Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 11, Issue 4, 2011

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Real-time PCR methods are able to rapidly detect a wide panel of microorganisms. These methods are of interest in critically ill patients to determine the presence of bacteria in the blood and other biological samples, especially in those patients with prior antimicrobial treatment. In intensive care unit (ICU), the LightCycler SeptiFast (LC-SF) Test provides 1.5 to 2 fold higher positivity rate compared with conventional blood cultures. Although identification of the bacterium by LC-SF is rapid and sensitive, susceptibility test could not be performed using this technique, except the methicillin- resistance for Staphylococci. The conventional cultures remain necessary for samples in ICU because of the high incidence of multidrug-resistant bacteria and the need for antimicrobial susceptibility of the bacterium to treat the patient correctly. A negative result for a Gram positive or negative bacterium allows deescalating the initial antimicrobial treatment, and decreasing the pressure of selection. Moreover, it is necessary to understand and interpret a DNA signal knowing that a dead bacterial material may be detected in a patient without any infection. What is the clinical relevance of bacterial DNA present in the blood and does the DNAemia found reflect true infection? Cost-effectiveness of the real-time PCR should be determined. Meanwhile, this test should be restricted to severe clinical situations, especially ICU patients with severe sepsis. In the future, real-time PCR tests should include more pathogens and antimicrobial resistant targets.

Infection, inflammatory response, activation of coagulation cascade and sepsis are tightly interconnected. In the initial phase, sepsis is characterized by a pro-inflammatory state, while in the late phase, by an anti-inflammatory state which favors cytomegalovirus reactivation. Cytomegalovirus infection would accentuate the sepsis-induced immunologic effects increasing the risk for other infections. The rate of CMV infection is 17% in critically ill nonimmunocompromised patients, up to 30% in hematopoietic stem cell transplant and up to 60% in solid organ transplant recipients. Cytomegalovirus infection in critically ill patients is associated with prolonged ventilator support, nosocomial infections, prolonged hospital and/or ICU stay and increased mortality. In immunocompromised patients, cytomegalovirus causes direct effects (viral syndrome, pneumonia, meningo-encephalitis, and gastro-intestinal tract involvement) and indirect (immunomodulatory) effects. These indirect effects would predispose the patients to secondary infections, delay immune recovery after hematopoietic stem cell transplant, and increase the risk of EBV-related B-cell lymphoproliferative disease and allograft rejection. Cytomegalovirus serology is not useful for the diagnosis of active infections. Cytomegalovirus culture is impractical for clinical purposes. The shell vial assay has low sensitivity. pp65 antigen is a sensitive and specific diagnostic method. Real-time PCR is more sensitive and specific (earlier detection) than pp65 antigen test and it is a more reliable marker to monitor the clearance of viremia. Ganciclovir and valganciclovir are the first-line antiviral therapies for the treatment of immunocompromised patients, while foscarnet and cidofovir are reserved mainly for treatment of ganciclovir-resistant cytomegalovirus infections.

Hospital-acquired infections (HAI) represent the most common adverse event in the intensive care unit (ICU). Their prevalence is high and they are associated with increased morbidity and mortality. The environment plays a central role in the transmission of hospital-acquired pathogens (HAP) and in the pathogenesis of HAI. Many bacteria, especially multidrug resistant ones, can survive for several months in the hospital environment in particular in areas close to the patients. It has been proven that pathogens are transmitted from the environment to the patients. Many studies have concluded that current cleaning methods are microbiologically ineffective. This failure concerns daily cleaning as well as terminal cleaning after patient discharge. It has been demonstrated that improvements in environmental cleaning are associated with a decrease in the rate of HAP and of HAI. New cleaning methods could enhance hospital cleaning efficiency. Three new technologies seem promising because they are microbiologically effective, easy and safe to use: (1) hydrogen peroxide vapor and (2) UV light decontamination are used for terminal cleaning. These techniques are effective even in difficultly accessible areas. (3) ultramicrofibers which can be associated with a copper-based biocide can be used for daily cleaning. Other methods such as ozone, steam or high-efficiency particulate air filtration are not efficient enough to be considered serious contenders for the improvement of the quality of the hospital environment. These new technologies have not been yet linked to a decrease in the prevalence and the incidence in HAP and HAI. It remains difficult to justify the extra-cost associated with these new methods until more studies can confirm their effectiveness in the management of HAI.

The role of antibiotic pressure in the selection of antibiotic-resistant bacteria is still under debate in the scientific community and often confounded by scarce data on antibiotic usage. Several studies demonstrated that prior antibiotic exposure is likely to increase patient's colonization and infection by antimicrobial-resistant bacteria. Of even more concern is the significant mortality associated with these infections, in particular in critically ill patients. Therefore, the control of antibiotic usage in intensive care units (ICUs) is of paramount importance. Antibiotic stewardship programmes (ASP) have been demonstrated to represent a useful intervention to reduce the inappropriate antibiotic usage in hospitalized patients. A few trials were performed in ICU population with positive results. The major risk we foresee for the implementation of ASP for ICU patients is the lack of consideration of local ecology and strict quality indicators. The development of new pattern of antimicrobial resistance might be ascribed to an inappropriate ASP. European networks to define best strategies and antibiotic-care bundles need to be supported at national and international level. To optimize antibiotic use in the ICU and to fight against the spread of resistance, it is extremely important to adopt a multifaceted approach including ASP.

Several forms of supportive techniques for respiration in intensive care units (ICU) are currently available. The most widely used is invasive mechanical ventilation through the use of an endotracheal tube (ETT). ETTs are proved to be important contributors to the pathogenesis and development of ventilator-acquired pneumonia (VAP) as artificial airways interfere with a number of respiratory tract defence mechanisms and facilitate bacterial colonisation of the tracheobronchial tree. The occurrence of VAP is known to be one of the leading cause of morbidity and mortality in ICUs. On that basis, non-invasive techniques have been developed through the use of patient-ventilator interfaces in the form of facial masks which allow the development of ventilatory modalities working in synchrony with the patient. The purpose of this review is to examine the impact of non-invasive ventilation on the occurrence of ICU-acquired infections, most likely VAP, when used as an alternative for endotracheal intubation or when applied after early extubation. Regarding the reduction of endotracheal intubation, many studies have confirmed the net benefit of using non-invasive ventilation, mostly in chronic obstructive pulmonary diseases with acute hypercapnic ventilatory failure, in cardiogenic pulmonary edema, and in selected populations such as immunocompromised patients. Additionally, some studies have demonstrated a substantial benefit on hospital mortality. Early extubation with immediate application of non-invasive ventilation as a method to wean patients from invasive ventilation has shown a significant effect on hospital mortality. Overall, in our experience, patients with chronic obstructive pulmonary disease with hypercapnic acute respiratory failure are most likely benefiting from non-invasive ventilation either in the acute setting or during the immediate post-extubation phase. Acute cardiogenic patients must also receive primary respiratory non-invasive support. For immunocompromised patients, given the broad range of immunosuppression settings, the underlying condition should guide the decision of applying non-invasive support or not in a case by case approach.

P. aeruginosa is the bacteria most commonly responsible for hospital-acquired and ventilator-associated pneumonia. Numerous factors are encoded in its genome, and they explain its high virulence. P. aeruginosa also develops a quorum sensing (QS), which coordinates the expression of these factors. The type III secretion system, a needle-complex, allows exotoxin injections into eukaryotic cells and is involved in the pathogenesis of acute pneumonia. This pathogen develops a high level of resistance to all antibiotics, which leads to a shortage of treatment options for many patients. Thus, new preventive or therapeutic approaches are in development. Immunotherapy that uses monoclonal antibodies has been successfully tested in blocking the type III secretion system (anti-PcrV) or helping immune cells phagocytose P. aeruginosa. Inhibiting the quorum sensing has also been efficacious in vitro and in vivo. New antibacterial peptides may enlarge the panel of treatments in the near future. However, current treatment for patients still relies on antibiotics. The development of resistance to all classes of available antibiotics leads to colistin revival with good clinical results. Topical delivery through aerosol could allow for the increase in the antibiotic concentration inside the infection site while limiting its systemic toxicity. Finally, Candida airway colonization has been found to be associated with P. aeruginosa-associated pneumonia in ventilated patients. In addition to targeting the bacteria, reducing Candida airway colonization may also decrease the incidence of such infections.

Aim: To review available evidence for the role of adjunctive therapies in severe pneumonia. Methods: We focused on therapies that have attracted recently interest such as glucocorticosteroids (GCs), statins and recombinant activated protein-C. Results: Experimental animal and human studies showed that GCs are able to modulate the inflammatory response and may offer a benefit in patients with severe sepsis. Randomized trials in pneumonia are few, mostly limited in septic shock and ARDS patients. Recombinant activated protein C is a potent anticoagulant and profibrinolytic enzyme which can inhibit the systemic inflammatory response. Available data, although limited, showed that activated protein C can reduce mortality in severe sepsis, especially in severe pneumonia due to S. Pneumoniae. Statins have pleiotropic properties which can affect the inflammatory cascade. The use of statins has been found to be associated with decreased mortality in some studies with pneumina whereas the use of statins was associated with increased risk of death in others. However, data come from observational or retrospective studies. Conclusion: Treatment with GCs may modulate the inflammatory response in critically ill patients with pneumonia but a clear effect of steroids on survival is debatable. The administration of GCs should be considered in patients with severe pneumonia when vasopressor dependent septic shock. Activated protein-C may be considered in patients with severe CAP or HAP and sepsis or organ failure. The role of statins in the management of severe pneumonia remains controversial until data from clinical trails will be available.

Infection is a major cause of morbidity and mortality in intensive care units (ICU). The impact on prognostic of an inadequate antibiotic therapy is well established. The problem is due to the growing spread of resistant microorganisms, including both Gram-negative and Gram-positive pathogens, especially in the case of ICU-acquired infections. In this context, antibiotics with broad spectrum activity are usually required. Moreover, these antibiotics should reach high concentrations in tissues, especially in lungs, and should exert a bactericidal activity for the most severely ill patients, especially those with bloodstream infections. A frequent problem in clinical practice is the lack of data validating their use in the context of critically ill patients. In the present article, we review the newest antibiotics that could be of interest for severe ICU-acquired infections: tigecycline, moxifloxacine, the newer carbapenems, linezolide and daptomycine. We discuss their approved indications and identify the fields in which they could be used to treat infections acquired in the ICU.

Microaspiration of contaminated oropharyngeal secretions and gastric contents frequently occurs in intubated critically ill patients, and plays a major role in the pathogenesis of ventilator-associated pneumonia. Risk factors for microaspiration include impossible closure of vocal cords, longitudinal folds in high-volume low-pressure polyvinyl chloride cuffs, and underinflation of tracheal cuff. Zero positive end expiratory pressure, low peak inspiratory pressure, tracheal suctioning, nasogastric tube and enteral nutrition increase the risk for microaspiration. Other patient related factors include supine position, coma, sedation, and hyperglycemia. Technetium 99 labelled enteral feeding is probably the most accurate marker of microaspiration in critically ill patients. However, use of this radioactive marker is restricted to nuclear medicine departments. Blue methylene is a reliable qualitative marker of microaspiration. However, fiberoptic bronchoscopy is required to diagnose microaspiration of blue dye in ICU patients. Quantitative pepsin measurement in tracheal aspirates is accurate in diagnosing microaspiration of gastric contents in critically ill patients. In addition, this marker is easy to use in routine practice. However, pepsin should be detected rapidly after aspiration. In vitro, and clinical studies suggested that semirecumbent position, polyurethane cuffs, positive end expiratory pressure, low-volume low-pressure cuff, and continuous control of cuff pressure were efficient in reducing microaspiration in ICU patients. Other preventive measures such as subglottic aspiration, tapered shape cuff, guayule latex cuff, lateral horizontal patient position, gastrostomy tube, and postpyloric feeding require further investingation.