key: cord-0005745-ocnce92z
authors: Torres, Antoni; Chalmers, James D.; Dela Cruz, Charles S.; Dominedò, Cristina; Kollef, Marin; Martin-Loeches, Ignacio; Niederman, Michael; Wunderink, Richard G.
title: Challenges in severe community-acquired pneumonia: a point-of-view review
date: 2019-01-31
journal: Intensive Care Med
DOI: 10.1007/s00134-019-05519-y
sha: 141b49f60097a85275850ceeb9fc97e58000d039
doc_id: 5745
cord_uid: ocnce92z

PURPOSE: Severe community-acquired pneumonia (SCAP) is still associated with substantial morbidity and mortality. In this point-of-view review paper, a group of experts discuss the main controversies in SCAP: the role of severity scores to guide patient settings of care and empiric antibiotic therapy; the emergence of pathogens outside the core microorganisms of CAP; viral SCAP; the best empirical treatment; septic shock as the most lethal complication; and the need for new antibiotics. METHODS: For all topics, the authors describe current controversies and evidence and provide recommendations and suggestions for future research. Evidence was based on meta-analyses, most recent RCTs and recent interventional or observational studies. Recommendations were reached by consensus of all the authors. RESULTS AND CONCLUSIONS: The IDSA/ATS criteria remain the most pragmatic tool to predict ICU admission. The authors recommend a combination of a beta-lactam/beta-lactamase inhibitor or a third G cephalosporin plus a macrolide in most SCAP patients, and to empirically cover PES (P. aeruginosa, extended spectrum beta-lactamase producing Enterobacteriaceae, methicillin-resistant S. aureus) pathogens when at least two specific risk factors are present. In patients with influenza CAP, the authors recommend the use of oseltamivir and avoidance of the use of steroids. Corticosteroids can be used in case of refractory shock and high systemic inflammatory response.

During recent decades, the number of patients requiring intensive care management due to severe community-acquired pneumonia (SCAP) has increased globally, especially among the elderly, patients with comorbidities and the immunocompromised [1] . A large populationbased surveillance study on hospitalized CAP patients found that 21% of patients required intensive care unit (ICU) admission, with 26% of them needing mechanical ventilation [2] . SCAP hospital mortality is still high, ranging from 25% to more than 50% [3, 4] . Since delays from hospitalization to ICU admission have been related to increased mortality [5] , several scoring systems have been evaluated in order to promptly identify patients requiring intensive care management and to guide empiric antibiotic therapy [6] .

Streptococcus pneumoniae remains the main pathogen responsible of CAP, regardless of age and comorbidities [7] . However, approximately 6% of CAP are caused by antibiotic-resistant pathogens [8] . Furthermore, the implementation of multiplex polymerase chain reaction (PCR) techniques has identified respiratory viruses, mainly influenza virus and rhinovirus, as important CAP causative pathogens [2] .

Early adequate antibiotic administration is crucial in SCAP management [9] ; however, the optimal strategy is still far from being established. Initial antimicrobial therapy lacking activity against the offending pathogens has been associated with greater mortality [10] . The cluster RCT from Postma et al. [11] showed the same efficacy when comparing beta-lactam monotherapy with betalactam plus macrolide or quinolone. The constant debate regarding the superiority of β-lactam plus macrolide compared to β-lactam plus fluoroquinolones in SCAP is still open [12] .

Septic shock is the most lethal complication of SCAP. Corticosteroids are recommended in refractory septic shock, although some controversies still remain. Due to the emergence of pathogens outside the core microorganisms of CAP [13] , new antibiotics are urgently needed.

In this point-of-view review paper, a group of experts discuss the current main controversies regarding SCAP: severity scores, pathogens outside the core microorganisms of CAP (PES pathogens), viral SCAP, empirical treatment, septic shock and the potential role of new antibiotics. All the topics include four sections: the current controversy, the evidence, suggested recommendations and suggestions for future research. The evidence was based on meta-analyses, most recent RCTs and recent interventional or observational studies that the panel considered important for the question. Recommendations were reached by consensus of all the authors and are summarized in Table 1 .

Severity assessment is an essential component of the initial evaluation of CAP patients [14] . To date, there is no consensus on the optimal assessment tool or how it should be applied in clinical practice [15, 16] .

Some "real-world" problems may complicate the interpretation of studies that investigate scores for ICU admission prediction [15] . In one study, 1/3 of patients presenting to hospital had advanced directives or do not attempt resuscitation (DNAR) orders in place that made ICU admission inappropriate [17] . Second, many studies include patients who require mechanical ventilation or vasopressor treatment at admission in "prediction" studies, making a prediction score moot [18] . Third, the number of adult ICU beds [19] , the threshold for ICU admission and the characteristics of patients admitted to ICU are highly variable across different healthcare systems. Finally, there is still relatively little evidence that implementation of severity tools into clinical practice results in improved outcomes [20] .

The two most widely used severity assessment tools in CAP, the pneumonia severity index (PSI) and the CURB65 score, perform well to predict 30-day mortality, but are less useful in identifying SCAP requiring ICU admission [15] . This reflects the strong influence of age on both scoring systems, and the low value provided to respiratory failure and other organ dysfunctions which are often a major driver of ICU admission.

Alternative scoring systems have been proposed that are more focused on organ dysfunction. The IDSA/ATS 2007 criteria (Table 2) predict both mortality and future requirements for mechanical ventilation and vasopressor support as a surrogate of ICU admission [21] . Simplification of these criteria with the removal of less common organ dysfunctions is possible without losing prognostic accuracy. Lim et al. [20] conducted a before and after implementation study in which the IDSA/ATS criteria were used to triage patients. This resulted in a reduced mortality (from 23.8 to 5.7%), an increased use of ICU resources (52.9% of patients admitted to the ICU vs..

A group of experts discuss current controversies regarding severe community-acquired pneumonia and provide a summary of recommendations.

The IDSA/ATS criteria remain the most pragmatic and robust tools to predict patients requiring ICU admission We recommend empirically covering PES pathogens in SCAP when at least two specific risk factors are present

We recommend the use of prompt therapy with oseltamivir in patients with influenza CAP and avoidance of the use of steroids. Zanamivir can be used in cases of treatment failure and/or confirmed oseltamivir resistance

We recommend a combination of a beta-lactam/beta-lactamase inhibitor or a third G cephalosporin plus a macrolide in most SCAP patients Patients with SCAP and septic shock should be managed with current practice guidelines. Corticosteroids can be used in cases of refractory shock and high systemic inflammatory response Based on available data, new antibiotics providing existing limitations in empiric therapy (including macrolide resistant species and MRSA) are needed 38.6% previously) and reduced delayed ICU admissions. Similar criteria are included in the SMART-COP tool [22] . Recently, it has been shown that Sepsis-3 criteria can also help to identify patients at risk of ICU admission, although disease-specific tools still have the best discrimination for mortality [6] .

The IDSA/ATS 2007 criteria remain the most pragmatic and robust tools for predicting patients requiring ICU admission. Major criteria identify patients requiring immediate ICU care, while minor criteria (either the simplified or standard version) identify patients with a higher likelihood of requiring ICU care and benefiting from more aggressive therapy or closer observation [15, 20, 21] . PSI and CURB65 should not be used to guide ICU care as they can be misleading. Biomarkers such as C reactive protein, proadrenomedullin, procalcitonin and others have been suggested to provide additional information about CAP prognosis [23, 24] . None are currently fully validated and ready for implementation in clinical practice.

We need data demonstrating the utility of severity scores to predict a complicated course of CAP, to help improving patient allocation (need for ICU admission) and to identify patients likely to respond to specific therapies, including corticosteroids or macrolides [23] [24] [25] . Finally, we need data demonstrating a lower mortality rate when these scoring systems are used. 

Guidelines for CAP recommend empiric therapy for pathogens outside the core microorganisms of CAP, including methicillin-resistant S. aureus (MRSA), P. aeruginosa and other drug-resistant Gram-negatives, in selected patients with severe illness [26] . However, the incidence of these pathogens in CAP is low and often varies with geography and patient characteristics. The healthcare-associated pneumonia (HCAP) definition is not a good predictor of these pathogens [27] . Identifying patients at higher risk could avoid the overuse of broadspectrum empiric therapy.

In one study of 267 ICU-admitted CAP patients, one in six Pseudomonas were resistant to third-generation cephalosporins with antipseudomonal activity. Common pathogens included E. coli (8.2%), P. aeruginosa

Stenotrophomas maltophilia (0.7%) and Acinetobacter baumannii (0.3%) [28] . In one review, the incidence of Gram-negative CAP was estimated to be between 5 and 30%, but not all these organisms were resistant and not all patients were in the ICU [29] . Shindo et al. reported 8.6% of CAP and 26.6% of HCAP caused by drug-resistant pathogens [30] ; however, the number of patients treated in ICU was not stated. Similarly, in another study, 5.2% of CAP and 10.9% of HCAP were caused by pathogens outside the core microorganisms of CAP, but only 57 of 889 were treated in ICU [31] . One recent development is the concept of PES (P. aeruginosa, extended-spectrum beta-lactamase producing Enterobacteriaceae and MRSA) pathogens. PES pathogens have been identified in 6% of CAP patients with an etiologic diagnosis, with P. aeruginosa being the most common; 20-30% of patients with PES pathogens required ICU admission, more often than those without these pathogens [13] . In another study of 705 CAP patients, PES pathogens were found in 7.2% patients but ICU admission was needed in only 5.9% cases, a rate similar to those without PES pathogens [32] .

Risk factors for PES pathogens have been identified, although most studies are not specific to ICU patients (Table 3 ). Webb et al. divided risk factors into therapyrelated (extrinsic factors), patient-related (intrinsic factors) and those related to selective antibiotic pressure [27] . In one study, risk factors were prior antibiotic therapy, gastric acid-suppressive therapy, tube feeding and non-ambulatory status [30] , while in another study were CAP severity, prior antibiotic therapy, recent hospitalization, poor functional status, dialysis and immune suppression [31] . In a study of bacteremic CAP due to PES pathogens, risk factors for these pathogens were prior antibiotic therapy, low C-reactive protein (CRP) and the absence of pleuritic chest pain [33] .

Some studies have focused on risks for specific pathogens. A multinational study of 3193 patients found P. aeruginosa in 4.2% and antibiotic-resistant P. aeruginosa in 2% [34] . Risk factors for P. aeruginosa were In another study, risk factors for P. aeruginosa CAP included male sex, chronic respiratory diseases, lower CRP and higher PSI. However, the only risk factor for antibiotic-resistant P. aeruginosa was prior antibiotic therapy [8] . Risk factors for MRSA included many of the above plus chronic dialysis, prior MRSA infection/colonization, recurrent skin infections and severe comorbidities [30, 35] . The studies that investigate risk factors for PES pathogens often use the term "multidrug resistent" (MDR), although they include indistinctly MDR and non-MDR microorganisms, mainly P. aeruginosa. In this manuscript we decided to use the acronym PES because we believe it reflects better the need for a different antibiotic treatment covering these pathogens (carbapenems +/linezolid) compared to the standard one required for the "core" CAP pathogens.

We recommend covering PES pathogens when specific risk factors are present, including prior antibiotic therapy, recent hospitalization, recent P. aeruginosa or MRSA infection or colonization, poor functional status and immune suppression. When patients have at least 2 risk factors, the frequency of PES pathogens can exceed 25%, thus requiring empiric therapy against these pathogens. [30, 31] .

We need prospective studies using invasive sampling methods and new molecular diagnostic tests in a population of CAP patients treated exclusively in ICU. We need to identify patients at higher risk of PES pathogens through accurate scoring systems and to determine a threshold above which empiric therapy for these pathogens is justified. Finally, we need to be aware of SCAP microbiology future changes induced by influenza and pneumococcal vaccination, in both adults and children.

Before the appearance of influenza pandemics, respiratory viruses were uncommonly diagnosed and affected essentially patients with comorbidities [36] . In fact, influenza virus A is the most frequent respiratory virus identified, followed by human rhinovirus, human respiratory syncytial virus (RSV) and influenza B virus. RSV is now recognized as a significant problem in the elderly, persons with cardiopulmonary diseases and immunocompromised hosts [37] . A major controversy in patients with suspected severe viral CAP (svCAP) is twofold: the use of unnecessary antibiotics when the primary cause of pneumonia is viral without co-infection, and possible treatments with antiviral agents.

Currently, recommendations for patients with svCAP are focused on rapid recognition of the pathogen and antiviral treatment with Neuraminidase Inhibitors (NAIs).

Recommendations regarding NAIs administration are controversial. The Cochrane review of the topic in 2014 concluded that oseltamivir did not reduce hospitalizations and complications due to influenza [38] . Two systematic reviews and meta-analyses found that benefits in patients who were otherwise healthy did not outweigh its risks [39, 40] . However, another meta-analysis found that oseltamivir was effective in the prevention of influenza at individual and household levels. In critically ill patients, observational studies have found a benefit to a prompt use of oseltamivir [41] . On the other hand, zanamivir has been proposed by different guidelines, especially in immunosuppressed patients, based on a potential antiviral resistance to oseltamivir among circulating influenza viruses that is currently low [42] . Inhaled zanamivir is not recommended because of the lack of data regarding its use in patients with severe influenza disease. The use of corticosteroids has re-emerged in patients with SCAP based on recent randomized control trials (RCT) and systematic review and meta-analysis [43, 44] . In patients with svCAP, the use of corticosteroids has not been associated with survival benefit but with an increased risk of nosocomial infections [45] . A recent observational study found that corticosteroid administration as adjuvant therapy to standard antiviral treatment in critically ill patients with severe influenza pneumonia was associated with increased ICU mortality [46] .

Regarding RSV, not many treatment options are available, while a phase 2b RCT of presatovir for the treatment of RSV in lung transplant recipients has been recently published with no positive results.

We suggest maintaining an active communication with sentinel national and continental centers, and a local routine surveillance program in hospital settings [47] . We advocate diagnosing svCAP in accordance with a seasonal activity pattern. We encourage prompt treatment with oseltamivir in patients with svCAP within the first 48 h from influenza diagnosis. We recommend not using zanamivir regularly and only on the basis of treatment failure and confirmed oseltamivir mutations. A RCT has not demonstrated a superior effect of zanamivir compared to oseltamivir; all treatments had a similar safety profile in hospitalised patients with severe influenza [48] . We recommend avoiding the use of steroids in patients with svCAP due to futile effect and an increased risk of super-infections in all subgroups of patients including the immunosuppressed. In cases of RSV, there is no available treatment at the present time.

The best preferable evidence to determine the effect of NAIs should come from RCTs. Currently, only very few patients with high severity rates and a PSI above 90 have been enrolled in RCTs for SCAP [49] . In addition, in patients with infections, performing a RCT with or without antibiotics will foremost be inappropriate and unethical. Although there is sufficient evidence that antivirals decrease viral loads, their use in SCAP is still a matter of controversy [50] . Studies analyzing the timing of NAIs administration could provide further positive results. Regarding the use of corticosteroids, a RCT could be conducted in svCAP patients with high inflammation and severity.

No RCT has specifically targeted SCAP. Only one allowed enrollment of mechanically ventilated patients, while the rest specifically excluded SCAP patients [51] . Conversely, epidemiologic data suggest that SCAP patients may have a different etiologic spectrum than patients hospitalized outside the ICU [2, 52] , including a high incidence of viral infection. Therefore, whether antibiotics appropriate for non-ICU patients are safe and efficacious in SCAP is unclear. Moreover, rapid diagnostic tests offer the possibility for specific treatment. If they demonstrate high sensitivity for atypical pathogens, fluoroquinolone monotherapy may even be superior to macrolides. Whether other effects of macrolides are beneficial in cases other than S. pneumoniae is debatable, and beta-lactams are clearly not needed for atypicals.

The controversy is threefold: (1) is beta-lactam/macrolide combination therapy superior to other beta-lactam treatments? (2) Are additional antibiotics required for PES pathogens? And (3) is prolonged antibiotic therapy needed for all patients with only positive viral testing?

Non-interventional trials suggest that beta-lactam/macrolide combination therapy is associated with lower mortality, especially in patients with pneumococcal bacteremia [53] .

However, the study by Postma et al. [11] found no difference in 90-day mortality when comparing beta-lactam alone with beta-lactam/macrolide or quinolones. The study exhibits two important limitations: first, 25% of patients had no chest X-ray confirmation; second, most patients had a low-grade severity pneumonia, as measured by the PSI scale. Another RCT study [54] found a lower rate of readmissions and a higher rate of clinical cure only in patients with PSI categories IV and V pneumonia receiving beta-lactam plus macrolide.

Observational studies of beta-lactam/quinolone combination therapy for SCAP suggest better outcome than beta-lactam monotherapy. One prospective study found combination therapy with an early quinolone was slightly superior to a cephalosporin alone [51] . Three theories support the benefit of empirical macrolide combination: (1) better coverage of atypical pathogens, including Legionella, (2) suppression of exotoxin production from S. pneumoniae [55] , and (3) host immunomodulatory effects. The latter two clearly differentiate between macrolides and quinolones, although both are effective against atypical pathogens. The underlying assumption that most of these culture-negative cases are S. pneumoniae is questionable with greater use of the highlyeffective conjugate pneumococcal vaccines [56] . Some data support the use of quinolones for proven severe Legionella [57] . Methicillin-sensitive strains are likely covered adequately with standard empirical therapy. However, empirical coverage of MRSA for all SCAP patients does not improve outcomes [58] . Gross hemoptysis, leukopenia, skin rashes, and rapidly progressive or necrotizing infiltrates are relatively distinctive for the toxigenic community-acquired strain [59] . Observational studies suggest a better outcome with the use of antibiotics that interfere with ribosomal synthesis, such as linezolid or clindamycin [60] . Whether more rapid killing associated with the cephalosporin ceftaroline obviates the need for toxin suppression is unknown [61] .

Patients with SCAP who are at risk for pathogens usually considered nosocomial represent a therapeutic dilemma. Unfortunately, piperacillin/tazobactam, the most commonly prescribed antibiotic for suspected drug-resistant pathogens, has recently been shown to have adverse outcomes in patients with E. coli and K. pneumoniae bloodstream infection and ceftriaxone resistance [62] .

In cases of svCAP, the overwhelming majority of patients receive empirical antibiotics despite infrequently documented bacterial superinfection. Short-course prophylactic antibiotics may prevent bacterial superinfection while prolonged courses predispose to nosocomial infections, disrupting gut and lung microbiomes.

It is worth pointing out that some SCAP cases require longer antibiotic administration. These include SCAP caused by S. aureus, patients with pleural effusions, pulmonary abscess and, patients with initial inadequate antibiotic treatment.

We recommend a combination of a beta-lactam/betalactamase inhibitor or a third G cephalosporin plus a macrolide for most SCAP patients. Legionella, if documented, should be treated with a quinolone. Empirical linezolid should be reserved to patients with risk factors for community-acquired MRSA. Empirical broader spectrum therapy for Gram-negative pathogens should be limited to patients with several risk factors for PES pathogens.

We need a RCT of usual treatment (cephalosporin/ macrolide) with additional empirical coverage for PES pathogens versus pathogen-specific therapy based on rapid diagnostic testing. We need interventional studies investigating the duration of SCAP antibiotic treatment according to procalcitonin and rapid molecular diagnostic techniques. Finally, we need a RCT of short-course antibiotic therapy for SCAP patients with only viral detection on molecular testing.

Pneumonia is the most common cause of septic shock [63] . Despite improvements in the overall survival from severe sepsis, mortality from SCAP remains high-up to 50% in some studies [64] . Reasons for this discrepancy remain unclear, but it suggests the possibility that SCAP represents a unique subset of septic shock that deserves a unique set of guidelines for management. The high mortality in SCAP, despite early and adequate antibiotic treatment, may be a result of inadequate infection control and/or dysregulated inflammatory responses. The latter possibility raises the perennial question in the management of SCAP of whether or not to employ systemic corticosteroid therapy.

Current strategies to manage patients with SCAP and shock include the identification of pathogens using available diagnostics [65] , early and appropriate (including combination) antimicrobial administration [66] , hemodynamic resuscitation [67] , and, for some patients, appropriate management of acute respiratory failure or ARDS [68] .

Two recent RCTs, the ADRENAL and the APPROC-CHSS, supported the use of adjunct corticosteroid therapy in septic shock (Table 4) , both studies demonstrating a reduction in the number of vasopressor-and ventilatordependent days [69, 70] . In these studies, 34% and 59% of patients had pulmonary infections, respectively. The APPROCCHSS demonstrated a small mortality benefit, a feature some authors attributed to the inclusion of mineralocorticoids in the treatment protocol. However, this finding may be better explained by the higher baseline mortality in the latter trial, which would fit with the general trend in steroid trials dating back to 2002 (including the French Trial, HYPRESS, and CORTICUS), which showed the greatest benefit of therapy in the sickest populations [71] [72] [73] . A recent network meta-analysis of 23 septic shock studies supported with strong evidence the role of corticosteroids in shock reversal [74] . The use of steroids in SCAP (with or without shock) remains controversial [43, 44, [75] [76] [77] [78] [79] [80] [81] [82] [83] , although many studies have shown significant reductions in length of stay and time to clinical stability. Increasing evidence suggests that patients with strong inflammatory responses, such as those with highly elevated CRP, may represent a subset of SCAP patients who would benefit from such corticosteroid treatment [43] . Conversely, corticosteroid use in patients with versus CAP has been related to increased mortality [84] . There is currently insufficient evidence to support other adjuvant therapies in SCAP, such as immunoglobulins, G-CSF or statins [85] .

Patients with SCAP and shock should be managed according to current practice guidelines. Adjunctive therapy, including systemic corticosteroids, should be reserved for SCAP patients with refractory septic shock or with high systemic inflammatory response (as measured by CRP).

Studies are still needed to clarify why SCAP mortality remains high despite improvements in overall sepsis outcomes. Host inflammatory responses (both of the lung and systemic) require better characterization to determine the potential role of immune modulators in SCAP. Finally, additional studies are needed to better assess patients' immune phenotype and to determine who should receive steroids and other immunosuppressive therapies.

Treatment success in SCAP rests on prompt delivery of antibiotics targeting the likely causative organisms. An important controversy is whether existing antibiotics are adequate therapies or whether new antimicrobials are needed.

Initial inappropriate empiric therapy in SCAP is primarily driven by the failure to cover a specific pathogen (e.g., MRSA) or the presence of a resistant bacterial pathogen (e.g., macrolide-resistant S. pneumoniae) [86] . The need to empirically cover both "typical" bacterial pathogens (S. pneumonia, Haemophilus influenza, MMSA) and "atypical" pathogens (Mycoplasma pneumoniae, Legionella [87, 88] . Based on the available data, it appears that new antibiotics providing coverage for the currently existing limitations in empiric therapy are needed (Table 5) .

Lefamulin is a novel semisynthetic pleuromutilin that inhibits bacterial growth by binding to the peptidyl transferase center of the 50S ribosomal subunit [89] . Pleuromutilins are not typically affected by resistance to other antibiotic classes (including macrolides, fluoroquinolones, and tetracyclines). Two phase 3 trials (LEAP 1intravenous to oral lefamulin; LEAP 2-oral only) have demonstrated comparable (non-inferior) outcomes to moxifloxacin (https ://inves tors.nabri va.com/stati c-files /5c34b 447-99cc-4739-b9d6-d4ea4 c7d13 b9 (Accessed 12 July 2018).

Omadacycline is from the aminomethylcycline class created by chemical modification of minocycline. It inhibits protein synthesis by binding to the 30S ribosomal subunit. Chemical modifications enable it to be active against the two main forms of bacterial resistance to the tetracyclines: efflux and ribosomal protection. Results from the phase 3 OPTIC trial comparing once-daily oral and intravenous omadacycline to oral and intravenous moxifloxacin demonstrated noninferiority (https ://globe newsw ire.com/news-relea se/2017/04/03/95380 1/0/en/Parat ek-Annou nces-Posit ive-Phase -3-Study -of-Omada cycli ne-in-Commu nity-Acqui red-Bacte rial-Pneum onia.html (Accessed 12 July 2018).

Delafloxacin (Baxdela ™ ) is a potent fluoroquinolone with structural differences allowing it to move better than other fluoroquinolones through an acidic medium facilitating transmembrane passage into bacteria. Delafloxacin has a high affinity for both topoisomerase IV and DNA gyrase targets, giving it activity against Gram-positive and Gram-negative bacteria, as well as anaerobes and intracellular microorganisms [90] . The results of a phase 3 trial comparing delafloxacin to moxifloxacin for hospitalized patients with CAP are awaited.

Solithromycin (Solithera ™ ) is a fourth-generation macrolide and the first fluoroketolide in clinical development. Solithromycin has potent in vitro activity against the most common CAP pathogens, including fluoroquinolone-resistant isolates of S. pneumoniae. Two phase 3 trials of oral and intravenous to oral therapy for CAP demonstrated comparable results to moxifloxacin [91] . However, due to concerns over potential liver toxicity, the FDA recommended that the company initiate a new clinical study to better evaluate the drug's safety profile in 9000 patients.

Nemonoxacin is a novel nonfluorinated quinolone with a wide antimicrobial spectrum covering Gram-positive cocci and Gram-negative bacilli, including the common CAP pathogens. One published phase 2 trial and two unpublished phase 3 trials suggest that Nemonoxacin is non-inferior to levofloxacin for the treatment of CAP [92, 93] .

Ceftaroline fosamil (Teflaro ™ ) is an N-phosphonoamino water-soluble prodrug cephalosporin with the active form, ceftaroline, possessing broad-spectrum in vitro antimicrobial activity. The spectrum of activity includes typical CAP bacterial pathogens and its high affinity for PBP2a allows coverage of MRSA [94] . The high superiority of ceftaroline compared to ceftriaxone in bacterial pneumonia was demonstrated in the FOCUS 1 and 2 trials [61] .

The current role of the new antibiotics in SCAP is almost unknown, since the majority of them have not been studied in this specific subgroup of patients. Ceftaroline could be added to the list of beta-lactams for the empirical or targeted treatment of SCAP.

We need observational and/or RCT studies of new antibiotics in the specific SCAP population. Non-traditional agents, such as monoclonal antibodies, that may minimize or avoid the emergence of resistance should also be explored.

SCAP is a major challenge in ICU due to its high mortality, complications, short and long-term consequences. However, the optimal care is still not well standardized. SCAP remains a small section of general CAP recommendations, and performing interventional and RCTs in this subgroup of patients may be difficult. In this point-of-view review paper, we provide literature evidence, suggested recommendations and suggestions for future research regarding six seminal questions of SCAP management: (1) who needs to be admitted to ICU? (2) When should PES pathogens be suspected? (3) How should severe viral CAP be managed? (4) What is the optimal empirical antibiotic treatment for SCAP? (5) When should corticosteroids in SCAP with septic shock be used? And (6) what is the current evidence regarding new antibiotics and the pipe-line for coming years?

Ten-year trends in intensive care admissions for respiratory infections in the elderly

Communityacquired pneumonia requiring hospitalization among U.S. adults

Communityacquired pneumonia as an emergency condition

Predictors of severe sepsis among patients hospitalized for communityacquired pneumonia

Community-acquired pneumonia on the intensive care unit: secondary analysis of 17,869 cases in the ICNARC Case Mix Programme Database

New sepsis definition (sepsis-3) and community-acquired pneumonia mortality. A validation and clinical decision-making study

Estimating the burden of pneumococcal pneumonia among adults: a systematic review and meta-analysis of diagnostic techniques

Community-acquired pneumonia due to multidrug-and non-multidrug-resistant pseudomonas aeruginosa

Severe community-acquired pneumonia: current management and future therapeutic alternatives

Impact of antibiotic therapy in severe community-acquired pneumonia: data from the Infauci study

Antibiotic treatment strategies for community-acquired pneumonia in adults

Is beta-lactam plus macrolide more effective than beta-lactam plus fluoroquinolone among patients with severe community-acquired pneumonia?: a systemic review and meta-analysis

Risk factors associated with potentially antibiotic-resistant pathogens in communityacquired pneumonia

Severity scores and community-acquired pneumonia. Time to move forward

Severity assessment tools to guide ICU admission in community-acquired pneumonia: systematic review and meta-analysis

-hospital deaths among adults with community-acquired pneumonia

Validation of the Infectious Diseases Society of America/ American Thoratic Society minor criteria for intensive care unit admission in community-acquired pneumonia patients without major criteria or contraindications to intensive care unit care

Rocket science and the Infectious Diseases Society of America

Comparison of medical admissions to intensive care units in the United States and United Kingdom

IDSA/ATS minor criteria aid pre-intensive care unit resuscitation in severe community-acquired pneumonia

Simplification of the IDSA/ATS criteria for severe CAP using meta-analysis and observational data

SMART-COP: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia

Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial

Initial inflammatory profile in community-acquired pneumonia depends on time since onset of symptoms

Severity assessment scores to guide empirical use of antibiotics in community acquired pneumonia

Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults

Predicting risk of drugresistant organisms in pneumonia: moving beyond the HCAP model

Are third-generation cephalosporins unavoidable for empirical therapy of communityacquired pneumonia in adult patients who require ICU admission? A retrospective study

The respiratory threat posed by multidrug resistant Gram-negative bacteria

Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia

A therapeutic strategy for all pneumonia patients: a 3-year prospective multicenter-cohort study using risk factors for multidrug resistant pathogens to select initial empiric therapy

Risk factors for drug-resistant pathogens in immunocompetent patients with pneumonia: evaluation of PES pathogens

Bacteraemia and antibioticresistant pathogens in community acquired pneumonia: risk and prognosis

Burdenand risk factors for Pseudomonas aeruginosa community-acquired pneumonia: a multinational point prevalence study of hospitalised patients

Global initiative for meticillin-resistant Staphylococcus aureus pneumonia (GLIMP): an international, observational cohort study

Increased incidence of co-infection in critically ill patients with influenza

Frequency of respiratory virus infections and next-generation analysis of influenza A/ H1N1pdm09 dynamics in the lower respiratory tract of patients admitted to the ICU

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials

Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals

Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial

Corticosteroids for pneumonia

The pharmacological management of severe influenza infection-'existing and emerging therapies

Corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study

Neces-SARI-ly?

Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial

Placebo-controlled trials of treatments for communityacquired pneumonia: review of the literature and discussion of feasibility and potential value

Critics attack chief medical officer's advice to use antivirals for flu

Comparison of levofloxacin and cefotaxime combined with ofloxacin for ICU patients with community-acquired pneumonia who do not require vasopressors

Severe community-acquired pneumonia: characteristics and prognostic factors in ventilated and non-ventilated patients

Effectiveness of combination therapy versus monotherapy with a third-generation cephalosporin in bacteraemic pneumococcal pneumonia: a propensity score analysis

beta-Lactam monotherapy vs. beta-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial

Clarithromycin alone and in combination with ceftriaxone inhibits the production of pneumolysin by both macrolide-susceptible and macrolide-resistant strains of Streptococcus pneumoniae

Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults

The association of antibiotic treatment regimen and hospital mortality in patients hospitalized with Legionella pneumonia

Empiric therapy directed against MRSA in patients admitted to the intensive care unit does not improve outcomes in community-acquired pneumonia

Factors predicting mortality in necrotizing community-acquired pneumonia caused by Staphylococcus aureus containing Panton-Valentine leukocidin

Methicillin resistance is not a predictor of severity in community-acquired Staphylococcus aureus necrotizing pneumonia-results of a prospective observational study

Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia

Effect of piperacillin-tazobactam vs. meropenem on 30-day mortality for patients with e coli or klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial

Patients with community acquired pneumonia admitted to European intensive care units: an epidemiological survey of the GenOSept cohort

Determining best outcomes from community-acquired pneumonia and how to achieve them

The use of polymerase chain reaction amplification for the detection of viruses and bacteria in severe community-acquired pneumonia

Delays from first medical contact to antibiotic administration for sepsis

Surviving sepsis campaign: international guidelines for management of sepsis and septic shock

Management of ARDS in adults

Adjunctive glucocorticoid therapy in patients with septic shock

Hydrocortisone plus fludrocortisone for adults with septic shock

Hydrocortisone therapy for patients with septic shock

Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock

Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial

Corticosteroids in septic shock: a systematic review and network meta-analysis

Corticosteroid therapy for severe community-acquired pneumonia: a meta-analysis

Corticosteroids in Patients hospitalized with community-acquired pneumonia: systematic review and individual patient data metaanalysis

Efficacy of corticosteroid treatment for severe community-acquired pneumonia: a meta-analysis

Adjunctive therapies for community-acquired pneumonia: a systematic review

Corticosteroids in the treatment of community-acquired pneumonia in adults: a meta-analysis

Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis

Adjunctive systemic corticosteroids for hospitalized community-acquired pneumonia: systematic review and meta-analysis

Adjunctive corticotherapy for community acquired pneumonia: a systematic review and meta-analysis

Efficacy and safety of corticosteroids for community-acquired pneumonia: a systematic review and meta-analysis

Corticosteroids as adjunctive therapy in the treatment of influenza

Nonantibiotic adjunctive therapies for community-acquired pneumonia (corticosteroids and beyond): where are we with them?

A case series of macrolide treatment failures in community acquired pneumonia

The effect of macrolide resistance on the presentation and outcome of patients hospitalized for Streptococcus pneumoniae pneumonia

Macrolide-resistant Mycoplasma pneumoniae prevalence and clinical aspects in adult patients with communityacquired pneumonia in China: a prospective multicenter surveillance study

In vitro activity of lefamulin tested against Streptococcus pneumoniae with defined serotypes, including multidrug-resistant isolates causing lower respiratory tract infections in the united states

In vitro activity of delafloxacin against contemporary bacterial pathogens from the United States and Europe

Spotlight on solithromycin in the treatment of community-acquired bacterial pneumonia: design, development, and potential place in therapy

A randomized, double-blind, multicenter Phase II study comparing the efficacy and safety of oral nemonoxacin with oral levofloxacin in the treatment of communityacquired pneumonia

Managing community acquired pneumonia in the elderly-the next generation of pharmacotherapy on the horizon

Ceftaroline fosamil for the treatment of community-acquired pneumonia: from FOCUS to CAPTURE