations of the triazoles and liposomal preparations should be explored.
Antifungal Agents↗
Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection.
Lipoproteins are able to neutralize bacterial lipopolysaccharide (LPS) and thereby inhibit the proinflammatory cytokine response. In a previous study, we demonstrated that hypercholesterolemic low density lipoprotein receptor knock-out (LDLr-/-) mice are protected against lethal endotoxemia and gram-negative infection. In the present study we investigated the susceptibility of apolipoprotein E knock-out mice (apoE-/-) to LPS and to Klebsiella pneumoniae. These mice have increased plasma lipoprotein concentrations in the very low density lipoprotein (VLDL)-sized fraction. Despite 8 -fold higher plasma cholesterol levels compared to controls, and in contrast to LDLr-/- mice, apoE-/- mice were significantly more susceptible to endotoxemia and to K. pneumoniae infection. Circulating TNFalpha concentrations after intravenously injected LPS were 4 - to 5-fold higher in apoE-/- mice, whereas IL-1alpha, IL-1beta, and IL-6 did not differ. This TNF response was not due to an increased cytokine production capacity of cells from apoE-/- mice, as ex vivo cytokine production in response to LPS did not differ between apoE-/- and control mice. The LPS-neutralizing capacity of apoE-/- plasma was significantly less than that of controls. Most likely, the absence of apoE itself in the knock-out mice explains the failure to neutralize LPS, despite the very high cholesterol concentrations.
Animals↗
Bacterial lipopolysaccharide binds and stimulates cytokine-producing cells before neutralization by endogenous lipoproteins can occur.
Lipoproteins are able to bind to lipopolysaccharide (LPS) and neutralize its deleterious effects. However, it is not clear why the LPS-binding capacity of circulating lipoproteins, which is 10- to 10 000-fold above the maximal LPS concentrations found in septic patients, is not sufficient to inhibit the effects of LPS during an infection, whereas infusion of exogenous lipoproteins has a potent inhibitory action. In this study, the kinetics of LPS-neutralization by VLDL, LDL, and HDL were investigated, at lipoprotein-to-LPS ratios found in severe Gram-negative sepsis. At least 4-8-h preincubation of LPS with either LDL or HDL were necessary to inhibit 50% of the LPS-induced TNF-alpha production by human peripheral blood mononuclear cells (PBMC), whereas after 24 h of preincubation LDL or HDL strongly inhibited the TNF-alpha synthesis (70-90%, P<0.01). VLDL was the least effective lipoprotein fraction. In contrast, FITC-LPS bound to PBMC much more rapidly, with 70% of the total binding after 30 min, and 90% after 1-h incubation. The increase of LDL or HDL concentrations up to 10-fold (as in experimental models of hyperlipoproteinaemia) was able not only to further decrease TNF-alpha production after long LPS-lipoproteins preincubation periods, but also to improve the kinetics of LPS neutralization. In conclusion, LPS binds and stimulates the mononuclear cells in circulation before neutralization by endogenous lipoproteins can occur. Additional increase in the lipoprotein-to-LPS molar ratio (e.g. by infusion of exogenous lipoproteins) accelerates the kinetics of LPS neutralization, and may be useful as adjunctive therapy in severe Gram-negative infections.
Dose-Response Relationship, Drug↗
Host impairments in patients with neoplastic diseases.
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Agranulocytosis↗
Delay in administering the first dose of antibiotics in patients admitted to hospital with serious infections.
The interval from the time of admission to the emergency room until the administration of antibiotics in patients presenting with a serious infectious disease was analysed. Fifty patients presumptively diagnosed in the emergency room as having a serious infection (respiratory tract, urinary tract, erysipelas, fever with neutropenia or bacteremia) needing immediate empirical antibiotic treatment were enrolled in the study. A median interval from time of admission to administration of antibiotics of 5 hours was determined (range 0.6-13.3 h). The interval was significantly shorter in patients admitted at night than in patients admitted during office hours (3.7 vs. 6.0 h, P< 0.05). There was no difference with respect to the presenting features, body temperature, laboratory values at presentation or number of cultures performed. In 41 of the 50 patients blood samples were taken for culture. More than 80% of the patients received an antibiotic chosen in accordance with hospital guidelines. The analysis revealed that the median delay of 5 hours before patients received their initial dose of antibiotic depended on several factors. Attempts to provide optimal antimicrobial therapy should thus concentrate not only on the correct choice and dosage of a drug but also on prompt institution of therapy.
Adult↗
LPS-induced cytokine production and expression of beta2-integrins and CD14 by peripheral blood mononuclear cells of patients with homozygous familial hypercholesterolemia.
It has been suggested that proinflammatory cytokines such as tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1), as well as adhesion molecules such as beta2-integrins and CD14, play a role in the pathogenesis of atherosclerosis. Familial hypercholesterolemia (FH) is an autosomal disease in which defective or absent LDL receptors are the cause for extreme LDL concentrations and early development of atherosclerosis. We studied lipopolysaccharide-induced cytokine production and the expression of adhesion molecules by mononuclear cells of three homozygous FH patients and compared them with first-degree relatives and healthy controls. There was a tendency towards increased cytokine production by cells of FH patients, whereas the expression of adhesion molecules was not modified compared to controls. In addition, LDL-apheresis inhibited IL-1 and TNF production and the expression of CD11a, CD11b, CD11c and CD14 by the mononuclear cells of FH patients and this may be an additional beneficial effect of LDL-apheresis apart of decreasing LDL concentrations.
Adolescent↗