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Biomedical subjects

B J Kullberg

Publications and source records attributed to B J Kullberg.

At least 55 records · Page 3Linked to original sources
PubMed2000

Earlier initiation of antibiotic treatment for severe infections after interventions to improve the organization and specific guidelines in the emergency department.

OBJECTIVE: To examine whether combined interventions improve the timely administration of antibiotic therapy and acquisition of material for culture from patients admitted to the emergency department with a serious infectious disease. METHODS: Guidelines and educational programs were developed to facilitate timely antibiotic administration: guidelines on handling patients with serious infections and on ordering immediate treatment, guidelines on obtaining culture samples, lectures to medical and nursing staff, improvement of availability of antibiotics in the emergency department, and removal of financial restraints on stocking and ordering of antibiotics. Fifty consecutive patients were evaluated after this series of interventions and compared with the results in 50 patients evaluated before the interventions. The interval from presentation to the emergency department until the administration of antibiotics, number of samples taken for microbiological investigations, and number of patients receiving a first dose of antibiotic at routinely scheduled drug distribution rounds were evaluated. RESULTS: The median time to the initial dose of antibiotics administered decreased from 5.0 hours to 3.2 hours (P = .04). The number of blood cultures obtained did not change. The percentage of sputum cultures obtained increased from 28% to 50%, and the percentage of urine cultures obtained increased from 50% to 100%. The percentage of patients whose first dose of antibiotic was delayed until a routinely scheduled drug distribution round decreased from 54% to 32% (P = .03). CONCLUSIONS: Combined interventions to expedite diagnostic and therapeutic actions through directed clinical practice guidelines and organizational measures are successful. This may lead to a substantial quality improvement in the process of care.

Aged↗
PubMed2000

Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia.

In addition to stimulating IFN-gamma synthesis, IL-18 also possesses inflammatory effects by inducing synthesis of the proinflammatory cytokines TNF and IL-1beta and the chemokines IL-8 and macrophage inflammatory protein-1alpha. We hypothesized that neutralization of IL-18 would have a beneficial effect in lethal endotoxemia in mice. IL-1beta converting enzyme (ICE)-deficient mice, lacking the ability to process mature IL-18 and IL-1beta, were completely resistant to lethal endotoxemia induced by LPS derived from either Escherichia coli or Salmonella typhimurium. In contrast, both wild-type and IL-1beta-/- mice were equally susceptible to the lethal effects of LPS, implicating that absence of mature IL-18 or IFN-gamma but not IL-1beta in ICE-/- mice is responsible for this resistance. However, IFN-gamma-deficient mice were not resistant to S. typhimurium LPS, suggesting an IFN-gamma-independent role for IL-18. Anti-IL-18 Abs protected mice against a lethal injection of either LPS. Anti-IL-18 treatment also reduced neutrophil accumulation in liver and lungs. The increased survival was accompanied by decreased levels of IFN-gamma and macrophage inflammatory protein-2 in anti-IL-18-treated animals challenged with E. coli LPS, whereas IFN-gamma and TNF concentrations were decreased in treated mice challenged with S. typhimurium. In conclusion, neutralization of IL-18 during lethal endotoxemia protects mice against lethal effects of LPS. This protection is partly mediated through inhibition of IFN-gamma production, but mechanisms involving decreased neutrophil-mediated tissue damage due to the reduction of either chemokines (E. coli LPS) or TNF (S. typhimurium LPS) synthesis by anti-IL-18 treatment may also be involved.

Animals↗
PubMed2000

Acellular components of Chlamydia pneumoniae stimulate cytokine production in human blood mononuclear cells.

Accumulating evidence suggest that infection with Chlamydia pneumoniae is associated with atherosclerosis, but the mechanisms involved remain unclear. Inflammation is important in the initial phase of atherogenesis, and cytokines are important in the initiation and progression of inflammation. The aim of this study was to assess the capacity of acellular components of C. pneumoniae to stimulate the production of pro-inflammatory cytokines and chemokines. Peripheral blood mononuclear cells were stimulated in vitro with sonicated C. pneumoniae. Significant amounts of TNF-alpha, IL-1, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) were produced. Inhibition of endotoxin using polymyxin B revealed that chlamydial endotoxin plays a minor role in the cytokine induction. Neutralization of TNF by TNF-binding protein and blockade of IL-1 receptors by IL-1 receptor antagonist revealed that TNF, IL-1 and IL-6 production was independent from each other, whereas IL-8 synthesis was strongly dependent on endogenous TNF and IL-1. In contrast, synthesis of MCP-1 and MIP-1alpha was dependent on endogenous TNF, but not IL-1. In conclusion, acellular components of C. pneumoniae are a potent stimulus for cytokine production, and this mechanism may have an important role in the inflammatory aspects of atherogenesis.

Cells, Cultured↗
PubMed2000

Interleukin-18 induces production of proinflammatory cytokines in mice: no intermediate role for the cytokines of the tumor necrosis factor family and interleukin-1beta.

Interleukin-18 (IL-18) is not only a co-stimulus for the induction of interferon-gamma but also has direct proinflammatory effects by inducing tumor necrosis factor-alpha (TNF-alpha), IL-1, IL-8 and IL-6. However, the cascade of events leading to induction of cytokines by IL-18 is unclear. The aim of the present study was to investigate whether murine IL-18 stimulates production of proinflammatory cytokines, and to assess whether induction of second-wave cytokines such as IL-6 by IL-18 is driven by intermediary induction of endogenous cytokines of the TNF family or IL-1beta. When mouse peritoneal macrophages were stimulated in vitro with recombinant murine IL-18, there was a dose-dependent induction of TNF, IL-1alpha, and IL-1beta. IL-6 synthesis was also strongly induced by IL-18 and, as revealed by studies in knockout mice, this production was not dependent on interactions between endogenous cytokines of the TNF/TNF receptor family: TNF-alpha, lymphotoxin-alpha, Fas/Fas ligand (L) or CD40/CD40L. Moreover, the induction of IL-6 was also independent of endogenous IL-1beta, as macrophages isolated from IL-1beta deficient mice produced normal amounts of IL-6 after stimulation with IL-18. In conclusion, murine IL-18 has pleiotropic proinflammatory activities by inducing production of TNF-alpha, IL-1alpha, IL-1beta and IL-6, which could have important consequences for the pathophysiology of infectious and autoimmune diseases.

Animals↗
PubMed2000

Apolipoprotein E-deficient mice have an impaired immune response to Klebsiella pneumoniae.

BACKGROUND: All lipoproteins are able to bind to bacterial lipopolysaccharide (LPS), thereby neutralizing its deleterious effects. However, we demonstrated, recently, that in the absence of apolipoprotein E (apoE), eight-fold increased very-low-density lipoprotein levels were not sufficient to protect apoE-deficient (apoE-/-) mice against LPS. During a live Gram-negative infection, mechanisms other than LPS-neutralization may play a role in the pathogenesis of the disease. In the present study we further examined the role of apoE in Gram-negative sepsis. METHODS: Survival, bacterial outgrowth in liver, spleen, kidneys and blood, and tumour necrosis factor-alpha (TNF-alpha) production were measured in apoE-/- mice and control C57BL/6J mice, after an intravenous infection with Klebsiella pneumoniae. RESULTS: Mice that lack apoE showed higher mortality in response to K. pneumoniae than control mice (90% vs. 23% respectively after 2 weeks). ApoE-/- mice had 10-100 times more outgrowth of the bacteria in their organs than controls. Furthermore, circulating TNF-alpha concentrations 90 min after a challenge, were almost twice as high in the apoE-/- mice compared to controls (13.0 +/- 2.9 ng mL-1 vs. 7.6 +/- 3.8 ng mL-1). When apoE-/- and control mice were rendered neutropenic, the discrepancy in survival and outgrowth of K. pneumoniae disappeared. CONCLUSIONS: The apoE-/- mice were more susceptible than control C57BL/6 mice to a K. pneumoniae infection. The absence of apoE may render these mice more susceptible, since this protein is of importance in the detoxification of lipopolysaccharide of Gram-negative bacteria. On the other hand, the phagocytic capacity of granulocytes seems to be decreased in apoE-/- mice, resulting in increased outgrowth and mortality.

Animals↗
PubMed2000

Increased production of interleukin 4 by CD4+ and CD8+ T cells from patients with tuberculosis is related to the presence of pulmonary cavities.

In tuberculosis, cellular immunity is considered to be responsible for the eradication of infection but also for damage of host tissues. In animal models, the balance between Th1-type cytokines, especially interferon (IFN)-gamma, and Th2-type cytokines, primarily interleukin (IL)-4, seems crucial for these effects. Reports on Th1-type and Th2-type cytokines in human tuberculosis are conflicting, and little is known about their role in tissue damage. Flow-cytometric assessment of cytokine responses was performed in human immunodeficiency virus (HIV)-seronegative patients with active tuberculosis and in healthy controls. Patients and controls showed no significant difference in expression of IFN-gamma. However, patients showed a striking increase in production of IL-4 in CD4+ as well as CD8+ T cells. Most remarkably, the expression of IL-4 was especially elevated in patients with cavitary tuberculosis. The Th2-type response with increased production of IL-4 in patients with tuberculosis may antagonize host defense and lead to tissue necrosis.

Adolescent↗
PubMed2000

Circulating cytokines as mediators of fever.

The febrile response is thought to be mediated by endogenous mediators, generically called "endogenous pyrogens." In the classical model of pathogenesis, induction of fever is mediated by the release of pyrogenic cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and interferons into the bloodstream in response to exogenous pyrogens. These mediators act at the level of the organum vasculosum of the lamina terminalis in the central nervous system (CNS), inducing synthesis of prostaglandins, which are the central mediators of the coordinated responses leading to fever. However, analysis of recent data suggests that multiple pathways may be involved in the induction of fever by cytokines, such as local cytokine production leading to signaling through vagal fibers, release of cytokine-induced circulating mediators at the tissue level, the use of membrane-bound cytokines as mediators, or the local release of cytokines in the hypothalamus by circulating activated monocytes. In addition, certain bacterial products can stimulate cytokine production directly at the level of hypothalamus, probably by activation of Toll-like receptors. A multipathway mechanism for the induction of fever is therefore suggested.

Central Nervous System↗
PubMed2000

Selective digestive decontamination in patients in intensive care. The Dutch Working Group on Antibiotic Policy.

Selective digestive decontamination (SDD) is the most extensively studied method for the prevention of infection in patients in intensive care units (ICUs). Despite 27 prospective randomized studies and six meta-analyses, routine use of SDD is still controversial. In this review, we summarize the available scientific information on effectiveness of SDD in ICU patients. The effects of SDD have been studied in different combinations of the concept, using different antibiotics. Comparison of the individual studies, therefore, is difficult. In most studies, SDD resulted in significant reductions in the number of diagnoses of ventilator-associated pneumonia. However, incidences of ventilator-associated pneumonia in control groups ranged from 5% to 85%. Moreover, these reductions in incidences of ventilator-associated pneumonia in individual studies were not associated with improved patient survival, reductions of duration of ventilation or ICU stay, or reductions in antibiotic use. The numbers of patients studied are too small to determine effects on patient survival. Although two meta-analyses suggested a 20% mortality reduction when using the full concept of SDD (topical and systemic prophylaxis) these results should be interpreted with caution. Formal cost-benefit analyses of SDD have not been performed. SDD is associated with the selection of microorganisms that are intrinsically resistant to the antibiotics used. However, the studies are too small and too short to investigate whether SDD will lead to development of antibiotic resistance. As long as the benefits of SDD (better patient survival, reduction in antibiotic use or improved cost-effectiveness) have not been firmly established, the routine use of SDD for mechanically ventilated patients is not advised.

Antibiotic Prophylaxis↗
PubMed2000

Modulation of LPS-, PHA- and M. tuberculosis-mediated cytokine production by pentoxifylline and thalidomide.

Pentoxifylline and thalidomide have been used to downregulate the production of TNF-alpha in several disease entities including mycobacterial infections and autoimmune disorders. These drugs inhibit the production of TNF-alpha by different mechanisms, but little is known about possible synergism and modulation of other cytokines. Pentoxifylline and thalidomide inhibited the in vitro stimulated production of TNF-alpha, IL-1 beta and IFN-gamma in blood mononuclear cells. No significant modulation of antiinflammatory cytokines was found. When used together, these agents demonstrated additive inhibition, but no synergism. Modulation of cytokine response was similar when different stimuli were used, including M. tuberculosis in tuberculin-positive individuals. Therefore, the balance between efficacy and toxicity may be more favourable when pentoxifylline and thalidomide are used together instead of either drug alone. Clinical studies are needed to establish this advantage when anti-cytokine strategies are considered.

Cells, Cultured↗
PubMed2000

Combined treatment: antifungal drugs with antibodies, cytokines or drugs.

To improve present results with antifungal drugs, modulation of the host immune response is being explored. Human phagocytes of various lineages work cooperatively in vitro with antifungal drugs to inhibit or kill fungal pathogens, and this activity is augmented by several recombinant cytokines. Monoclonal antibodies against the cryptococcal capsule have been shown to act as an adjunct in enhancing the outcome of cryptococcosis in animal models. This approach is now being pursued in systematic clinical trials. In experimental candidiasis, several manipulations of the immune system, via administration of cytokines, gene deletion or antibodies to cytokines, have been shown to significantly affect survival and fungal clearance in vivo. This approach has already been demonstrated to be of benefit with recombinant human granulocyte-colony stimulating factor adjunct therapy of human candidiasis. Combining antifungal drugs of different classes may enhance their therapeutic effect.

Animals↗
PubMed1999

[Choice of antibiotics in uncomplicated cystitis; application of 'system of objectified judgement analysis' (SOJA) method].

OBJECTIVE: To determine the drug of choice for the treatment of uncomplicated cystitis. METHOD: Drug selection was performed by means of the so-called 'system of objectified judgement analysis' (SOJA) method by a working group of 11 persons. The following selection criteria were used: pharmacokinetics, interactions, probability of hitting (the probability that the microorganism is sensitive to the antibiotic), development of resistance, specific use in urinary tract infections, efficacy, side effects, dosage-frequency, duration of treatment, cost and documentation. The following drugs were included in the study: amoxicillin (with or without clavulanic acid), nitrofurantoin, sulfamethizole, trimethoprim, co-trimoxazole, ciprofloxacin, norfloxacin, ofloxacin and fosfomycin trometamol. RESULTS: Fosfomycin and nitrofurantoin slow release showed the highest scores. The main selection criteria that determined the selection of a drug were especially specific use in urinary tract infections, development of resistance, probability of hitting and cost. CONCLUSION: Fosfomycin and nitrofurantoin slow release best fulfill the requirements for drugs in the treatment of uncomplicated cystitis. No comparative studies have been performed with the 3-day treatment of uncomplicated cystitis with nitrofurantoin slow release or with trimethoprim. Fluoroquinolones play no important part in the treatment of uncomplicated cystitis, mainly because of the risk of development of resistance.

Anti-Infective Agents↗
PubMed1999

[Clinical results and costs due to improved antibiotics policies].

Major reasons to conduct antibiotic policies are to improve the quality of patient care, to limit the emergence of resistance, and to contain costs. Many studies have addressed overconsumption and misuse of antibiotics. Studies have shown a correlation between antibiotic use in hospitals and the development of microbial resistance. Recommendations for the content and management of future antibiotic policy strategies in hospitals include educational programmes, consultation by infectious diseases physicians, restriction of the formulary, timely narrowing of empirical broad spectrum therapy ('streamlining'), and automatic stop orders. A recent study in a Dutch university hospital revealed overconsumption of antibiotics for prophylaxis in surgery and undertreatment with antibiotics in internal medicine departments. Intervention resulted in better compliance with guidelines, reduction of the consumption of antibiotics in surgical prophylaxis, and cost containment. However optimation of antimicrobial therapy also sometimes resulted in an increase of antimicrobial drug consumption.

Anti-Bacterial Agents↗
PubMed1999

[Cytokines and immunotherapy in infectious diseases].

Cytokines are essential mediators in infection and inflammation. Almost all cytokines have not only positive but also noxious effects: the proinflammatory cytokines released during severe infections in high concentrations lead to organ damage and death. The antagonistic anti-inflammatory cytokines inhibit the defense against infections. Immunotherapy through modulation of the cytokine response may aim at inhibition of the proinflammatory and reinforcement of the anti-inflammatory cytokine response, so as to limit the damage of inflammation. In patients with sepsis this has so far been little successful, probably owing to the multiple effects of the cytokines. Inhibition of proinflammatory cytokines was successful, on the other hand, in patients with rheumatoid arthritis or Crohn's disease. Another possibility is to aim, on the contrary, at reinforcement of the proinflammatory and inhibition of the anti-inflammatory cytokine response, to strengthen the resistance of the host. This has given favourable results in a limited number of infections.

Adjuvants, Immunologic↗
PubMed1999

Increased susceptibility of TNF-alpha lymphotoxin-alpha double knockout mice to systemic candidiasis through impaired recruitment of neutrophils and phagocytosis of Candida albicans.

TNF-alpha and lymphotoxin-alpha (LT) are members of the TNF family, and these cytokines play crucial roles in the defense against infection with Candida albicans. The aim of the present study was to investigate the role of endogenous TNF and LT during disseminated candidiasis in TNF-/-LT-/- knockout mice. The TNF- and LT-deficient animals had a significantly increased mortality following C. albicans infection compared with control mice, and this was due to a 10- to 1000-fold increased outgrowth of the yeast in their organs. No differences between TNF-/-LT-/- mice and TNF+/+LT+/+ were observed when mice were rendered neutropenic, suggesting that activation of neutrophils mediates the beneficial effects of endogenous TNF and LT. Histopathology of the organs, combined with neutrophil recruitment experiments, showed a dramatic delay in the neutrophil recruitment at the sites of Candida infection in the TNF-/-LT-/- mice. Moreover, the neutrophils of deficient animals were less potent to phagocytize Candida blastospores than control neutrophils. In contrast, the killing of Candida and the oxygen radical production did not differ between neutrophils of TNF-/-LT-/- and TNF+/+LT+/+ mice. Peak circulating IL-6 was significantly higher in TNF-/-LT-/- mice during infection. Peritoneal macrophages of TNF-/-LT-/- mice did not produce TNF, and synthesized significantly lower amounts of IL-1alpha, IL-1beta, IL-6, and macrophage-inflammatory protein-1alpha than macrophages of TNF+/+LT+/+ animals did. In conclusion, endogenous TNF and/or LT contribute to host resistance to disseminated candidiasis, and their absence in TNF-/-LT-/- mice renders the animals susceptible through impaired recruitment of neutrophils and impaired phagocytosis of C. albicans.

Animals↗
PubMed1999

[Toxic shock-like syndrome caused by streptococci].

Since the mid-eighties an increase of severe infections with invasive group A streptococci (GAS) has been noticed throughout the world, not only in the elderly but in healthy adults as well. The acute presenting infection starts with fever, enanthema, generalised erythema, rapidly progressing into shock and multiorgan failure, and is called streptococcal toxic shock syndrome (STSS). Despite surgical and antibiotic therapy with penicillin and clindamycin the mortality is high. There are as yet insufficient data in patients with STSS to decide between penicillin en clindamycin. Intravenous administration of high dose gammaglobulin, advocated in the USA, might neutralize the exotoxins, but the effectiveness of this therapy has not been established yet.

Adult↗
PubMed1999

[European strategy for control of resistance to antibiotics].

The problem of international spread of bacterial resistance requires development of a strategy at worldwide or at least at European level. Clinically relevant monitoring systems for resistance and use of antibiotics have to be implemented to support the guidelines on prescription of antibiotics. Every hospital should establish an 'antibiotics team' controlling the prescription of antimicrobials and the observance of local formulary agreements. Veterinary use of growth promoting antimicrobials related to substances used in human medicine should be terminated. Future research should be aimed at resolving the problem of resistance to antimicrobials.

Animals↗