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EUROPEAN RESPIRATORY JOURNAL ERS OFFICIAL DOCUMENTS I. MARTIN-LOECHES ET AL. ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia Ignacio Martin-Loeches 1,2,3,4,28, Antoni Torres 3,4,28, Blin Nagavci5, Stefano Aliberti 6,7, Massimo Antonelli 8, Matteo Bassetti 9...

EUROPEAN RESPIRATORY JOURNAL ERS OFFICIAL DOCUMENTS I. MARTIN-LOECHES ET AL. ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia Ignacio Martin-Loeches 1,2,3,4,28, Antoni Torres 3,4,28, Blin Nagavci5, Stefano Aliberti 6,7, Massimo Antonelli 8, Matteo Bassetti 9, Lieuwe Bos10, James D. Chalmers11, Lennie Derde 12, Jan de Waele13, Jose Garnacho-Montero14, Marin Kollef15, Carlos Luna 16, Rosario Menendez17, Michael Niederman18, Dmitry Ponomarev19,20, Marcos Restrepo21, David Rigau22, Marcus J. Schultz Emmanuel Weiss25, Tobias Welte 26 and Richard Wunderink 27 10,23,24 , 1 Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organisation (MICRO), St James’s Hospital, Dublin, Ireland. 2Trinity College Dublin, Dublin, Ireland. 3CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain. 4 Pulmonary Department, Hospital Clinic, Universitat de Barcelona, IDIBAPS, ICREA, Barcelona, Spain. 5Faculty of Medicine, Institute for Evidence in Medicine, Medical Centre – University of Freiburg, University of Freiburg, Freiburg, Germany. 6Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy. 7Respiratory Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy. 8 Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 9Infectious Disease Clinic, Ospedale Policlinico San Martino IRCCS, Department of Health Sciences, University of Genoa, Genoa, Italy. 10Department of Intensive Care and Laboratory for Experimental Intensive Care and Anesthesiology (LEICA), Amsterdam UMC, location AMC, Amsterdam, The Netherlands. 11Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK. 12Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 13Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium. 14 Intensive Care Unit, University Hospital Virgen Macarena, Sevilla, Spain. 15Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. 16Neumonología, Hospital de Clínicas, UBA, Buenos Aires, Argentina. 17Pneumology Service, University and Politechnic Hospital La Fe, Valencia, Spain. 18Pulmonary and Critical Care Medicine, New York Presbyterian/Weill Cornell Medical Center, New York, NY, USA. 19Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada. 20Department of Intensive Care, E.N. Meshalkin National Medical Research Center, Novosibirsk, Russian Federation. 21South Texas Veterans Health Care System, Audie L. Murphy Memorial Veterans Hospital, and University of Texas Health, San Antonio, TX, USA. 22Centre Cochrane Iberoamericà – Institut d’Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 23Mahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand. 24Nuffield Department of Medicine, University of Oxford, Oxford, UK. 25Department of Anaesthesiology and Critical Care, Hôpital Beaujon, DMU PARABOL, AP-HP Nord and Université de Paris, Clichy, France. 26Department of Respiratory Medicine and Infectious Disease, Member of the German Center of Lung Research, Hannover School of Medicine, Hannover, Germany. 27 Department of Medicine, Division of Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 28Authors contributed equally to this work. Corresponding author: Ignacio Martin-Loeches ([email protected]) Shareable abstract (@ERSpublications) Severe community-acquired pneumonia (sCAP) is associated with high morbidity and mortality, and while European and non-European guidelines are available for CAP, there are no specific guidelines for sCAP http://bit.ly/3DpnwA3 Cite this article as: Martin-Loeches I, Torres A, Nagavci B, et al. ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia. Eur Respir J 2023; 61: 2200735 [DOI: 10.1183/13993003.00735-2022]. The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2023. For reproduction rights and permissions contact [email protected] Received: 12 April 2022 Accepted: 1 Dec 2022 Abstract Background Severe community-acquired pneumonia (sCAP) is associated with high morbidity and mortality, and while European and non-European guidelines are available for community-acquired pneumonia, there are no specific guidelines for sCAP. Materials and methodology The European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Latin American Thoracic Association (ALAT) launched a task force to develop the first international guidelines for sCAP. The panel comprised a total of 18 European and four non-European experts, as well as two methodologists. Eight clinical questions for sCAP diagnosis and treatment were chosen to be addressed. Systematic literature searches were performed in several databases. Meta-analyses were performed for evidence synthesis, whenever possible. The quality of evidence was assessed with GRADE https://doi.org/10.1183/13993003.00735-2022 Eur Respir J 2023; 61: 2200735 EUROPEAN RESPIRATORY JOURNAL ERS/ESICM/ESCMID/ALAT GUIDELINES | I. MARTIN-LOECHES ET AL. (Grading of Recommendations, Assessment, Development and Evaluation). Evidence to Decision frameworks were used to decide on the direction and strength of recommendations. Results Recommendations issued were related to diagnosis, antibiotics, organ support, biomarkers and coadjuvant therapy. After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention and implications to health equity, recommendations were made for or against specific treatment interventions. Conclusions In these international guidelines, ERS, ESICM, ESCMID and ALAT provide evidence-based clinical practice recommendations for diagnosis, empirical treatment and antibiotic therapy for sCAP, following the GRADE approach. Furthermore, current knowledge gaps have been highlighted and recommendations for future research have been made. Introduction Community-acquired pneumonia (CAP) is a very common respiratory infectious disease. General incidence ranges between 1 and 25 cases per 1000 inhabitants per year. Incidence of this disease is higher in males, those with human immunodeficiency virus (HIV), and individuals with comorbidities, especially COPD. Approximately 40% of patients with CAP will require hospitalisation, and 5% of these patients will be admitted to the intensive care unit (ICU), primarily due to shock or the need for invasive or non-invasive mechanical ventilation. Severe CAP (sCAP) is accepted terminology used to describe ICU-admitted patients with CAP as they might require organ support. Data from a large cohort (CAPNETZ) have shown that the highest mortality is observed in patients who do not meet these criteria initially but deteriorate over the course of time (sCAP on admission: 17%; sCAP on day 4 to 7: 48%). The availability of ICU beds varies widely between countries and between country regions, and the criteria for ICU admission are also very different from country to country; as a result, these factors may lead to different findings, as patients being admitted to an ICU can present very diverse clinical severities. Although 30-day mortality of hospitalised patients with CAP has decreased over the past decade , mortality due to sCAP remains unacceptably high. Two large, monocentre and multicentre observational studies from Spain and the USA recently confirmed such an increased mortality. Overall mortality due to sCAP was 20% higher when patients presented with either shock (22% higher) or invasive mechanical ventilation (25% higher), or both (30% higher). Furthermore, sCAP is one of the most common causes of acute respiratory distress syndrome, and it is reported in ∼3% of patients hospitalised with pneumococcal CAP. With respect to the microbiological causes of sCAP, few studies have specifically reported on aetiologies. In 2019, a large, monocentre observational study showed that Streptococcus pneumoniae, Staphylococcus aureus, viruses and Legionella spp. comprise the most frequent causative pathogens. However, other, so-called “non-core” pathogens such as Pseudomonas aeruginosa and Enterobacterales cause a variable proportion of cases. Prevalence of the latter pathogens will depend on risk factors present in patients and, consequently, the referral population of each hospital. Polymicrobial infections have been observed more often in mechanically ventilated patients (24% versus 14%). In recent years, the clinical use of rapid molecular techniques has demonstrated that viruses such as influenza, respiratory syncytial virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) perhaps constitute the initial cause of sCAP, alongside mixed viral–bacterial infections with S. pneumoniae and S. aureus (20–30%). Recommendations for managing sCAP are usually included as a subsection in general CAP management guidelines. In 2019, the American Thoracic Society and Infectious Diseases Society of America (ATS/ IDSA) published a series of recommendations , whilst other recommendations have come from individual countries. These guidelines only cover some aspects, e.g. criteria for ICU admission and empirical treatment. With regards to ICU admission, the former ATS/IDSA criteria includes one major or three minor criteria to follow plus a combination of antibiotics for empirical treatment, including a beta-lactam antibiotic plus either a macrolide (as first option) or quinolone (as second option). However, the most current guidelines either lack inclusion of, or insufficiently develop, other aspects of CAP management, e.g. the use of rapid molecular techniques for microbial diagnosis, benefits of non-invasive mechanical ventilation, antibiotic coverage of “non-core” pathogens, use of co-adjuvant corticosteroids, and aspiration pneumonia. For such reasons, the members of this panel have agreed on the need to develop more specific recommendations for sCAP. The European Respiratory Society (ERS) launched a task force to develop new international guidelines for sCAP. Other European societies, including the European Society of Intensive Care Medicine (ESICM) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (Latin American Thoracic Association; ALAT), were invited to participate and appointed their representatives. https://doi.org/10.1183/13993003.00735-2022 2 EUROPEAN RESPIRATORY JOURNAL ERS/ESICM/ESCMID/ALAT GUIDELINES | I. MARTIN-LOECHES ET AL. The following are considerations for adult sCAP outlined by the panel: 1) sCAP refers to CAP requiring ICU admission. However, as criterion for ICU admission can be heterogeneous in the absence of shock or need for mechanical ventilation, recommendations for this population should be cautiously provided. 2) In these guidelines, we will not consider immunosuppressed patients, e.g. those receiving corticosteroids or chemotherapy, undergoing transplantation, with either haematological malignancies or HIV, with a CD4 count lower than 200. Scope and purpose The purpose of this document is to provide guidance on the most effective treatments and management strategies for adult patients with sCAP, pragmatically defined as those admitted to ICU. These guidelines are intended mainly for healthcare workers in respiratory and intensive care medicine managing adults with sCAP. These guidelines may also be of interest to general internists, infectious disease specialists, pharmacists, microbiologists and policy-makers. Methodology Composition of the task force panel The guidelines were developed by an ERS, ESICM, ESCMID and ALAT task force, which consisted of a multidisciplinary group of clinicians with recognised expertise in managing patients with respiratory tract infections across Europe and North America. Two methodologists (D. Rigau and B. Nagavci) provided expertise in guideline development and the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach [14, 15]. Both I. Martin-Loeches (Ireland) and A. Torres (Spain) chaired the panel. All panel members disclosed potential conflicts of interest according to ERS policies at the start of the project. Formulation of questions and selection of outcomes These guidelines were developed according to the ERS methodology for guideline development. A total of eight clinical questions were formulated using the PICO (Patients, Intervention, Comparison, Outcomes) format, and outcomes for each clinical question were rated by voting as being not important, important or critical for decision-making processes. Initially the question about biomarkers aimed to study procalcitonin (PCT) and C-reactive protein (CRP), but the panel decided to focus on only on PCT due to its greater clinical relevance, so no specific searches were performed for CRP. The questions were agreed by the members of the task force as topics relevant in sCAP. The topics were multidisciplinary and agreed upon unanimously by all the members. SARS-CoV-2 was not included in this guideline as there are many documents already published on this topic. The inclusion criteria were adult patients with sCAP and the exclusion criteria was immunosuppression. The guideline panel held three face-to-face meetings and several videoconferences throughout the course of the project. Literature searches and evidence synthesis The systematic literature searches were performed by an information specialist, on literature published from January 1995. They were conducted via OVID in MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews, between April 2019 and February 2020. Supplementary searches (for two research questions) were performed in PubMed in December 2021, for which initial searches were not sufficient. Manual searches were conducted periodically, for newly published studies. The search strategies are provided in the supplementary material. At least two task force members responsible for each clinical question reviewed all the titles and abstracts. They agreed on the inclusion of full-text manuscripts. In cases of uncertainty, consensus was reached by discussions held with the ERS methodologists. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowcharts for each question are shown in the supplementary material. However, due to technical issues, exclusion reasons were not recorded for all questions. Risk of bias in randomised controlled trials (RCTs) was assessed using the Cochrane risk-of-bias tool for randomised trials , and for non-randomised studies, an adapted version of this tool was used. For evidence synthesis, meta-analyses were used whenever clinical and statistical criteria were fulfilled. Otherwise, narrative synthesis of evidence was used. Assessment of quality of evidence and making of recommendations The quality of evidence and strength of recommendations was assessed using the GRADE approach, and Evidence to Decision (EtD) frameworks were used to decide on the direction and strength of recommendations [20, 21]. Recommendations are graded as strong or conditional after considering: the quality of evidence; balance of desirable and undesirable consequences of compared management options; assumptions about the relative importance of outcomes; implications for resource use; and acceptability and feasibility of implementation. https://doi.org/10.1183/13993003.00735-2022 3 EUROPEAN RESPIRATORY JOURNAL ERS/ESICM/ESCMID/ALAT GUIDELINES | I. MARTIN-LOECHES ET AL. Evidence summary of findings tables and EtDs (available in the supplementary material) were generated for each clinical question by the working groups of panel experts and externally commissioned collaborators. The panel formulated the clinical practice recommendations and decided on their direction and strength by either consensus, or voting (majority) when consensus was not possible. Following the GRADE approach, strong recommendations are worded as “we recommend”, whilst conditional recommendations are worded as “we suggest”. A strong recommendation was made for an intervention when the panel was certain that the desirable effects of the intervention outweighed the undesirable effects, and a strong recommendation against was made when the opposite was true. A conditional recommendation for an intervention was made when desirable effects probably outweighed the undesirable effects, but appreciable uncertainty exists; a conditional recommendation against an intervention was made when the opposite was true. Good practice statements, following the GRADE approach, were issued in those situations in which a large body of indirect evidence showed benefit (or lack of it) of the recommended action and when, in addition, applying GRADE would be an unproductive use of the panel’s limited resources. Question 1: In patients with sCAP, should rapid microbiological techniques be added to current testing of blood and respiratory tract samples? Recommendations If the technology is available, we suggest sending a lower respiratory tract sample (either sputum or endotracheal aspirates) for multiplex PCR testing (virus and/or bacterial detection) whenever non-standard sCAP antibiotics are prescribed or considered (conditional recommendation, very low quality of evidence). Evidence overview and rationale Out of 4119 screened references, one systematic review (comprised of 28 observational studies) and one RCT were included as relevant and were assessed according to the GRADE criteria. These studies focused on microbiological identification of respiratory viral pathogens. Additional manual searches were undertaken to identify studies on bacterial or antibiotic-resistant bacterial pathogens to supplement further the recommendation. This supplementary body of evidence was analysed narratively and was not assessed with GRADE. The greatest potential benefit of multiplex PCR testing is the ability to rapidly adjust antibiotics for unsuspected antibiotic-resistant pathogens (supplementary material). The 48- to 72-h interval of inappropriate antibiotic therapy during the wait for results for most culture-based diagnoses has been shown to be associated with adverse outcomes in CAP. The greater adverse effects of inappropriate antibiotics for P. aeruginosa and Acinetobacter spp. and the high specificity of PCR warrant a recommendation. Excessively broad antibiotic therapy has also been associated with adverse outcomes [26, 27]. Potential harms of excess antibiotics for the individual patient include drug toxicity itself and selection for more antibiotic-resistant pathogens, including superinfection pneumonia and Clostridium difficile infection. Adverse effects for wider society include an increased risk of antibiotic-resistant infections being spread and any costs associated. Potential harms for use of multiplex PCR assays include cost and the potential for inappropriate escalation of antibiotics based on a false-positive PCR result. Evidence would suggest that in most cases of positive PCR, negative culture cases are false-negative [28, 29]. This culture/PCR discordance is less likely to occur with antibiotic-resistant pathogens that require antibiotics different from usual CAP therapy. No appropriate cost–benefit analysis is available, as most potential benefits of multiplex PCR testing have yet to consider testing costs and antibiotic acquisition costs. The presumption of this recommendation is that all patients will have empirically been started on beta-lactam (e.g. ceftriaxone, cefotaxime or amoxicillin-equivalent) combination therapy with either a fluoroquinolone or macrolide, in accordance with several clinical guidelines for sCAP. Use of additional diagnostic testing should be assessed when either escalating therapy (for pathogens not covered by usual therapy) or in de-escalation to a single agent of the combination or an even narrower agent than that used for empirical therapy. Therefore, the strongest case for use of multiplex PCR testing is whenever non-standard sCAP antibiotics are prescribed or considered. Unfortunately, most literature on molecular diagnostics does not directly address this issue. Instead, PCR results are directly compared to those obtained in routine clinical laboratory culture, with an occasional https://doi.org/10.1183/13993003.00735-2022 4 EUROPEAN RESPIRATORY JOURNAL ERS/ESICM/ESCMID/ALAT GUIDELINES | I. MARTIN-LOECHES ET AL. analysis of theoretical changes in antibiotic therapy that would occur if treatments were based on results [31–33]. Since respiratory tract cultures are clearly neither 100% sensitive nor 100% specific, only clinical data can determine the true safety of antibiotic management based on PCR results. The limited number of pathogens on any multiplex PCR platform still raises uncertainty about rare pathogens that might respond to prescribed antibiotics. Despite very robust operating characteristics, the limited data on clinical management based on PCR results constitute the rationale for classification as only moderate evidence to support use. We also have restricted our recommendations to commercially available platforms. In addition, we have focused on multiplex PCR technology rather than more limited PCR assays or other molecular techniques. However, using other molecular techniques with similar operating characteristics, such as multiplex PCR platforms, would be expected to have similar benefits and risks. The exception is the use of a limited PCR panel for S. aureus and mecA gene detection only in potential cases of methicillin-resistant S. aureus (MRSA). Regarding the detection of the mecA gene, 1) MRSA colonisation cannot be distinguished from an infection, and 2) the detection of S. aureus is mandatory, because a large proportion of Coagulase-negative staphylococci (CoNS) also carries this gene. This limited assay has an extensive application and is the only PCR assay employed in an RCT to manage administration of vancomycin or linezolid in ventilated patients with suspected MRSA pneumonia, including those with sCAP. Additional considerations Many institutions may have already purchased the diagnostic platform for different multiplex PCR panels. Costs for consumables will likely exceed those of most empirical antibiotic prescriptions for sCAP. That said, cost savings will be in the more-difficult-to-measure endpoints of clinical outcomes and antibiotic resistance selection. Optimal implementation requires rapid notification of results to the prescribing physician, even within a 24-h period. Logistics on how testing can be continuously available, and results reported, is a major implementation consideration. Suggested research priorities Safety of discontinuing empirical beta-lactam in patients with sCAP with only Legionella or Mycoplasma sp. detection by PCR. Safety of discontinuing all antibiotics in viral CAP after a negative bacterial multiplex PCR. Safety of discontinuing all antibiotics in cases with negative bacterial and viral multiplex PCRs and no other indications for antibiotics. Pathogens causing sCAP when both bacterial and viral multiplex PCRs are negative. Alternative diagnostic approach, e.g. metagenomic sequencing for PCR and cases of negative cultures. Alternative empirical antibiotic strategy in cases with high clinical suspicion for CAP and negative multiplex PCR. Question 2: In hypoxaemic patients with sCAP, can either non-invasive mechanical ventilation or high-flow nasal oxygen be used initially – rather than supplemental standard oxygen administration – to avoid intubation and reduce mortality? Recommendations In patients with sCAP and acute hypoxaemic respiratory failure not needing immediate intubation, we suggest using high-flow nasal oxygen (HFNO) instead of standard oxygen (conditional recommendation, very low quality of evidence). Non-invasive mechanical ventilation (NIV) might be an option in certain patients with persistent hypoxaemic respiratory failure not needing immediate intubation, irrespective of HFNO (conditional recommendation, low quality of evidence). Evidence overview and rationale Amongst published studies, the physiological effects of high-flow oxygen have been well elucidated. The ability to deliver high fractions of inspired oxygen, with low levels of positive pressure in the airways yielding a mild positive end-expiratory pressure effect and flushing out the upper airways, generates a washout of dead space [35–40]. The first pilot studies of HFNO conducted in adult ICU-admitted patients with acute respiratory failure included patients with CAP. These studies reported that HFNO was more comfortable, provided better oxygenation, and was associated with a lower respiratory rate in comparison to standard oxygen therapy [41–43]. Additionally, breathing efforts during spontaneous ventilation can worsen lung injury and cause patient self-inflicted lung injury. One large-scale RCT that also included https://doi.org/10.1183/13993003.00735-2022 5 EUROPEAN RESPIRATORY JOURNAL ERS/ESICM/ESCMID/ALAT GUIDELINES | I. MARTIN-LOECHES ET AL. patients with CAP and compared high-flow oxygen therapy with standard oxygen and facemask NIV showed a reduction in the intubation rate in patients with arterial oxygen tension to inspiratory oxygen fraction (PaO2/FIO2) ratio ⩽200 mmHg treated with HFNO. However, recent physiological data have shown that NIV delivered by a helmet was more efficient than HFNO in reducing patients’ respiratory effort (ultimately reducing transpulmonary pressure), particularly in patients with intense baseline inspiratory effort and more severe oxygenation impairment (PaO2/FIO2 ratio 150 mg·L−1. With the intervention, there was significantly less ( p=0.02) late treatment failure (13% versus 31%, including radiographic progression, late mechanical ventilation, and late septic shock). There was a 5% absolute reduction (nonsignificant) in mortality with corticosteroid therapy. Hyperglycaemia occurred in 18% of patients receiving corticosteroids and 12% of patients with placebo (nonsignificant). Older RCTs were smaller [80–84] and conducted between 1993 and 2011. Two were multicentre studies [80, 82], and two were single-centre based [81, 83]. All compared hydrocortisone to placebo, given for 7 days in three studies and for 1 day in the other. Doses ranged from 240–300 mg per day in the prolonged therapy studies [80–82, 84] to 10 mg·kg−1 in the single-dose study. When all studies were combined, there was a significant reduction in ICU mortality with a risk ratio of 0.36 (95% CI 0.16–0.82). A 2019 meta-analysis found that adjunctive low dose corticosteroid was associated with favourable outcomes in sCAP due to all-cause mortality, incidence of septic shock and requirement for mechanical ventilation, without increasing risk of adverse events. Combining data from the four other studies, using multiple day dosing, there was a reduction in septic shock with a risk ratio of 0.15 (95% CI 0.06–0.38). The study by CONFALONIERI et al. included 24 patients randomised to hydrocortisone 200 mg bolus and then 10 mg·h−1 for 7 days, compared to 24 patients receiving placebo. By day 8, compared to the placebo group, patients receiving corticosteroids had a significant improvement in oxygenation (PaO2/FIO2 ratio) and chest radiographic score, as well as a reduction in delayed septic shock, hospital length of stay and mortality (ICU and hospital). The outcomes that were evaluated are regarded as clinically important and of benefit to patients. Mortality is the most important benefit; however, length of stay, radiographic improvement and duration of mechanical ventilation also have direct benefits for patients. This is a conditional recommendation for the intervention. The desirable effects are large; however, the quality of evidence is low, and the risk of bias is high. This recommendation is based on several RCTs, with most participants admitted to ICU. Additional considerations Corticosteroids are widely available and inexpensive. Given the modest cost, corticosteroids have been considered for years in patient groups where mortality is high. In patients with Pneumonia Severity Index risk classes IV/V, corticosteroids and antibiotic strategy resulted in USD 70 587 worth of savings and an 82.6% chance of being cost-effective when compared to antibiotics alone. According to one cost-effectiveness study , the use of steroids would be associated with savings in those with sCAP, but the effect in patients with sCAP with shock remains unknown. Suggested research priorities Determine which corticosteroid shows a better profile in balancing potential adverse effects and including the different type of pathogens. Determine those phenotypes of patients and biomarkers that would help identify who would most benefit from corticosteroid use (and which type: hydrocortisone, methylprednisolone, etc.). Determine long-term effects of corticosteroid use (on ICU-acquired myopathy/polyneuropathy, delirium) as well as potential long-term outcomes in terms of lung function and recovery. Question 7: Does the use of a prediction score for drug-resistant pathogens lead to more appropriate therapy and improved outcomes (mortality, treatment failure, duration of antibiotic therapy, prolonged ICU stay)? Recommendations We suggest integrating specific risk factors (eventually computed into clinical scores) based on local epidemiology and previous colonisation to guide decisions regarding drug-resistant pathogens (excluding those immunocompromised) and empirical antibiotic prescription in sCAP patients (conditional recommendation, moderate quality of evidence). https://doi.org/10.1183/13993003.00735-2022 11 EUROPEAN RESPIRATORY JOURNAL ERS/ESICM/ESCMID/ALAT GUIDELINES | I. MARTIN-LOECHES ET AL. Evidence overview and rationale Following the healthcare-associated pneumonia (HCAP) definition, international guidelines recommended to treat those patients with empirical therapy directed at drug-resistant pathogens (DRP) and not to use this definition anymore. To better tailor empirical antibiotic selection for patients at risk of DRP, several studies have identified reproducible risk factors for drug resistance that can be classified into four categories: pathogen acquisition related to healthcare exposure; colonisation persistence (immunosuppression, chronic lung disease, history of colonisation or infection with DRP); antibiotic-mediated selective pressure promoting resistance; and factors altering host physiology (cognitive/neurological impairment, gastric acid suppression, etc.). These risk factors have been computed to create risk prediction models shown to accurately estimate the risk of DRP. In a recent systematic review, 14 published risk prediction methods for DRP were identified, of which eight were externally validated (page 107, supplementary material) [88–95]. They are characterised by high sensitivity and generally low specificity that may favour overtreatment. However, most of these scores have high negative predictive values (mostly more than 90%), suggesting that their use may allow broad-spectrum regimens and spare a proportion of patients with low risk scores. Prospective implementation results have been published for only two of these risk prediction scores [26, 86]. Out of 1696 screened references, one prospective implementation cohort was included in the review, by MARUYAMA et al. , who conducted a prospective, multicentre cohort study including 1089 patients to evaluate whether the algorithm from NIEDERMAN and BRITO may avoid the overuse of broad-spectrum therapy in patients with sCAP whilst maintaining good outcomes. In a subgroup of 894 cases of CAP (6.3% DRP incidence), adherence was 80.3%; however, only 2.7% received inadequate therapy. While broad-spectrum antibiotics were recommended by the protocol in 16.3% of cases, 28.9% received it. Therefore, the algorithm provided accurate recommendations without promoting the overuse of antibiotics that occurred when the protocol was not followed. WEBB et al. conducted a quasi-experimental pre-post implementation study with electronic CAP clinical decision support (ePNa) including the DRIP score. A total of 2169 adult admissions were analysed. Whilst the average effects of ePNa on mortality, length of stay, and cost were not statistically significant, the use of the DRIP score was associated with a reduction in broad-spectrum antibiotic use (OR 0.62, 95% CI 0.39–0.98; p=0.039). Further high-quality studies are needed to confirm these findings. Both inadequate and unnecessary antibiotic spectrum use is associated with poor outcomes. Accurately predicting which patients require DRP coverage is an important clinical objective. The timely initiation of appropriate antimicrobial therapy is the cornerstone of initial management of severe infections. Failure to initiate appropriate empirical therapy in patients with sepsis and septic shock has been associated with a substantial increase in morbidity and mortality. Conversely, broad-spectrum antibiotics can promote antimicrobial resistance; their unnecessary use in CAP is associated with elevated mortality, longer hospital stay, higher costs and an increased risk of Clostridioides difficile infections. Early administration of narrow-spectrum, guideline-recommended antimicrobial regimens is associated with decreased mortality. However, an alarming increase in antimicrobial resistance, together with observations showing an increased mortality in patients receiving inappropriate initial antibiotic spectrum, has led to sepsis guidelines recommending the use of broad-spectrum antibiotics. Consequently, the use of broad-spectrum antibiotics for CAP has substantially increased to cover DRP such as MRSA, P. aeruginosa, Acinetobacter spp., ESBL-producing Enterobacterales, and S. maltophilia [100, 101]. In the multinational Global Initiative for MRSA CAP (GLIMP) cohort, the global prevalence of MRSA was 3%, with a higher rate of 5% noted in the USA. The prevalence of P. aeruginosa was 4%, whilst that of Enterobacterales was 6%, of which 19% were multidrug-resistant [8, 102–104]. In another point prevalence study that included 3193 patients in 54 countries with confirmed diagnosis of CAP, the prevalence of P. aeruginosa and antibiotic-resistant P. aeruginosa were 4.2% and 2%, respectively. Additional considerations Using DRP prediction models to guide decisions regarding non-core pathogen coverage in patients with sCAP could reduce costs in several ways. Firstly, it may reduce the rate of inappropriate therapy and be associated with improved patient outcomes and lower healthcare costs. Secondly, using a DRP prediction score could favour narrow-spectrum treatment in a proportion of patients with low risk scores. It may, therefore, be associated with lower direct costs due to reductions made in costly drug acquisition and the risk of emergence of multidrug-resistant bacteria, which can incur further costs. However, the cost– benefit of using narrow-spectrum antimicrobials has not been clearly demonstrated. https://doi.org/10.1183/13993003.00735-2022 12 EUROPEAN RESPIRATORY JOURNAL ERS/ESICM/ESCMID/ALAT GUIDELINES | I. MARTIN-LOECHES ET AL. Suggested research priorities Prospective studies in which investigators explore whether using specific clinical scores to guide decisions regarding drug-resistant pathogen coverage in patients with sCAP may modify the rate of adequate antimicrobial treatment and patient outcomes. Question 8: Do patients with sCAP and aspiration risk factors have better outcomes (mortality, length of stay, treatment failure) if treated with a risk-based therapy regimen instead of standard sCAP antibiotics? Recommendation In patients with sCAP and aspiration risk factors we suggest standard CAP therapy regimen and not specific therapy targeting anaerobic bacteria (ungraded, good practice statement). Evidence overview and rationale There are no data (randomised or non-randomised) regarding sCAP and suspected aspiration pneumonia that compare standard therapy and specific therapy targeting anaerobic bacteria. Most standard antibiotic regimens (e.g. beta-lactam/beta-lactamase inhibitors, carbapenems, moxifloxacin) contain some anti-anaerobic coverage and this is the reason why regimens specifically targeting anaerobes are not more effective. Standard sCAP regimen does stratify patients based on risks for multidrug resistance. It does not, however, provide specific anaerobic therapy, although many of the agents do provide coverage as part of their broad-spectrum nature. One recent review advised using agents with anti-anaerobic activity (ampicillin/sulbactam, amoxicillin/clavulanate, moxifloxacin or a carbapenem) if the patient has poor dentition that could be a source of oral anaerobes. Based on the available data, specific anti-anaerobic therapy is not needed for aspiration pneumonia of any severity. In several studies, both regimens that are standard for CAP and those specifically targeting anaerobic bacteria were equally effective; however, none exclusively focused on sCAP [107, 108]. A systematic review showed efficacy of many therapies. Nevertheless, none were superior for any specific outcome, thus providing no data to answer the PICO question directly. Anaerobic coverage is potentially valuable since oropharyngeal bacteria such as Peptostreptococcus, Bacteroides spp., Fusobacterium spp. and Prevotella spp. could be aspirated and contribute to CAP pathogenesis. In elderly patients with risk of aspiration, such as those coming from a nursing home and needing ICU care, protected bronchoalveolar lavage sampling showed that Gram-negative pathogens and anaerobes were present in 49% and 16% of cases, respectively. In lung abscess, anaerobes respond better to clindamycin than other antibiotics. However, in aspiration pneumonia, this does not appear to be the case [111, 112]. There are no prospective, randomised and controlled studies of aspiration pneumonia in patients with sCAP. However, in studies of aspiration pneumonia of varying severity, anti-anaerobic therapy was compared to antibiotics usually used for CAP. These studies showed equivalence between clindamycin, ampicillin/sulbactam and a carbapenem (randomised, controlled trial of mild–moderate pneumonia) ; ampicillin/sulbactam and azithromycin (prospective cohort, non-randomised) ; meropenem and cefepime (open-label, randomised) ; ceftriaxone and ampicillin/sulbactam (retrospective, non-randomised) ; and moxifloxacin and levofloxacin/metronidazole (open-label, randomised). When taken collectively, there is no evidence to support that standard recommended therapy for sCAP would be less effective than any regimen specifically targeting anaerobes. Additional considerations Essentially all antibiotic regimens carry an increased risk of Clostridioides difficile infection. Furthermore, suspicion of aspiration does not add further complexity when choosing antibiotics for sCAP, except for the selection of specific agents listed above for patients with poor dentition. Suggested research priorities Clinical features that would help in distinguishing aspiration pneumonia from chemical pneumonitis. Determination of treatment duration, specifically if short courses would be beneficial even in patients with sCAP on invasive mechanical ventilation. Biomarkers that would help distinguish aspiration pneumonia from chemical pneumonitis. Conclusions Several clinical practice guidelines have been published for diagnosis and treatment of adult patients with CAP. However, they were not intended for patients with sCAP. The societies collaborating for development https://doi.org/10.1183/13993003.00735-2022 13 EUROPEAN RESPIRATORY JOURNAL ERS/ESICM/ESCMID/ALAT GUIDELINES | I. MARTIN-LOECHES ET AL. TABLE 1 Summary of research questions and recommendations Questions Recommendations Question 1: In patients with sCAP, should rapid microbiological techniques be added to current testing of blood and respiratory tract samples? If the technology is available, we suggest sending a lower respiratory tract sample (either sputum or endotracheal aspirates) for multiplex PCR testing (virus and/or bacterial detection) whenever non-standard sCAP antibiotics are prescribed or considered (conditional recommendation, very low quality of evidence) In patients with sCAP and acute hypoxaemic respiratory failure not needing immediate intubation, we suggest using HFNO instead of standard oxygen (conditional recommendation, very low quality of evidence) NIV might be an option in certain patients with persistent hypoxaemic respiratory failure not needing immediate intubation, irrespective of HFNO (conditional recommendation, low quality of evidence) We suggest the addition of macrolides, not fluoroquinolones, to beta-lactams as empirical antibiotic therapy in hospitalised patients with sCAP (conditional recommendation, very low quality of evidence) We suggest the use of PCT to reduce the duration of antibiotic treatment in patients with sCAP (conditional recommendation, low quality of evidence) Question 2: In hypoxaemic patients with sCAP, can either NIV or HFNO be used initially – rather than supplemental standard oxygen administration – to avoid intubation and reduce mortality? Question 3: When using initial empirical therapy for sCAP, should a macrolide or fluoroquinolone be used as part of combination therapy, to reduce mortality and adverse clinical outcomes? Question 4: In patients with sCAP, can serum PCT be used to reduce the duration of antibiotic therapy and improve other outcomes in comparison to standard of care not guided by serial biomarker measurements? Question 5: Should oseltamivir be added to standard therapy in patients with sCAP and confirmed influenza? Question 6: Does the addition of steroids to antibiotic therapy in specific sCAP populations lead to better outcomes in comparison to when steroid therapy is not used? Question 7: Does the use of a prediction score for drug-resistant pathogens lead to more appropriate therapy and improved outcomes (mortality, treatment failure, duration of antibiotic therapy, prolonged ICU stay)? Question 8: Do patients with sCAP and aspiration risk factors have better outcomes (mortality, length of stay, treatment failure) if treated with a risk-based therapy regimen instead of standard sCAP antibiotics? We suggest the use of oseltamivir for patients with sCAP due to influenza confirmed by PCR (conditional recommendation, very low quality of evidence) When PCR is not available to confirm influenza, we suggest the use of empirical oseltamivir during the influenza season (conditional recommendation, very low quality of evidence) In patients with sCAP, we suggest the use of corticosteroids if shock is present (conditional recommendation, low quality of evidence) We suggest integrating specific risk factors (eventually computed into clinical scores) based on local epidemiology and previous colonisation to guide decisions regarding drug-resistant pathogens (excluding those immunocompromised) and empirical antibiotic prescription in sCAP patients (conditional recommendation, moderate quality of evidence) In patients with sCAP and aspiration risk factors we suggest standard CAP therapy regimen and not specific therapy targeting anaerobic bacteria (ungraded, good practice statement) sCAP: severe community-acquired pneumonia; NIV: non-invasive ventilation; HFNO: high-flow nasal oxygen; PCT: procalcitonin; ICU: intensive care unit; CAP: community-acquired pneumonia. of this document considered that such patients would benefit from specific recommendations, due to potential differences in treatment effects between moderately and critically ill patients with sCAP (table 1). These are the first published guidelines for patients with sCAP. There are other published guidelines in the literature; however, the present document aims to focus on the most severe spectrum of the patients with CAP. The current recommendations will benefit physicians dealing with the care of critically ill patients and will help standardise the current treatment and management of sCAP. Implementation is obviously challenging, depending on the healthcare systems and resources allocated; however, these guidelines provide clear, focused and concise recommendations that patients with the highest severity of disease and mortality risk would benefit from. Additionally, these recommendations have used a multidisciplinary approach since their conception, involving specialists from different healthcare systems and medical domains, following the GRADE approach, in order to ease implementation and obtain a transversal approach. Furthermore, current knowledge gaps have been highlighted and recommendations for future research have been made. Acknowledgements: We would like to thank Kellee Kaulback, the information specialist from McMaster University, for undertaking the literature searches. https://doi.org/10.1183/13993003.00735-2022 14 EUROPEAN RESPIRATORY JOURNAL ERS/ESICM/ESCMID/ALAT GUIDELINES | I. MARTIN-LOECHES ET AL. This article is being published concurrently in the European Respiratory Journal (https://doi.org/10.1183/13993003. 00735-2022) and Intensive Care Medicine (https://doi.org/10.1007/s00134-023-07033-8). The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Published in volume 61, issue 4 of the European Respiratory Journal on 4 April 2023; republished 6 April and 4 May 2023 to address typographical errors in the author list and affiliation details. This document was endorsed by the ERS executive committee on 16 January 2023, ALAT on 11 January 2023, ESCMID on 15 December 2022 and ESICM on 19 January 2023. The guidelines published by the European Respiratory Society (ERS) incorporate data obtained from a comprehensive and systematic literature review of the most recent studies available at the time. Health professionals are encouraged to take the guidelines into account in their clinical practice. However, the recommendations issued by this guideline may not be appropriate for use in all situations. It is the individual responsibility of health professionals to consult other sources of relevant information, to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and the patient’s caregiver where appropriate and/or necessary, and to verify rules and regulations applicable to drugs and devices at the time of prescription. Conflict of interest: I. Martin-Loeches reports grants from GE, consulting fees from Gilead and MSD, lecture honoraria from MSD, Gilead and Mundipharma, and advisory board and lectures for Pfizer, MSD and Menarini, outside the submitted work. A. Torres reports consulting fees and lecture honoraria from Pfizer, Poliphor, MSD, Jansen and OM Pharma, and advisory board and lectures for Pfizer, MSD, Atriva, Jansen and Menarini, outside the submitted work. B. Nagavci serves as the ERS methodologist. S. Aliberti reports grants from Insmed Incorporated, Chiesi, and Fisher & Paykel, royalties from McGraw Hill, consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon, AstraZeneca UK Limited, CSL Behring GmbH, Grifols, Fondazione Charta, Boehringer Ingelheim, Chiesi, Zcube Srl, Menarini and MSD Italia Srl, lecture honoraria from GlaxoSmithKline Spa, and advisory board participation with Insmed Incorporated, Insmed Italy, AstraZeneca UK Limited and MSD Italia Srl, outside the submitted work. M. Antonelli reports grants from GE, consulting fees from Gilead, lecture honoraria from MSD, Chiesi, Fisher & Pickel, and Orphan, and a leadership role at ESICM, outside the submitted work. M. Bassetti reports research grants and/or advisor/consultant and/or speaker/chairman for Bayer, Biomerieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Shionogi and ThermoFisher, outside the submitted work. L. Bos reports grants from the Dutch Lung Foundation (young investigator grant), the Dutch Lung Foundation and Health Holland ( public–private partnership grant), Dutch Lung Foundation (Dirkje Postma Award), IMI COVID19 initiative and Amsterdam UMC fellowship, outside the submitted work. J. Chalmers reports research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis and Insmed, and received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer and Zambon, outside the submitted work, and is chief editor of the ERJ. L. Derde reports grants from European Union’s FP7 grant PREPARE (602525); EU FP7-HEALTH-2013-INNOVATION-1, grant number 602525, H2020 RECOVER grant agreement number 101003589, ZonMw grant ANAkinra voor de behandeling van CORonavirus infectious disease 2019 op de Intensive Care (ANACOR-IC) project number 10150062010003, lecture honoraria from Netherlands International Sepsis Symposium, travel support from ESICM, ISICEM, Weimar sepsis Update, European Respiratory Society, Critical Care Reviews, UPMC Pittsburgh, International Sepsis Forum and ANZICS/ACCCN ASM, and advisory board participation with Sepsis Canada International; REMAP-CAP has received drugs as part of the trial interventions; and the following leadership positions: chair, international trial steering committee, REMAP-CAP (2021–present), coordinating committee member, ECRAID (2021–present), member expert panel on COVID-19 therapeutics, European Commission (2021–present), member “Pandemic Preparedness Plan” committee, KNAW (2021–present), chair elect Education and Training Committee (2019–2021), chair Clinical Training Committee, ESICM (2019–2021), task force infectious threats, NVIC (chair 2019–2021), outside the submitted work. J. de Waele reports grants from Flanders Research Foundation and consulting fees from Pfizer and MSD, outside the submitted work. M. Kollef reports consulting fees from Merck, Pfizer and Shionogi, outside the submitted work. C. Luna reports grants as principal investigator in clinical trials, has participated on adjudication committee for diagnosis in clinical trials, has received honoraria for lectures on pulmonary infections, has received economical support for attending to the ERS and ATS meetings, and has participated on an advisory board for pneumococcal vaccines, outside the submitted work. R. Menendez reports lecture honoraria from, and participated on advisory boards for Pfizer, Advanz Pharma, Gilead Sciences and GSK, and travel support from Pfizer, Gilead and Advanz Pharma, outside the submitted work. M. Niederman reports grants from Shionogi, Merck and Bayer, consulting fees from Pfizer, Merck, Shionogi, Bayer, Nabriva and Thermo-Fisher, and participation on an advisory board for Fab’entec, outside the submitted work. D. Rigau formerly served as ERS methodologist. M. Schultz received grants from Zonmw (Netherlands Organisation For Health Research And Development) and financial support from Hamilton Medical AG, Switzerland, outside of this project. E. Weiss reports speaker and travel fees from MSD, Akcea Therapeutics and LFB, outside the submitted work. T. Welte https://doi.org/10.1183/13993003.00735-2022 15 EUROPEAN RESPIRATORY JOURNAL ERS/ESICM/ESCMID/ALAT GUIDELINES | I. MARTIN-LOECHES ET AL. reports grants from German Ministry of Research and Education, lecture honoraria from Advanz, Biotest, Thermo Fischer, MSD, Pfizer and Shionogi, outside the submitted work. R. 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