Upraising Stenotrophomonas maltophilia in Critically Ill Patients: A New Enemy?

Stenotrophomonas maltophilia (S. maltophilia), an important pathogen in immuno-compromised patients, has recently gained attention in patients admitted in intensive care units (ICU). We sought to investigate clinical features of infections caused by S. maltophilia in ICU patients and identify risk factors for mortality. We conducted a retrospective study in two multivalent non-COVID-19 ICUs of tertiary-teaching hospitals in Greece and Spain, including patients with isolated S. maltophilia from at least one clinical specimen along with clinical signs of infection. A total of 103 patients (66% male) were analyzed. Median age was 65.5 (54-73.3) years and mean APACHE II and SOFA scores upon ICU admission were 18.36 (±7.22) and 18.17 (±6.95), respectively. Pneumonia was the predominant clinical syndrome (72.8%), while 22% of cases were among hemato/oncology patients. Crude 28-day mortality rate was 54.8%, even though, 14-day clinical and microbiological response was 96%. Age, APACHE II on ICU admission, hemato-oncologic disease, and multi-organ failure were initially identified as potential predictors of mortality. In the multivariable analysis, only increasing age and hemato-oncologic disease were shown to be independent risk factors for 28-day mortality. High all-cause mortality was observed in critically ill patients with predominantly respiratory infections by S. maltophilia, despite initial clinical and laboratory response after targeted treatment. The study elucidates a potentially worrisome emerging pathogen in the ICU.

Evaluation of health outcomes after the implementation of rotational thromboelastometry in patients undergoing cardiac surgery.

BACKGROUND: Viscoelastic tests (rotational thromboelastometry, ROTEM®), together with the implementation of a specific algorithm for coagulation management in cardiac surgery, enable perioperative coagulopathy to be better controlled. METHODS: Retrospective cohort study including 675 patients who underwent cardiac surgery with cardiopulmonary bypass. The incidence of allogeneic blood transfusions and clinical postoperative complications were analyzed before and after ROTEM® implementation. RESULTS: Following viscoelastic testing and the implementation of a specific algorithm for coagulation management, the incidence of any allogeneic blood transfusion decreased (41.4% vs 31.9%, p = .026) during the perioperative period. In the group monitored with ROTEM®, decreased incidence of transfusion was observed for packed red blood cells (31.3% vs 19.8%, p = .002), fresh frozen plasma (9.8% vs 3.8%, p = .008), prothrombin complex concentrate administration (0.9% vs 0.3%, p = .599) and activated recombinant factor VII (0.3% vs 0.0%, p = .603). Increased incidence was observed for platelet transfusion (4.8% vs 6.8%, p = .530) and fibrinogen concentrate (0.9% vs 3.5%, p = .066), tranexamic acid (0.0% vs 0.6%, p = .370) and protamine administration (0.6% vs 0.9%, p = .908). Similar results were observed in the postoperative period, but with a decreased incidence of platelet transfusion (4.8% vs 3.8%, p = .813). In addition, statistically significant reductions were detected in the incidence of postoperative bleeding (9.5% vs 5.3%, p = .037), surgical reexploration (6.0% vs 2.9%, p = .035), and length of Intensive Care Unit (ICU) stay (6.0 days vs 5.3 days, p = .026). CONCLUSIONS: The monitoring of hemostasis by ROTEM® in cardiac surgery, was associated with decreased incidence of allogeneic blood transfusion, clinical hematologic postoperative complications and lengths of ICU stay.

Role of Isolated Limb Perfusion in the Era of Targeted Therapies and Immunotherapy in Melanoma. A Systematic Review of The Literature.

BACKGROUND: Isolated limb perfusion (ILP) is a locoregional procedure indicated by the unresectable melanoma of the limbs. Its complexity and highly demanding multidisciplinary approach means that it is a technique only implemented in a few referral centers around the globe. This report aims to examine its potential role in the era of targeted therapies and immunotherapy by conducting a systematic review of the literature on ILP. METHODS: PubMed, Embase and Cochrane Library were searched. The eligibility criteria included publications from 2000-2020 providing valid data o effectiveness, survival or toxicity. Studies in which the perfusion methodology was not clearly described, letters to the editor, non-systematic reviews and studies that applied outdated clinical guidelines were excluded. To rule out studies of a low methodological quality and assess the risk of bias, the following aspects were also required: a detailed description of the applied ILP regimen, the clinical context, follow-up periods, analyzed clinical endpoints, and the number of analyzed ILPs. The disagreements were resolved by consensus. The results are presented in tables and figures. RESULTS: Twenty-seven studies including 2637 ILPs were selected. The median overall response rate was 85%, with a median complete response rate of 58.5%. The median overall survival was 38 months, with a 5-year overall survival of 35%. The toxicity was generally mild according to Wieberdink toxicity criteria. DISCUSSION: ILP still offer a high efficacy in selected patients. The main limitation of our review is the heterogeneity and age of most of the articles, as well as the absence of clinical trials comparing ILP with other procedures, making it difficult to transfer its results to the current era. CONCLUSIONS: ILP is still an effective and safe procedure for selected patients with unresectable melanoma of the limbs. In the era of targeted therapies and immunotherapy, ILP remains an acceptable and reasonable palliative treatment alternative, especially to avoid limb amputations. The ongoing clinical trials combining systemic therapies and ILP will provide more valuable information in the future to clarify the potential synergism of both strategies.

Low Levels of Granulocytic Myeloid-Derived Suppressor Cells May Be a Good Marker of Survival in the Follow-Up of Patients With Severe COVID-19.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a disease (coronavirus disease 2019, COVID-19) that may develop into a systemic disease with immunosuppression and death in its severe form. Myeloid-derived suppressive cells (MDSCs) are inhibitory cells that contribute to immunosuppression in patients with cancer and infection. Increased levels of MDSCs have been found in COVID-19 patients, although their role in the pathogenesis of severe COVID-19 has not been clarified. For this reason, we raised the question whether MDSCs could be useful in the follow-up of patients with severe COVID-19 in the intensive care unit (ICU). Thus, we monitored the immunological cells, including MDSCs, in 80 patients admitted into the ICU. After 1, 2, and 3 weeks, we examined for a possible association with mortality (40 patients). Although the basal levels of circulating MDSCs did not discriminate between the two groups of patients, the last measurement before the endpoint (death or ICU discharge) showed that patients discharged alive from the ICU had lower levels of granulocytic MDSCs (G-MDSCs), higher levels of activated lymphocytes, and lower levels of exhausted lymphocytes compared with patients who had a bad evolution (death). In conclusion, a steady increase of G-MDSCs during the follow-up of patients with severe COVID-19 was found in those who eventually died.

A case of pan-resistant Burkholderia cepacia complex bacteremic pneumonia, after lung transplantation treated with a targeted combination therapy.

We describe a case of one patient with cystic fibrosis who developed a pan-resistant Burkholderia cepacia complex rapidly progressive bacteraemic pneunonia, following bilateral lung transplantation. The patient was treated with a targeted combination antibiotic therapy (meropenem plus ceftazidime/avibactam plus high doses of nebulized colistimethate sodium). Evolution of the disease was complicated by multiple organ system dysfunction. Finally, clinical improvement and microbiological cure was achieved.

Initial Antifungal Strategy Reduces Mortality in Critically Ill Patients With Candidemia: A Propensity Score-Adjusted Analysis of a Multicenter Study.

OBJECTIVE: The objective of this study was to evaluate the impact of the empirical therapy with fluconazole or an echinocandin on 30- and 90-day mortality in critically ill patients with candidemia. The outcome of patients in whom the empirical echinocandin was deescalated to fluconazole was also assessed. DESIGN: Retrospective, observational multicenter study. SETTING: Medical and surgical ICUs in nine Spanish hospitals. PATIENTS: Adult patients (≥ 18 yr) with an episode of Candida bloodstream infection during ICU admission from January 2011 to April 2016. INTERVENTIONS: Patient characteristics, infection-related variables, therapeutic interventions, and metastatic complications were reviewed. A propensity score-adjusted multivariable analysis was performed to identify the risk factors significantly associated with 30-day and 90-day mortality. MEASUREMENTS AND MAIN RESULTS: A total of 294 patients were diagnosed of candidemia in the participant ICUs. Sixty patients were excluded (other antifungals in the primary therapy or the patient died without empirical antifungal therapy). The study group comprised 115 patients who received fluconazole (30-day mortality, 37.4%) and 119 patients treated empirically with an echinocandin (30-day mortality, 31.9%). The use of an echinocandin in the empirical therapy was a protective factor for 30-day (odds ratio, 0.32; 95% CI, 0.16-0.66; p = 0.002) and 90-day mortality (odds ratio, 0.50; 95% CI, 0.27-0.93; p = 0.014) in the propensity score- adjusted multivariable analysis. Deescalation of the empirical echinocandin to fluconazole was not associated with a higher mortality or the occurrence of long-term complications. CONCLUSIONS: Empirical use of an echinocandin in critically ill patients with documented candidemia reduces mortality at 30 and 90 days significantly. Deescalation of the empirical echinocandin to fluconazole is safe and effective in fluconazole-susceptible infections.

Adequate antibiotic therapy prior to ICU admission in patients with severe sepsis and septic shock reduces hospital mortality.

INTRODUCTION: In patients with severe sepsis and septic shock as cause of Intensive Care Unit (ICU) admission, we analyze the impact on mortality of adequate antimicrobial therapy initiated before ICU admission. METHODS: We conducted a prospective observational study enrolling patients admitted to the ICU with severe sepsis or septic shock from January 2008 to September 2013. The primary end-point was in-hospital mortality. We considered two groups for comparisons: patients who received adequate antibiotic treatment before or after the admission to the ICU. RESULTS: A total of 926 septic patients were admitted to ICU, and 638 (68.8%) had available microbiological isolation: 444 (69.6%) received adequate empirical antimicrobial treatment prior to ICU and 194 (30.4%) after admission. Global hospital mortality in patients that received treatment before ICU admission, between 0-6h ICU, 6-12h ICU, 12-24h ICU and after 24 hours since ICU admission were 31.3, 53.2, 57.1, 50 and 50.8% (p<0.001). The multivariate analysis showed that urinary focus (odds ratio (OR) 0.20; 0.09-0.42; p<0.001) and adequate treatment prior to ICU admission (OR 0.37; 0.24-0.56; p<0.001) were protective factors whereas APACHE II score (OR 1.10; 1.07-1.14; p<0.001), septic shock (OR 2.47; 1.57-3.87; p<0.001), respiratory source (OR 1.91; 1.12-3.21; p=0.016), cirrhosis (OR 3.74; 1.60-8.76; p=0.002) and malignancy (OR 1.65; 1.02-2.70; p=0.042) were variables independently associated with in-hospital mortality. Adequate treatment prior to ICU was a protective factor for mortality in patients with severe sepsis (n=236) or in septic shock (n=402). CONCLUSIONS: The administration of adequate antimicrobial therapy before ICU admission is decisive for the survival of patients with severe sepsis and septic shock. Our efforts should be directed to assure the correct administration antibiotics before ICU admission in patients with sepsis.

A research agenda on the management of intra-abdominal candidiasis: results from a consensus of multinational experts.

INTRODUCTION: intra-abdominal candidiasis (IAC) may include Candida involvement of peritoneum or intra-abdominal abscess and is burdened by high morbidity and mortality rates in surgical patients. Unfortunately, international guidelines do not specifically address this particular clinical setting due to heterogeneity of definitions and scant direct evidence. In order to cover this unmet clinical need, the Italian Society of Intensive Care and the International Society of Chemotherapy endorsed a project aimed at producing practice recommendations for the management of immune-competent adult patients with IAC. METHODS: A multidisciplinary expert panel of 22 members (surgeons, infectious disease and intensive care physicians) was convened and assisted by a methodologist between April 2012 and May 2013. Evidence supporting each statement was graded according to the European Society of Clinical Microbiology and Infection Diseases (ESCMID) grading system. RESULTS: Only a few of the numerous recommendations can be summarized in the Abstract. Direct microscopy examination for yeast detection from purulent and necrotic intra-abdominal specimens during surgery or by percutaneous aspiration is recommended in all patients with nonappendicular abdominal infections including secondary and tertiary peritonitis. Samples obtained from drainage tubes are not valuable except for evaluation of colonization. Prophylactic usage of fluconazole should be adopted in patients with recent abdominal surgery and recurrent gastrointestinal perforation or anastomotic leakage. Empirical antifungal treatment with echinocandins or lipid formulations of amphotericin B should be strongly considered in critically ill patients or those with previous exposure to azoles and suspected intra-abdominal infection with at least one specific risk factor for Candida infection. In patients with nonspecific risk factors, a positive mannan/antimannan or (1→3)-ß-D-glucan (BDG) or polymerase chain reaction (PCR) test result should be present to start empirical therapy. Fluconazole can be adopted for the empirical and targeted therapy of non-critically ill patients without previous exposure to azoles unless they are known to be colonized with a Candida strain with reduced susceptibility to azoles. Treatment can be simplified by stepping down to an azole (fluconazole or voriconazole) after at least 5-7 days of treatment with echinocandins or lipid formulations of amphotericin B, if the species is susceptible and the patient has clinically improved. CONCLUSIONS: Specific recommendations were elaborated on IAC management based on the best direct and indirect evidence and on the expertise of a multinational panel.

Epidemiology, species distribution, antifungal susceptibility, and outcome of candidemia across five sites in Italy and Spain.

Candidemia has become an important bloodstream infection that is frequently associated with high rates of mortality and morbidity, and its growing incidence is related to complex medical and surgical procedures. We conducted a multicenter study in five tertiary care teaching hospitals in Italy and Spain and evaluated the epidemiology, species distribution, antifungal susceptibilities, and outcomes of candidemia episodes. In the period of 2008 to 2010, 995 episodes of candidemia were identified in these hospitals. The overall incidence of candidemia was 1.55 cases per 1,000 admissions and remained stable during the 3-year analysis. Candida albicans was the leading agent of infection (58.4%), followed by Candida parapsilosis complex (19.5%), Candida tropicalis (9.3%), and Candida glabrata (8.3%). The majority of the candidemia episodes were found in the internal medicine department (49.6%), followed by the surgical ward, the intensive care unit (ICU), and the hemato-oncology ward. Out of 955 patients who were eligible for evaluation, 381 (39.9%) died within 30 days from the onset of candidemia. Important differences in the 30-day mortality rates were noted between institutions: the lowest mortality rate was in the Barcelona hospital, and the highest rate was in the Udine hospital (33.6% versus 51%, respectively; P = 0.0005). Overall, 5.1% of the 955 isolates tested were resistant or susceptible dose dependent (SDD) to fluconazole, with minor differences between the hospitals in Italy and Spain (5.7% versus 3.5%, respectively; P = 0.2). Higher MICs for caspofungin were found, especially with C. parapsilosis complex (MIC90, 1 µg/ml). Amphotericin B had the lowest MICs. This report shows that candidemia is a significant source of morbidity in Europe, causing a substantial burden of disease and mortality.

Cost-effectiveness of the Surviving Sepsis Campaign protocol for severe sepsis: a prospective nation-wide study in Spain.

CONTEXT: Severe sepsis is associated with high mortality and increased costs. The 'Surviving Sepsis Campaign' (SSC) protocol was developed as an international initiative to reduce mortality. However, its cost-effectiveness is unknown. OBJECTIVE: To determine the cost-effectiveness of the SSC protocol for the treatment of severe sepsis in Spain after the implementation of an educational program compared with the conventional care of severe sepsis. DESIGN: Observational prospective before-and-after study. SETTING: 59 medical-surgical intensive care units located throughout Spain. PATIENTS: A total of 854 patients were enrolled in the pre-educational program cohort (usual or standard care of severe sepsis) and 1,465 patients in the post-educational program cohort (SSC protocol care of severe sepsis). INTERVENTIONS: The educational program aimed to increase adherence to the SSC protocol. The SSC protocol included pharmacological and medical interventions. MAIN OUTCOME MEASURES: Clinical (hospital mortality) and economic (health-care resource and treatment costs) outcomes were recorded. A health-care system perspective was used for costs. The primary outcome was incremental cost-effectiveness ratio (ICER). RESULTS: Patients in the SSC protocol care cohort had a lower risk of hospital mortality (44.0% vs. 39.7%, P = 0.04). However, mean costs per patient were 1,736 euros higher in the SSC protocol care cohort (95% CI 114-3,358 euros), largely as a result of increased length of stay. Mean life years gained (LYG) were higher in the SSC protocol care cohort: 0.54 years (95% CI 0.02-1.05 years). The adjusted ICER of the SSC protocol was 4,435 euros per LYG. Nearly all (96.5%) the bootstrap replications were below the threshold of 30,000 euros per LYG. CONCLUSION: The SSC protocol seems to be a cost-effective option for treating severe sepsis in Spain.

Nosocomial outbreak of infection with pan-drug-resistant Acinetobacter baumannii in a tertiary care university hospital.

OBJECTIVE: To describe what is, to our knowledge, the first nosocomial outbreak of infection with pan-drug-resistant (including colistin-resistant) Acinetobacter baumannii, to determine the risk factors associated with these types of infections, and to determine their clinical impact. DESIGN: Nested case-control cohort study and a clinical-microbiological study. SETTING: A 1,521-bed tertiary care university hospital in Seville, Spain. PATIENTS: Case patients were inpatients who had a pan-drug-resistant A. baumannii isolate recovered from a clinical or surveillance sample obtained at least 48 hours after admission to an intensive care unit (ICU) during the time of the epidemic outbreak. Control patients were patients who were admitted to any of the "boxes" (ie, rooms that partition off a distinct area for a patient's bed and the equipment needed to care for the patient) of an ICU for at least 48 hours during the time of the epidemic outbreak. RESULTS: All the clinical isolates had similar antibiotic susceptibility patterns (ie, they were resistant to all the antibiotics tested, including colistin), and, on the basis of repetitive extragenic palindromic-polymerase chain reaction, it was determined that all of them were of the same clone. The previous use of quinolones and glycopeptides and an ICU stay were associated with the acquisition of infection or colonization with pan-drug-resistant A. baumannii. To control this outbreak, we implemented the following multicomponent intervention program: the performance of environmental decontamination of the ICUs involved, an environmental survey, a revision of cleaning protocols, active surveillance for colonization with pan-drug-resistant A. baumannii, educational programs for the staff, and the display of posters that illustrate contact isolation measures and antimicrobial use recommendations. CONCLUSIONS: We were not able to identify the common source for these cases of infection, but the adopted measures have proven to be effective at controlling the outbreak.

Management of invasive Candida infections in non-neutropenic critically ill patients: from prophylaxis to early therapy.

Echinocandins are the treatment of choice for patients with severe forms of candidaemia, including neutropenic patients and those episodes presenting with shock. There is little distinction between the three available echinocandins (caspofungin, anidulafungin and micafungin), but there is more clinical experience with caspofungin. Identifying patients who will benefit from early antifungal therapy using clinical tools such as the 'Candida Score' is an interesting strategy that may reduce the high mortality in critically ill patients with invasive fungal infections.

Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis.

INTRODUCTION: Genetic variations may influence clinical outcomes in patients with sepsis. The present study was conducted to evaluate the impact on mortality of three polymorphisms after adjusting for confounding variables, and to assess the factors involved in progression of the inflammatory response in septic patients. METHOD: The inception cohort study included all Caucasian adults admitted to the hospital with sepsis. Sepsis severity, microbiological information and clinical variables were recorded. Three polymorphisms were identified in all patients by PCR: the tumour necrosis factor (TNF)-alpha 308 promoter polymorphism; the polymorphism in the first intron of the TNF-beta gene; and the IL-10-1082 promoter polymorphism. Patients included in the study were followed up for 90 days after hospital admission. RESULTS: A group of 224 patients was enrolled in the present study. We did not find a significant association among any of the three polymorphisms and mortality or worsening inflammatory response. By multivariate logistic regression analysis, only two factors were independently associated with mortality, namely Acute Physiology and Chronic Health Evaluation (APACHE) II score and delayed initiation of adequate antibiotic therapy. In septic shock patients (n = 114), the delay in initiation of adequate antibiotic therapy was the only independent predictor of mortality. Risk factors for impairment in inflammatory response were APACHE II score, positive blood culture and delayed initiation of adequate antibiotic therapy. CONCLUSION: This study emphasizes that prompt and adequate antibiotic therapy is the cornerstone of therapy in sepsis. The three polymorphisms evaluated in the present study appear not to influence the outcome of patients admitted to the hospital with sepsis.

A bedside scoring system ("Candida score") for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization.

OBJECTIVE: To obtain a score for deciding early antifungal treatment when candidal infection is suspected in nonneutropenic critically ill patients. DESIGN: Analysis of data collected from the database of the EPCAN project, an ongoing prospective, cohort, observational, multicenter surveillance study of fungal infection and colonization in intensive care unit (ICU) patients. SETTING: Seventy-three medical-surgical ICUs of 70 teaching hospitals in Spain. PATIENTS: A total of 1,699 ICU patients aged 18 yrs and older admitted for at least 7 days between May 1998 and January 1999 were studied. INTERVENTIONS: Surveillance cultures of urine, tracheal, and gastric samples were obtained weekly. Patients were grouped as follows: neither colonized nor infected (n=719), unifocal or multifocal Candida colonization (n=883), and proven candidal infection (n=97). The odds ratio (OR) for each risk factor associated with colonization vs. proven candidal infection was estimated. A logistic regression model was performed to adjust for possible confounders. The "Candida score" was obtained according to the logit method. The discriminatory power was evaluated by the area under the receiver operating characteristics curve. MEASUREMENTS AND MAIN RESULTS: In the logit model, surgery (OR=2.71, 95% confidence interval [CI], 1.45-5.06); multifocal colonization (OR=3.04, 95% CI, 1.45-6.39); total parenteral nutrition (OR=2.48, 95% CI, 1.16-5.31); and severe sepsis (OR=7.68, 95% CI, 4.14-14.22) were predictors of proven candidal infection. The "Candida score" for a cut-off value of 2.5 (sensitivity 81%, specificity 74%) was as follows: parenteral nutrition, +0.908; surgery, +0.997; multifocal colonization, +1.112; and severe sepsis, +2.038. Central venous catheters were not a significant risk factor for proven candidal infection (p=.292). CONCLUSIONS: In a large cohort of nonneutropenic critically ill patients in whom Candida colonization was prospectively assessed, a "Candida score">2.5 accurately selected patients who would benefit from early antifungal treatment.

Steroid-induced myopathy in patients intubated due to exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: To determine incidence, risk factors and impact on various outcome parameters of the development of acute quadriplegic myopathy in a selected population of critically ill patients. SETTING: A prospective cohort study carried out in the intensive care unit of a tertiary-level university hospital. PATIENTS: All patients admitted due to acute exacerbation of chronic obstructive pulmonary disease who required intubation and mechanical ventilation, and received high doses of intravenous corticosteroids. INTERVENTIONS: A neurophysiological study was performed in all cases at the onset of weaning. Muscular biopsy was taken when the neurophysiological study revealed a myopathic pattern. MEASUREMENTS AND RESULTS: Twenty-six patients were enrolled in the study. Nine patients (34.6%) developed myopathy. Only seven patients were treated with muscle relaxants. Histology confirmed the diagnosis in the three patients who underwent muscle biopsy. APACHE II score at admission, the rate of sepsis and the total doses of corticosteroids were significantly higher in patients with myopathy compared with those patients that did not develop it. Myopathy is associated with an increase in the duration of mechanical ventilation [15.4 (9.2) versus 5.7 (3.9) days; p<0.006], the length of ICU stay [23.6 (10.7) versus 11.4 (7.05) days; p<0.003] and hospital stay [33.3 (19.2) versus 21.2 (16.1) days; p<0.034)]. Myopathy was not associated with increased mortality. CONCLUSIONS: In the population under study, severity of illness at admission, the development of sepsis and the total dose of corticosteroids are factors associated with the occurrence of myopathy after the administration of corticosteroids. Myopathy was associated with prolonged mechanical ventilation and in-hospital stay.