Reinaldo Salomão

Device-Associated Nosocomial Infections in 55 Intensive Care Units of 8 Developing Countries

Context We know little about medical deviceassociated infections in developing countries. Contribution Prospective surveillance of 21069 patients who were hospitalized in 55 intensive care units in 46 hospitals in Central and South America, India, Morocco, and Turkey showed high rates (22.5 infections per 1000 intensive care unit days) of device-associated infections. Infections included ventilator-associated pneumonia (24.1 cases/1000 ventilator days), central venous catheterrelated bloodstream infections (12.5 cases/1000 catheter days), and catheter-associated urinary tract infections (8.9 cases/1000 catheter days). Eighty-four percent of Staphylococcus aureus infections were caused by methicillin-resistant strains, 51% of Enterobacteriaceae isolates were ceftriaxone-resistant, and 59% of Pseudomonas aeruginosa isolates were fluoroquinolone-resistant. Implications Medical deviceassociated infections pose major risks in developing countries. The Editors Surveillance of health careassociated infections, especially in high-risk hospital settings, such as the intensive care unit (ICU) (1, 2), has become an integral feature of infection control and quality assurance in all U.S. hospitals. The Centers for Disease Control and Prevention (CDC) Study of the Efficacy of Nosocomial Infection Control (SENIC) Project (3) showed that surveillance can help prevent health careassociated infections. Standards for institutional surveillance have been adopted in the United States (1), the United Kingdom (4), Australia (5), Canada (6), and Germany (7). A growing body of literature has shown that health careassociated infections are a major cause of patient illness and death in developed countries (8, 9). Device-associated infections, particularly ventilator-associated pneumonia (1012), central venous catheter (CVC)associated bloodstream infections (1315), and catheter-associated urinary tract infections (16, 17), pose the greatest threat to patient safety in the ICU (18). Surveillance of health careassociated infection has been standardized by the CDCs National Nosocomial Infection Surveillance (NNIS) System by providing simple unambiguous definitions, especially for device-associated infections (1921). Targeted surveillance and calculation of device-associated infection rates per 1000 device days allows benchmarking with similar other hospitals and detection of unique institutional problems that need redress. Most published studies of ICU-acquired infections have come from hospitals in industrialized western countries (1, 8, 1019, 22, 23). Relatively few data have been reported from developing countries (9, 2427), especially rates of device-associated infections by using standardized definitions. We report the initial findings of an International Nosocomial Infection Control Consortium (INICC) surveillance study from January 2002 through December 2005. The consortium was established by Dr. Rosenthal in 1998 when selected hospitals in Latin America began collecting surveillance data on health careassociated infections for inclusion in a regional database. Consortium hospitals provide general medical and surgical inpatient services to adults and children who require short-term care. All data from the participating hospitals were collected by using standardized NNIS System protocols and definitions (1921). The consortium has initially focused on surveillance and prevention of device-associated infections in adult and pediatric ICUs and high-risk nurseries. Methods Setting Most current participating hospitals and ICUs joined the consortium since 2002 after hearing Dr. Rosenthal (the INICC chairman) speak in their country or after learning about the INICC from its Web site (www.inicc.org), but some hospitals were actively solicited. Study data were collected between 2002 and 2005 in 55 ICUs in 46 hospitals from 8 developing countries: Argentina, Brazil, Colombia, India, Mexico, Morocco, Peru, and Turkey. The consortium requires each member hospital to have an infection control team, comprising a physician and an infection control practitioner, and a microbiology laboratory that can isolate and identify aerobic pathogens from clinical cultures and perform in vitro susceptibility testing by using standardized methods (28). The person responsible for surveillance in each institution must have had at least 3 years of infection control experience (Table 1). In most of the hospitals, the team had access to electronic patient data. Table 1. Features of the International Nosocomial Infection Control Consortium Hospitals and Intensive Care Units* The institutional review board at each hospital approved the study protocol. Patient confidentiality is protected by coding the recorded information, with patient identities available only to the individual hospitals infection control team. Infection Control Practices at the Study Sites Hand hygiene adherence varies in the different countries and ICUs, ranging from 20% to 70% (2932). A recent study in all participating ICUs found a 50% overall rate of hand hygiene adherence (32), similar to that of recent studies in the United States and Europe (33). Use of sterile dressings on CVC insertion sites also ranges widely (29, 34, 35). Open infusion systems (rigid or semirigid containers that must admit air to empty) rather than closed systems (fully collapsible containers that do not require any external vent to empty the solution; the container residue after administration does not exceed 5% of the nominal volume) or combinations of open and closed systems are universally used to deliver intravenous fluids and medications in the study hospitals (35). Surveillance and Case Report Forms Each center established an augmented infection control program, with the initial major emphasis on active surveillance of health careassociated infections and process surveillance of hand hygiene adherence and invasive device care. During the study, we determined the rates of ventilator-associated pneumonia, CVC-associated bloodstream infection, and catheter-associated urinary tract infection monthly by using current CDC NNIS System definitions (1921). Designated surveillance forms were used for all patients in the study ICUs, both patients with and those without health careassociated infection. The following data were to be recorded daily on the forms for each patient: temperature and blood pressure, invasive devices, all cultures done, imaging studies, and antibiotic use. Previous studies have shown that fever, hypotension, cultures, and initiation of antimicrobial therapy are powerful markers for the presence of a health careassociated infection (36). A mean average severity of illness score was also recorded for each patient at ICU admission by using the CDC NNIS System criteria (19). Points were totaled, with 1 point for surgical patients who require routine postoperative observation only, 2 points for physiologically stable nonsurgical patients who require overnight observation, 3 points for patients who need continuous nursing care and monitoring, 4 points for physiologically unstable patients who require intensive nursing and medical care and need frequent reassessment and adjustment of therapy, and 5 points for physiologically unstable patients who are in a coma or in shock and require cardiopulmonary resuscitation or intensive medical and nursing care with frequent reassessment. If a patient was determined to have acquired a health careassociated infection, the date of onset, site of infection, infecting microorganisms, and antimicrobial susceptibilities were also recorded. Definitions Ventilator-Associated Pneumonia Ventilator-associated pneumonia is indicated in a mechanically ventilated patient with a chest radiograph that shows new or progressive infiltrates, consolidation, cavitation, or pleural effusion. The patient must also have at least 1 of the following criteria: new onset of purulent sputum or change in character of sputum; organism cultured from blood; or isolation of an etiologic agent from a specimen obtained by tracheal aspirate, bronchial brushing or bronchoalveolar lavage, or biopsy. Laboratory-Confirmed CVC-Associated Bloodstream Infection Central venous catheterassociated bloodstream infection is laboratory-confirmed when a patient with a CVC has a recognized pathogen that is isolated from 1 or more percutaneous blood cultures after 48 hours of vascular catheterization and is not related to an infection at another site. The patient also has at least 1 of the following signs or symptoms: fever (temperature 38C), chills, or hypotension. With skin commensals (for example, diphtheroids, Bacillus spp., Propionibacterium spp., coagulase-negative staphylococci, or micrococci), the organism is cultured from 2 or more blood cultures. Clinically Suspected CVC-Associated Bloodstream Infection Central venous catheterassociated bloodstream infection is clinically suspected when a patient with a CVC has at least 1 of the following clinical signs with no other identified cause: fever (temperature 38C), hypotension (systolic blood pressure 90 mm Hg), or oliguria (urine output 20 mL/h) with blood cultures not obtained or no organisms recovered from blood cultures, infections not apparent at another site, and antimicrobial therapy instituted by the physician. Catheter-Associated Urinary Tract Infection For the diagnosis of catheter-associated urinary tract infection, the patient must meet 1 of 2 criteria. The first criterion is when a patient with a urinary catheter has 1 or more of the following symptoms with no other recognized cause: fever (temperature 38C), urgency, or suprapubic tenderness when the urine culture is positive for 105 colony-forming units per mL or more, with no more than 2 microorganisms isolated. The second criterion is when a patient with a urinary catheter has at least 2 of the following criteria with no other recognized cause: positive dipstick analysis for leukocyte esterase or nitr

High rate of non-albicans candidemia in Brazilian tertiary care hospitals

In order to evaluate the epidemiology of candidemia in Brazil, we performed a prospective multicenter study conducted in six general hospitals from São Paulo and Rio de Janeiro, We enrolled a total of 145 candidemic patients (85 males) with a median age of 32 years. Non-albicans species accounted for 63% of all episodes and the species most frequently causing candidemia were C. albicans (37%), C. parapsilosis (25%), C. tropicalis (24%), C. rugosa (5%), and C. glabrata (4%). Systemic azoles were used before the onset of candidemia in only six patients. There were no differences in the coexisting exposures or underlying diseases associated with the species most frequently causing candidemia. The overall crude mortality rate was 50%. Nosocomial candidemias in our tertiary hospitals are caused predominantly by non-albicans species, which are rarely fluconazole resistant. This predominance of non-albicans species could not be related to the previous use of azoles.

Risk factors for death in patients with candidemia.

OBJECTIVE To analyze possible risk factors for death among patients with nosocomial candidemia. To identify risk factors for death in patients with candidemia, we analyzed demographic, clinical, and microbiological data. SETTING Six tertiary hospitals in Brazil. PATIENTS A cohort of 145 patients with candidemia. DESIGN 26 possible risk factors for death, including age, underlying disease, signs of deep-seated infection, neutropenia, number of positive blood cultures, removal of a central venous catheter, etiologic agent of the candidemia, susceptibility pattern of the isolate to amphotericin B, and antifungal treatment were evaluated by univariate stepwise logistic regression analysis. RESULTS Non-albicans species accounted for 63.4% of the candidemias. Risk factors for death in univariate analysis were older age, catheter retention, poor performance status, candidemia due to species other than Candida parapsilosis, hypotension, candidemia due to species other than Candida parapsilosis, and no antifungal treatment. In multivariate analysis, older age and nonremoval of a central venous catheter were the only factors associated with an increased risk for death. CONCLUSIONS These data suggest that patients with candidemia and a central venous catheter should have the catheter removed.

Inflammatory response after myocardial revascularization with or without cardiopulmonary bypass

BACKGROUND Tumor necrosis factor-alpha has been implicated in complications seen after cardiac operations with cardiopulmonary bypass. The release of tumor necrosis factor-alpha and its possible effects were studied in patients undergoing coronary artery bypass grafting with and without cardiopulmonary bypass. METHODS Twenty patients were studied, 10 with (group 1) and 10 without cardiopulmonary bypass (group 2). Serial blood samples were obtained before, during, and up to 48 hours after operation. Circulating tumor necrosis factor-alpha levels, leukocyte counts, and erythrocyte sedimentation rates were measured. Hemodynamic variables (blood pressure and heart rate), temperature, orotracheal intubation time, postoperative bleeding, and inotropic drug requirements were compared. RESULTS Serum levels of tumor necrosis factor-alpha were detected in 6 patients (60%) in group 1 and none in group 2. The patients in group 1 had more hypotension than those in group 2 (7.4 +/- 1.0 mm Hg versus 8.5 +/- 0.7 mm Hg), required more inotropic drugs (8 patients versus 1 patient), and had a higher heart rate (114 +/- 8 beats per minute versus 98 +/- 10 beats per minute), a higher temperature (37.1 degrees +/- 0.5 degrees C versus 36.6 degrees +/- 0.3 degrees C), increased postoperative bleeding (820 +/- 120 mL versus 360 +/- 84 mL), a longer orotracheal intubation time (13.6 +/- 2.2 hours versus 9.3 +/- 1.4 hours), and a more pronounced leukocytosis. CONCLUSIONS Cardiopulmonary bypass induces the whole-body inflammatory response through the release of tumor necrosis factor alpha, resulting in adverse systemic effects.

Bacterial sensing, cell signaling, and modulation of the immune response during sepsis.

ABSTRACT Since the definition of systemic inflammatory response syndrome/sepsis was originally proposed, a large amount of new information has been generated showing a much more complex scenario of inflammatory and counterinflammatory responses during sepsis. Moreover, some fundamental mechanisms of sensing and destroying invading microorganisms have been uncovered, which include the discovery of TLR4 as the lipopolysaccharide (LPS) gene, implications of innate immune cells as drivers of the adaptive response to infection, and the modulation of multiple accessory molecules that stimulate or inhibit monocyte/macrophage and lymphocyte interactions. The complexity of the infection/injury-induced immune response could be better appreciated with the application of genomics and proteomics studies, and LPS was a useful tool in many of these studies. In this review, we discuss aspects of bacterial recognition and induced cellular activation during sepsis. Because of the relevance of endotoxin (LPS) research in the field, we focus on LPS and host interactions as a clue to understand microorganisms sensing and cell signaling, then we discuss how this response is modulated in septic patients.

TLR2, TLR4, CD14, CD11B, and CD11c expressions on monocytes surface and cytokine production in patients with sepsis, severe sepsis, and septic shock

ABSTRACT Bacterial recognition and induced cellular activation are fundamental for the host control of infection, yet the limit between protective and harmful response is still inexact. Forty-one patients were enrolled in this study: 14 with sepsis, 12 with severe sepsis, and 15 with septic shock. Seventeen healthy volunteers (HV) were included as control. The expression of TLR2, TLR4, CD14, CD11b, and CD11c was analyzed on monocytes surface in whole blood. sCD14 was measured in serum, and TNF-&agr;, IL-6, and IL-10 cytokine levels were measured in PBMC supernatants after LPS, IL-1&bgr;, and TNF-&agr; stimuli by ELISA. An increase in sCD14 and a decreased mCD14 were found in patients as compared with HV (P < 0.001). However, no differences in the expression of TLR2, TLR4, and CD11c were found among the groups. A trend toward differential expression of CD11b was observed, with higher values found in patients with sepsis as compared with HV. A negative regulation of the inflammatory cytokine production was observed in patients with severe sepsis and shock septic in relation to sepsis and HV, regardless of the stimulus. No significant difference in IL-10 production was found among the groups. In this study, we show that the inflammatory response is associated with the continuum of clinical manifestations of sepsis, with a strong inflammatory response in the early phase (sepsis) and a refractory picture in the late phases (severe sepsis and septic shock). Correlation between cell surface receptors and cytokine production after IL-1&bgr; and TNF-&agr; stimuli and the observation of a single and same standard response with the different stimulus suggest a pattern of immunology response that is not dependent only on the expression of the evaluated receptors and that is likely to have a regulation in the intracellular signaling pathways.

TLR signaling pathway in patients with sepsis.

The pathogenesis of sepsis involves complex interaction between the host and the infecting microorganism. Bacterial recognition and signaling are essential functions of the cells of innate immune systems and drive a coordinated immune response. One of the more intriguing aspects of sepsis is the fact that the protective and damaging host response are part of the same process, that is, the inflammatory response that is aimed to control the infectious process also underscores many of the pathophysiological events of sepsis. The discovery of Toll-like receptors (TLRs) in humans, and the early recognition of TLR-4 as the receptor that signals LPS bioactivity were major breakthroughs not only in the field of sepsis but also in immunology as a whole. In this article, we aimed to review TLR expression and signaling in the context of sepsis. The results obtained by our group show that TLR and other cellular surface receptors may be differently regulated on mononuclear cells and neutrophils, and that they are dynamically modulated across the stages of sepsis. Toll-like receptor signaling gene expression in mononuclear cells is decreased in more severe forms of the disease. In contrast, up-regulated genes are seen along the clinical spectrum of sepsis in neutrophils.

Outbreak of Candida rugosa candidemia: an emerging pathogen that may be refractory to amphotericin B therapy

Candida rugosa has been rarely reported as a human pathogen. We retrospectively evaluated a cluster of Candida rugosa candidemia cases occurring in six hospitalized patients from a tertiary care teaching hospital in São Paulo, Brazil. Genetic relatedness among the six C. rugosa outbreak isolates was characterized by RAPD assay using 3 different 10-mer primers and by pulsed field gel electrophoresis. The source of the outbreak was not identified. All patients had been subjected to invasive medical procedures, including central venous catheterization, surgery or dialysis. Two patients were undergoing amphotericin B therapy prior to the onset of candidemia. The crude mortality rate was very high, despite antifungal therapy. C. rugosa may represent an emerging pathogen associated with invasive medical procedures, able to infect immunocompetent hosts causing serious systemic infection refractory to amphotericin B therapy.

Impaired production of interferon-gamma and tumor necrosis factor-alpha but not of interleukin 10 in whole blood of patients with sepsis.

It has been demonstrated that lipopolysaccharide (LPS)-induced cytokine response in patients with sepsis differ from the normal host, yet this has not been controlled for the presence of underlying disease. We studied the ability of LPS and killed gram-negative bacteria (GNB) to induce tumor necrosis factor (TNF)-&agr; and interleukin (IL) 10, and of phytohemagglutinin (PHA) to induce interferon (IFN)-&ggr;, in whole blood from patients with sepsis (SP, n = 20), patients with matched underlying disease and without sepsis (control patients, n = 20), and healthy volunteers (HV, n = 20). LPS-induced TNF-&agr; production was lower in SP (median = 638 pg/mL) compared with control patients (4060 pg/mL;P = 0.003), and control patients production was lower compared with HV (5329 pg/mL;P < 0.001). Pseudomonas aeruginosa-induced TNF-&agr; production was lower in SP (1443 pg/mL) than in control patients (7319 pg/mL;P < 0.05), and was not different between control patients and HV (6612 pg/mL;P = 0.6). IFN&ggr; production was lower in SP (948 pg/mL) compared with control patients (5516 pg/mL;P < 0.001), and the control patients production was lower compared with HV (11,282 pg/mL;P < 0.001). IL-10 production was not different among the three groups. Down-regulation of TNF-&agr; production in patients with sepsis, although not restricted to them, was more pronounced with LPS than with GNB. Although the presence of underlying disease may be involved in the regulatory mechanisms of host response, the use of controls with matched underlying diseases provides strong evidence for the septic condition in the down-regulation of inflammatory response in patients with sepsis.

ABANDON THE MOUSE RESEARCH SHIP? NOT JUST YET!

ABSTRACT Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiologic alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently, the lay press severely criticized the translational relevance of mouse models in critical care medicine. A series of provocative editorials were elicited by a highly publicized research report in the Proceedings of the National Academy of Sciences (PNAS; February 2013), which identified an unrecognized gene expression profile mismatch between human and murine leukocytes following burn/trauma/endotoxemia. Based on their data, the authors concluded that mouse models of trauma/inflammation are unsuitable for studying corresponding human conditions. We believe this conclusion was not justified. In conjunction with resulting negative commentary in the popular press, it can seriously jeopardize future basic research in critical care medicine. We will address some limitations of that PNAS report to provide a framework for discussing its conclusions and attempt to present a balanced summary of strengths/weaknesses of use of mouse models. While many investigators agree that animal research is a central component for improved patient outcomes, it is important to acknowledge known limitations in clinical translation from mouse to man. The scientific community is responsible to discuss valid limitations without overinterpretation. Hopefully, a balanced view of the strengths/weaknesses of using animals for trauma/endotoxemia/critical care research will not result in hasty discount of the clear need for using animals to advance treatment of critically ill patients.