Adjunctive immunotherapeutic agents in patients with sepsis and septic shock: a multidisciplinary consensus of 23.

BACKGROUND: In the last decades, several adjunctive treatments have been proposed to reduce mortality in septic shock patients. Unfortunately, mortality due to sepsis and septic shock remains elevated and NO trials evaluating adjunctive therapies were able to demonstrate any clear benefit. In light of the lack of evidence and conflicting results from previous studies, in this multidisciplinary consensus, the authors considered the rational, recent investigations and potential clinical benefits of targeted adjunctive therapies. METHODS: A panel of multidisciplinary experts defined clinical phenotypes, treatments and outcomes of greater interest in the field of adjunctive therapies for sepsis and septic shock. After an extensive systematic literature review, the appropriateness of each treatment for each clinical phenotype was determined using the modified RAND/UCLA appropriateness method. RESULTS: The consensus identified two distinct clinical phenotypes: patients with overwhelming shock and patients with immune paralysis. Six different adjunctive treatments were considered the most frequently used and promising: (i) corticosteroids, (ii) blood purification, (iii) immunoglobulins, (iv) granulocyte/monocyte colony-stimulating factor and (v) specific immune therapy (i.e. interferon-gamma, IL7 and AntiPD1). Agreement was achieved in 70% of the 25 clinical questions. CONCLUSIONS: Although clinical evidence is lacking, adjunctive therapies are often employed in the treatment of sepsis. To address this gap in knowledge, a panel of national experts has provided a structured consensus on the appropriate use of these treatments in clinical practice.

Antibiotic prophylaxis in trauma: Global Alliance for Infection in Surgery, Surgical Infection Society Europe, World Surgical Infection Society, American Association for the Surgery of Trauma, and World Society of Emergency Surgery guidelines.

ABSTRACT: Trauma is a complex disease, and the use of antibiotic prophylaxis (AP) in trauma patients is common practice. However, considering the increasing rates of antibiotic resistance, AP use should be questioned and limited only to specific cases. Antibiotic stewardship is of paramount importance in fighting resistance spread. Definitive rules or precise indications about AP in trauma remain unclear. The present article describes the indications of AP in traumatic lesions to the head, brain, torso, maxillofacial, extremities, skin, and soft tissues endorsed by the Global Alliance for Infection in Surgery, Surgical Infection Society Europe, World Surgical Infection Society, American Association for the Surgery of Trauma, and World Society of Emergency Surgery.

Source control in emergency general surgery: WSES, GAIS, SIS-E, SIS-A guidelines.

Intra-abdominal infections (IAI) are among the most common global healthcare challenges and they are usually precipitated by disruption to the gastrointestinal (GI) tract. Their successful management typically requires intensive resource utilization, and despite the best therapies, morbidity and mortality remain high. One of the main issues required to appropriately treat IAI that differs from the other etiologies of sepsis is the frequent requirement to provide physical source control. Fortunately, dramatic advances have been made in this aspect of treatment. Historically, source control was left to surgeons only. With new technologies non-surgical less invasive interventional procedures have been introduced. Alternatively, in addition to formal surgery open abdomen techniques have long been proposed as aiding source control in severe intra-abdominal sepsis. It is ironic that while a lack or even delay regarding source control clearly associates with death, it is a concept that remains poorly described. For example, no conclusive definition of source control technique or even adequacy has been universally accepted. Practically, source control involves a complex definition encompassing several factors including the causative event, source of infection bacteria, local bacterial flora, patient condition, and his/her eventual comorbidities. With greater understanding of the systemic pathobiology of sepsis and the profound implications of the human microbiome, adequate source control is no longer only a surgical issue but one that requires a multidisciplinary, multimodality approach. Thus, while any breach in the GI tract must be controlled, source control should also attempt to control the generation and propagation of the systemic biomediators and dysbiotic influences on the microbiome that perpetuate multi-system organ failure and death. Given these increased complexities, the present paper represents the current opinions and recommendations for future research of the World Society of Emergency Surgery, of the Global Alliance for Infections in Surgery of Surgical Infection Society Europe and Surgical Infection Society America regarding the concepts and operational adequacy of source control in intra-abdominal infections.

Rationale and clinical application of antimicrobial stewardship principles in the intensive care unit: a multidisciplinary statement.

BACKGROUND: Antimicrobial resistance represents a major critical issue for the management of the critically ill patients hospitalized in the intensive care unit (ICU), since infections by multidrug-resistant bacteria are characterized by high morbidity and mortality, high rates of treatment failure, and increased healthcare costs worldwide. It is also well known that antimicrobial resistance can emerge as a result of inadequate antimicrobial therapy, in terms of drug selection and/or treatment duration. The application of antimicrobial stewardship principles in ICUs improves the quality of antimicrobial therapy management. However, it needs specific considerations related to the critical setting. METHODS: The aim of this consensus document gathering a multidisciplinary panel of experts was to discuss principles of antimicrobial stewardship in ICU and to produce statements that facilitate their clinical application and optimize their effectiveness. The methodology used was a modified nominal group discussion. CONCLUSION: The final set of statements underlined the importance of the specific interpretation of antimicrobial stewardship's principles in critically ill patient management, quasi-targeted therapy, the use of rapid diagnostic methods, the personalization of antimicrobial therapies' duration, obtaining microbiological surveillance data, the use of PK/PD targets, and the use of specific indicators in antimicrobial stewardship programs.

Implementation Strategies for Preventing Healthcare-Associated Infections across the Surgical Pathway: An Italian Multisociety Document.

Healthcare-associated infections (HAIs) result in significant patient morbidity and can prolong the duration of the hospital stay, causing high supplementary costs in addition to those already sustained due to the patient's underlying disease. Moreover, bacteria are becoming increasingly resistant to antibiotics, making HAI prevention even more important nowadays. The public health consequences of antimicrobial resistance should be constrained by prevention and control actions, which must be a priority for all health systems of the world at all levels of care. As many HAIs are preventable, they may be considered an important indicator of the quality of patient care and represent an important patient safety issue in healthcare. To share implementation strategies for preventing HAIs in the surgical setting and in all healthcare facilities, an Italian multi-society document was published online in November 2022. This article represents an evidence-based summary of the document.

Targeted Therapy of Severe Infections Caused by Staphylococcus aureus in Critically Ill Adult Patients: A Multidisciplinary Proposal of Therapeutic Algorithms Based on Real-World Evidence.

(1) Introduction: To develop evidence-based algorithms for targeted antibiotic therapy of infections caused by Staphylococcus aureus in critically ill adult patients. (2) Methods: A multidisciplinary team of four experts had several rounds of assessment for developing algorithms concerning targeted antimicrobial therapy of severe infections caused by Staphylococcus aureus in critically ill patients. The literature search was performed by a researcher on PubMed-MEDLINE (until August 2022) to provide evidence for supporting therapeutic choices. Quality and strength of evidence was established according to a hierarchical scale of the study design. Two different algorithms were created, one for methicillin-susceptible Staphylococcus aureus (MSSA) and the other for methicillin-resistant Staphylococcus aureus (MRSA). The therapeutic options were categorized for each different site of infection and were selected also on the basis of pharmacokinetic/pharmacodynamic features. (3) Results: Cefazolin or oxacillin were the agents proposed for all of the different types of severe MSSA infections. The proposed targeted therapies for severe MRSA infections were different according to the infection site: daptomycin plus fosfomycin or ceftaroline or ceftobiprole for bloodstream infections, infective endocarditis, and/or infections associated with intracardiac/intravascular devices; ceftaroline or ceftobiprole for community-acquired pneumonia; linezolid alone or plus fosfomycin for infection-related ventilator-associated complications or for central nervous system infections; daptomycin alone or plus clindamycin for necrotizing skin and soft tissue infections. (4) Conclusions: We are confident that targeted therapies based on scientific evidence and optimization of the pharmacokinetic/pharmacodynamic features of antibiotic monotherapy or combo therapy may represent valuable strategies for treating MSSA and MRSA infections.

Tissue Penetration of Antimicrobials in Intensive Care Unit Patients: A Systematic Review-Part I.

The challenging severity of some infections, especially in critically ill patients, makes the diffusion of antimicrobial drugs within tissues one of the cornerstones of chemotherapy. The knowledge of how antibacterial agents penetrate tissues may come from different sources: preclinical studies in animal models, phase I-III clinical trials and post-registration studies. However, the particular physiopathology of critically ill patients may significantly alter drug pharmacokinetics. Indeed, changes in interstitial volumes (the third space) and/or in glomerular filtration ratio may influence the achievement of bactericidal concentrations in peripheral compartments, while inflammation can alter the systemic distribution of some drugs. On the contrary, other antibacterial agents may reach high and effective concentrations thanks to the increased tissue accumulation of macrophages and neutrophils. Therefore, the present review explores the tissue distribution of beta-lactams and other antimicrobials acting on the cell wall and cytoplasmic membrane of bacteria in critically ill patients. A systematic search of articles was performed according to PRISMA guidelines, and tissue/plasma penetration ratios were collected. Results showed a highly variable passage of drugs within tissues, while large interindividual variability may represent a hurdle which must be overcome to achieve therapeutic concentrations in some compartments. To solve that issue, off-label dosing regimens could represent an effective solution in particular conditions.

Tissue Penetration of Antimicrobials in Intensive Care Unit Patients: A Systematic Review-Part II.

In patients that are admitted to intensive care units (ICUs), the clinical outcome of severe infections depends on several factors, as well as the early administration of chemotherapies and comorbidities. Antimicrobials may be used in off-label regimens to maximize the probability of therapeutic concentrations within infected tissues and to prevent the selection of resistant clones. Interestingly, the literature clearly shows that the rate of tissue penetration is variable among antibacterial drugs, and the correlation between plasma and tissue concentrations may be inconstant. The present review harvests data about tissue penetration of antibacterial drugs in ICU patients, limiting the search to those drugs that mainly act as protein synthesis inhibitors and disrupting DNA structure and function. As expected, fluoroquinolones, macrolides, linezolid, and tigecycline have an excellent diffusion into epithelial lining fluid. That high penetration is fundamental for the therapy of ventilator and healthcare-associated pneumonia. Some drugs also display a high penetration rate within cerebrospinal fluid, while other agents diffuse into the skin and soft tissues. Further studies are needed to improve our knowledge about drug tissue penetration, especially in the presence of factors that may affect drug pharmacokinetics.

Effectiveness of a Multifaced Antibiotic Stewardship Program: A Pre-Post Study in Seven Italian ICUs.

Multidrug resistance has become a serious threat for health, particularly in hospital-acquired infections. To improve patients' safety and outcomes while maintaining the efficacy of antimicrobials, complex interventions are needed involving infection control and appropriate pharmacological treatments in antibiotic stewardship programs. We conducted a multicenter pre-post study to assess the impact of a stewardship program in seven Italian intensive care units (ICUs). Each ICU was visited by a multidisciplinary team involving clinicians, microbiologists, pharmacologists, infectious disease specialists, and data scientists. Interventions were targeted according to the characteristics of each unit. The effect of the program was measured with a panel of indicators computed with data from the MargheritaTre electronic health record. The median duration of empirical therapy decreased from 5.6 to 4.6 days and the use of quinolones dropped from 15.3% to 6%, both p < 0.001. The proportion of multi-drug-resistant bacteria (MDR) in ICU-acquired infections fell from 57.7% to 48.8%. ICU mortality and length of stay remained unchanged, indicating that reducing antibiotic administration did not harm patients' safety. This study shows that our stewardship program successfully improved the management of infections. This suggests that policy makers should tackle multidrug resistance with a multidisciplinary approach based on continuous monitoring and personalised interventions.

Orthopaedic Implant-Associated Staphylococcal Infections: A Critical Reappraisal of Unmet Clinical Needs Associated with the Implementation of the Best Antibiotic Choice.

Infections associated with orthopaedic implants represent a major health concern characterized by a remarkable incidence of morbidity and mortality. The wide variety of clinical scenarios encountered in the heterogeneous world of infections associated with orthopaedic implants makes the implementation of an optimal and standardized antimicrobial treatment challenging. Antibiotic bone penetration, anti-biofilm activity, long-term safety, and drug choice/dosage regimens favouring outpatient management (i.e., long-acting or oral agents) play a major role in regards to the chronic evolution of these infections. The aim of this multidisciplinary opinion article is to summarize evidence supporting the use of the different anti-staphylococcal agents in terms of microbiological and pharmacological optimization according to bone penetration, anti-biofilm activity, long-term safety, and feasibility for outpatient regimens, and to provide a useful guide for clinicians in the management of patients affected by staphylococcal infections associated with orthopaedic implants Novel long-acting lipoglycopeptides, and particularly dalbavancin, alone or in combination with rifampicin, could represent the best antibiotic choice according to real-world evidence and pharmacokinetic/pharmacodynamic properties. The implementation of a multidisciplinary taskforce and close cooperation between microbiologists and clinicians is crucial for providing the best care in this scenario.

The Impact of Fast Microbiology in Intensive Care Units in the Era of Antibiotic Resistance: An Observational Retrospective Study.

The increasing prevalence of multi-drug-resistant bacteria responsible for bloodstream infections (BSIs) makes therapeutic choices progressively more complex. Fast microbiology quickly detects the presence of pathogens and clinically relevant determinants of antibiotic resistance, offering the potential for early administration of antibiotics. In this retrospective observational study, we comparatively evaluated the performances of FilmArray and the current standard method using blood samples collected from intensive care unit (ICU) patients with suspected BSI. A full agreement with the standard was observed in 97/102 samples (95.1 ± 4.2%), a mismatch in 3/102 samples (2.9 ± 3.2%) and detection failure in 2/102 cases (1.96 ± 2.7%). Statistical analysis demonstrated a near-perfect/perfect level of agreement between the two methods, with an overall degree of agreement of 95%. The high performance demonstrated by the FilmArray could allow a "watch and wait" approach helping clinicians in decision-making processes related to choice and initiation of the antimicrobial therapy, thus avoiding ineffective and excessive use of drugs.

An evidence-based multidisciplinary approach focused at creating algorithms for targeted therapy of infection-related ventilator associated complications (IVACs) caused by Enterobacterales in critically ill adult patients.

INTRODUCTION: Prompt implementation of appropriate targeted antibiotic therapy representsa valuable approach in improving clinical and ecological outcome in critically septic patients. Thismultidisciplinary opinion article aims to develop evidence-based algorithms for targeted antibiotictherapy of infection-related ventilator associated complications (IVACs) caused by Enterobacterales,which are among the most common pathogens associated with these conditions. AREAS COVERED: A multidisciplinary team of four experts had several rounds of assessment for developingalgorithms devoted to targeted antimicrobial therapy of IVACs caused by Enterobacterales.A literature search was performed on PubMed-MEDLINE (until March 2021) to provide evidence forsupporting therapeutic choices. Quality and strength of evidence was established according toa hierarchical scale of the study design. Six different algorithms with associated recommendations concerning therapeutic choice and dosing optimization were suggested according to the susceptibilitypattern of Enterobacterales: multi-susceptible, extended-spectrum beta-lactamase (ESBL)-producing,AmpC beta-lactamase-producing, Klebsiella pneumoniae carbapenemase (KPC)-producing, OXA-48-producing, and metallo-beta-lactamase (MBL)-producing Enterobacterales. EXPERT OPINION: The implementation of algorithms focused on prompt revision of antibiotic regimensguided by results of conventional and rapid diagnostic methodologies, appropriate place in therapy ofnovel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and PK/PD optimization of antibiotic dosing regimens is strongly suggested.

High dose coupled plasma filtration and adsorption in septic shock patients. Results of the COMPACT-2: a multicentre, adaptive, randomised clinical trial.

PURPOSE: This study aimed at evaluating the efficacy and safety of high-dose (> 0.2 L/kg of treated plasma per day) coupled plasma filtration-adsorption (CPFA) in treating patients with septic shock. METHODS: Multicentre, randomised, adaptive trial, performed in 12 Italian intensive care units (ICUs). Patients aged 14 or more, admitted to the ICU with septic shock, or had developed it during the stay were eligible. The final outcome was mortality at discharge from the last hospital at which the patient received care. RESULTS: Between May 2015, and October 2017, 115 patients were randomised. The first interim analysis revealed a number of early deaths, prompting an unplanned analysis. Last hospital mortality was non-significantly higher in the CPFA (55.6%) than in the control group (46.2%, p = 0.35). The 90-day survival curves diverged in favour of the controls early after randomisation and remained separated afterwards (p = 0.100). An unplanned analysis showed higher mortality in CPFA compared to controls among patients without severe renal failure (p = 0.025); a dose-response relationship was observed between treated plasma volume and mortality (p = 0.010). CONCLUSION: The COMPACT-2 trial was stopped due to the possible harmful effect of CPFA in patients with septic shock. The harmful effect, if present, was particularly marked in the early phase of septic shock. Patients not requiring renal replacement therapy seemed most exposed to the possible harm, with evidence of a dose-response effect. Until the mechanisms behind these results are fully understood, the use of CPFA for the treatment of patients with septic shock is not recommended.

A pandemic recap: lessons we have learned.

On January 2020, the WHO Director General declared that the outbreak constitutes a Public Health Emergency of International Concern. The world has faced a worldwide spread crisis and is still dealing with it. The present paper represents a white paper concerning the tough lessons we have learned from the COVID-19 pandemic. Thus, an international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making. With the present paper, international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making.

Acute abdomen in the immunocompromised patient: WSES, SIS-E, WSIS, AAST, and GAIS guidelines.

Immunocompromised patients are a heterogeneous and diffuse category frequently presenting to the emergency department with acute surgical diseases. Diagnosis and treatment in immunocompromised patients are often complex and must be multidisciplinary. Misdiagnosis of an acute surgical disease may be followed by increased morbidity and mortality. Delayed diagnosis and treatment of surgical disease occur; these patients may seek medical assistance late because their symptoms are often ambiguous. Also, they develop unique surgical problems that do not affect the general population. Management of this population must be multidisciplinary.This paper presents the World Society of Emergency Surgery (WSES), Surgical Infection Society Europe (SIS-E), World Surgical Infection Society (WSIS), American Association for the Surgery of Trauma (AAST), and Global Alliance for Infection in Surgery (GAIS) joined guidelines about the management of acute abdomen in immunocompromised patients.

Recognition in Emergency Department of Septic Patients at Higher Risk of Death: Beware of Patients without Fever.

Background and Objectives: Chances of surviving sepsis increase markedly upon prompt diagnosis and treatment. As most sepsis cases initially show-up in the Emergency Department (ED), early recognition of a septic patient has a pivotal role in sepsis management, despite the lack of precise guidelines. The aim of this study was to identify the most accurate predictors of in-hospital mortality outcome in septic patients admitted to the ED. Materials and Methods: We compared 651 patients admitted to ED for sepsis (cases) with 363 controls (non-septic patients). A Bayesian mean multivariate logistic regression model was performed in order to identify the most accurate predictors of in-hospital mortality outcomes in septic patients. Results: Septic shock and positive qSOFA were identified as risk factors for in-hospital mortality among septic patients admitted to the ED. Hyperthermia was a protective factor for in-hospital mortality. Conclusions: Physicians should bear in mind that fever is not a criterium for defining sepsis; according to our results, absence of fever upon presentation might be indicative of greater severity and diagnosis of sepsis should not be delayed.

An Evidence-Based Multidisciplinary Approach Focused at Creating Algorithms for Targeted Therapy of BSIs, cUTIs, and cIAIs Caused by Enterobacterales in Critically Ill Adult Patients.

Prompt implementation of appropriate targeted antibiotic therapy represents a valuable approach in improving clinical and ecological outcome in critically septic patients. This multidisciplinary opinion article focused at developing evidence-based algorithms for targeted antibiotic therapy of bloodstream (BSIs), complicated urinary tract (cUTIs), and complicated intrabdominal infections (cIAIs) caused by Enterobacterales. The aim was to provide a guidance for intensive care physicians either in appropriately placing novel antibiotics or in considering strategies for sparing the broadest-spectrum antibiotics. A multidisciplinary team of experts (one intensive care physician, one infectious disease consultant, one clinical microbiologist and one MD clinical pharmacologist), performed several rounds of assessment to reach agreement in developing six different algorithms according to the susceptibility pattern (one each for multi-susceptible, extended-spectrum beta-lactamase-producing, AmpC beta-lactamase-producing, Klebsiella pneumoniae carbapenemase (KPC)-producing, OXA-48-producing, and Metallo-beta-lactamase (MBL)-producing Enterobacterales). Whenever multiple therapeutic options were feasible, a hierarchical scale was established. Recommendations on antibiotic dosing optimization were also provided. In order to retrieve evidence-based support for the therapeutic choices proposed in the algorithms, a comprehensive literature search was performed by a researcher on PubMed-MEDLINE from inception until March 2021. Quality and strength of evidence was established according to a hierarchical scale of the study design. Only articles published in English were included. It is expected that these algorithms, by allowing prompt revision of antibiotic regimens whenever feasible, appropriate place in therapy of novel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and pharmacokinetic/pharmacodynamic optimization of antibiotic dosing regimens, may be helpful either in improving clinical outcome or in containing the spread of antimicrobial resistance.

D-Dimer as Biomarker for Early Prediction of Clinical Outcomes in Patients With Severe Invasive Infections Due to Streptococcus Pneumoniae and Neisseria Meningitidis.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection; no current clinical measure adequately reflects the concept of dysregulated response. Coagulation plays a pivotal role in the normal response to pathogens (immunothrombosis), thus the evolution toward sepsis-induced coagulopathy could be individuate through coagulation/fibrinolysis-related biomarkers. We focused on the role of D-dimer assessed within 24 h after admission in predicting clinical outcomes in a cohort of 270 patients hospitalized in a 79 months period for meningitis and/or bloodstream infections due to Streptococcus pneumoniae (n = 162) or Neisseria meningitidis (n = 108). Comparisons were performed with unpaired t-test, Mann-Whitney-test or chi-squared-test with continuity correction, as appropriate, and multivariable logistic regression analysis was performed with Bayesian model averaging. In-hospital mortality was 14.8% for the overall population, significantly higher in S. pneumoniae than in N. meningitidis patients: 19.1 vs. 8.3%, respectively (p = 0.014). At univariable logistic regression analysis the following variables were significantly associated with in-hospital mortality: pneumococcal etiology, female sex, age, ICU admission, SOFA score, septic shock, MODS, and D-dimer levels. At multivariable analysis D-dimer showed an effect only in N. meningitidis subgroup: as 500 ng/mL of D-dimer increased, the probability of unfavorable outcome increased on average by 4%. Median D-dimer was significantly higher in N. meningitidis than in S. pneumoniae patients (1,314 vs. 1,055 ng/mL, p = 0.009). For N. meningitidis in-hospital mortality was 0% for D-dimer <500 ng/mL, very low (3.5%) for D-dimer <7,000 ng/mL, and increased to 26.1% for D-dimer >7,000 ng/mL. Kaplan-Meier analysis of in-hospital mortality showed for N. meningitidis infections a statistically significant difference for D-dimer >7,000 ng/mL compared to values <500 ng/mL (p = 0.021) and 500-3,000 ng/mL (p = 0.002). For S. pneumoniae the mortality risk resulted always high, over 10%, irrespective by D-dimer values. In conclusion, D-dimer is rapid to be obtained, at low cost and available everywhere, and can help stratify the risk of in-hospital mortality and complications in patients with invasive infections due to N. meningitidis: D-dimer <500 ng/mL excludes any further complications, and a cut-off of 7,000 ng/mL seems able to predict a significantly increased mortality risk from much <10% to over 25%.

The role of procalcitonin in reducing antibiotics across the surgical pathway.

Procalcitonin (PCT) is widely considered as a highly sensitive biomarker of bacterial infection, offering general and emergency surgeons a key tool in the management of surgical infections. A multidisciplinary task force of experts met in Bologna, Italy, on April 4, 2019, to clarify the key issues in the use of PCT across the surgical pathway. The panelists presented the statements developed for each of the main questions regarding the use of PCT across the surgical pathway. An agreement on the statements was reached by the Delphi method, and this document reports the executive summary of the final recommendations approved by the expert panel.