[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.

Association between protective efficacy of anti-lipopolysaccharide (LPS) antibodies and suppression of LPS-induced tumor necrosis factor alpha and interleukin 6. Comparison of O side chain-specific antibodies with core LPS antibodies.

Two-core LPS antibodies, the rabbit J5 polyclonal antiserum and the human anti-lipid A IgM mAb HA-1A, did not improve the survival of mice challenged with E. coli O111 or P. aeruginosa 3, or with the LPS extracted from them, and did not decrease the incidence of Shwartzman reactions in rabbits challenged with O111 LPS. In contrast, O side chain-specific rabbit antisera were protective in these models. The protection afforded by O side chain-specific antisera against endotoxin lethality was associated with decreased LPS-induced serum TNF and IL-6 levels, whereas core LPS antibodies had no effect on TNF or IL-6 levels. The absence of reduction of LPS-induced cytokines levels by core LPS antibodies suggests that these antibodies are not able to prevent the interactions between LPS and target cells.

[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.

Single daily dose treatment of severe refractory infections with ceftriaxone. Cost savings and possible parenteral outpatient treatment.

Ceftriaxone sodium, a new cephalosporin with a very broad spectrum of action and a very long serum half-life, was administered to 127 patients in the treatment of 133 severe infections at our institution in Lausanne, Switzerland. Eighty infections had previously been treated unsuccessfully with other antimicrobials to which the pathogens were most often resistant. Sixty-five episodes were treated with two daily injections until there was an improvement in the patient's clinical condition, while 67 infections were treated from the start by a single daily injection. The results in the two groups were similar. One hundred fifteen infections (86%) were cured or improved, ten (8%) did not respond to therapy or recurred, and eight (6%) were not evaluable. The treatment was well tolerated, even by the 18 patients who received the drug for more than four weeks. The administration of a single daily dose instead of four doses as with standard antibiotic regimens produced a saving of Sfr 84,000 (+42,000) in the 127 patients. The single daily dose also made it possible to treat 25 of the 127 severely ill patients as outpatients, with a saving of Sfr 388,500 (+195,000) with respect to the hospital costs that would have been incurred for the same time period.

Tolerance study of ceftriaxone compared with amoxicillin in patients with pneumonia.

The safety of ceftriaxone was compared with that of amoxicillin in a randomized study of 91 patients with community-acquired pneumonia. The origin of infection was similar in the two groups. It was proven or probable Streptococcus pneumoniae in 50 percent of the patients and remained uncertain in 40 percent. Ninety percent of the patients who received ceftriaxone were clinically cured compared with 69 percent of those given amoxicillin (p less than 0.05). However, this difference was not apparent among the patients with proven or probable pneumococcal pneumonia. No severe clinical side effects were observed. Cutaneous reactions were more prevalent in the amoxicillin group, whereas mild diarrhea and mucosal candidiasis were more frequent in the ceftriaxone group. Reversible neutropenia was observed in two patients treated with ceftriaxone and none of those treated with amoxicillin.

High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group.

PURPOSE AND PATIENTS: We measured the serum concentrations of interleukin-6 (IL-6) in 70 patients with established septic shock caused predominantly by gram-negative bacteria. The aims of the study were to determine whether and for how long IL-6 was detectable in the circulation of these patients, to assess whether IL-6 levels were associated with patients' outcomes, and, finally, to examine the interplay between IL-6, tumor necrosis factor (TNF), interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN-gamma). RESULTS: IL-6 was detected in 64% of the patients at study entry but in only 18% on Day 1 and 2% on Day 10. Serum levels of IL-6 were higher (median: 3.5 ng/mL, range: less than 0.1 to 305 ng/mL) in patients dying of fulminant septic shock than in those surviving (median: 0.5 ng/mL, range: less than 0.1 to 135 ng/mL; p = 0.003) or in those with a transient reversal of shock but who ultimately died of a relapse of shock (median: less than 0.1 ng/mL, range: less than 0.1 to 12.5 ng/mL; p = 0.005). However, no cutoff values of IL-6 confidently predicted the outcome of an individual patient. The serum concentrations of IL-6 measured at study entry correlated with the duration of survival (r = -0.51, p = 0.004) and with the levels of TNF-alpha (r = 0.53; p less than 0.0001) but not with the levels of either IL-1 beta (r = 0.01, p = 0.90) or IFN-gamma (r = 0.06, p = 0.60). CONCLUSIONS: These results indicate that circulating levels of IL-6 are detectable in a majority of patients with gram-negative septic shock. Concentrations of IL-6 peaked near the onset of shock and rapidly decreased to undetectable levels within approximately 24 hours in most patients. Levels of IL-6 measured at study entry correlated with levels of TNF and with patients' outcomes. Yet, IL-6 does not appear to be a clinically useful laboratory test for predicting the outcome of an individual patient.

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.

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.

An extreme form of the hyperdynamic syndrome in septic shock.

We classified 41 patients in septic shock on the basis of cardiac index (CI) after volume expansion with plasma protein solution, in order to obtain adequate filling pressures. Five had decreased CI (less than 3.5 1/min per m2), 31 had moderately increased CI (3.5 - 7.0 1/min per m2) and 5 had extreme hyperdynamic shock with CI superior to 7.0 1/min per m2. Among the patients with increased CI, those with extreme hyperdynamic state (EHS) had lower total systemic and pulmonary arteriolar resistances (370 vs 658 and 52 vs 119 dynes X s X cm-5, respectively) and a higher stroke index (67 vs 46 ml/m2), in spite of similar right atrial pressures. In this latter group, blood lactate was higher (6.5 vs 2.1 mmol/l), acidosis was more severe and coagulation disorders more pronounced; all five patients maintained an extremely high CI until death, which supervened after a brief episode of sinus bradycardia. A similar clinical course was rarely observed in the remaining moderately hyperdynamic group, in which mortality rate was significantly lower (35%). Three of five patients with EHS (compared to 2 of 31 in the moderately hyperdynamic group) had liver cirrhosis, the fourth died of fulminant meningococcemia and the fifth had prolonged polymicrobial bacteremia before adequate treatment was begun. Thus, underlying liver disease or particularly severe and uncontrolled infection seems to predispose to EHS. It is concluded that septic shock with extremely high cardiac output and excessively low peripheral resistances represents a distinct subset with more severe metabolic and coagulation disorders, an unusual hemodynamic evolution and a particularly poor prognosis.

Immunotherapy with antibodies to core lipopolysaccharide: a critical appraisal.

The unknowns persisting in the understanding of the mode of action of anti-core lipopolysaccharide antibodies are discussed, and a study of two anti-lipid A monoclonal antibodies is reviewed. This article also critically analyzes the results of the recent clinical trials with monoclonal antibodies.

[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.

Anti-lipopolysaccharide antibodies in gram-negative bacteremia.

The experimental and clinical studies underlying the concept of cross-protection afforded by core lipopolysaccharides (LPS) antibodies are reviewed. These studies did not allow to clarify the epitope(s) and the effector mechanism(s) involved in the protection. Recently, two antilipid A IgM monoclonal antibodies, called E5 and HA-1A, have been investigated in patients with Gram-negative infections and a clinical picture of septicemia. E5 reduced the mortality of patients, bacteremic or not, but only as long as they were not in shock. A confirmatory study has been initiated. In contrast to E5, HA-1A protected patients in shock, but only when they were bacteremic at randomization. However, experimental studies have yielded contradictory results concerning the protective power of this antibody. Although the clinical studies suggest a beneficial effect of both antibodies in some patients, no definitive conclusions can be drawn until the extensive data will be published, and until further experimental investigations will have clarified the protective power of these antibodies.

[Indications for passive immunotherapy in infectious diseases]. / Indications de l'immunothérapie passive dans les maladies infectieuses.

The most important indications for passive immunotherapy in the field of infectious diseases are reviewed. Intramuscular immunoglobulins are useful in prophylaxis and treatment of diseases due to bacterial exotoxins and in prophylaxis of some viral infections. However, their efficacy against bacterial infections has not been demonstrated. Intravenous immunoglobulins have theoretical advantages in these infections. The few clinical studies performed in neonates and in patients of surgical intensive care units have suggested modest benefits. However, these studies did not allow to decide whether intravenous immunoglobulins have a role in these situations. Another approach still under investigation is to administer polyclonal antibodies directed against the central part of the endotoxin, the structure of which is well preserved among gram-negative bacteria. These antibodies have improved the survival of patients with gram-negative bacteremia or septic shock. When given prophylactically, they have reduced the incidence of gram-negative shock and related mortality in patients from surgical intensive care units. Further studies are in progress to determine the class and the precise specificity of these protective antibodies.

Monoclonal anti-endotoxin antibodies for the treatment of gram-negative bacteremia and septic shock.

The role of anti-endotoxin antibodies in the management of gram-negative bacteremia and the experimental and clinical studies on the cross-protection afforded by core LPS antibodies are reviewed. These studies did not achieve clarification of the epitope(s) and effector mechanism(s) involved in protection. Recently, two anti-lipid A IgM monoclonal antibodies, designated E5 and HA-1A, have been investigated in patients with gram-negative bacterial infections and clinical manifestations of septicemia. E5 reduced the mortality of patients if they were not in shock, whether they were bacteremic or not. A confirmatory study has been initiated. In contrast to E5, HA-1A protected patients whether they were in shock or not, but only when they were bacteremic at randomization. Although these studies suggest beneficial effects, the type of patients who may benefit from this expensive therapy should be further defined. Further investigations are needed to clarify the mechanisms of protection of these antibodies.

[Use of antibiotics for the prevention of bacterial pneumonia in surgical intensive care units]. / Utilisation des antibiotiques pour la prévention des pneumonies bactériennes dans les Unités de soins intensifs chirurgicaux.

Bacterial pneumonia is responsible for high mortality in surgical intensive care patients which is partly attributable to a high incidence of gram-negative bacillary pneumonia. In these patients alterations to epithelial cell surfaces promote colonization of the oropharynx by gram-negative bacilli. The alterations are directly related to the severity of the patients' underlying disease and not to the hospital environment. Prospective studies on prophylactic administration of antibiotics to decrease the incidence of nosocomial pneumonia are reviewed. In these studies antibiotic have been administered either locally in the respiratory tract or systemically by the i.v. route. In both cases a moderate decrease in the incidence of pneumonia was observed, but selection of resistant bacteria occurred. Pneumonia appearing despite antibiotic prophylaxis was difficult to treat and had a high mortality. Therefore, local or intravenous antibiotic administration for routine prophylaxis of pneumonia seems to do more harm than good in patients from intensive care units.

Controversies in the use of passive immunotherapy for bacterial infections in the critically ill patient.

Several preparations of standard immunoglobulins for intravenous use have been tested as adjunctive therapy for bacterial infections in premature neonates and in critically ill adults after major surgery, trauma, and burn. The use of intravenous immunoglobulins in these settings is controversial because the efficacy and cost-effectiveness of this treatment are still not definitively established. Specific preparations of immunoglobulins against Pseudomonas aeruginosa for intramuscular administration have shown promising efficacy, and preparations for intravenous administration are now under investigation. Cross-protection against a wide range of gram-negative infections has been attempted by the administration of antiserum to the core glycolipid of lipopolysaccharide prepared from volunteers immunized with the J5 mutant of Escherichia coli 0111. Treatment with this preparation improved the survival rate of patients with gram-negative bacteremia and, when administered prophylactically to high-risk surgical patients, prevented shock and death related to gram-negative infections. The mechanism of protection of the J5 antiserum is not clearly understood because of our inability to measure the actual protective antibody in polyclonal J5 antiserum. Thus, the preparation of readily available cross-protective hyperimmune immunoglobulins is hampered because there is presently no method of selecting appropriate donors or high-titered plasma pools.