[2011 news in infections diseases: selected readings]. / Quelques nouveautés en maladies infectieuses.

A study published in 1998 linking MMR vaccine and autism was recently retracted by the Lancet because the data were falsified. The impressive reduction of invasive pneumococcal diseases with the 7-valent pneumococcal conjugate vaccine is due to a more than 90% reduction in rates of infections due to vaccinal serotypes at the expense of a slight increase in non-vaccinal serotypes. Genes encoding resistance factors to several antibiotic classes were detected in 30000-year-old samples. New Delhi metallo-beta-lactamase 1 was frequently detected in street water in New Dehli. Azithromycin decreased COPD exacerbations in a select group of patients with COPD at the cost of more frequent small decrements in hearing. Cranberry juice did not prevent recurrent urinary tract infections. Some patients with persistent symptoms after Lyme disease had higher levels of anti-Borrelia antibodies than cured patients.

[Severe sepsis and septic shock]. / Sepsis severe et choc septique.

Severe sepsis and septic shock are frequent pathologies accounting for approximately 11% of all admissions in intensive care units (ICU). In the United States, between 1979 and 2000 the incidence of sepsis increased by 8,7% annually and septic shock) remains the second most frequent cause of death in non-coronary ICU. Although our understanding of the host defense mechanisms against infections and of the pathogenesis of septic shock have progressed during the last decade, these progresses have not yet yielded the anticipated advantages. Recent new therapeutic approaches, especially early-goal directed therapy, activated protein C (drotrecogin alpha activated), moderate doses of corticosteroids and intensive insulin therapy have given encouraging results.

[Evaluation of antibiotic prophylaxis in neutropenic patients with hematologic malignancies]. / Evaluation de la prophylaxie antibiotique chez les patients neutropéniques avec hémopathie maligne.

The benefits of oral prophylaxis for neutropenia have remained controversial up to now. We evaluated retrospectively the effect of antibiotic prophylaxis with ciprofloxacin and penicillin on the prevention of bacterial infections in 112 cases of prolonged neutropenia in adult patients treated for haematological malignancies. 41 patients received prophylaxis between December 1993 and November 1994 while 71 patients did not receive prophylaxis between December 1994 and November 1995. There were no significant differences between groups in age, sex, type or stage of haemopathy, type of chemotherapy and duration of neutropenia. The antibiotic prophylaxis reduced the number of overall infections (p = 0.05) and the number of gram-negative bacteraemias (p = 0.02). The median time to the onset of fever, the duration of fever, the duration of antibiotic treatment, the duration of hospitalization or admission to the intensive care unit, the number of serious complications or death were not influenced by antibiotic prophylaxis. The prophylaxis did not reduce the overall incidence of bacteraemia, of clinically documented infections or of fever of unknown origin. This retrospective study confirms that oral prophylaxis with ciprofloxacin and penicillin decreases the incidence of infections and, in particular, of gram-negative bacteraemia, but does not modify the overall morbidity and mortality in our patients. In view of the risk of emergence of bacterial resistance, these data do not support the routine use of oral antibiotic prophylaxis in neutropenic patients with haematological malignancies.

Treatment of sepsis: past and future avenues.

In recent years, the concept has emerged that the host's inflammatory response contributes substantially to the development of septic shock and organ failure. Experimental observations prompted large scale randomised clinical trials with a variety of agents such as glucocorticoids, ibuprofen, antiendotoxin monoclonal antibodies, antagonists of platelet-activating factor, of bradykinin or of interleukin-1 receptor, and monoclonal anti-tumour necrosis factor (TNF) antibodies or soluble dimeric TNF receptor fusion proteins. All these major studies of immunomodulators in sepsis have yielded disappointing results despite showing promise during preliminary clinical studies. However, these recent failures do not mean that septic shock will forever remain an insurmountable medical challenge. Many lessons have been learned from these studies. and certain mistakes in their study design will be avoided in the future. Our understanding of the pathophysiology of sepsis and septic shock is increasing markedly; potential new treatment strategies are available and could be explored to improve the outcome of patients with sepsis.

Cytokines, nitrite/nitrate, soluble tumor necrosis factor receptors, and procalcitonin concentrations: comparisons in patients with septic shock, cardiogenic shock, and bacterial pneumonia.

OBJECTIVES: To determine and compare the respective concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, soluble TNF receptors, nitrite/nitrate (NO2-/NO3-), and procalcitonin in the plasma of patients with septic shock, cardiogenic shock, and bacterial pneumonia without shock; and to assess the predictive value of these mediators in defining patients with septic shock. DESIGN: Cohort study, comparing normal volunteers (controls) and patients with septic shock, cardiogenic shock, and bacterial pneumonia. SETTING: A collaborative study among an intensive care unit, an emergency room, and three research laboratories. PATIENTS: Mediators were measured at various times in 15 patients with septic shock (during the shock phase and during the recovery phase), in seven patients with cardiogenic shock during the shock phase, and in seven patients with severe bacterial pneumonia on day 1 of admission. INTERVENTIONS: Blood samples were collected at various times during the course of the disease. MEASUREMENTS AND MAIN RESULTS: TNF-alpha values were highest in the acute phase of septic shock (53 to 131 pg/mL during septic shock), while patients with bacterial pneumonia had intermediate concentrations (32 pg/mL). TNF-alpha concentrations were normal in patients with cardiogenic shock. IL-6 concentrations were highest in patients with acute septic shock (85 to 385 pg/mL). However, in contrast to TNF-alpha concentrations, IL-6 concentrations were normal in patients with bacterial pneumonia and increased in patients with cardiogenic shock (78 pg/mL). Soluble TNF receptors were increased in all three groups vs. controls, with the highest increase in patients with septic shock. NO2-/NO3- concentrations were highest (72 to 140 mM) in patients with septic shock, and were < 40 mM in the other groups of patients. Procalcitonin concentrations were only markedly increased in patients with septic shock (72 to 135 ng/mL, compared with approximately 1 ng/mL in the three other groups). The best predictive value for septic shock was found to be the measurements of NO2-/NO3- and procalcitonin concentrations. CONCLUSIONS: These observations showed that increase of proinflammatory cytokines was a consequence of inflammation, not of shock. In this study comparing various shock and infectious states, measurements of NO2-/NO3- concentration and procalcitonin concentration represented the most suitable tests for defining patients with septic shock.

Sepsis and septic shock.

Focal infectious processes may produce a systemic syndrome whose description has been recently standardized by the definitions of sepsis, severe sepsis and septic shock. This classification should only be used as an adjunct to the microbiological and clinical diagnosis of a given infection. The incidence of sepsis and septic shock has been increasing over recent decades, but the ratio of gram-negative to gram-positive causative organisms has remained largely similar (most often between 1:1 and 3:2). Recent advances in understanding of the pathophysiology of sepsis and septic shock have made it possible to delineate more clearly the role of bacterial products such as lipopolysaccharide, exotoxins or cell wall fragments. These products are able either to directly trigger inflammatory pathways, or to stimulate target cells (such as monocytic cells, PMN or endothelial cells) to produce pro-inflammatory cytokines. Management of the infectious process itself with antibiotics, and with surgery if needed, is the cornerstone of the therapy of sepsis and septic shock. More recent approaches aim at inhibiting the bioactivity of bacterial or pro-inflammatory mediators. Up to now, however, none of these approaches has led to therapeutic modalities that can be applied routinely to patients.

Similarities and disparities between core-specific and O-side-chain-specific antilipopolysaccharide monoclonal antibodies in models of endotoxemia and bacteremia in mice.

We have previously described cross-reactive antilipopolysaccharide (anti-LPS), or anti-endotoxin, monoclonal antibodies (MAbs) which provide cross-protection in several systems of endotoxin bioactivity. The protective effects of the murine cross-reactive MAb WN1 222-5 (immunoglobulin G2a(kappa) [IgG/2a(kappa)]) and of its chimerized version, SDZ 219-800 [human IgG1(kappa)], have now been evaluated in lethality models against LPS from three different serotypes and in bacterial infection models. We confirmed the protective activity of the two MAbs in D-galactosamine-sensitized mice challenged with LPS of other E. coli serotypes (O18, O127, and O111). The protective effect correlated with the suppression of tumor necrosis factor formation. Furthermore, WN1 222-5 enhanced bacterial clearance of intravenously administered E. coli O111 bacteria, thus protecting mice from death. However, the MAbs were unable to provide protection in a peritonitis model (intraperitoneal inoculation). Our study, therefore, shows that LPS cross-reactive antibodies are capable of mediating cross-protection against LPS and bacteria but that the selected models have a clear influence on the results.

[Treatment of severe infections: should one always administer an aminoglycoside?]. / Traitement des infections sévères: faut-il toujours administrer un aminoglycoside?

Until recently, aminoglycoside antibiotics were the cornerstone for the treatment of severe infections. The rationale for using combination therapy containing beta-lactams and aminoglycosides was not only to broaden the antimicrobial spectrum but also to achieve enhanced bacterial killing by synergism and to prevent the emergence of antibiotic resistance. However, with the advent of new potent broad-spectrum and highly bactericidal antibiotics, the necessity of combining beta-lactams with aminoglycosides should be reassessed. This review questions the use of aminoglycosides in three severe infections frequently observed in intensive care units, nosocomial pneumonia, nosocomial sepsis and severe diffuse peritonitis. A review of the literature suggests that the addition of an aminoglycoside to a broad-spectrum beta-lactam does not improve the outcome in nosocomial pneumonia and severe diffuse peritonitis. However, the lack of large prospective studies in severe sepsis or septic shock makes it impossible to draw any conclusion about the addition of an aminoglycoside, and the administration of these agents must be decided on an individual basis.

Polyclonal intravenous immune globulin for prevention and treatment of infections in critically ill patients.

Infections remain the leading cause of death among patients admitted to intensive care units (ICU). Infections due to Gram-negative bacteria are both frequent and difficult to treat. The poor outcome of such infections has been attributed to the endotoxin. The high mortality rate related to Gram-negative sepsis has prompted the testing of new, adjunctive therapies to prevent and treat infections in critically ill patients. Immunotherapy or immunoprophylaxis have long been investigated in this context. Passive immunotherapy consists of the administration of immune plasma or serum, or standard or hyperimmune purified immune globulins. Several clinical studies using such preparations to treat critically ill patients are reviewed in this article. While two studies using hyperimmune plasma or serum appeared to be successful, two studies using hyperimmune globulin failed to show a beneficial effect in the treatment or the prevention of Gram-negative septic shock. Regarding the infusion of standard intravenous immune globulin (IVIG) two studies have demonstrated a substantial benefit in the prevention of severe infections; the reduction of nosocomial pneumonia recorded in both trials and the shortness of stay in ICU may also afford savings in hospital costs. The cost effectiveness of such prophylactic administration of IVIG is worthy of further investigation.

Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients.

Nosocomial pneumonia and sepsis, as well as severe diffuse peritonitis, must be treated early in order to prevent complications such as septic shock and organ dysfunctions. With the availability of new broad-spectrum and highly bactericidal antibiotics, the need of combining beta-lactams with aminoglycosides for the treatment of severe infections should be reassessed. A prospective randomized controlled study was performed to compare imipenem monotherapy with a combination of imipenem plus netilmicin in the empiric treatment of nosocomial pneumonia, nosocomial sepsis, and severe diffuse peritonitis. A total of 313 patients were enrolled, and 280 were assessable. The antibiotic treatment was successful in 113 of 142 patients (80%) given the monotherapy and in 119 of 138 patients (86%) given the combination (P = 0.19). The failure rates for the most important type of infection, i.e., pneumonia, were similar in the two groups, as well as the number of superinfections. While creatinine increase was associated with factors not related to antibiotic therapy for all eight patients of the monotherapy group, no factor other than the antibiotics could be found for 6 of the 14 cases of nephrotoxicity observed in the combination group (P = 0.014). Finally, the emergence of Pseudomonas aeruginosa resistant to imipenem occurred in 8 monotherapy patients and in 13 combination therapy patients. In conclusion, imipenem monotherapy appeared as effective as the combination of imipenem plus netilmicin for the treatment of severe infection. The addition of netilmicin increased nephrotoxicity, and it did not prevent the emergence of P. aeruginosa resistant to imipenem.

Pathogenesis and potential strategies for prevention and treatment of septic shock: an update.

Septic shock is mediated by complex interactions of cells, cytokines, and humoral pathways. Clinical therapeutic strategies aimed at inhibiting selected pathways have been efficacious in subsets of patients. Experimental studies focusing on the activities of single cytokines have contributed to the understanding of the complex pathophysiology of septic shock. More precise delineation of the roles of each mechanism contributing to pathogenesis will permit the identification of subsets of patients who might benefit from particular therapeutic strategies and will guide the development of additional approaches to prevention and treatment.

IFN-gamma involvement in the severity of gram-negative infections in mice.

The role of IFN-gamma in the regulation of inflammation leading to gram-negative septic shock is still poorly understood. IFN-gamma blockade has been shown to improve the survival of animals challenged with i.v. bolus injections of LPS and gram-negative bacteria. We have investigated a model of focal Escherichia coli infection leading to peritonitis and septic shock. Mice were challenged i.p. with an inoculum near the LD50. The addition of rIFN-gamma together with bacteria increased the mortality and the level of blood TNF-alpha and IL-6. Conversely blockade of IFN-gamma with a neutralizing mAb significantly improved the survival of the mice. This beneficial effect was not associated with a stringent decrease in blood bacterial counts and TNF-alpha and IL-6 levels in survivors. In this model, the protective effect of anti-IFN-gamma mAb contrasted with the ineffectiveness of a neutralizing anti-TNF-alpha mAb. These findings suggest that overproduction of IFN-gamma might have a more detrimental role than overproduction of TNF-alpha during focal gram-negative infections.

Short time exposure to lipopolysaccharide is sufficient to activate human monocytes.

Very little is known about early events in LPS binding and about the duration of LPS exposure required to activate monocytes. In the present study, we have investigated the kinetics of LPS binding to human monocytes and the time of exposure required to trigger the synthesis of TNF-alpha. We directly followed the binding of FITC-labeled LPS to monocytes by flow cytometry or confocal laser microscopy. LPS was able to bind to the cell surface within 1 min of exposure, and was internalized within 5 min. Equilibrium was reached within 15 min at all but the lowest LPS concentration tested (10 ng/ml). Binding was dependent on the presence of LPS-binding protein, supplied either as a plasma component or in purified form, and inhibited by an anti-CD14 mAb (MY4). Polymyxin B, an inhibitor of LPS-mediated activation, essentially abrogated the LPS-binding protein- and CD14-dependent binding of LPS to monocytes. Using either the anti-CD14 mAb or polymyxin B to block further LPS binding, we found that 5 to 10 min of exposure was sufficient to trigger maximal TNF-alpha release. Similarly, monocytes washed after 5 to 15 min exposure to eliminate LPS also produced high levels of TNF-alpha transcripts without further presence of LPS in the medium. We conclude that a few minutes of exposure to physiologically relevant concentrations of LPS are sufficient to trigger both maximal binding and activation of monocytes.

Competition between bactericidal/permeability-increasing protein and lipopolysaccharide-binding protein for lipopolysaccharide binding to monocytes.

The bactericidal/permeability-increasing protein (BPI) inhibits the lipopolysaccharide (LPS)-mediated activation of monocytes. Due to its inhibitory activity for various LPS, BPI has therapeutic potential in endotoxic shock. To be efficient in vivo, BPI should overcome the action of LPS-binding protein (LBP), a serum molecule that increases the expression of LPS-inducible genes via CD14 of monocytes, rBPI23, a recombinant fragment of BPI, prevented in a dose-dependent manner the binding and the internalization of LPS mediated by LBP. Consequently, rBPI23 also inhibited LPS-induced tumor necrosis factor (TNF alpha) synthesis from monocytes. LPS- and LBP-mediated activation of monocytes was totally inhibited when LPS was preincubated with rBPI23. Adding rBPI23 at the same time as LBP resulted in an important but partial inhibition of TNF alpha release, but this inhibition vanished with delaying the time of addition of rBPI23. These studies suggest that the inhibitory activity of BPI is related to its ability to compete with LBP for LPS.

Immunotherapy of endotoxemia and septicemia.

Neutralization of endotoxin (lipopolysaccharide, LPS) would be of considerable benefit in the treatment of Gram-negative sepsis. Administration of anti-LPS antibodies is an old approach which has been renewed by improvements in monoclonal antibody technology. The antibodies directed at the conserved core region of LPS or at the lipid A which have been studied in humans are discussed in this review. Some of these antibodies appeared to be protective in animal models or in clinical trials, but discrepant results have been reported and the mechanism of the postulated protection was not clarified. The polyclonal antibody preparations have given variable results in patients. The clinical studies of anti-lipid A monoclonal antibodies seemed promising because both antibodies appeared to protect subsets of patients. However, the studies gave discrepant results concerning the type of patients reported to benefit from the administration of these antibodies. One of these antibodies, E5, appeared to improve the survival of patients with Gram-negative sepsis provided they were not in shock, but a second trial failed to confirm this. The other antibody, HA-1A, appeared to protect patients with Gram-negative sepsis who were in refractory shock, but only when they were bacteremic. This antibody was recently released on the market in some european countries. However, the FDA agency decided that a confirmatory study should be done before it could consider to approve HA-1A because a careful reanalysis suggested that the observed differences were only of marginal statistical significance. Therefore, this type of treatment has not yet clearly been shown to benefit patients. More studies are needed to delineate the role of core LPS antibodies in the management of Gram-negative sepsis.

[Cytokines and severe sepsis]. / Cytokines et sepsis graves.

During severe sepsis syndromes, almost every gene coding for cytokines may be activated. The primary purpose of this activation is to defend the organism against infection, but sometimes these inflammatory mediators go out of control. The reasons why this may occur is unclear because the regulation of cytokines production is still poorly understood. Metabolic effects, production of endothelial adhesion molecules and triggering of neutrophils are some important consequences of cytokine overstimulation which may lead to the clinical picture of septic shock. The major cytokines involved in septic shock are tumor necrosis factor alpha (TNF) and interleukin-1 (IL-1). Both may induce lethal shock in experimental models. The effects of these 2 cytokines are difficult to differentiate from one another because they share many similar biological effects, one can induce the synthesis of the other, and they are strikingly synergistic with each other. gamma-interferon may amplify the inflammatory response by stimulating the cells of monocytic lineage and by increasing TNF-receptor expression, thus participating in the pathogenesis of the septic syndrome. The role of other cytokines is still poorly known. Clinical studies with anti-TNF monoclonal antibodies or with an IL-1 receptor antagonist are under way.

Purification and characterization of murine lipopolysaccharide-binding protein.

The serum protein lipopolysaccharide (LPS)-binding protein (LBP) seems to play an important role in regulating host responses to LPS. Complexes of LPS and LBP form in serum and stimulate monocytes, macrophages, or polymorphonuclear leukocytes after binding to CD14. Previous reports have described the structure and properties of LBP from human and rabbit sera. Since mice are used in some experimental models of endotoxemia or gram-negative bacterial infections, information is needed about the properties of murine LBP. Murine LBP was purified by ion-exchange chromatography and high-pressure liquid chromatography; its NH2-terminal sequence (TNPGLVTRIT) was very similar to those of human and rabbit LBPs (80 to 90% amino acid identity). Murine LBP resembled LBPs from other species in that it promoted the binding of LPS to monocytes and enhanced the sensitivity of monocytes to LPS at least 100-fold. Mouse LBP, like rabbit and human LBPs, was found to be an acute-phase protein. Further in vivo studies with mice and anti-CD14 or anti-LBP reagents should help determine the role of LBP in response to LPS challenges.

Anti-endotoxin antibodies and other inhibitors of endotoxin.

Neutralization of endotoxin (lipopolysaccharide) would be of considerable benefit in the treatment of Gram-negative sepsis. Administration of anti-lipopolysaccharide antibodies is an old approach that has been renewed by improvements in monoclonal antibody technology. Experimental and clinical studies of antibodies directed at the conserved core region of lipopolysaccharide or at the lipid A are discussed. Some of these antibodies appear to be protective in animal models or in clinical trials, but discrepant results have been reported and the mechanism of the postulated protection was not clarified. Despite the availability of a monoclonal anti-lipid A antibody on the market in some European countries, this type of treatment should still be considered of unclear value until further experimental and clinical studies have reinvestigated the protection afforded by these antibodies. The use of detoxified lipid A analogs with lipopolysaccharide antagonist properties is another promising strategy that is discussed briefly in this review. Recently, substantial progress has been made in understanding how lipopolysaccharide triggers the immune system. A family of proteins possessing lipopolysaccharide-binding sites has been discovered. These proteins have a striking homology in DNA sequence, but they have different functions. The biological role of these proteins is now being actively investigated. New strategies to improve the outcome of Gram-negative sepsis may result from this research.