key: cord-0762646-x1aa6j6h
authors: Nair, Girish B.; Niederman, Michael S.
title: Updates on community acquired pneumonia management in the ICU
date: 2020-08-15
journal: Pharmacol Ther
DOI: 10.1016/j.pharmthera.2020.107663
sha: 33cd37d98967a5e68980a16df85697c871517a4d
doc_id: 762646
cord_uid: x1aa6j6h

While the world is grappling with the consequences of a global pandemic related to SARS-CoV-2 causing severe pneumonia, available evidence points to bacterial infection with Streptococcus pneumoniae as the most common cause of severe community acquired pneumonia (SCAP). Rapid diagnostics and molecular testing have improved the identification of co-existent pathogens. However, mortality in patients admitted to ICU remains staggeringly high. The American Thoracic Society and Infectious Diseases Society of America have updated CAP guidelines to help streamline disease management. The common theme is use of timely, appropriate and adequate antibiotic coverage to decrease mortality and avoid drug resistance. Novel antibiotics have been studied for CAP and extend the choice of therapy, particularly for those who are intolerant of, or not responding to standard treatment, including those who harbor drug resistant pathogens. In this review, we focus on the risk factors, microbiology, site of care decisions and treatment of patients with SCAP.

5 elevated BUN > 30 gm/dl (Braun, Kheir, Mashiach, Naffaa, & Azzam, 2014; Garau et al., 2008; Laserna et al., 2012; J. H. Lee et al., 2013; Prina et al., 2013; Walden et al., 2014) . Waterer et.al. studied avoidable factors contributing to CAP specific short-term mortality from a large prospective study including 832 patients, and found only 2 patients, who died had an identifiable lapse in quality of in-patient pneumonia care with delayed administration of antibiotics in presence of shock or antibiotic therapy not consistent with the IDSA/ATS 2007 CAP guidelines (Waterer et al., 2018) . Thus, SCAP mortality is closely associated with older age, presence of comorbidities and severity of disease on admission (Ito et al., 2017 )( Table -1 ).

Another factor that may influence outcomes in patients with SCAP is related delay in receiving appropriate treatment or admission to the ICU (Restrepo, Mortensen, Rello, Brody, & Anzueto, 2010) .

Most studies use an average of 6 hours as a cutoff for receiving appropriate antibiotics after being evaluated in the emergency department (Mandell et al., 2007; Metersky et al., 2006; Ruiz et al., 1999; Torres et al., 1991; Waterer, Kessler, & Wunderink, 2006) . In a study including 453 CAP patients, investigators noted a significant difference in 28-day mortality (11.7% vs. 23.4%) for those who were directly admitted to the ICU from the emergency room with an obvious need for ICU care, compared to those without obvious need for ICU care who had delayed admission (Renaud et al., 2009) . Hraiech et.al. noted a mortality advantage with CAP patients, who required mechanical ventilation within 72 hours of the onset of CAP compared to those who required mechanical ventilation 4 or more days after the onset of CAP (28% vs. 51%, p = 0.03) (Hraiech et al., 2013) . Hence, any delay in recognizing severe illness, identification of those at risk for mechanical ventilation or need for ICU level of care with an accompanying late delivery of appropriate therapy may adversely impact patient outcomes in severe CAP.

6

Identification of severe pneumonia early in the course seems favorable, but is fraught with complexity. Several investigators have proposed severity scoring systems to predict the risk of death but none has consistently shown improvement in mortality after implementation in clinical practice . The most widely used prognostic scoring systems are the Pneumonia Severity Index (PSI), the CURB-65 score, ATS/IDSA criteria for severe CAP, SMART-COP, CAP-PIRO and CURXO-80 (Table-2 ) (Charles et al., 2008; Espana et al., 2006; Mandell et al., 2007) . While both PSI and CURB-65 are good in predicting mortality with CAP patients, there is a poor correlation between mortality risk and the need for ICU admission . For example, young and previously healthy individuals may have a severe pneumonia, yet a low predicted mortality, but could still benefit from intensive respiratory and vasopressor support in an ICU.

The SMART-COP scoring system estimates the need for ICU care by predicting the need for intensive respiratory and vasopressor support (IRVS) (Charles et al., 2008) . It assigns points to 8 clinical features associated with the need for IRVS: systolic blood pressure < 90 mm Hg, multilobar infiltrates on chest x-ray, albumin < 3.5 g/dL, respiratory rate elevation (>25/min for those < age 50, and > 30/min for those > age 50), tachycardia (> 125/min), confusion, low oxygen (PaO2 < 70 mm Hg or saturation < 93% if < age 50 and PaO2 < 60 mm Hg or saturation <90% if > age 50), and arterial pH < 7.35. The abnormalities in systolic blood pressure, oxygenation and arterial pH each received 2 points, while the 5 other criteria received 1 point each. Using a cut off of at least 3 points, SMART COP has a sensitivity of 8 28-day mortality was not different between the PCT-based regimen and standard treatment groups with the exception of shorter duration of antimicrobial therapy in the PCT arm (Prkno, Wacker, Brunkhorst, & Schlattmann, 2013) . PCT or other biomarkers are not specific for pneumonia itself, and its overall use for disease severity is best achieved when used in combination with disease specific scoring system and clinical judgement.

S. pneumoniae remains the most common bacterial pathogen responsible of SCAP, regardless of age and comorbidities (Mandell et al., 2007) . Although antibiotic-resistant variants of S. pneumoniae, have become increasingly common, the ICU mortality related with pneumococcal pneumonia has decreased over the last decade (Gattarello et al., 2014) . In a study from Spain of SCAP patients spanning 3 time periods from 1999 -2013, S. pneumoniae was the most common pathogen isolated with an overall incidence of 41.7% and over 80% of all causes of bacteremia (Valles et al., 2016) . Other pathogens implicated with severe CAP include viruses (e.g., influenza, avian-origin influenza A -H7N9, novel H1N1, H3N2 influenza, respiratory syncytial virus, coronavirus illness of severe acute respiratory syndrome [SARS], Middle East respiratory syndrome coronavirus (MERS-CoV), atypical bacteria including L. pneumophila, M. pneumoniae, M. tuberculosis, and H. influenzae. S. aureus (including methicillinresistant forms, or MRSA) , enteric gram-negatives and, rarely, anaerobes may also be involved with severe disease based on risk factors. 9 common identified pathogens were due to a viral etiology (22%), followed by bacterial infection alone in 19% and 4% with mixed infection, but many had no identified pathogen. In those with SCAP, the viral pathogens were: rhinovirus (8%), influenza (6%), metapneumovirus, RSV, parainfluenza, coronavirus and adenovirus (Jain et al., 2015) . Influenza can lead to a primary viral pneumonia or to secondary bacterial infection with pneumococcus, S. aureus, or H. influenzae. Pandemics have become a global concern with multiple outbreaks, mostly with Influenza A(H1N1) in 2009, novel avian-origin influenza A (H7N9) in 2013 and in both instances bacterial coinfections, mostly with S. pneumoniae were common (Li et al., 2014; MacIntyre et al., 2018; Muscedere et al., 2013) . Most recently, a novel coronavirus disease that originated in Wuhan, China in 2019 (COVID-19) developed into a worldwide pandemic with high fatality rates overwhelming healthcare systems in many countries (Wu & McGoogan, 2020) .

Enteric gram-negatives (most commonly P. aeruginosa) can be found in up to 2% of identified CAP pathogens and are usually seen in patients who have prior structural lung disease, those who are on corticosteroids, those who had prior antibiotic therapy or had septic shock on admission (Falguera et al., 2009 ). Prina and colleagues report a 6% incidence of PES pathogens (P. aeruginosa, Enterobacteriaceae with extended-spectrum β-lactamases , and methicillin-resistant Staphylococcus aureus) from a cohort of 1,597 pneumonia patients with an etiological diagnosis (Prina et al., 2015) . They noted these patients had advanced age and were admitted with acute kidney injury, and had an increased 30-day mortality risk (adjusted odds ratio = 2.51). Both S. aureus and community-acquired strain of methicillin resistant S. aureus (CA-MRSA) can cause severe CAP, particularly as a complication of influenza infection (Deresinski, 2005; Mandell et al., 2007; Micek, Dunne, & Kollef, 2005) . The Global initiative for methicillin-resistant Staphylococcus aureus pneumonia (GLIMP) study reported a prevalence of confirmed MRSA in CAP patients to be up to 3% and MRSA was seen mostly in patients with a history of prior MRSA infection or colonization, recurrent skin infections or in those with severe pneumonia (Aliberti et al., 2016) . Aspiration pneumonia refers to a patient with features of CAP in the setting of oropharyngeal dysphagia or other conditions that promote large volumes of gastric or oropharyngeal contents reaching the lung. The IDSA/ATS 2019 guidelines do not recommend adding antibiotics for anaerobic coverage for suspected aspiration pneumonia in inpatient settings, except when lung abscess or empyema is suspected, as the majority of these pneumonias are caused by Gram negative pathogens (Metlay et al., 2019) . However, in the setting of SCAP, antibiotics should be directed towards upper airway colonizers, likely to be present at the time of the event, such as Gram-negative pathogens and S. Aureus.

Due to rampant use of broad-spectrum antibiotics, there is an ever-growing problem with antibiotic resistance. Use of antibiotics such as macrolides, beta-lactams, and quinolones, prior to admission to the ICU is a well-known predisposing factor for subsequent resistance to the same class of antibiotic particularly for Pneumococcus (Clavo-Sanchez et al., 1997; Ho et al., 2001; Ruhe & Hasbun, 2003; Vanderkooi, Low, Green, Powis, & McGeer, 2005) . Part of the issue is lack of newer antibiotics to keep up with the emergence of resistance to other classes or earlier generations of antibiotics (Pickens & Wunderink, 2019) . Recognizing the importance of curbing antimicrobial resistance, in 2014 White House released a Presidential Executive Order 13676 for Combating Antibiotic-Resistant Bacteria (CARB) (Pickens & Wunderink, 2019) .

In a multi-national study, the global prevalence of Drug resistant S. pneumoniae (DRSA) CAP was 1.3% with a higher rate in Africa (Aliberti et al., 2019) . Resistance pattern was higher for macrolides (0.6%) followed by penicillin resistance (0.5%). The majority of penicillin resistance is of the "intermediate" type (penicillin minimal inhibitory concentration *MIC+ of 0.1 to 1.0 mg/L) , but mortality J o u r n a l P r e -p r o o f Journal Pre-proof 11 is usually not increased until the penicillin MIC is more than 4 mg/L (Feikin et al., 2000) . Thus, it is still uncertain whether penicillin resistance leads to increased mortality (Choi, Chung, et al., 2012) .

Levofloxacin resistant pneumococcal pneumonia is seen with recent hospitalization, bronchopulmonary disease, cerebrovascular disease, and prior antibiotic use within 3 months (Seok et al., 2018) . Since the CAP guidelines recommend use of combination therapy in SCAP (a beta-lactam with either a macrolide or a quinolone), macrolide-resistance is not an issue, as most patients receive a beta-lactam which is effective against pneumococcus, even if macrolide resistance is present. Recently infections with hypervirulent carbapenem-resistant K. pneumoniae are increasingly being detected, but these organisms generally cause sepsis related with blood stream infection or nosocomial pneumonia (C. R.

Antibiotic stewardship with adherence to clinical pathways is recommended for combating antimicrobial resistance in CAP (Pickens & Wunderink, 2019) . These pathways are generally a stepwise, algorithmic approach for antibiotic initiation, de-escalation and duration of therapy. Adherence to CAP guidelines has generally been shown to improve outcomes and reduce pathogen resistance (Asadi et al., 2013) .

Pharmacotherapy in critically ill patients has unique pathobiology with altered pharmacokinetics and pharmacodynamics for most commonly used drugs, including β-lactams. The concentrations of the antibiotics fluctuate in plasma and extracellular fluid especially with acute kidney injury and hyperdynamic circulation, either of which can be seen in septic patients, with an impact on drug efficacy. Timely, accurate and empiric treatment for SCAP is essential to reduce mortality (Kumar et al., 2006; Leroy et al., 1995) . The current guidelines recommend the use of dual antibiotics: a β-lactam plus either a macrolide or a respiratory quinolone (levofloxacin or moxifloxacin) for patients with severe J o u r n a l P r e -p r o o f Journal Pre-proof pneumonia in the ICU(Figure-1), with no risks for drug resistant organisms (Metlay et al., 2019) . These recommendations are based on the likelihood of covering the common etiologic agents, but there is a lack of randomized controlled trials in patients with SCAP . In choosing antibiotics for SCAP, one also has to consider the role of emerging pathogens and viruses as etiologic agents for severe pneumonia (Jain et al., 2015) . On the other hand, if rapid diagnostic testing shows the presence of a specific pathogen, then therapy should be focused to the identified microbial agent.

Although the guideline provides direction on the best treatment strategies, several important controversies have emerged regarding the optimal course and choices of antibiotics in SCAP treatment.

These include: (a) combination therapy vs. monotherapy treatment strategy, (b) optimal treatment with aβ-lactam plus macrolide versus β-lactam plus fluoroquinolone, (c) need for additional antibiotics directed towards drug resistant or PES pathogens, (d) need for antibiotics in patients with identified viral pathogen, (e) optimal duration of treatment, (f) addition of corticosteroids.

Earlier evidence showed that combination therapy with a macrolide appeared to have a modest mortality benefit, especially in bacteremic SCAP patients with S. pneumoniae probably due to its ability for immunomodulatory effects (Baddour et al., 2004; Lodise, Kwa, Cosler, Gupta, & Smith, 2007; Metersky, Ma, Houck, & Bratzler, 2007; Weiss & Tillotson, 2005) . In a study of 865 patients, Adrie and colleagues reported no difference in 60 day mortality between a combination (β-lactam plus macrolide or fluoroquinolone) versus monotherapy (β-lactam alone) in SCAP patients, but there was survival advantage for patients, who had initial adequate antibiotic therapy (Adrie et al., 2013) . Rodriguez reported a survival advantage for SCAP patients, who required vasopressors and were on combination therapy with a β-lactam plus either a macrolide or quinolone compared to the use of monotherapy (Rodriguez et al., 2007) . Postma and colleagues in a cluster-randomized, non-ICU, hospitalized CAP patient population, compared β-lactam monotherapy to β-lactam -macrolide and J o u r n a l P r e -p r o o f Journal Pre-proof 13 fluoroquinolone monotherapy strategies, and found no statistical difference in 90-day mortality with the addition of a macrolide (Postma et al., 2015) . Sligl and associates found in a meta-analysis of severe CAP patients that combination therapy with a macrolide and β-lactam was associated with reduced mortality compared to other regimens (Sligl et al., 2014) . In another large systematic review including 137,574 patients, use of a macrolide was associated with reduced mortality (3.7% vs. 6.5%; RR, 0.78) compared with non-macrolide regimens, but the benefits were reduced when the results were restricted to randomized studies (Asadi et al., 2012) .Vardakas more recently reported another systematic review including 16,884 patients and found no difference in outcomes between the of a β-lactam plus macrolide versus β-lactam plus fluoroquinolone (Vardakas, Trigkidis, & Falagas, 2017) . Leroy and colleagues in a prospective, randomized study of 398 SCAP patients, showed similar clinical efficacy with levofloxacin monotherapy vs. combination therapy with cefotaxime and ofloxacin (79.1% vs. 79.5%, 95% CI, -10.13 -9.58% after adjustment for disease severity) (Leroy, Saux, Bedos, & Caulin, 2005) . However, in that study, combination therapy was better in patients requiring MV and those with septic shock were excluded. Thus, monotherapy is generally avoided in SCAP because effective dosing and safety of any single agent has not been established for ICU admitted CAP patients. Guideline concordant treatment with early initiation of antibiotics has been reliably shown to be effective in reducing CAP mortality (Gattarello et al., 2014) .

Early treatment failure in CAP could be due to infection with untreated Legionella pneumophila, which might occur in sporadic forms, drug resistant pneumococcus or infection with Gram-negative bacilli. There is an increase in the reported cases of Legionella lately in big cities and in those with diabetes, and those from poor neighborhoods (Farnham, Alleyne, Cimini, & Balter, 2014) . Quinolones are preferred over macrolides if Legionella is suspected (Yu et al., 2004) . The probability of being infected with drug resistant pathogens or enteric gram-negative organisms is likely related to the presence of cardiopulmonary disease or other risk factors, such as use of corticosteroids or prior history J o u r n a l P r e -p r o o f Journal Pre-proof 14 of resistant pathogens. Since the majority of aspiration pneumonia episodes are caused by Gram negative pathogens, the current IDSA/ATS 2019 guidelines do not recommend adding additional anaerobic coverage for suspected aspiration pneumonia (Metlay et al., 2019) . If Pseudomonas aeruginosa is suspected, treatment can be with a two-drug regimen, using an anti-pseudomonal betalactam (cefepime, imipenem, meropenem, piperacillin/tazobactam) plus ciprofloxacin or levofloxcin.

Alternatively, a three-drug regimen can be used, combining an anti-pseudomonal beta-lactam plus an aminoglycoside plus either an intravenous anti-pneumocccal quinolone (moxifloxacin or levofloxacin) or a macrolide (Mandell et al., 2007) . In CA-MRSA, either vancomycin or linezolid is preferred. Some authorities recommend the use of an antibiotic that inhibits toxin production, such as linezolid ( used alone) or clindamycin(added to vancomycin) in CA-MRSA, which may be particularly useful for patients with toxin-mediated necrotizing pneumonia (Micek et al., 2005) . In a study of 133 patients with Panton-Valentine leucocidin positive S. aureus, investigators noted significant survival advantage for patients, who have received treatment with an anti-toxin regimen compared to those without such a regimen (mortality rate of 6.1% vs. 52.3%, p <0.001) (Sicot et al., 2013) . The IDSA/ATS 2019 guidelines recommend empiric coverage for Pseudomonas and MRSA based on locally validated epidemiological risk factors for either pathogen to be present (Metlay et al., 2019) . However, many institutions do not have information like this, and instead we recommend using some of the traditional risk factors Appropriate duration of treatment in SCAP is not well established, but shorter duration of therapy for 5 to 7 days may be possible even in pneumococcal bacteremia, when patients have adequate clinical response to antibiotics, and no extrapulmonary infection (empyema, meningitis) (J. A. Ramirez & Bordon, 2001) . Serial measurements of biomarkers such as PCT can help with antibiotic deescalation without an increase in either mortality or treatment failure (Muller et al., 2010; Schuetz, Briel, et al., 2012; Schuetz, Muller, et al., 2012) . In a randomized trial of antibiotic therapy in the ICU, PCTguidance led to a reduction in duration of therapy compared to standard care in all patients, including those with severe CAP (Bouadma et al., 2010) . In a recent meta-analysis of 19 randomized controlled trials of CAP, including 4,861 , there were no difference in clinical cure rates between short course treatment defined as ≤6 days versus treatment for ≥7 days irrespective of patient setting or severity of pneumonia (Tansarli & Mylonakis, 2018) . In that study, short-course treatment was associated with fewer serious adverse events (RR = 0.73; 95 CI, 0.55 -0.97) and potentially lower mortality than longduration treatment (RR = 0.52; 95% CI, 0.33-0.82). The IDSA/ATS 2019 guideline recommends clinicians to continue antibiotics until the patient achieves stability using a validated measure of clinical stability including normalization of vital sign abnormalities, oxygen saturation, patient's ability to eat and normal mentation and the duration is not less than a total of 5 days (Metlay et al., 2019) .

With growing microbial resistance and continued need for appropriate coverage, several newer antibiotics have been studied in patients with CAP, with an ability to cover both typical, atypical and resistant CAP microbes, including newer generation cephalosporins, such as ceftaroline, ceftobiprole, ceftazidime-avibactam, and ceftolozane-tazobactam; newer macrolides like solithromycin; next J o u r n a l P r e -p r o o f Journal Pre-proof generation fluoroquinolones like nemonoxacin zabofloxacin and delafloxacin; tetracyclines like omadacycline, and potent semisynthetic agents such as lefamulin (Table-3) (Amalakuhan, Echevarria, & Restrepo, 2017) . However, their usage in SCAP is yet not completely understood, but offers potential antibiotic options that should be reserved for patients with resistant pathogens.

Ceftaroline is a fifth-generation cephalosporin with bactericidal activity against gram positive and negative pathogens, but also against MRSA and particularly against DRSP. In a meta-analysis of three randomized studies including 1916 CAP patients, ceftaroline (600 mg every 12 h) was superior to ceftriaxone (1-2 g every 24 h) for 5-7 days in an intention to treat analysis in patients with severe pneumonia(OR: 1.66; 95% CI 1.34, 2.06) (Taboada et al., 2016) . Ceftobiprole is another fifth-generation cephalosporin with extended spectrum activity gram-positive pathogens including MSSA, methicillinresistant coagulase-negative staphylococci, penicillin and ceftriaxone-resistant S. pneumoniae and gramnegative pathogens, such as P. aeruginosa and Enterobacteriaceae, but limited efficacy against MRSA (Cilloniz, Dominedo, Garcia-Vidal, & Torres, 2019) . Nicholson et.al. reported in a randomized study including 706 CAP patients that ceftobiprole (500 mg every 8 h) was not inferior to ceftriaxone as monotherapy ( 2gm every 24h) or combined with linezolid (600 mg every 12h) in IIT analysis and microbiological cure rates (Nicholson et al., 2012) .It is not approved for use in pneumonia in the US.

Ceftazidime-avibactam and Ceftolozane-tazobactarm are being tested for nosocomial pneumonia but have excellent activity against P. aeruginosa.

Solithromycin is a novel fourth generation macrolide and in two recent double-blind, randomized controlled, non-inferiority trials were comparable oral moxifloxacin in patients with mild to moderate CAP (Port Scores II-IV), buy it is not approved by the FDA (Barrera et al., 2016; File et al., 2016) . Nemonaxacin is a novel non-fluorinated quinolone and in a phase 3 study of CAP patients randomized to nemonoxacin (n = 356) or levofloxacin (n = 171) there was no difference in clinical or J o u r n a l P r e -p r o o f Journal Pre-proof microbiological cure rates between the groups at 7-10 days with comparable adverse side effects (Yuan et al., 2019) . Delafloxacin is another novel fluoroquinolone and in a phase 3 study in CAP patients, there was a 16-fold greater activity with delafloxacin compared to moxifloxacin for Gram-positive and fastidious Gram-negative pathogens with retained activity against resistant phenotypes found in S. pneumoniae (penicillin-, macrolide-, multiple-drug resistant), Haemophilus species (β-lactamase producing, macrolide-non-susceptible) and S. aureus (MRSA, fluoroquinolone-non-susceptible MSSA) (McCurdy et al., 2019) . Omadacycline is a recently approved aminomethycycline and in a recent randomized, double-blind trial, in CAP patients (PORT risk class of II, III, or IV) comparing omadacycline (100 mg intravenously every 12 hours for two doses, then 100 mg intravenously every 24 hours) to moxifloxacin (400 mg intravenously every 24 hours) there was a similar early clinical response with both antibiotics (Stets et al., 2019) . Lefamulin is a novel semi-synthetic antibiotic, in the pleuromutilin class, and has also recently been approved for CAP, and in the Phase 3 "LEAP 2", randomized clinical trial comparing early clinical response including CAP patients (PORT risk class of II, III, or IV) 5 days of oral lefamulin was not-inferior to 7-day oral treatment with moxifloxacin (Alexander et al., 2019) .

Lower respiratory tract infections constitute one of the most common causes for septic shock.

Although the overall incidence of CAP has come down, mortality related with SCAP and septic shock is still high (Hadfield & Bennett, 2018) . The role of corticosteroids in decreasing inflammation in patients with SCAP has been studied extensively with conflicting results. Potentially, corticosteroids reduce overwhelming inflammation by decreasing cytokines and help with inadequate adrenal response in critically ill patients, and may be useful in patients with pneumococcal meningitis (Salluh et al., 2008) .

Journal Pre-proof 18 Nie and associates in a meta-analysis involving 1001 patients did not find routine use of corticosteroids in CAP patients to be beneficial in reducing mortality, but in a subgroup analysis in patients with severe CAP, use of corticosteroids was associated with significant reduction in mortality (OR = 0.26, 95% CI: 0.11-0.64) (Nie, Zhang, Cheng, & Xiu, 2012) . In another randomized, prospective study administration of intravenous methylprednisolone (bolus of 0.5 mg/kg per 12 hours) in those with severe CAP and an elevated CRP >150 mg/L at admission, led to less treatment failure compared to placebo, without mortality benefit . Cheng and associates in another meta-analysis involving 4 randomized trials in severe CAP with 264 patients found significant in-hospital mortality benefit in the corticosteroid group compared with conventional therapy (OR = 0.39, 95% CI 0.17-0.90) (Cheng, Pan, Yang, & Gao, 2014) . More recently, another meta-analysis of severe CAP, including 8 RCTs with 528 patients found adjunctive corticosteroids use was associated with reduced all-cause mortality, ARDS and need for IMV (Bi et al., 2016) . Both the latter two studies should be looked at with caution as there was significant variation within the studies included and overall instability of pooled estimates.

Briel and associates pooled data from 1506 individual patients in 6 RCTs and analyzed the benefits of adjunctive corticosteroids using uniform outcome definitions (Briel et al., 2018) . In that study, corticosteroids in hospitalized CAP patients was not associated with mortality reduction, but improved time to clinical stability and length of hospital stay by 1 day.

The IDSA/ATS 2019 guideline gives a strong conditional recommendation against routine use of adjunctive steroids in patients treated for CAP (Metlay et al., 2019) . However, the data in severe CAP suggest that this group may be different, and recent studies with COVID-19 also suggest a benefit from corticosteroids for those with severe disease requiring either MV or oxygen alone compared to no respiratory support at the time of randomization (Horby et al., 2020) . We suggest using adjunctive glucocorticoids in SCAP patients with septic shock refractory to fluid resuscitation and with vasopressor use , especially in those with an elevated CRP >150 mg/L. Treatment can be with methylprednisolone J o u r n a l P r e -p r o o f Journal Pre-proof 0.5mg/Kg IV every 12 hours for 5 days and in those who can take oral medication, Prednisone 50 mg daily should be adequate. However, there should be caution in the setting of viral CAP, since metaanalyses in influenza patients, show increased mortality with corticosteroid use (Yang et al., 2015) .

Adjunctive immune therapy with different agents has been tried with limited success in SCAP.

Welte and colleagues in a phase II, double blind study of 160 SCAP patients, compared the efficacy of novel human polyclonal antibody preparation called Trimodulin, which contains different fractions of Immunoglobulins: IgG-56%, IgM-23% and IgA -21% to placebo in reducing ventilator free days and mortality (Welte et al., 2018) . Although the study did not show significant improvement in the primary end points, a subset analyses revealed Trimodulin to have significant mortality reduction in SCAP patients, who had high CRP and low IgM at baseline. Adjuvant granulocyte colony-stimulating factor (G-CSF) to antibiotics in severe CAP did not show benefit in mortality or in the course of illness resolution (Root et al., 2003) . Immunomodulatory therapy with mesenchymal stem cells showed potential benefits in animal models of pneumonia and is being studied in early clinical trials as adjunct therapy (Hackstein et al., 2015) . 

Initial use of one or two antibiotics for critically ill patients with community-acquired pneumonia: impact on survival and bacterial resistance

Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia: The LEAP 2 Randomized Clinical Trial

International prevalence and risk factors evaluation for drug-resistant Streptococcus pneumoniae pneumonia

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

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

Impact of guideline-concordant antibiotics and macrolide/beta-lactam combinations in 3203 patients hospitalized with pneumonia: prospective cohort study

Macrolide-based regimens and mortality in hospitalized patients with community-acquired pneumonia: a systematic review and meta-analysis

Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia

Efficacy and safety of oral solithromycin versus oral moxifloxacin for treatment of communityacquired bacterial pneumonia: a global, double-blind, multicentre, randomised, activecontrolled, non-inferiority trial (SOLITAIRE-ORAL). [Clinical Trial, Phase III Multicenter Study Randomized Controlled Trial Research Support

Efficacy and Safety of Adjunctive Corticosteroids Therapy for Severe Community-Acquired Pneumonia in Adults: An Updated Systematic Review and Meta-Analysis

Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial

Is elevated red cell distribution width a prognostic predictor in adult patients with community acquired pneumonia?

Corticosteroids in Patients Hospitalized With Community-Acquired Pneumonia: Systematic Review and Individual Patient Data Metaanalysis

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

Corticosteroid therapy for severe communityacquired pneumonia: a meta-analysis

Impact of penicillin nonsusceptibility on clinical outcomes of patients with nonmeningeal Streptococcus pneumoniae bacteremia in the era of the 2008 clinical and laboratory standards institute penicillin breakpoints

Viral infection in patients with severe pneumonia requiring intensive care unit admission

Ceftobiprole for the treatment of pneumonia

Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study

Viral communityacquired pneumonia in nonimmunocompromised adults

Methicillin-resistant Staphylococcus aureus: an evolutionary, epidemiologic, and therapeutic odyssey

Development and validation of a clinical prediction rule for severe community-acquired pneumonia

Risk factors and outcome of community-acquired pneumonia due to Gram-negative bacilli

Legionnaires' disease incidence and risk factors

Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance

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

SOLITAIRE-IV: A Randomized, Double-Blind, Multicenter Study Comparing the Efficacy and Safety of Intravenous-to-Oral Solithromycin to Intravenous-to-Oral Moxifloxacin for Treatment of Community-Acquired Bacterial Pneumonia

Prognosis and outcomes of patients with community-acquired pneumonia. A metaanalysis

Factors impacting on length of stay and mortality of community-acquired pneumonia

Decrease in mortality in severe community-acquired pneumococcal pneumonia: impact of improving antibiotic strategies

Prospectively defined murine mesenchymal stem cells inhibit Klebsiella pneumoniae-induced acute lung injury and improve pneumonia survival

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

Burden of Pneumonia-Associated Hospitalizations: United States

Risk factors for acquisition of levofloxacin

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

Time to intubation is associated with outcome in patients with community-acquired pneumonia

Prognostic factors in hospitalized community-acquired pneumonia: a retrospective study of a prospective observational cohort

Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults

Procalcitonin predicts patients at low risk of death from community-acquired pneumonia across all CRB-65 classes

Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock

Hypocapnia and hypercapnia are predictors for ICU admission and mortality in hospitalized patients with community-acquired pneumonia

Comparison of beta-lactam and macrolide combination therapy versus fluoroquinolone monotherapy in hospitalized Veterans Affairs patients with community-acquired pneumonia

The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09

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

Prevalence and Etiology of Community-acquired Pneumonia in Immunocompromised Patients Clinical Infectious Diseases

Usefulness of procalcitonin levels in community-acquired pneumonia according to the patients outcome research team pneumonia severity index

Efficacy of Delafloxacin Versus Moxifloxacin Against Bacterial Respiratory Pathogens in Adults with Community-Acquired Bacterial Pneumonia (CABP): Microbiology Results from the Delafloxacin Phase 3 CABP Trial

Antibiotics for bacteremic pneumonia: Improved outcomes with macrolides but not fluoroquinolones

Epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza

Antibiotic timing and diagnostic uncertainty in Medicare patients with pneumonia: is it reasonable to expect all patients to receive antibiotics within 4 hours?

Predictors of in-hospital vs postdischarge mortality in pneumonia

Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America

Pleuropulmonary complications of Panton-Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus: importance of treatment with antimicrobials inhibiting exotoxin production

Procalcitonin levels predict bacteremia in patients with community-acquired pneumonia: a prospective cohort trial

The occurrence and impact of bacterial organisms complicating critical care illness associated with 2009 influenza A(H1N1) infection

A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation

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

Principles and Practice of Antibiotic Stewardship in the ICU

Pneumonia in adults: diagnosis and management

Antibiotic treatment strategies for community-acquired pneumonia in adults

Thrombocytosis is a marker of poor outcome in community-acquired pneumonia

Risk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumonia

Procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock -a systematic review and metaanalysis

Early switch from intravenous to oral antibiotics in hospitalized patients with bacteremic community-acquired Streptococcus pneumoniae pneumonia

Adults Hospitalized With Pneumonia in the United States: Incidence, Epidemiology, and Mortality

Inflammatory biomarkers and prediction for intensive care unit admission in severe communityacquired pneumonia

New Sepsis Definition (Sepsis-3) and Community-acquired Pneumonia Mortality. A Validation and Clinical Decision-Making Study

Association between timing of intensive care unit admission and outcomes for emergency department patients with community-acquired pneumonia

Late admission to the ICU in patients with community-acquired pneumonia is associated with higher mortality

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the

Combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock

double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis

Streptococcus pneumoniae bacteremia: duration of previous antibiotic use and association with penicillin resistance

Severe community-acquired pneumonia. Risk factors and follow-up epidemiology

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

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

Adrenal response in severe community-acquired pneumonia: impact on outcomes and disease severity

Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis

Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections

Risk Factors for Community-Onset Pneumonia Caused by Levofloxacin-Nonsusceptible Streptococcus pneumoniae

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

Macrolides and mortality in critically ill patients with community-acquired pneumonia: a systematic review and

Omadacycline for Community-Acquired Bacterial Pneumonia

Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: individual patient data meta-analysis of randomized controlled trials

Systematic Review and Meta-analysis of the Efficacy of Short-Course Antibiotic Treatments for Community-Acquired Pneumonia in Adults

Challenges in severe community-acquired pneumonia: a point-of-view review

Severe community-acquired pneumonia. Epidemiology and prognostic factors

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

Evolution over a 15-year period of the clinical characteristics and outcomes of critically ill patients with severe community-acquired pneumonia

Predicting antimicrobial resistance in invasive pneumococcal infections

Fluoroquinolones or macrolides in combination with beta-lactams in adult patients hospitalized with community acquired pneumonia: a systematic review and meta-analysis

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

Delayed administration of antibiotics and atypical presentation in community-acquired pneumonia

The controversy of combination vs monotherapy in the treatment of hospitalized community-acquired pneumonia

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study). [Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial

Incidence of respiratory viruses in patients with community-acquired pneumonia admitted to the intensive care unit: results from the Severe Influenza Pneumonia Surveillance (SIPS) project

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention

Corticosteroids for the treatment of human infection with influenza virus: a systematic review and meta-analysis

Levofloxacin efficacy in the treatment of community-acquired legionellosis

Safety and efficacy of oral nemonoxacin versus levofloxacin in treatment of community-acquired pneumonia: A phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled, non-inferiority trial. [Clinical Trial, Phase III Comparative Study Multicenter Study Randomized Controlled Trial