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Producción Científica, Background: The use of novel sepsis biomarkers has increased in recent years. However, their prognostic value with respect to illness severity has not been explored. In this work, we examined the ability of mid-regional proadrenomedullin (MR-proADM) in predicting mortality in sepsis patients with different degrees of organ failure, compared to that of procalcitonin, C-reactive protein and lactate. Methods: This was a two-centre prospective observational cohort, enrolling severe sepsis or septic shock patients admitted to the ICU. Plasma biomarkers were measured during the first 12 h of admission. The association between biomarkers and 28-day mortality was assessed by Cox regression analysis and Kaplan–Meier curves. Patients were divided into three groups as evaluated by the Sequential Organ Failure Assessment (SOFA) score. The accuracy of the biomarkers for mortality was determined by area under the receiver operating characteristic curve (AUROC) analysis. Results: A total of 326 patients with severe sepsis (21.7%) or septic shock (79.3%) were enrolled with a 28-day mortality rate of 31.0%. Only MR-proADM and lactate were associated with mortality in the multivariate analysis: hazard ratio 8.5 versus 3.4 (p < 0.001). MR-proADM showed the best AUROC for mortality prediction at 28 days in the analysis over the entire cohort (AUROC [95% CI] 0.79 [0.74–0.84]) (p < 0.001). When patients were stratified by the degree of organ failure, MR-proADM was the only biomarker to predict mortality in all severity groups (SOFA ≤ 6, SOFA = 7–12, and SOFA ≥ 13), AUROC [95% CI] of 0.75 [0.61–0.88], 0.74 [0.66–0.83] and 0.73 [0.59–0.86], respectively (p < 0.05). All patients with MR-proADM concentrations ≤0.88 nmol/L survived up to 28 days. In patients with SOFA ≤ 6, the addition of MR-proADM to the SOFA score increased the ability of SOFA to identify non-survivors, AUROC [95% CI] 0.70 [0.58–0.82] and 0.77 [0.66–0.88], respectively (p < 0.05 for both). Conclusions: The performance of prognostic biomarkers in sepsis is highly influenced by disease severity. MRproADM accuracy to predict mortality is not affected by the degree of organ failure. Thus, it is a good candidate in the early identification of sepsis patients with moderate disease severity but at risk of mortality.

Objective The impact of endogenous immunoglobulin isotypes on the prognosis of patients with severe sepsis has not been sufficiently explored. The aim of this study was to evaluate the association between immunoglobulin levels in plasma and survival in patients with this condition. Design and patients A prospective multicentre cohort study was conducted. A total of 172 adult patients admitted to the intensive care unit (ICU) with severe sepsis or septic shock were recruited. Patients were classified based on deciles of immunoglobulin concentrations at diagnosis of sepsis. Categorical variables were created and tested for their association with survival during hospitalization in the ICU. Results Overall, 42 patients died in the ICU during the study. Kaplan–Meier analysis showed that immunoglobulin concentrations below 300 mg dL−1 for IgG1, 35 mg dL−1 for IgM and 150 mg dL−1 for IgA were associated with shorter survival times. Multivariate regression analysis showed that IgG1 < 300 mg dL−1 was a risk factor for mortality [odds ratio (OR) 2.50, 95% confidence interval (CI) 1.04–6.03; P = 0.042]. The combined presence of IgG1, IgM and IgA levels below the described thresholds had a synergistic impact on mortality risk (OR 5.27, 95% CI 1.41–19.69; P = 0.013). A similar effect was observed for combined low levels of IgG1 and IgA (OR 4.10, 95% CI 1.28–13.12; P = 0.018) and also of IgG1 and IgM (OR 3.10. 95% CI 1.13–8.49; P = 0.028). Conclusions The combined presence of low levels of the endogenous immunoglobulins IgG1, IgM and IgA in plasma is associated with reduced survival in patients with severe sepsis or septic shock. Assessment of the concentrations of these immunoglobulins could improve the results of treatment with exogenous immunoglobulins in patients with sepsis.

While our understanding of the pathogenesis and management of acute respiratory distress syndrome (ARDS) has improved over the past decade, estimates of its incidence have been controversial. The goal of this study was to examine ARDS incidence and outcome under current lung protective ventilatory support practices before and after the diagnosis of ARDS.This was a 1-year prospective, multicenter, observational study in 13 geographical areas of Spain (serving a population of 3.55 million at least 18 years of age) between November 2008 and October 2009. Subjects comprised all consecutive patients meeting American-European Consensus Criteria for ARDS. Data on ventilatory management, gas exchange, hemodynamics, and organ dysfunction were collected.A total of 255 mechanically ventilated patients fulfilled the ARDS definition, representing an incidence of 7.2/100,000 population/year. Pneumonia and sepsis were the most common causes of ARDS. At the time of meeting ARDS criteria, mean PaO(2)/FiO(2) was 114 ± 40 mmHg, mean tidal volume was 7.2 ± 1.1 ml/kg predicted body weight, mean plateau pressure was 26 ± 5 cmH(2)O, and mean positive end-expiratory pressure (PEEP) was 9.3 ± 2.4 cmH(2)O. Overall ARDS intensive care unit (ICU) and hospital mortality was 42.7% (95%CI 37.7-47.8) and 47.8% (95%CI 42.8-53.0), respectively.This is the first study to prospectively estimate the ARDS incidence during the routine application of lung protective ventilation. Our findings support previous estimates in Europe and are an order of magnitude lower than those reported in the USA and Australia. Despite use of lung protective ventilation, overall ICU and hospital mortality of ARDS patients is still higher than 40%.

Background: The existence of different degrees of inflammatory reaction and right ventricular dysfunction after pulmonary resection is well known, though its detection and clinical relevance have not been sufficiently evaluated. The introduction of new biomarkers, particularly brain natriuretic peptide (BNP) and its prohormone (proBNP), together with dynamic imaging techniques such as echocardiography, could prove useful in assessing such response. The aim of this study is to describe the kinetic curve of these biomarkers during uncomplicated pulmonary resection surgery. Furthemore we have studied the right ventricular function by echocardiography in these patients Methods: Demographic data, antecedents and certain perioperative parameters, as well as plasma proBNP, troponin T and C-reactive protein (CRP) levels, were recorded in 38 patients who underwent pneumonectomy (n= 13 ) and lobectomy (n=25), before and 24, 48 and 72 hours after the operation. A transthoracic echocardiogram was carried out preoperatively and 72 hours after surgery. Results: ProBNP showed a significant increase 24 hours after surgery, with a maximum peak after 72 hours (p

Interventricular septum rupture following blunt chest trauma is a rare cardiac injury that sometimes is difficult to diagnose. It has a high mortality rate, especially when in cases of hemodynamic instability requiring early surgical repair. We report the case of an 18-year old man who suffered blunt thoracoabdominal trauma and hemorrhagic shock who required emergency abdominal surgery on three occasions. He was diagnosed of traumatic rupture of interventricular septum that had not been detected in the initial echocardiography, but was suspected after the right heart catheterism. Urgent cardiac surgery was performed 72 hours later because of hemodynamic instability.

Summary Objectives Immunological dysregulation is now recognised as a major pathogenic event in sepsis. Stimulation of immune response and immuno-modulation are emerging approaches for the treatment of this disease. Defining the underlying immunological alterations in sepsis is important for the design of future therapies with immuno-modulatory drugs. Methods Clinical studies evaluating the immunological response in adult patients with Sepsis and published in PubMed were reviewed to identify features of immunological dysfunction. For this study we used key words related with innate and adaptive immunity. Results Ten major features of immunological dysfunction (FID) were identified involving quantitative and qualitative alterations of [antigen presentation](FID1), [T and B lymphocytes] (FID2), [natural killer cells] (FID3), [relative increase in T regulatory cells] (FID4), [increased expression of PD-1 and PD-ligand1](FID5), [low levels of immunoglobulins](FID6), [low circulating counts of neutrophils and/or increased immature forms in non survivors](FID7), [hyper-cytokinemia] (FID8), [complement consumption] (FID9), [defective bacterial killing by neutrophil extracellular traps](FID10). Conclusions This review article identified ten major features associated with immunosuppression and immunological dysregulation in sepsis. Assessment of these features could help in utilizing precision medicine for the treatment of sepsis with immuno-modulatory drugs.

This work was funded by the Instituto de Salud Carlos III (CB06/06/1088, PI10/00393, PI14/00844, FI11/00074) and by the European Regional Development Funds “A way of making Europe.” MPY was supported by a post-doctoral fellowship from Fundación Ramón Areces, Madrid, Spain., Acosta-Herrera, M., Pino-Yanes, M., Blanco, J., Ballesteros, J.C., Ambrós, A., Corrales, A., Gandía, F., Subirá, C., Domínguez, D., Baluja, A., Añón, J.M., Adalia, R., Pérez-Méndez, L., Flores, C., Villar, J., Fernández, L.R., Espinosa, E., Campo, R.D., Fernández, R., Rodríguez, J.A., álvarez, J., González, E., Hernández, O., Solano, R., Pérez-Crespo, J., Arellano, P., Zavala, E., Martínez, J., Torres, A., Badia, J., Alba, F., Corpas, R., Muriel, A., Sagredo, V., Taboada, F., Albaiceta, G.M., Bobillo, F., Tamayo, L., Labattut, A.G., Carriedo, D., Collado, J., Diaz, F.J., Valledor, M., Antuña, M., de Frutos, M., López, M.J., Cortina, J.J., Saldaña, T., Caballero, A., álvarez, T., álvarez, B., Sandoval, J.

In Spain, as in most of the world, the incidence of acute carbon monoxide poisoning is probably underestimated.During an eighteen-month period we studied, by means of a standardized data collection form, all the cases of acute carbon monoxide poisoning that were diagnosed in 2 university hospitals.During the study, 154 patients were diagnosed with carbon monoxide poisoning. The mean age was 32.2+/-15.5 years. The two principal exposure sites were the kitchen (43%) and bathroom (23%). The majority of the cases related to malfunction of the water heater (30%) and of the central heating (23%) and 68% occurred in the home. Improper combustion of butane (31%), propane (13%), and natural gas (12%) were most frequent. The most prevalent clinical manifestations were headache (94%), dizziness (56%), nausea (45%), loss of consciousness (38%), and weakness (34%). Five patients died. In 14.4%, symptoms suggested delayed neurological syndrome. The largest number of cases of poisoning occurred during the months of December and January.Compared with previous Spanish series or with the antecedent year, acute carbon monoxide poisoning has a high prevalence in our region. Two factors appear to be essential to the accurate diagnosis of acute carbon monoxide poisoning: 1) the ability of emergency room physicians to recognize the clinical symptoms of carbon monoxide poisoning and 2) access to a carbon monoxide-oximeter.

Identification of patients at increased risk of death is dramatically important in severe sepsis. Cytokines have been widely assessed as potential biomarkers in this disease, but none of the cytokines studied has evidenced a sufficient specificity or sensitivity to be routinely employed in clinical practice. In this pilot study, we profiled 17 immune mediators in the plasma of 29 consecutively recruited patients with severe sepsis or septic shock, during the first 24h following admission to the ICU, by using a Bio-Plex Human Cytokine 17-Plex Panel (Bio-Rad). Patients were 66.1year old in average. Twelve patients of our cohort died during hospitalization at the ICU, eight of them in the first 72h due to multiorganic dysfunction syndrom (MODS). Levels in plasma of three pro-inflammatory mediators (IL-6, IL-8, MCP-1) and of an immunosuppressive one (IL-10) were higher in those patients with fatal outcome. We developed a combined score with those cytokines showing to better predict mortality in our cohort based on the results of Cox regression analysis. This way, IL-6, IL-8 and IL-10 were included in the score. Patients were split into two groups based on the percentile 75 (P75) of the plasma levels of these three interleukins. Those patients showing at least one interleukin value higher than P75 were given the value "1". Those patients showing IL-6, IL-8, IL-10 levels below P75 were given the value "0". Hazard ratios for mortality at day 3 and day 28th obtained with the combined score were 2-3-fold higher than those obtained with the individual interleukins values. In conclusion, we have described a combined cytokine score associated with a worse outcome in patients with sepsis, which may represent a new avenue to be explored for guiding treatment decisions in this disease.

Background: Severe disease caused by 2009 pandemic influenza A/H1N1virus is characterized by the presence of hypercytokinemia. The origin of the exacerbated cytokine response is unclear. As observed previously, uncontrolled influenza virus replication could strongly influence cytokine production. The objective of the present study was to evaluate the relationship between host cytokine responses and viral levels in pandemic influenza critically ill patients. Methods: Twenty three patients admitted to the ICU with primary viral pneumonia were included in this study. A quantitative PCR based method targeting the M1 influenza gene was developed to quantify pharyngeal viral load. In addition, by using a multiplex based assay, we systematically evaluated host cytokine responses to the viral infection at admission to the ICU. Correlation studies between cytokine levels and viral load were done by calculating the Spearman correlation coefficient. Results: Fifteen patients needed of intubation and ventilation, while eight did not need of mechanical ventilation during ICU hospitalization. Viral load in pharyngeal swabs was 300 fold higher in the group of patients with the worst respiratory condition at admission to the ICU. Pharyngeal viral load directly correlated with plasma levels of the pro-inflammatory cytokines IL-6, IL-12p70, IFN-gamma, the chemotactic factors MIP-1 beta, GM-CSF, the angiogenic mediator VEGF and also of the immuno-modulatory cytokine IL-1ra ( p < 0.05). Correlation studies demonstrated also the existence of a significant positive association between the levels of these mediators, evidencing that they are simultaneously regulated in response to the virus. Conclusions: Severe respiratory disease caused by the 2009 pandemic influenza virus is characterized by the existence of a direct association between viral replication and host cytokine response, revealing a potential pathogenic link with the severe disease caused by other influenza subtypes such as H5N1., The authors would like to thank also to the Nursery teams who kindly collected the samples and to Lucia Rico and Veronica Iglesias for their precious laboratory assistance. The study was scientifically supported by the Spanish Society for Critical Care Medicine (SEMICYUC). Funding: MICCIN-FIS/JCYL-IECSCYL-SACYL (Spain): Programa de Investigacion Comisionada en Gripe, GR09/0021-EMER07/050-PI081236-RD07/0067. This work was also supported by Grants or Contracts from ATCC/CDC USA, and University Health Network and IDR Canada (DJK).

Introduction Several lesions have been described as post-intubation complications. Most frequent are injuries of the pharynx/larynx or trachea. Cranial nerve injury following routine endo-tracheal intubation appears to be rare, and most reports describe Tapia's syndrome with hypoglossus/recurrent laryngeal nerve paralysis; cases that describe only bilateral hypoglossus palsy are infrequent. The cause is attributed to neuropathy of the nerve, provoked by compression following inflation of the cuff within the larynx or damage after neck hyperextension during a difficult intubation. However, similar cases after non-traumatic intubation have not been reported. Case presentation We report here a case of bilateral hypoglossus palsy in a young man undergoing a diagnostic anterior mediastinotomy that was attributed to prolonged non-complicated oro-tracheal intubation. Progressive recovery of function by the patient supports neuropraxic damage as the cause. Conclusion To avoid such problems, special attention should be paid to the correct positioning of the head during surgery or during rapidly performed tracheostomy if prolonged intubation is anticipated.

Interventricular septum rupture following blunt chest trauma is a rare cardiac injury that sometimes is difficult to diagnose. It has a high mortality rate, especially when in cases of hemodynamic instability requiring early surgical repair. We report the case of an 18-year old man who suffered blunt thoracoabdominal trauma and hemorrhagic shock who required emergency abdominal surgery on three occasions. He was diagnosed of traumatic rupture of interventricular septum that had not been detected in the initial echocardiography, but was suspected after the right heart catheterism. Urgent cardiac surgery was performed 72 hours later because of hemodynamic instability.

Objetivo Evaluar la reproducibilidad en la recogida de datos y su influencia en el calculo de la gravedad y del riesgo predicho de muerte para los modelos APACHE II, APACHE III adaptado para Espana y SAPS II. Diseno Estudio multicentrico, prospectivo y observacional de cohortes. Ambito Nueve Unidades de Cuidados Intensivos (UCI) en Espana. Pacientes Inclusion consecutiva de los pacientes ingresados en el periodo de estudio. Se excluyeron los pacientes menores de 16 anos, con estancia en UCI menor de 24 horas, los ingresados para implante programado de marcapasos y los reingresados en UCI dentro del mismo ingreso hospitalario. Intervencion Ninguna. Variables de interes principales Se recogieron los datos necesarios para el calculo de las puntuaciones de gravedad y del riesgo predicho de muerte. Se seleccionaron el 10% de los pacientes por muestreo aleatorio simple y se recogieron los mismos datos por un grupo independiente de intensivistas. Finalmente se compararon los datos recogidos por los dos grupos de intensivistas. Resultados Se encontraron diferencias significativas en el APS ( acute physiology score ) y puntuacion de gravedad calculados para el APACHE III y SAPS II, y en el riesgo de muerte predicho por SAPS II. El porcentaje de acuerdos en el diagnostico de ingreso en UCI fue del 50% para los modelos APACHE II y III. En la mayoria de los pacientes (76,58% en el APACHE II y 79,82% en el APACHE III) la diferencia en el riesgo predicho de muerte debido a la diferente asignacion del diagnostico de ingreso en UCI fue menor del 10%. Conclusiones En este estudio el APS se mostro como el factor mas influyente en la reproducibilidad de los indices de gravedad y del calculo del riesgo predicho de muerte. El diagnostico de ingreso en UCI no mostro un impacto importante en la reproducibilidad del riesgo predicho de muerte.

Purpose Critical illness results in derangements of all components of the immune response. Nonetheless, most of the efforts evaluating immune status in critically ill patients have been done in the field of sepsis. Here we have evaluated the immunity status at intensive care unit (ICU) admission in a cohort of nonseptic critically ill patients and its influence on their outcome. Material and methods Ninety patients 18 years and older admitted to our ICU were studied for levels of immunoglobulin (Ig) G, IgM, IgA, CD3 + CD4 + T cells, CD3 + CD8 + T cells, B cells, natural killer (NK) cells, and C3 and C4 complement factors in peripheral blood in the next 24 hours after admission to the ICU. Patients with infection, sepsis, immunodeficiency, or concomitant immunosuppressive therapy were excluded. Results Levels of IgM, CD3 + T cells, CD4 + T cells, CD8 + T cells, and B lymphocytes correlated inversely with age. In turn, levels of CD3 + T cells, CD4 + T cells, CD8 + T cells, and C3 factor of the complement system correlated inversely with Acute Physiology and Chronic Health Evaluation II score. Multivariate Cox regression analysis censored at 28 days evidenced that levels of IgM played a protective role, whereas levels of NK cells behaved as a risk factor for mortality. Kaplan-Meier curves showed a cutoff of 58 mg/dL for IgM and 140 cells/mm 3 for NK cells. Conclusions In conclusion, our results demonstrate that IgM plays a protective role in critically ill patients with no sepsis, whereas NK cell counts seem to play a deleterious one. Aging and severity at admission affect levels of key factors of the immune system in the blood of these patients.

Producción Científica, In an attempt to evaluate the quantitative changes in the status of immunocompetence in severe sepsis over time and its potential influence on clinical outcome, we monitored the evolution of immunoglobulins (Igs) (IgG, IgA and IgM), complement factors (C3 and C4) and lymphocyte subsets (CD4+ T cells, CD8+ T cells, B cells (CD19+) and natural killer (NK) cells (CD3-CD16+CD56+)) in the blood of 50 patients with severe sepsis or septic shock at day 1, day 3 and day 10 following admission to the ICU. Twenty-one patients died, ten of whom died within the 72 hours following admission to the ICU. The most frequent cause of death (n = 12) was multiorgan dysfunction syndrome. At day 1, survivors showed significantly higher levels of IgG and C4 than those who ultimately died. On the contrary, NK cell levels were significantly higher in the patients who died. Survivors exhibited a progressive increase from day 1 to day 10 on most of the immunological parameters evaluated (IgG, IgA, IgM, C3, CD4+, CD8+ T cells and NK cells). Multivariate Cox regression analysis, including age, sex, APACHE II score, severe sepsis or septic shock status and each one of the immunological parameters showed that NK cell counts at day 1 were independently associated with increased risk of death at 28 days (hazard ratio = 3.34, 95% CI = 1.29 to 8.64; P = 0.013). Analysis of survival curves provided evidence that levels of NK cells at day 1 (> 83 cells/mm3) were associated with early mortality. Our results demonstrate the prognostic role of NK cells in severe sepsis and provide evidence for a direct association of early counts of these cells in blood with mortality.

Introduction: Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown. Methods: We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1. Results: The majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum. Conclusions: Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome., This work has been developed by an international team pertaining to the Spanish-Canadian Consortium for the Study of Influenza Immunopathogenesis. The authors would like to thank also to the Nursery teams who kindly collected the samples. The authors would like to thank Nikki Kelvin for language revision of this article. The study was scientifically sponsored by the Spanish Society for Critical Care Medicine (SEMICYUC). Funding: MICCIN-FIS/JCYL-IECSCYL-SACYL (Spain): Programa de Investigacion Comisionada en Gripe, GR09/0021 EMER07/050 PI081236 RD07/0067. CIHR NIH-Sardinia Recherche-LKSF Canada support DJK.

Sepsis is a leading cause of admission to non-cardiological intensive care units (ICUs) and the second leading cause of death among ICU patients. We present the first extensive dataset on the epidemiology of severe sepsis treated in ICUs in Spain. We conducted a prospective, observational, multicentre cohort study, carried out over two 3-month periods in 2002. Our aims were to determine the incidence of severe sepsis among adults in ICUs in a specific area in Spain, to determine the early (48 h) ICU and hospital mortality rates, as well as factors associated with the risk of death. A total of 4,317 patients were admitted and 2,619 patients were eligible for the study; 311 (11.9%) of these presented at least 1 episode of severe sepsis, and 324 (12.4%) episodes of severe sepsis were recorded. The estimated accumulated incidence for the population was 25 cases of severe sepsis attended in ICUs per 100,000 inhabitants per year. The mean logistic organ dysfunction system (LODS) upon admission was 6.3; the mean sepsis-related organ failure assessment (SOFA) score on the first day was 9.6. Two or more organ failures were present at diagnosis in 78.1% of the patients. A microbiological diagnosis of the infection was reached in 209 episodes of sepsis (64.5%) and the most common clinical diagnosis was pneumonia (42.8%). A total of 169 patients (54.3%) died in hospital, 150 (48.2%) of these in the ICU. The mortality in the first 48 h was 14.8%. Factors associated with early death were haematological failure and liver failure at diagnosis, acquisition of the infection prior to ICU admission, and total LODS score on admission. Factors associated with death in the hospital were age, chronic alcohol abuse, increased McCabe score, higher LODS on admission, ΔSOFA 3-1 (defined as the difference in the total SOFA scores on day 3 and on day 1), and the difference of the area under the curve of the SOFA score throughout the first 15 days. We found a high incidence of severe sepsis attended in the ICU and high ICU and hospital mortality rates. The high prevalence of multiple organ failure at diagnosis and the high mortality in the first 48 h suggests delays in diagnosis, in initial resuscitation, and/or in initiating appropriate antibiotic treatment.