Intravenous immunoglobulin for adjunctive treatment of severe infections in ICUs Purpose of review This review focuses on the emerging literature regarding the use of intravenous immunoglobulins (IVIg) in critically ill patients with severe infections. The aim is to provide an accessible summary of the most recent evidence of IVIg use in sepsis and septic shock and to help clinicians to understand why there is still equipoise regarding the potential benefit of this adjunctive therapy in this setting. Recent findings Observational studies with propensity score matching analyses and investigating the effect of IVIg in severe infections including necrotizing soft tissue infection have been recently published. These studies suffer important flaws precluding robust conclusion to be drawn. Some recent randomized controlled trials raised interesting findings supportive of personalized medicine but are likely to be underpowered or confounded. Summary Insufficient evidence is available to support IVIg use in sepsis and septic shock, apart from the specific case of streptococcal toxic shock syndrome. Current literature suggests that IVIg efficacy in sepsis or septic shock could depend on the IVIg preparation (IgM-enriched or minimal IgM), time of administration (<24 h), dose, and the inflammatory/immunomodulation profile of the patients. Investigator-initiated research, incorporating these parameters, is warranted to determine whether IVIg benefits critically ill patients with severe infection.

Meningitis and encephalitis management in the ICU Purpose of review Management of patients with meningitis and encephalitis oftentimes requires ICU level of care. This article is an update on management for meningitis and encephalitis with focus on clinical care in the ICU. Information provided is based on a review of recent studies with focus on studies since 2017. Recent findings Advances in diagnostic and treatment approach for different pathogens are presented. Nosocomial meningitis now constitutes a major part of brain infections seen in ICUs in the developed world. Advances in ICU care of central nervous system (CNS) infections include application of newer diagnostic methods, improved understanding and delivery of antibiotics to the CNS, infection prevention for nosocomial infections, and application of neuromonitoring where indicated. Summary Advances in diagnostics and therapeutic approach to CNS infections are continually made. For intensivists, focus on neuromonitoring and brain resuscitation in critically ill patients with CNS infections may present a path to enhance preservation of brain function and improve outcomes. Video abstract http://links.lww.com/COCC/A22.

Diagnosing invasive pulmonary aspergillosis in ICU patients: putting the puzzle together Purpose of review The approach to diagnose invasive pulmonary aspergillosis in the absence of lung biopsy in ICU patients is reviewed. This approach should be based on four pillars: mycology, medical imaging, underlying conditions, and acute disease expression. Recent findings Diagnosing invasive pulmonary aspergillosis in the absence of histopathologic evidence is a matter of probability weighting. Initiating antifungal therapy in an early phase and with a lower likelihood of disease might outweigh further diagnostic workout with further delay in appropriate treatment. However, in ICU patients, a preemptive antifungal strategy has not been established yet. Summary For mycology, a positive galactomannan test on serum or broncho-alveolar lavage fluid is highly indicative of invasive pulmonary aspergillosis. The meaning of positive culture results, lateral-flow device test, or PCR-assay is ambiguous. A negative galactomannan or PCR test has high negative predictive value. Clinical features suggestive for invasive fungal disease on CT-scan are highly indicative but rare in ventilated patients. An immunocompromised status indicates high-risk. chronic obstructive pulmonary disease, hepatic cirrhosis, and AIDS indicate moderate risk. Invasive pulmonary aspergillosis in the absence of underlying conditions is rare. Acute diseases frequently associated with invasive pulmonary aspergillosis include sepsis and/or respiratory insufficiency because of influenza, acute respiratory distress syndrome, or pneumonia.

Optimizing therapy of bloodstream infection due to extended-spectrum β-lactamase-producing Enterobacteriaceae Purpose of review Infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) are increasing worldwide. Carbapenems are usually regarded as the antibiotics of choice for the treatment of serious ESBL infections. However, because of the alarming emergence or carbapenem resistance, interest in effective alternatives has emerged. The present review summarizes the findings published on the antibiotics currently available for treatment of patients with an ESBL-E bloodstream infection (BSI). Recent findings Meropenem and imipenem are the drugs recommended for treatment of ESBL BSIs in critically ill patients, and in infections with high bacterial loads or elevated β-lactam minimum inhibitory concentrations. Ertapenem should be reserved for patients with less severe presentations, and should be used at high doses. In milder presentations or BSIs from low-risk sources, other carbapenem-sparing alternatives could be considered: cephamycins, fluoroquinolones, and particularly a β-lactam/β-lactam inhibitor combination (particularly piperacillin/tazobactam). Optimized dosing of piperacillin/tazobactam is recommended (high doses and extended infusion). There are few data on the use of the promising newly available drugs (e.g. ceftolozane/tazobactam, ceftazidime/avibactam, cefiderocol, and plazomicin), and it seems reasonable to reserve them as last-resort drugs. Summary Carbapenems should be used in patients with serious infections; alternatives could be used individually, particularly for definitive treatment of patients with milder presentations.

Severe influenza: overview in critically ill patients Purpose of review Overview of influenza infection, focusing on outcome and complications in critically ill patients. We also discuss relevant elements in immunopathogenesis and their role as predictors of severity. Recent findings Pandemic influenza A (H1N1) virus circulates seasonally and remains the predominant subtype among intensive care patients. Mortality in acute respiratory failure (ARF) is around 20%, independent of influenza subtypes. During severe infection, the imbalance between pro-inflammatory and anti-inflammatory molecules, such as Th1 and Th17 cytokines, is associated with complicated infections and mortality. Primary viral pneumonia presents in more than 70% of ICU influenza patients and more than 50% develop acute respiratory distress syndrome. Bacterial secondary infection occurs in 20% of severe cases and Streptococcus pneumoniae and Staphylococcus aureus remain the prevalent pathogens. Myocarditis and late-onset cardiovascular complications are associated with mortality. Antiviral therapy within 48 h after onset, avoidance of corticosteroids and rescue therapies for ARF or myocarditis, such as extracorporeal membrane oxygenation, improve survival. Summary The present review summarizes current knowledge on pathogenesis and clinical manifestations of severe influenza. Immunological dysfunction during viral infection correlates with severity and mortality among ICU patients. A theranostics strategy should be implemented to improve outcomes.

Optimal and responsible use of antibiotics Purpose of review In this review, we focus on the dual face of antibiotic therapy in the critically ill that must harmonize the need for early, appropriate and adequate antibiotic therapy in the individual-infected patient with the obligation to limit antibiotic selection pressure as much as possible to preserve its future potential. Recent findings Recent articles have highlighted and detailed the various aspects, which determine antibiotic efficacy, and have identified adjunctive treatments, such as source control, which impact outcome. In addition, settings and indications where antibiotics do not improve outcome and may cause harm have been identified. Summary Reconciling antibiotic efficacy with the limitations of their use is feasible but requires a dedicated and sustained effort throughout the whole process of clinical decision-making, from initial suspicion of sepsis to its definitive treatment.

How should we treat acinetobacter pneumonia? Purpose of review To describe recent data about Acinetobacter baumannii pneumonia epidemiology and the therapeutic options including adjunctive nebulized therapy. Recent findings A. baumannii is a major cause of nosocomial pneumonia in certain geographic areas affecting mainly debilitated patients, with prolonged hospitalization and broad-spectrum antimicrobials. Inappropriate empirical treatment has clearly been associated with increased mortality in A. baumannii pneumonia. Carbapenems may not be considered the treatment of choice in areas with high rates of carbapenem-resistant A. baumannii. Nowadays, polymyxins are the antimicrobials with the greatest level of in-vitro activity. Colistin is the antimicrobial most widely used although polymyxin B is associated with less renal toxicity. It is clear that lung concentrations of polymyxins are suboptimal in a substantial proportion of patients. This issue has justified the use of combination therapy or adjunctive nebulized antibiotics. Current evidence does not allow us to recommend combination therapy for A. baumannii pneumonia. Regarding nebulized antibiotics, it seems reasonable to use in patients who are nonresponsive to systemic antibiotics or A. baumannii isolates with colistin minimum inhibitory concentrations close to the susceptibility breakpoints. Cefiderocol, a novel cephalosporin active against A. baumannii, may represent an attractive therapeutic option if ongoing clinical trials confirm preliminary results. Summary The optimal treatment for multidrug-resistant A. baumannii pneumonia has not been established. New therapeutic options are urgently needed. Well designed, randomized controlled trials must been conducted to comprehensively evaluate the effectiveness and safety of nebulized antibiotics for the treatment of A. baumannii pneumonia.

Challenges in conducting long-term outcomes studies in critical care Purpose of review Evaluating longer term mortality, morbidity, and quality of life in survivors of critical illness is a research priority. This review details the challenges of long-term follow-up studies of critically ill patients and highlights recently proposed methodological solutions. Recent findings Barriers to long-term follow-up studies of critical care survivors include high rates of study attrition because of death or loss to follow-up, data missingness from experienced morbidity, and lack of standardized outcome as well as reporting of key covariates. A number of recent methods have been proposed to reduce study patients attrition, including minimum data set selection and visits to transitional care or home settings, yet these have significant downsides as well. Conducting long-term follow-up even in the absence of such models carries a high expense, as personnel are very costly, and patients/families require reimbursement for their time and inconvenience. Summary There is a reason why many research groups do not conduct long-term outcomes in critical care: it is very difficult. Challenges of long-term follow-up require careful consideration by study investigators to ensure our collective success in data integration and a better understanding of underlying mechanisms of mortality and morbidity seen in critical care survivorship.

Population enrichment for critical care trials: phenotypes and differential outcomes Purpose of review Sepsis and acute respiratory distress syndrome (ARDS) are two heterogenous acute illnesses where numerous RCTs have indeterminate results. We present a narrative review on the recent developments in enriching patient populations for future sepsis and ARDS trials. Recent findings Many researchers are actively pursuing enrichment strategies to reduce heterogeneity to increase the sensitivity of future trials. Enrichment refers to the use of measurable patient characteristics, known before randomisation, to refine trial populations. Biomarkers could increase the diagnostic certainty of sepsis, whereas chest radiology training to enhance reliability of interpretation and stabilisation period of mechanical ventilation have been considered to increase the diagnostic certainty of ARDS. Clinical and biomarker data analyses identifies four to six sepsis clinical phenotypes and two ARDS clinical phenotypes. Similarly, leukocyte gene expression data identifies two to four sepsis molecular phenotypes. Use of a test-dose identifies ARDS subpopulations who are likely to benefit from higher PEEP. Early-phase trials report how a biomarker that is altered by the intervention, such as lymphocyte count for recombinant interleukin-7 therapy and higher check point inhibitor expression for anti-check point treatments in sepsis, could identify a higher treatment effect population for future trials. Summary Enrichment reduces heterogeneity and will enhance the sensitivity of future trials. However, enrichment, even when it identifies more homogenous populations, may not be efficient to deploy in trials or clinical practice.