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INTRODUCTION — Community-acquired pneumonia (CAP) is defined as an acute infection of the pulmonary parenchyma in a patient who has acquired the infection in the community, as distinguished from hospital-acquired (nosocomial) pneumonia (HAP).
CAP is a common and potentially serious illness [1-5]. It is associated with considerable morbidity and mortality, particularly in older adult patients and those with significant comorbidities. (See "Prognosis of community-acquired pneumonia in adults".)
The treatment of CAP in adults who require hospitalization will be reviewed here. A variety of other important issues related to CAP are discussed separately. These include:
●The diagnostic approach to patients with CAP (see "Diagnostic approach to community-acquired pneumonia in adults")
●How one makes the decision to admit patients with CAP to the hospital (see "Community-acquired pneumonia in adults: Risk stratification and the decision to admit")
●Treatment recommendations for CAP in patients treated in the outpatient setting (see "Treatment of community-acquired pneumonia in adults in the outpatient setting")
●The evidence for efficacy of different antibiotic medications in the empiric treatment of CAP and issues related to drug resistance (see "Antibiotic studies for the treatment of community-acquired pneumonia in adults")
●The epidemiology and microbiology of CAP (see "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults")
●Pneumonia in special populations, such as aspiration pneumonia, immunocompromised patients, HAP, and ventilator-associated pneumonia (VAP) (see "Aspiration pneumonia in adults" and "Pulmonary infections in immunocompromised patients" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults")
MANAGEMENT OF HEALTHCARE-ASSOCIATED PNEUMONIA — As noted above, community-acquired pneumonia (CAP) is defined as an acute infection of the pulmonary parenchyma in a patient who has acquired the infection in the community, as distinguished from hospital-acquired (nosocomial) pneumonia (HAP).
A third category of pneumonia, designated healthcare-associated pneumonia (HCAP), was included in prior HAP guidelines  (but not current HAP guidelines ) to identify patients thought to be at increased risk for multidrug-resistant (MDR) pathogens coming from community settings. HCAP referred to pneumonia acquired in healthcare facilities such as nursing homes, hemodialysis centers, and outpatient clinics or during a recent hospitalization. The rationale for the separate designation of HCAP (and its association with HAP) was that patients with HCAP were thought to be at higher risk for MDR organisms. However, several studies have shown that many patients defined as having HCAP are not at high risk for MDR pathogens [8-10]. Furthermore, although interaction with the healthcare system is potentially a risk for MDR pathogens, underlying patient characteristics are also important independent determinants of risk for MDR pathogens. It is anticipated that patients previously designated as HCAP will be included in the next update of the Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) CAP guidelines because patients with HCAP frequently present from the community and are initially cared for in emergency departments.
For these reasons, we feel that patients previously classified as having HCAP should be managed in a similar way to those with CAP, with the need for therapy targeting MDR pathogens being considered on a case-by-case basis. Specific risk factors for resistance that should be assessed include recent receipt of antimicrobials, comorbidities, functional status, and severity of illness [11,12]. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting".)
INDICATIONS FOR HOSPITALIZATION AND ICU ADMISSION — Determination of whether a patient with community-acquired pneumonia (CAP) can be treated safely as an outpatient or requires hospitalization with or without intensive care unit (ICU) admission is essential before selecting an antibiotic regimen. Severity of illness is the most critical factor in making this determination, but other factors should also be taken into account. These include ability to maintain oral intake, likelihood of compliance, history of substance abuse, mental illness, cognitive impairment, living situation, and patient functional status. These issues with appropriate references are discussed in detail elsewhere. (See "Community-acquired pneumonia in adults: Risk stratification and the decision to admit".)
Summarized briefly, prediction rules have been developed to assist in the decision of site of care for CAP. The two most commonly used prediction rules are the Pneumonia Severity Index (PSI) and CURB-65. The PSI is better studied and validated but requires a more complicated assessment (calculator 1) . PSI risk class correlates directly with mortality rate; risk class I is associated with a 0.1 percent mortality rate, compared with 0.6 percent for class II, 0.9 to 2.8 percent for class III, 8.2 to 9.3 percent for class IV, and 27.0 to 29.2 percent for class V . On the basis of these mortality rates, risk class I and II patients can generally be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients require hospitalization .
CURB-65 uses five prognostic variables :
●Confusion (based upon a specific mental test or disorientation to person, place, or time)
●Urea (blood urea nitrogen in the United States) >7 mmol/L (20 mg/dL)
●Respiratory rate ≥30 breaths/minute
●Blood pressure (BP) (systolic <90 mmHg or diastolic ≤60 mmHg)
●Age ≥65 years
The authors of the original CURB-65 report suggested that patients with a CURB-65 score of 0 to 1, who comprised 45 percent of the original cohort and 61 percent of the later cohort, were at low risk and could probably be treated as outpatients. Those with a score of 2 should be admitted to the hospital, and those with a score of 3 or more should be assessed for care in the intensive care unit (ICU), particularly if the score was 4 or 5 (calculator 2).
A simplified version (CRB-65), which does not require testing for blood urea nitrogen, may be appropriate for decision-making in primary care practitioners' offices . With the CRB-65 score, admission to the hospital is recommended if 1 or more points are present.
Other severity scoring systems have been developed that focus on severe CAP, such as SMART-COP  and the Severe CAP (SCAP) score ; there is less experience with these scoring systems compared with the other systems described above (See "Community-acquired pneumonia in adults: Risk stratification and the decision to admit", section on 'Admission to intensive care' and "Community-acquired pneumonia in adults: Risk stratification and the decision to admit", section on 'Severe community-acquired pneumonia score'.)
Clinical judgment should be used for all patients, incorporating the prediction rule scores as a component of the decision for hospitalization or ICU admission, but not as an absolute determinant . Limitations in the PSI scoring are the complexity of the system and the failure to account for comorbidities and social factors, such as homelessness, for making site of care decisions [20-22].
In a retrospective cohort study of over one million Medicare beneficiaries (aged >64 years) admitted to hospitals in the United States with pneumonia, ICU admission for patients with disease of marginal severity was associated with improved survival and no difference in costs compared with general ward admission, suggesting that ICU admission may benefit such patients . Patients living closer than the median differential distance (<3.3 miles) to a hospital with high ICU admission rates were significantly more likely to be admitted to the ICU than patients living farther away (36 versus 23 percent). Because most ill patients with pneumonia will seek care at the nearest hospital, patients who live close to a hospital with high ICU admission rates are more likely to be admitted to the ICU on a discretionary basis. In adjusted analyses, for the 13 percent of patients whose admission appeared to be discretionary (dependent only on distance), ICU admission was associated with a significantly lower adjusted 30-day mortality than patients admitted to a general ward (14.8 versus 20.5 percent). There were no differences in Medicare spending or hospitalization costs between the two groups. These results suggest a potential benefit of using broader ICU admission criteria but should be confirmed in a randomized trial.
PRINCIPLES OF ANTIMICROBIAL THERAPY — Community-acquired pneumonia (CAP) can be caused by a variety of pathogens (table 1 and table 2 and figure 1) [2,24,25]. The predominant bacterial pathogen is Streptococcus pneumoniae. Other common pathogens include Haemophilus influenzae, the atypical bacteria (Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella spp), oropharyngeal aerobes and anaerobes (in the setting of aspiration), and respiratory viruses. A randomized trial and a retrospective study have suggested that Staphylococcus aureus is increasing as a cause of CAP requiring admission to the hospital (some are due to community-associated methicillin-resistant S. aureus [MRSA] strains) [26,27]. Gram-negative bacilli (Enterobacteriaceae and Pseudomonas aeruginosa) are the cause of CAP in some patients. The frequency of other causes, such as Mycobacterium tuberculosis, Chlamydia psittaci (cause of psittacosis), C. burnetii (cause of Q fever), and endemic fungi vary in different epidemiologic settings.
Studies utilizing molecular diagnostic methods have reported the rate of detection of a viral etiology in patients with CAP at approximately 30 percent; influenza has been identified in many of these patients (table 1 and figure 1) [28-31]. The rate of mixed viral-bacterial infection is approximately 20 percent; such mixed infections have been found to be associated with more severe CAP and longer hospitalization than CAP caused by bacteria alone . (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Viruses'.)
The choice of initial therapy is complicated by the emergence of antibiotic resistance among S. pneumoniae, the most common bacterium responsible for CAP, as well as concern for MRSA in severe CAP. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Microbiology' and "Antibiotic studies for the treatment of community-acquired pneumonia in adults", section on 'Drug resistance and choice of therapy'.)
Empiric therapy and pathogen-directed therapy — Antibiotic therapy is typically begun on an empiric basis, since the causative organism is not identified in an appreciable proportion of patients (table 1 and table 2) [2,4,5,33]. Antibiotics should be started as soon as possible once the diagnosis of CAP is considered likely. The clinical features and chest radiographic findings are not sufficiently specific to determine etiology and influence treatment decisions. The Gram stain of respiratory secretions can be useful for directing the choice of initial therapy if performed on a good quality sputum sample and interpreted by skilled examiners using appropriate criteria . (See "Diagnostic approach to community-acquired pneumonia in adults", section on 'Sputum'.)
Benefit from a pathogen-directed approach to treatment, particularly for moderate to severe CAP, may emerge as rapid, more sensitive diagnostic tests become more widely available. However, there has been some concern that narrowing the coverage spectrum of antibiotics when a specific pathogen is identified may undertreat patients who have concurrent infection with atypical organisms.
This concern was not borne out in a prospective randomized trial comparing pathogen-directed treatment (PDT) and empiric broad-spectrum antibiotic treatment (EAT) in 262 hospitalized patients with CAP . PDT was based upon microbiologic studies (rapid diagnostic tests) or clinical presentation; EAT patients received a beta-lactam-beta-lactamase inhibitor plus erythromycin or, if admitted to the intensive care unit (ICU), ceftazidime and erythromycin. Overall, clinical outcomes (length of stay, 30-day mortality, fever resolution, and clinical failure) were the same for both groups. Adverse events were more frequent in the EAT group but were primarily related to the specific antimicrobial choice (ie, erythromycin).
Despite the use of empiric therapy, testing for a microbial diagnosis is important in clinical or epidemiologic settings, suggesting possible infection with an organism that requires treatment different from standard empiric regimens. These include Legionella species, seasonal influenza, avian (H5N1, H7N9) influenza, Middle East respiratory syndrome coronavirus, community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), Mycobacterium tuberculosis, and agents of bioterrorism such as anthrax. Molecular diagnostic tests for detection of respiratory pathogens have been rapidly evolving and are becoming increasingly available in clinical microbiology laboratories. Many of these tests combine sensitivity, specificity, and rapid turnaround time to allow identification of a pathogen early in the course of patient management and will allow for more specific use of antimicrobial agents with pathogen-directed therapy . (See "Diagnostic approach to community-acquired pneumonia in adults" and "Sputum cultures for the evaluation of bacterial pneumonia", section on 'Community-acquired pneumonia'.)
The selection of antimicrobial regimens for empiric therapy is based upon a number of factors, including:
●The most likely pathogen(s). (See 'Common pathogens' below.)
●Clinical trials proving efficacy. (See "Antibiotic studies for the treatment of community-acquired pneumonia in adults".)
●Risk factors for antimicrobial resistance. The choice of empiric therapy must take into account the emergence of antibiotic resistance among S. pneumoniae, the most common cause of CAP in adults who require hospitalization. (See 'Risk factors for drug resistance' below.)
●Medical comorbidities, which may influence the likelihood of a specific pathogen and may be a risk factor for treatment failure.
●Epidemiologic factors such as travel and concurrent epidemics (eg, Middle East respiratory syndrome coronavirus, avian influenza). (See "Middle East respiratory syndrome coronavirus: Virology, pathogenesis, and epidemiology" and "Epidemiology, transmission, and pathogenesis of avian influenza" and "Avian influenza A H7N9: Epidemiology, clinical manifestations, and diagnosis".)
Additional factors that may affect the choice of antimicrobial regimen include the potential for inducing antimicrobial resistance, pharmacokinetic and pharmacodynamic properties, safety profile, and cost .
The effectiveness of empiric antimicrobial regimens may be decreased by the emergence of newly recognized pathogens, such as CA-MRSA. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology", section on 'Community-associated MRSA infection'.)
Common pathogens — Although a variety of bacterial pathogens can cause CAP, a limited number are responsible for the majority of cases. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Microbiology'.)
With respect to patients who require hospitalization but not admission to an ICU, the most frequently isolated pathogens are S. pneumoniae, respiratory viruses (eg, influenza, parainfluenza, respiratory syncytial virus, rhinovirus), and, less often, M. pneumoniae, H. influenzae, C. pneumoniae, and Legionella (table 2).
The distribution is different in patients with CAP who require admission to an ICU. S. pneumoniae is most common, but Legionella, gram-negative bacilli, Staphylococcus aureus, and influenza are also important (table 2). Community-associated MRSA typically produces a necrotizing pneumonia with high morbidity and mortality. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'S. aureus'.)
Risk factors for CAP due to gram-negative bacilli include previous antibiotic therapy, recent hospitalization, immunosuppression, pulmonary comorbidity (eg, cystic fibrosis, bronchiectasis, or repeated exacerbations of chronic obstructive pulmonary disease that require frequent glucocorticoid and/or antibiotic use), probable aspiration, and multiple medical comorbidities (eg, diabetes mellitus, alcoholism) [2,36-38]. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Gram-negative bacilli'.)
The 2007 Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines on the management of CAP recommend empiric antibiotic therapy directed against P. aeruginosa in patients with gram-negative bacilli on Gram stain, since such a regimen will also cover other gram-negative bacilli, such as Klebsiella pneumoniae . (See "Pseudomonas aeruginosa pneumonia" and "Clinical features, diagnosis, and treatment of Klebsiella pneumoniae infection", section on 'Community-acquired pneumonia'.)
Risk factors for drug resistance — Risk factors for and other issues related to drug resistance in patients with CAP are discussed in detail elsewhere. (See "Antibiotic studies for the treatment of community-acquired pneumonia in adults", section on 'Drug resistance and choice of therapy'.)
Summarized briefly, risk factors for drug-resistant S. pneumoniae in adults include:
●Age >65 years
●Beta-lactam, macrolide, or fluoroquinolone therapy within the past three to six months
●Immunosuppressive illness or therapy
●Exposure to a child in a daycare center
Another risk factor is prior exposure to the healthcare setting such as from prior hospitalization or from residence in a long-term care facility.
Recent therapy or a repeated course of therapy with beta-lactams, macrolides, or fluoroquinolones are risk factors for pneumococcal resistance to the same class of antibiotic . Thus, an antimicrobial agent from an alternative class is preferred for a patient who has recently received one of these agents.
The impact of discordant drug therapy, which refers to treatment of an infection with an antimicrobial agent to which the causative organism has demonstrated in vitro resistance, appears to vary with antibiotic class and possibly with specific agents within a class. Most studies have been performed in patients with S. pneumoniae infection and suggest that current levels of beta-lactam resistance generally do not cause treatment failure when appropriate agents (eg, amoxicillin, ceftriaxone, cefotaxime) and doses are used. Cefuroxime is a possible exception with beta-lactams and there appears to be an increased risk of macrolide failure in patients with macrolide-resistant S. pneumoniae. (See "Antibiotic studies for the treatment of community-acquired pneumonia in adults", section on 'Outcomes with discordant drug therapy'.)
Establishing an etiologic diagnosis is particularly important when drug resistance is likely. The diagnostic approach to CAP is presented separately. (See "Diagnostic approach to community-acquired pneumonia in adults".)
GUIDELINES — A number of medical societies have issued guidelines for the treatment of community-acquired pneumonia (CAP) [2,40-42]. The antibiotic regimens advocated by a collaboration between the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) in 2007  and the British Thoracic Society (BTS) in 2009  are summarized in the Tables (table 3 and table 4).
The following discussion will review antibiotic therapy in patients with CAP who require hospitalization. Guideline recommendations for therapy in patients with CAP treated in the outpatient setting are presented separately. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting".)
●For hospitalized patients on the general wards, the IDSA/ATS guidelines recommend an antipneumococcal fluoroquinolone (eg, levofloxacin, moxifloxacin, gemifloxacin) or the combination of a beta-lactam plus a macrolide (table 3) .
●For patients with severe CAP requiring intensive care unit (ICU) admission, the IDSA/ATS guidelines recommend a beta-lactam (ceftriaxone, cefotaxime, ampicillin-sulbactam) plus either intravenous azithromycin or an antipneumococcal fluoroquinolone unless there is concern for Pseudomonas or methicillin-resistant Staphylococcus aureus (MRSA) infection. If Pseudomonas is a concern, an antipseudomonal agent (piperacillin-tazobactam, imipenem, meropenem, or cefepime) PLUS an antipseudomonal fluoroquinolone (ciprofloxacin or high-dose levofloxacin) should be used. If MRSA is a concern, either vancomycin or linezolid should be added (table 3) . (See 'Admitted to an ICU' below.)
In studies from different regions of the world, atypical pathogens account for 20 to 30 percent of cases of CAP in hospitalized patients . However, the value of providing empiric coverage for atypical pathogens (eg, Mycoplasma pneumoniae, C. pneumoniae, Legionella pneumophila) is debated . One reason for this is that testing for M. pneumoniae and C. pneumoniae is not usually done and, until 2012, there were no United States Food and Drug Administration (FDA)-cleared polymerase chain reaction tests to detect them. Thus, their role in an individual case or in population-based studies is not well elucidated. (See "Diagnostic approach to community-acquired pneumonia in adults", section on 'Chlamydia pneumoniae' and "Diagnostic approach to community-acquired pneumonia in adults", section on 'Mycoplasma pneumoniae'.)
The issue of coverage of atypical bacteria was addressed in a meta-analysis of 28 randomized trials of over 5000 patients with CAP requiring hospitalization; most trials compared fluoroquinolone monotherapy with non-atypical monotherapy . There was no significant difference in mortality (relative risk 1.14, 95% CI 0.84-1.55) or adverse effects between the atypical arm and non-atypical arm. There was a nonsignificant trend toward clinical success when treatment covered atypical bacteria, a difference that disappeared when only methodologically high quality trials were evaluated. Clinical success was significantly higher in the atypical arm for Legionella pneumophila. The trials were not designed to compare the time to response with different regimens.
A well-designed trial is required to more definitively determine the need to cover atypical pathogens in empiric regimens for CAP requiring hospitalization .
TREATMENT REGIMENS — Antibiotic recommendations for hospitalized patients with community-acquired pneumonia (CAP) are divided by the site of care (intensive care unit [ICU] or non-ICU). Most hospitalized patients are initially treated with an intravenous regimen. However, many patients without risk factors for severe pneumonia can be treated with oral therapy, especially with highly bioavailable agents such as the fluoroquinolones .
Hospitalized patients with CAP are initially treated with empiric antibiotic therapy. When the etiology of CAP has been identified based upon reliable microbiologic methods and there is no laboratory or epidemiologic evidence of coinfection, treatment regimens may be simplified and directed to that pathogen. The results of diagnostic studies that provide identification of a specific etiology within 24 to 72 hours can be useful for guiding continued therapy. (See "Diagnostic approach to community-acquired pneumonia in adults".)
Pathogen-specific therapy is discussed separately (table 5). (See "Pneumococcal pneumonia in adults" and "Mycoplasma pneumoniae infection in adults" and "Pneumonia caused by Chlamydia pneumoniae in adults" and "Treatment and prevention of Legionella infection" and "Pseudomonas aeruginosa pneumonia" and "Clinical features, diagnosis, and treatment of Klebsiella pneumoniae infection" and "Treatment of seasonal influenza in adults".)
Pneumonia in patients admitted to the hospital from long-term care facilities is not considered community acquired. It is categorized as healthcare-associated pneumonia (HCAP) and is discussed separately. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults" and "Causes of infection in long-term care facilities: An overview".)
Not in the ICU
●Combination therapy with ceftriaxone (1 to 2 g intravenously [IV] daily), cefotaxime (1 to 2 g IV every eight hours), ceftaroline (600 mg IV every 12 hours), ertapenem (1 g IV daily), or ampicillin-sulbactam (1.5 to 3 g IV every six hours) plus a macrolide (azithromycin [500 mg IV or orally daily] or clarithromycin [500 mg twice daily] or clarithromycin XL [two 500 mg tablets once daily]). Doxycycline (100 mg orally or IV twice daily) may be used as an alternative to a macrolide. Oral administration of a macrolide or doxycycline is appropriate only for selected patients without evidence of or risk factors for severe pneumonia.
If the patient has risk factors for drug-resistant pathogens, such as Pseudomonas or methicillin-resistant Staphylococcus aureus (MRSA), coverage for these organisms should be included, as discussed in the following section. Risk factors for Pseudomonas and MRSA are discussed below. (See 'Empiric therapy' below and 'Community-acquired MRSA' below.)
Both the macrolides and the fluoroquinolones can cause a prolonged QT interval, which can result in torsades de pointes and death. Studies assessing the risk-benefit ratio of azithromycin are reviewed elsewhere. Since the use of macrolides (and azithromycin in particular) has been associated with reduced mortality in CAP patients who require hospitalization, the risks and benefits should be considered when selecting a regimen. For the general population, azithromycin can be prescribed without significant concern; for patients at high risk of QT interval prolongation, the use of azithromycin should be weighed against the risk of cardiac effects. For patients with known QT interval prolongation, we favor doxycycline since it has not been associated with QT interval prolongation. However, doxycycline should be avoided during pregnancy. It should also be noted that doxycycline has been less well studied for the treatment of CAP than the macrolides and fluoroquinolones. Patients at particular risk for QT prolongation include those with existing QT interval prolongation, hypokalemia, hypomagnesemia, significant bradycardia, bradyarrhythmias, uncompensated heart failure, and those receiving certain antiarrhythmic drugs (eg, class IA [quinidine, procainamide] or class III [dofetilide, amiodarone, sotalol] antiarrhythmic drugs). Older adult patients may also be more susceptible to drug-associated QT interval prolongation. (See "Fluoroquinolones", section on 'QT interval prolongation and arrhythmia' and "Azithromycin, clarithromycin, and telithromycin", section on 'QT interval prolongation and cardiovascular events' and "Acquired long QT syndrome" and "Pharmacology of azoles", section on 'Selected clinical effects'.)
There is concern that widespread use of fluoroquinolones will promote the development of fluoroquinolone resistance among respiratory pathogens (as well as other colonizing pathogens) and may lead to an increased incidence of Clostridium difficile colitis . In addition, empiric use of fluoroquinolones should not be used for patients at risk for Mycobacterium tuberculosis without an appropriate assessment for tuberculosis infection. The administration of a fluoroquinolone in patients with tuberculosis has been associated with a delay in diagnosis, increase in resistance, and poor outcomes. (See "Antibiotic studies for the treatment of community-acquired pneumonia in adults", section on 'Fluoroquinolone resistance' and "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology", section on 'Antibiotic use'.)
When aspiration pneumonia is suspected, it is important to cover oral anaerobes. This is discussed in detail separately. (See "Aspiration pneumonia in adults", section on 'Treatment'.)
Antiviral treatment is recommended as soon as possible for all persons with suspected or confirmed influenza requiring hospitalization or who have progressive, severe, or complicated influenza infection, regardless of previous health or vaccination status . (See "Treatment of seasonal influenza in adults".)
Tigecycline — Tigecycline is a broad-spectrum antibiotic, which has been approved by the US Food and Drug administration (FDA) for CAP but not for hospital-acquired pneumonia. In September 2010, the FDA issued a safety announcement regarding an increased mortality risk associated with the use of tigecycline compared with other drugs observed in a pooled analysis of 13 trials . The increased risk was seen most clearly in patients treated for hospital-acquired pneumonia, particularly ventilator-associated pneumonia; however, there was no difference in mortality rate for CAP. In 2013, the FDA added a boxed warning in reaction to an analysis showing an increased risk of death in patients receiving tigecycline for FDA-approved uses, including CAP . The boxed warning states that tigecycline should be reserved for use in situations when alternative agents are not suitable. Thus, we generally do not recommend tigecycline for the treatment of CAP, except in patients who cannot take either a fluoroquinolone or a beta-lactam. We only use tigecycline in patients who do not have severe CAP (non-ICU patients) and whose pneumonia is not caused by MRSA.
In the 2013 FDA analysis of 10 clinical trials conducted for FDA-approved uses (CAP, complicated skin and skin structure infections, complicated intraabdominal infections), tigecycline was associated with increased mortality compared with other antibacterial agents (2.5 versus 1.8 percent, adjusted risk difference 0.6 percent [95% CI 0.0-1.2 percent]) . Most deaths resulted from worsening infections, complications of infection, or underlying comorbidities.
Admitted to an ICU
Empiric therapy — Patients requiring admission to an ICU are more likely to have risk factors for resistant pathogens, including community-associated MRSA and Legionella spp [2,54]. As noted above, establishing an etiologic diagnosis is particularly important in such patients. (See "Diagnostic approach to community-acquired pneumonia in adults".)
●In patients without risk factors for or microbiologic evidence of Pseudomonas aeruginosa or MRSA, we recommend intravenous combination therapy with a potent anti-pneumococcal beta-lactam (ceftriaxone 1 to 2 g daily, cefotaxime 1 to 2 g every eight hours, ceftaroline 600 mg IV every 12 hours, or ampicillin-sulbactam 3 g every six hours) plus either an advanced macrolide (azithromycin 500 mg daily) or a respiratory fluoroquinolone (levofloxacin 750 mg daily or moxifloxacin 400 mg daily) (table 3). Although the optimal doses of the beta-lactams (ceftriaxone, cefotaxime, ampicillin-sulbactam) have not been studied adequately, we favor the higher doses, at least initially, until the minimum inhibitory concentrations (MICs) against possible isolates (eg, Streptococcus pneumoniae) are known.
●In patients (particularly those with bronchiectasis or chronic obstructive pulmonary disease [COPD] and frequent antimicrobial or glucocorticoid use) who may be infected with Pseudomonas aeruginosa or other resistant gram-negative pathogens, therapy should include agents effective against pneumococcus, P. aeruginosa, and Legionella spp. Acceptable regimens include combination therapy with a beta-lactam antibiotic and an antipseudomonal fluoroquinolone, such as the following regimens:
•Piperacillin-tazobactam (4.5 g every six hours) or
•Imipenem (500 mg IV every six hours) or
•Meropenem (1 g every eight hours) or
•Cefepime (2 g every eight hours) or
•Ceftazidime (2 g every eight hours)
•Ciprofloxacin (400 mg every eight hours) or
•Levofloxacin (750 mg daily)
The fluoroquinolones may be administered orally when the patient is able to take oral medications, as they have excellent bioavailability. The dose of levofloxacin is the same when given intravenously and orally, while the dose of ciprofloxacin is 750 mg orally twice daily. (See "Fluoroquinolones", section on 'Pharmacokinetics'.)
●For penicillin-allergic patients, the type and severity of reaction should be assessed. The great majority of patients who are allergic to penicillin by skin testing can still receive cephalosporins (especially third-generation cephalosporins) or carbapenems. If there is a history of a mild reaction to penicillin (not an IgE-mediated reaction, Stevens Johnson syndrome, or toxic epidermal necrolysis), it is reasonable to administer a cephalosporin or carbapenem using a simple graded challenge (eg, give 1/10 of dose, observe closely for one hour, then give remaining 9/10 of dose, observe closely for one hour). Skin testing is indicated in some situations. For penicillin-allergic patients, if a skin test is positive or if there is significant concern to warrant avoidance of a cephalosporin or carbapenem, options include aztreonam (2 g IV every eight hours) plus a respiratory fluoroquinolone (levofloxacin 750 mg daily or moxifloxacin 400 mg daily) plus an aminoglycoside. Indications and strategies for skin testing are reviewed elsewhere. (See "Penicillin-allergic patients: Use of cephalosporins, carbapenems, and monobactams".)
●Patients with past allergic reactions to cephalosporins may be treated with aztreonam (2 g IV every eight hours), with the possible exception of those allergic to ceftazidime. Ceftazidime and aztreonam have similar side chain groups, and cross-reactivity between the two drugs is variable. The prevalence of cross-sensitivity has been estimated at <5 percent of patients, based upon limited data. Patients with past reactions to ceftazidime that were life threatening or suggestive of anaphylaxis (involving urticaria, bronchospasm, and/or hypotension) should not be given aztreonam unless evaluated by an allergy specialist. In contrast, a reasonable approach in those with mild past reactions to ceftazidime (eg, uncomplicated maculopapular rash) would involve informing the patient of the low risk of cross-reactivity and administering aztreonam with a graded challenge (1/100, 1/10, full dose, each separated by one hour of observation). (See "Cephalosporin-allergic patients: Subsequent use of cephalosporins and related antibiotics", section on 'Use of carbapenems and monobactams'.)
●Empiric therapy for CA-MRSA should be given to hospitalized patients with severe CAP, as defined by any of the following: admission to the ICU, septic shock, mechanical ventilation, necrotizing or cavitary infiltrates, or empyema . We also suggest empiric therapy of MRSA in patients with severe CAP who have any of the following risk factors: gram-positive cocci in clusters seen on sputum Gram stain, known colonization with MRSA, risk factors for colonization with MRSA (eg, end-stage renal disease, contact sport participants, injection drug users, those living in crowded conditions, men who have sex with men, prisoners), recent influenza-like illness, antimicrobial therapy (particularly with a fluoroquinolone) in the prior three months, necrotizing or cavitary pneumonia, presence of empyema.
In such patients, we recommend treatment for MRSA with the addition of vancomycin (15 mg/kg IV every 12 hours, adjusted to a trough level of 15 to 20 mcg/mL and for renal function; in seriously ill patients, a loading dose of 25 to 30 mg/kg may be given) or linezolid (600 mg IV every 12 hours) until the results of culture and susceptibility testing are known. Clindamycin (600 mg IV or orally three times daily) may be used as an alternative to vancomycin or linezolid if the isolate is known to be susceptible. Ceftaroline is active against most strains of MRSA but is not FDA approved for pneumonia caused by S. aureus. Linezolid may be given orally when the patient is able to receive oral medications. If MRSA is not isolated, coverage for this organism should be discontinued. (See 'Community-acquired MRSA' below.)
Fluoroquinolone monotherapy — The role of monotherapy with a respiratory fluoroquinolone has not been established for severe CAP. In an observational study of 270 patients with CAP and shock, the 58 percent treated with combination antibiotic therapy (with a third-generation cephalosporin and a macrolide) had a significantly higher 28-day in-ICU survival than the 42 percent who received fluoroquinolone monotherapy (hazard ratio [HR] 1.69, 95% CI 1.09-2.60) . Survival was not different comparing combination and monotherapy in ICU patients without shock. If the patient has pneumococcal meningitis, monotherapy with a fluoroquinolone is not recommended. (See "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Streptococcus pneumoniae'.)
Macrolide-containing regimens — Observational studies have suggested that combination regimens containing a macrolide plus a beta-lactam result in better clinical outcomes in patients with severe CAP, especially bacteremic pneumococcal pneumonia; this is likely due to the immunomodulatory effects of macrolides [57-60]. However, in a randomized trial of CAP patients admitted to non-ICU inpatient wards, a beta-lactam alone was noninferior to beta-lactam-macrolide combination therapy or fluoroquinolone monotherapy . (See "Antibiotic studies for the treatment of community-acquired pneumonia in adults", section on 'Combination therapy'.)
Influenza therapy — Antiviral treatment is recommended as soon as possible for all persons with suspected or confirmed influenza requiring hospitalization or who have progressive, severe, or complicated influenza infection, regardless of previous health or vaccination status . (See "Treatment of seasonal influenza in adults".)
Community-acquired MRSA — As discussed above, strong consideration should be given for empiric treatment for community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), with vancomycin or linezolid in hospitalized patients with severe CAP, including those with septic shock and those requiring mechanical ventilation [55,62]. Other risk factors that warrant empiric treatment of CA-MRSA include: gram-positive cocci in clusters seen on sputum Gram stain, known colonization with MRSA, risk factors for colonization with MRSA (eg, end-stage renal disease, contact sport participants, injection drug users, those living in crowded conditions, men who have sex with men, prisoners), recent influenza-like illness, antimicrobial therapy (particularly with a fluoroquinolone) in the prior three months, necrotizing or cavitary pneumonia, and presence of empyema.
Although data regarding the therapy of pneumonia caused by CA-MRSA are limited, a randomized trial showed superiority in clinical outcomes, but not mortality, of linezolid compared with vancomycin in hospital-acquired or healthcare-associated pneumonia caused by MRSA . In contrast, in a meta-analysis of nine randomized trials of patients with hospital-acquired pneumonia that compared linezolid and vancomycin, there were no differences in mortality or clinical response . The treatment of MRSA pneumonia is discussed in detail separately. (See "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Methicillin-resistant Staphylococcus aureus'.)
Although community-acquired MRSA is typically susceptible to more antibiotics than hospital-acquired MRSA, it appears to be more virulent . CA-MRSA often causes a necrotizing pneumonia [66,67]. The strain causing CA-MRSA is known as "USA 300" and the gene for Panton Valentine Leukocidin (PVL) characterizes this strain [68-72]. However, an animal study suggests that the virulence of CA-MRSA strains is probably not due to PVL . In addition, one study of patients with hospital-acquired pneumonia due to MRSA observed that the severity of infection and clinical outcome was not influenced by the presence of the PVL gene . It is possible that other cytolytic toxins play a role in the pathogenesis of CA-MRSA infections. Vancomycin does not decrease toxin production, whereas linezolid has been shown to reduce toxin production in experimental models [75,76]. (See "Virulence determinants of community-acquired methicillin-resistant Staphylococcus aureus".)
One concern with vancomycin is the increasing MICs of MRSA that have emerged in recent years, which may reduce the efficacy of vancomycin in pulmonary infection. In patients with a MRSA isolate with an increased vancomycin MIC (>2 mcg/mL), we prefer linezolid. Vancomycin-intermediate and vancomycin-resistant S. aureus infection is discussed in greater detail separately. (See "Vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus infections".)
When vancomycin is used, trough concentrations should be monitored in order to ensure that a target trough concentration between 15 and 20 mcg/mL is achieved. There may be important differences in potency and toxicity based on the supply source of generic formulations of vancomycin . (See "Vancomycin: Parenteral dosing and serum concentration monitoring in adults".)
Factors associated with rapid mortality include infection with influenza, the need for ventilator or inotropic support, onset of respiratory distress syndrome, hemoptysis, and leukopenia. In a report of 51 cases of CAP caused by Staphylococcus aureus (79 percent of which were MRSA), 39 percent had a white blood cell [WBC] count <4000/microL, and this finding was associated with a poor prognosis. In contrast, a WBC >10,000/microL appeared to be protective .
Timing of antimicrobial initiation — We recommend that antimicrobials be administered as soon as possible after diagnosing CAP and before leaving the emergency department or clinic . Although several studies have suggested a survival benefit to early initiation of antibiotics, some experts have questioned whether it is an independent risk factor for this outcome. It is important to note, however, that a delay in antimicrobial therapy for seriously ill patients can adversely affect outcomes.
A 2016 systematic review included eight studies that evaluated time to initiation of antibiotics and noted that all of the studies were observational in design and therefore represented low quality evidence . The four studies that showed an association between early initiation of antibiotics and reduced mortality were the largest of the studies and three of them included patients ≥65 years of age with greater illness severity at presentation. In contrast, the four smallest studies included adults of all ages with less severe illness and found no association between early antibiotic initiation and mortality.
The following studies illustrate the range of findings:
●In a retrospective study of 13,771 Medicare patients, antibiotic administration within four hours of hospital arrival was associated with reductions in mortality (6.8 compared with 7.4 percent with delay in antibiotics) and length of stay (0.4 days shorter) .
●In a matched-propensity analysis of national data from the British Thoracic Society CAP audit that included 13,725 patients with CAP, adjusted 30-day inpatient mortality was lower for adults who first received antibiotics in four or fewer hours compared with more than four hours (adjusted odds ratio 0.84, 95% CI 0.74-0.94) . However, it is not clear whether early antibiotics result in lower mortality or whether they are a marker for overall quality of care.
●A retrospective study of 603 patients with CAP at a single academic center found no difference in the time to clinical stability between those who received antibiotics within four hours and those whose treatment was later .
●The time to first antibiotic dose was not independently associated with mortality in other small observational studies [83,84]. In one of these studies, delay in antibiotics was more common in patients with an altered mental status or signs of sepsis . Time to first antibiotic dose was possibly a marker of comorbidities driving both an atypical presentation and mortality rather than directly contributing to the outcome. Diagnostic uncertainty led to delay of initial antimicrobial therapy in another study .
●A retrospective study of 548 patients found that when the required time to first antibiotic dose changed from eight hours to four hours, a reduction in the accuracy of the initial diagnosis of CAP occurred, although the mean time to first antibiotic dose was similar in both groups .
Clinical response to therapy — With appropriate antibiotic therapy, some improvement in the patient's clinical course is usually seen within 48 to 72 hours (table 6). Patients who do not demonstrate some clinical improvement within 72 hours are considered nonresponders. (See 'The nonresponding patient' below.)
The time course of the clinical response to therapy is illustrated by the following observations:
●In a prospective, multicenter cohort study of 686 adults hospitalized with CAP, the median time to becoming afebrile was two days when fever was defined as 38.3ºC (101ºF), and three days when defined as either 37.8ºC (100ºF) or 37.2ºC (99ºF) . However, fever in patients with lobar pneumonia may take three days or longer to improve.
●In a second prospective, multicenter trial of 1424 patients hospitalized with CAP, the median time to stability (defined as resolution of fever, heart rate <100 beats/min, respiratory rate <24 breaths/min, systolic blood pressure of ≥90 mmHg, and oxygen saturation ≥90 percent for patients not receiving prior home oxygen) was four days .
Although a clinical response to appropriate antibiotic therapy is seen relatively quickly, the time to resolution of all symptoms and radiographic findings is more prolonged. With pneumococcal pneumonia, for example, the cough usually resolves within eight days and auscultatory crackles clear within three weeks. (See "Pneumococcal pneumonia in adults".)
In addition, as many as 87 percent of inpatients with CAP have persistence of at least one pneumonia-related symptom (eg, fatigue, cough with or without sputum production, dyspnea, chest pain) at 30 days compared with 65 percent by history in the month prior to the onset of CAP . Patients should be told that some symptoms can last this long so that they are able to set reasonable expectations for their clinical course. (See "Prognosis of community-acquired pneumonia in adults", section on 'Mortality and symptom resolution'.)
Radiographic response — Radiographic improvement typically lags behind the clinical response [90-93]. This issue was addressed in a prospective multicenter trial of 288 patients hospitalized for severe CAP; the patients were followed for 28 days in order to assess the timing of resolution of chest radiograph abnormalities . The following findings were noted:
●At day 7, 56 percent had clinical improvement but only 25 had resolution of chest radiograph abnormalities.
●At day 28, 78 percent had attained clinical cure but only 53 percent had resolution of chest radiograph abnormalities. The clinical outcomes were not significantly different between patients with and without deterioration of chest radiograph findings during the follow-up period.
●Delayed radiographic resolution was independently associated with multilobar disease. In other studies, the timing of radiologic resolution of the pneumonia varied with patient age and the presence of underlying lung disease [91,92]. The chest radiograph usually cleared within four weeks in patients younger than 50 years of age without underlying pulmonary disease. In contrast, resolution could be delayed for 12 weeks or more in older individuals and in those with underlying lung disease.
Switch to oral therapy — Patients requiring hospitalization for CAP are generally begun on intravenous therapy. They can be switched to oral therapy when they are improving clinically, hemodynamically stable, able to take oral medications, and have a normally functioning gastrointestinal tract (algorithm 1) .
If the pathogen has been identified, the choice of oral antibiotic therapy is based upon the susceptibility profile (table 5). If a pathogen is not identified, the choice of antibiotic for oral therapy is usually either the same as the intravenous antibiotic or in the same drug class. If neither S. aureus nor a resistant gram-negative bacillus has been isolated from a good quality sputum specimen, then empiric therapy for these organisms is not necessary. The choice of oral regimen depends on the risk of drug-resistant S. pneumoniae and on the initial IV regimen:
●In patients who are treated with the combination of an intravenous beta-lactam and a macrolide who have risk factors for drug-resistant S. pneumoniae (DRSP), we replace the intravenous beta-lactam with high-dose amoxicillin (1 g orally three times daily) to complete the course of therapy. When DRSP is not a concern, amoxicillin can be given at a dose of 500 mg orally three times daily or 875 mg orally twice daily. In patients who have already received 1.5 g of azithromycin who do not have Legionella pneumonia, we do not continue atypical coverage. Conversely, in patients who have not received 1.5 g of azithromycin, we give amoxicillin in combination with a macrolide or doxycycline. An alternative for patients without risk factors for DRSP is to give a macrolide or doxycycline alone to complete the course of therapy. The dosing for macrolides and doxycycline is:
•Azithromycin – 500 mg once daily
•Clarithromycin – 500 mg twice daily
•Clarithromycin XL – Two 500 mg tablets (1000 mg) once daily
•Doxycycline – 100 mg twice daily
●Patients who are treated initially with an IV respiratory fluoroquinolone can switch to the oral formulation of the same agent (eg, levofloxacin 750 mg once daily or moxifloxacin 400 mg once daily) to complete the course of therapy.
The duration of therapy is discussed below. (See 'Duration of therapy' below.)
Two prospective observational studies in 253 patients evaluated the clinical outcome of an early switch from intravenous to oral therapy in the treatment of CAP [94,95]. Patients met the following criteria prior to switching: resolution of fever, improvement in respiratory function, decrease in white blood cell count, and normal gastrointestinal tract absorption. Only two patients failed treatment and the protocol was associated with high patient satisfaction .
Similar outcomes were noted in a multicenter randomized trial in the Netherlands of 265 patients with CAP (mean age 70) admitted to non-intensive care wards . Patients were initially treated with three days of intravenous antibiotics and, when clinically stable, were assigned either to oral antibiotics to complete a total course of ten days or to a standard regimen of seven days of intravenous antibiotics. There was no difference in 28-day mortality (4 versus 2 percent) or clinical cure rate (83 versus 85 percent), while the length of hospital stay was reduced in the oral switch group by a mean of 1.9 days (9.6 versus 11.5 days).
In another randomized trial, a three-step pathway that involved early mobilization of patients in combination with the use of objective criteria for switching to an oral antibiotic regimen and for deciding on hospital discharge was compared to usual care . The median length of stay was significantly shorter in the patients who were assigned to the three-step pathway (3.9 versus 6.0 days). In addition, the median duration of intravenous antibiotics was significantly shorter in the patients who were assigned to the three-step pathway (2.0 versus 4.0 days). More patients assigned to usual care experienced adverse drug reactions (4.5 versus 16 percent). No significant differences were observed in the rate of readmission, the case-fatality rate, or patients’ satisfaction with care.
Documentation of pneumococcal bacteremia does not appear to alter the effect of switching to oral therapy early (no clinical failures in 18 such patients switched based upon the above criteria in one report) .
Duration of hospitalization — We suggest hospital discharge when the patient is clinically stable from the pneumonia, can take oral medication, has no other active medical problems, and has a safe environment for continued care; we suggest not keeping the patient overnight for observation following the switch. Early discharge based on clinical stability and criteria for switch to oral therapy is encouraged to reduce unnecessary hospital costs and hospital-associated risks, including iatrogenic complications and greater risk for antimicrobial resistance.
Several studies have shown that it is not necessary to observe stable patients overnight after switching from intravenous to oral therapy, although this has been common practice [2,99,100]. As an example, a retrospective review of the United States Medicare National Pneumonia Project database compared outcomes between patients hospitalized for CAP who were not (n = 2536) and were (n = 2712) observed overnight after switching to oral therapy . The following findings were noted:
●No significant difference in 14-day hospital readmission rate (7.8 versus 7.2 percent)
●No significant difference in the 30-day mortality rate (5.1 versus 4.4 percent)
The importance of clinical stability at discharge was illustrated in a prospective observational study of 373 Israeli patients discharged with a diagnosis of CAP . On the last day of hospitalization, seven parameters of instability were evaluated (temperature >37.8ºC [100ºF], respiratory rate [RR] >24 breaths/min, heart rate [HR] >100 beats/min, systolic blood pressure [SBP] ≤90 mmHg, oxygen saturation <90 percent on room air, inability to receive oral nutrition, and change of mental status from baseline). At 60 days post discharge, patients with at least one parameter of instability at discharge were significantly more likely to have died or required readmission than patients with no parameters of instability (death rates, 14.6 versus 2.1 percent; readmission rates, 14.6 versus 6.5 percent).
As noted above, in one trial, a three-step pathway that involved early mobilization of patients in combination with the use of objective criteria for switching to an oral antibiotic regimen and for deciding on hospital discharge was compared with usual care . The median length of stay was significantly shorter in the patients who were assigned to the three-step pathway (3.9 versus 6.0 days).
Duration of therapy — Based upon the available data, we agree with the recommendation of the IDSA/ATS guidelines that patients with CAP should be treated for a minimum of five days . Thus, the recommended duration for patients with good clinical response within the first two to three days of therapy is five to seven days total. Support for this recommendation comes from a meta-analysis of 15 randomized controlled trials of almost 2800 patients with mild to moderate CAP, which found comparable clinical outcomes with less than seven days compared with more than seven days of antimicrobial therapy; however, only two of these trials were specifically about hospitalized patients . (See "Antibiotic studies for the treatment of community-acquired pneumonia in adults", section on 'Duration of therapy'.)
Before stopping therapy, the patient should be afebrile for 48 to 72 hours, breathing without supplemental oxygen (unless required for preexisting disease), and have no more than one clinical instability factor (defined as HR >100 beats/min, RR >24 breaths/min, and SBP ≤90 mmHg) (algorithm 2) .
A longer duration of therapy is needed in the following settings:
●If the initial therapy was not active against the subsequently identified pathogen (see 'The nonresponding patient' below)
●If extrapulmonary infection is identified (eg, meningitis or endocarditis)
●If the patient has pneumonia caused by P. aeruginosa, S. aureus, or Legionella spp, or pneumonia caused by some unusual and less common pathogens (eg, Burkholderia pseudomallei, fungus)
●If the patient has necrotizing pneumonia, empyema, or lung abscess .
The duration of therapy in these patients should be individualized based upon the clinical response to treatment and patient comorbidities. For the treatment of MRSA pneumonia without metastatic infection, duration will vary, with a recommendation of 7 to 21 days depending upon the extent of infection . A 7- to 10-day course is generally appropriate for patients who respond within 72 hours. In a study of ventilator-associated pneumonia (VAP) due to MRSA (although not likely due to the USA 300 strain that causes community-acquired MRSA pneumonia), eight days of therapy was as effective as 15 days of therapy .
Patients are often treated with antibiotics for longer than necessary. Antimicrobial stewardship programs can help to shorten the duration of antibiotics and narrow the spectrum of antibiotics .
Procalcitonin has been evaluated for guiding the decision to stop antibiotics since the procalcitonin level appears to correlate with the likelihood of a bacterial infection . The use of procalcitonin-guided algorithms in patients with CAP appears to be effective at reducing the duration of antibiotics without sacrificing patient safety. In a 2012 Cochrane meta-analysis of 14 randomized trials in which an algorithm was used to aid with the decision to discontinue antibiotics in patients who were unlikely to have bacterial pneumonia, no difference in mortality was seen among those whose care was guided by the procalcitonin result and those whose care was not . In most of the trials, among clinically stable patients, a procalcitonin concentration <0.25 mcg/L led to a recommendation to discontinue antibiotics and a concentration <0.1 mcg/mL led to a strong recommendation to discontinue antibiotics. The uses of procalcitonin in patients suspected of having CAP is discussed in detail separately. (See "Diagnostic approach to community-acquired pneumonia in adults", section on 'Procalcitonin and CRP'.)
Glucocorticoids — There has been interest in using glucocorticoids as adjunctive therapy to antibiotics in hospitalized patients with CAP in an attempt to reduce the inflammatory response to pneumonia, which is likely to contribute to the morbidity of the disease. We generally give glucocorticoids to severely ill (ie, patients admitted to the intensive care unit [ICU]), especially to those with a high systemic inflammatory response (C-reactive protein >15 mg/dL [>150 mg/L]) [108,109]. However, we are less likely to give glucocorticoids to patients at increased risk of adverse effects due to glucocorticoids. In patients at elevated risk of adverse effects, clinicians should make the decision about whether to give glucocorticoids on a case-by-case basis. There is limited evidence that infections caused by certain pathogens (influenza virus, Aspergillus spp) may be associated with worse outcomes in the setting of glucocorticoid use [110,111]; given these concerns, we avoid adjunctive glucocorticoids if one of these pathogens is detected. (See "Treatment and prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Effect of glucocorticoids'.)
We generally use glucocorticoids in ICU patients but not in patients admitted to medical wards for the following reasons:
●A meta-analysis showed only a modest mortality benefit in hospitalized patients with CAP who received glucocorticoids, but severely ill patients are most likely to derive a benefit from glucocorticoids; the reason for this is that severely ill patients have a higher baseline risk of poor outcomes and would therefore be expected to have a higher absolute risk reduction with glucocorticoids .
●CAP is caused by many different pathogens, but, in most patients, the pathogen is not identified. Little is known about whether there are varying harms or benefits of glucocorticoids depending upon the causative pathogen. As noted above, we avoid glucocorticoids when influenza or Aspergillus is the causative pathogen as glucocorticoids may be associated with worse outcomes when one of these organisms is implicated [110,111].
●Many of the randomized trials included in the meta-analysis mentioned above excluded patients at increased risk of adverse effects from glucocorticoids, including immunocompromised patients, pregnant women, patients who had gastrointestinal bleeding within the past three months, and patients at increased risk of neuropsychiatric side effects . The incidence of some of these adverse effects may have therefore been underestimated. On the other hand, none of these conditions are absolute contraindications to glucocorticoid use. We consider the potential risks and benefits of glucocorticoids in each patient and decide whether to give adjunctive glucocorticoids when the potential benefits outweigh the potential risks.
When we give glucocorticoids to patients who are unable to take oral medications, we use methylprednisolone 0.5 mg/kg IV every 12 hours. For patients who can take oral medications, we use prednisone 50 mg orally daily. We continue glucocorticoids for a total of five days.
Regarding the efficacy of adjunctive glucocorticoids, individual randomized trials have shown varying results. Several trials showed improved clinical outcomes in patients with CAP receiving glucocorticoids but no mortality reduction [113-115], and one small trial of patients with severe CAP showed a mortality reduction . Another trial did not demonstrate improved outcomes (clinical cure or mortality) . A 2015 meta-analysis of randomized trials that included hospitalized patients with CAP suggested a modest mortality benefit . Patients who received adjunctive glucocorticoids had a reduction in all-cause mortality of borderline statistical significance (relative risk [RR] 0.67, 95% CI 0.45-1.01; risk difference 2.8 percent), as well as a reduction in use of mechanical ventilation (RR 0.45, 95% CI 0.26-0.79; risk difference 5.0 percent) and acute respiratory distress syndrome (ARDS; RR 0.24, 95% CI 0.10-0.56; risk difference 6.2 percent). Such patients also had decreased time to clinical stability (mean difference -1.2 days, -2.1 to -0.4 days) and decreased duration of hospitalization (mean difference -1.0 days, -1.8 to -0.2 days). They also had an increased frequency of hyperglycemia requiring treatment (RR 1.49, 95% CI 1.01-2.19; risk difference 3.5 percent) but no increase in the rate of gastrointestinal bleeding.
Subgroup analyses suggested that the relative effect on mortality varied according to severity of CAP, with a mortality benefit observed in those with severe CAP (RR 0.39, 95% CI 0.20-0.77) but not in those with less severe CAP (RR 1.0, 95% CI 0.79-1.26) . The authors believed that the difference in effect on mortality between the subgroups was likely to be spurious since they were based on differences between studies rather than within studies and because they were driven to a large extent by a small study that was stopped early for benefit. Based on the overall results of this meta-analysis, there are likely to be benefits for both severely ill hospitalized patients and for hospitalized patients who are not severely ill. In addition, in one randomized trial, glucocorticoids were associated with reduced time to clinical stability in both severely ill patients and non-severely ill patients . However, as noted above, severely ill patients have a higher baseline risk of poor outcomes and would therefore be expected to have a higher absolute risk reduction with glucocorticoids.
Several additional meta-analyses have been published since the one describe above, and there is general agreement of improved outcome with use of glucocorticoids [118-120].
In a randomized trial that included 120 patients in Spain with severe CAP and a high inflammatory response (defined as a CRP concentration >150 mg/L), there was less treatment failure among patients who received methylprednisolone than in those who received placebo (13 versus 31 percent; odds ratio 0.34, 95% CI 0.14-0.87), but there was no difference in the rate of in-hospital mortality . A limitation of this trial is that the primary driver of the difference in treatment effect was radiographic progression, but it remains unclear what this clinical finding represents (acute respiratory distress syndrome versus uncontrolled pneumonia versus a Jarisch-Herxheimer–like reaction) or whether less radiographic progression leads to lower mortality .
It should be noted that different glucocorticoid formulations (eg, IV methylprednisolone, oral prednisone), doses, and routes of administration were used in different trials and the optimal regimen is unknown. In most trials, patients received glucocorticoids for five to seven days, but it is possible that a longer duration is required for maximum benefit to be achieved. The US Department of Veterans Affairs is currently conducting a trial, the Extended Steroid in CAP(e) (ESCAPe) study, in which hospitalized patients with CAP requiring intensive care unit care are randomly assigned to placebo or methylprednisolone at an initial dose of either 40 mg or 20 mg per day for 7 days, followed by tapering doses over 13 days . The primary outcome is all-cause 60-day mortality.
Tissue factor pathway inhibitor — A recombinant tissue factor pathway inhibitor, tifacogin, which is a systemic inhibitor of coagulation, has been evaluated in an international multicenter randomized trial of patients with severe CAP . Despite evidence of biologic activity, tifacogin was not associated with a mortality benefit compared with placebo. Therefore, tifacogin is not recommended in patients with severe CAP.
Statins — HMG CoA reductase inhibitors (statins) appear to have antiinflammatory properties, and some studies of patients taking a statin chronically have suggested that they might reduce the risk of infection, including pneumonia, and infection-related mortality. However, many of these studies had potential flaws, and other studies have not shown these benefits. (See "Statins: Possible noncardiovascular benefits", section on 'Sepsis and infections' and "Investigational and ineffective therapies for sepsis", section on 'Statins'.)
No studies have evaluated the potential benefit of the addition of a statin as an adjunctive therapy in patients with CAP [54,124]. In one trial, the adjunctive use of a statin in patients with ventilator-associated pneumonia did not lead to a mortality benefit or improvement in other clinical outcomes and the trial was stopped early for futility . (See "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Lack of benefit of statins'.)
Clinical follow-up after discharge — Patients who have been discharged from the hospital with CAP should have a follow-up visit, usually within one week. In addition, a later visit is often indicated to assess for resolution of pneumonia.
Follow-up chest radiograph — Chest radiograph findings usually clear more slowly than clinical manifestations. (See 'Radiographic response' above.).
Among patients who have clinical resolution following treatment for CAP, we recommend restricting follow-up chest radiographs to patients >50 years of age; follow-up chest radiograph is particularly important for males and smokers in this age group. When indicated, we suggest that follow-up chest radiographs be performed 7 to 12 weeks following treatment to document resolution of the pneumonia and exclude underlying diseases, such as malignancy . In contrast, routine chest radiograph for follow-up of all CAP patients who are responding clinically is unnecessary.
The data to support follow-up chest radiographs in older patients comes from a large population-based cohort study of patients with CAP in which new lung cancer was diagnosed within 90 days of CAP in 1.1 percent and within five years in 2.3 percent . On multivariate analysis, the characteristic most strongly associated with lung cancer was an age >50 years (adjusted hazard ratio [HR] 19.0, 95% CI 5.7-63.6); other risk factors were male sex (adjusted HR 1.8, 95% CI 1.1-2.9) and smoking (adjusted HR 1.7, 95% CI 1.0-3.0). Since nearly 99 percent of patients will not have lung cancer after CAP, the authors suggested that routine follow-up chest radiograph is not warranted in patients <50 years of age, except in patients who do not experience a resolution of pneumonia symptoms. This study also indicated that the greatest yield for the diagnosis of cancer would occur if routine follow-up chest radiographs were restricted to patients >50 years of age.
The nonresponding patient — Issues relating to nonresolving pneumonia are discussed in detail separately. This section will be limited to a general overview of nonresponding pneumonia in patients with CAP who require hospitalization. (See "Nonresolving pneumonia".)
Most patients with CAP show clinical improvement within 72 hours of initial antibiotic treatment. It has been estimated that 6 to 15 percent of hospitalized patients with CAP do not respond within this time frame, and the failure rate may be as high as 40 percent in patients initially admitted to an ICU [2,128-130]. These patients have significantly increased mortality compared with responders [2,129,130]. (See "Prognosis of community-acquired pneumonia in adults", section on 'The nonresponding patient'.)
Two general patterns of nonresponse have been described in patients with CAP [2,128]:
●Progressive pneumonia or clinical deterioration, with requirement for ventilator support and/or septic shock usually occurring in the first 72 hours. Deterioration after 72 hours is often due to an intercurrent complication, progression of the underlying infection, or a superimposed nosocomial infection. Many patients who ultimately require ICU admission for CAP are initially admitted to a non-ICU ward and then transferred because of clinical deterioration (59 of 113 in one report, 50 in the first 24 hours) .
●Persistent or nonresponding pneumonia, defined as the absence of or delay in achieving clinical stability after 72 hours of antibiotic therapy.
The most common causes of treatment failure are lack of or delayed response by the host despite appropriate antibiotics and infection with an organism that is not covered by the initial antibiotic regimen [2,128,132]. Patient-related factors include severity of illness, neoplasia, aspiration pneumonia, and neurologic disease (table 7) . Lack of responsiveness to initial therapy may be due to drug-resistant organisms, unusual pathogens (eg, Legionella spp, viruses, fungi including Pneumocystis jirovecii [formerly P. carinii], or Mycobacterium tuberculosis), or an infectious complication, such as postobstructive pneumonia (due to carcinoma or an aspirated foreign body), empyema, abscess, or superimposed nosocomial pneumonia [2,128,133].
In a review of treatment failure in 49 hospitalized patients with CAP, a definite diagnosis was established in 32 and a probable diagnosis was made in 9 . The major causes were infection with a pathogen not detected in the initial evaluation (atypical or unusual pathogens or pathogens associated with the development of empyema), persistent infection with the same pathogen, usually reflecting resistance to initial empiric therapy, and nosocomial infection with a new pathogen, most often associated with ventilator-associated pneumonia.
In addition, treatment failure may be wrongly presumed when the infiltrates are responding slowly but the patient has developed a superimposed problem [2,93,128,134]. These include noninfectious entities, such as drug fever, malignancy, interstitial lung disease (eg, bronchiolitis obliterans organizing pneumonia), inflammatory conditions, or heart failure, or a hospital-acquired infection of another body system (eg, intravascular catheter infection, urinary tract infection due to an indwelling urinary catheter, or Clostridium difficile infection) (table 7). Noninfectious causes were considered responsible for nine of the treatment failures in the above series of 49 patients .
Treatment failure may also be incorrectly diagnosed in patients who have repeat sputum cultures that grow a new pathogen. The upper airway of hospitalized patients receiving antibiotics may become colonized, particularly with gram-negative bacilli and S. aureus, and may be misinterpreted as contributing to the pneumonia. Thus, repeat sputum cultures should be interpreted with caution.
Risk factors — A number of studies have evaluated risk factors for nonresponse in hospitalized patients with CAP [129,130,135]. The rate of treatment failure in different large series was 13 and 15 percent overall [129,135], with early treatment failure (lack of response or worsening at 48 to 72 hours) occurring in 6 percent .
A prospective multicenter study identified risk factors for treatment failure in CAP, which occurred in 15 percent of 1424 hospitalized patients . Independent risk factors were multilobar pneumonia, cavitation on chest radiograph, pleural effusion, liver disease, leukopenia, and a high Pneumonia Severity Index (PSI). Three factors were protective: influenza vaccination, chronic obstructive pulmonary disease, and treatment with a fluoroquinolone.
A second observational analysis of 1383 hospitalized adults with CAP identified the following risk factors for early treatment failure (lack of response or worsening at 48 to 72 hours) :
●Pneumonia caused by MRSA, Legionella, or gram-negative bacilli (Enterobacteriaceae or Pseudomonas aeruginosa)
●Treatment with an antimicrobial agent to which the causative organism was not susceptible
Further evaluation — When evaluating a patient who is not responding to therapy, the initial approach may include repeating the history (including travel and pet exposures to look for unusual pathogens), chest radiograph, and sputum and blood cultures [2,128]. If this is unrevealing, then further diagnostic procedures, such as chest computed tomography [CT], bronchoscopy, and lung biopsy can be performed. (See "Nonresolving pneumonia".)
●Chest CT can detect pleural effusion, lung abscess, or central airway obstruction, all of which can cause treatment failure. It may also detect noninfectious causes such as bronchiolitis obliterans organizing pneumonia . Since empyema and parapneumonic effusion can contribute to nonresponse, thoracentesis should be performed in all nonresponding patients with significant pleural fluid accumulation.
●Bronchoscopy can evaluate the airway for obstruction due to a foreign body or malignancy, which can cause a postobstructive pneumonia. Protected brushings and bronchoalveolar lavage (BAL) may be obtained for microbiologic and cytologic studies; in some cases, transbronchial biopsy may be helpful. The microbiologic evaluation of the nonresponding patient can be complicated by the effect of the initial antimicrobial therapy that may reduce the yield of pathogen isolation or select for colonization with resistant organisms. In addition, BAL may reveal evidence of noninfectious disorders or, if there is a lymphocytic rather than neutrophilic alveolitis, viral or Chlamydia infection .
Thoracoscopic or open lung biopsy may be performed if all of these procedures are nondiagnostic and the patient continues to be ill. The advent of thoracoscopic procedures has significantly reduced the need for open lung biopsy and its associated morbidity.
Management — Failure to respond to antibiotics usually results in one or more of the following: patient transfer to a higher level of care, further diagnostic testing, and/or escalation of or change in treatment . There is no convincing evidence of benefit from combination antibiotic therapy in patients with progressive disease  with the exception of those with severe bacteremic pneumococcal pneumonia requiring admission to an ICU; in such patients, the most commonly used combination regimens were a beta-lactam plus a macrolide or vancomycin plus a macrolide . This is a presumed reflection of the primary importance of severe illness at presentation or delayed treatment response due to host factors. (See "Nonresolving pneumonia" and "Pneumococcal pneumonia in adults", section on 'Bacteremic pneumonia'.)
Risk factors for rehospitalization — Risk factors for rehospitalization were assessed in a multicenter randomized trial of hospitalized patients with CAP . Among 577 patients, 70 (12 percent) were rehospitalized within 30 days; 52 were related to comorbidities (most commonly cardiovascular, pulmonary, or neurologic); and 14 were related to pneumonia. Factors that were independently associated with rehospitalization included less than a high school education, unemployment, coronary artery disease, and chronic obstructive pulmonary disease.
In a similar study of 1117 patients from a single center, 81 (7 percent) were rehospitalized within 30 days; 29 due to pneumonia-related causes and the remainder due to pneumonia-unrelated causes . Risk factors for pneumonia-related rehospitalization were initial treatment failure and one or more instability factors (eg, vital signs or oxygenation) on discharge; risk factors for non-pneumonia-related readmissions were age ≥65 and decompensated comorbidities (most commonly cardiac or pulmonary).
VACCINATION — Patients with community-acquired pneumonia (CAP) should be appropriately vaccinated for influenza and pneumococcal infection . Screening for influenza vaccination status is warranted during influenza season (eg, from October through March in the northern hemisphere) in all patients. Screening for pneumococcal vaccination status is warranted in patients age 65 or older or with other indications for vaccination (table 8). Vaccination can be administered at any time during hospitalization after the patient has become stable. (See "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults".)
SMOKING CESSATION — Smoking cessation should be a goal for hospitalized patients with community-acquired pneumonia (CAP) who smoke . (See "Overview of smoking cessation management in adults".)
VALUE-BASED PURCHASING MEASURES — The Centers for Medicare and Medicaid Services (CMS) has established Value-Based Purchasing (VBP) measures to assess the quality of hospital care for pneumonia patients. The VBP measures for CAP include two outcome measures (30-day mortality and 30-day readmission rate) . Hospital-specific outcomes regarding these measures are publically reported .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Community-acquired pneumonia in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Community-acquired pneumonia in adults (The Basics)")
●Beyond the Basics topics (see "Patient education: Pneumonia in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Most initial treatment regimens for hospitalized patients with community-acquired pneumonia (CAP) are empiric. A limited number of pathogens are responsible for the majority of cases (table 1 and table 2 and figure 1). The most commonly detected pathogen is Streptococcus pneumoniae. Other common pathogens include Haemophilus influenzae, the atypical bacteria (Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella spp), oropharyngeal aerobes and anaerobes (in the setting of aspiration), and respiratory viruses. Antibiotics should be started as soon as possible once the diagnosis of bacterial CAP is considered likely. (See 'Principles of antimicrobial therapy' above and 'Empiric therapy and pathogen-directed therapy' above.)
●Despite the use of empiric therapy, testing for a microbial diagnosis is important in clinical or epidemiologic settings suggesting possible infection with an organism that requires treatment different from standard empiric regimens. These include Legionella species, seasonal influenza, avian (eg, H5N1, H7N9) influenza, Middle East respiratory syndrome coronavirus, community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), Mycobacterium tuberculosis, and agents of bioterrorism. (See 'Empiric therapy and pathogen-directed therapy' above.)
●Emerging drug-resistant S. pneumoniae (DRSP) complicates the use of empiric treatment. Treatment failures have been demonstrated with use of macrolides for macrolide-resistant organisms. Most pneumococci respond to higher dose beta-lactams other than cefuroxime. (See 'Risk factors for drug resistance' above.)
●For hospitalized patients not requiring intensive care unit (ICU) admission, we suggest initial combination therapy with an anti-pneumococcal beta-lactam (ceftriaxone, cefotaxime, ceftaroline, ertapenem, or ampicillin-sulbactam) plus a macrolide (azithromycin or clarithromycin XL), or monotherapy with a respiratory fluoroquinolone (levofloxacin, moxifloxacin, or gemifloxacin) (Grade 1B). We suggest that monotherapy with tigecycline be limited to patients intolerant of beta-lactams and fluoroquinolones (Grade 2B). Coverage for drug-resistant pathogens, such as Pseudomonas or MRSA, should be included in patients with risk factors. Doxycycline may be used as an alternative to a macrolide, especially in patients at high risk of QT interval prolongation. Oral therapy with a macrolide or doxycycline is appropriate only for selected patients without evidence of or risk factors for severe pneumonia. (See 'Not in the ICU' above.)
●For hospitalized patients requiring ICU care, we suggest initial combination therapy with an anti-pneumococcal beta-lactam (ceftriaxone, cefotaxime, ceftaroline, or ampicillin-sulbactam) plus either intravenous (IV) therapy with azithromycin or a respiratory fluoroquinolone (levofloxacin or moxifloxacin) plus, if MRSA is suspected, vancomycin (15 mg/kg IV every 12 hours, adjusted to a trough level of 15 to 20 mcg/mL and for renal function; in seriously ill patients, a loading dose of 25 to 30 mg/kg may be given) or linezolid (600 mg IV every 12 hours) (Grade 2B). Coverage for other drug-resistant pathogens, such as Pseudomonas, should be included in patients with risk factors. (See 'Admitted to an ICU' above.)
●For most patients with CAP who require intensive care unit admission, we recommend adjunctive glucocorticoids (Grade 1B). We are more likely to give glucocorticoids to more severely ill patients, especially those with a high systemic inflammatory response (C-reactive protein >15 mg/dL [>150 mg/L]), and we are less likely to give glucocorticoids to patients at increased risk of adverse effects. In patients at elevated risk of adverse effects, clinicians should make the decision about whether to give glucocorticoids on a case-by-case basis. When we give glucocorticoids to patients who are unable to take oral medications, we use methylprednisolone 0.5 mg/kg IV every 12 hours. For patients who can take oral medications, we use prednisone 50 mg orally daily. We continue glucocorticoids for a total of five days. There is limited evidence that infections caused by certain pathogens (eg, influenza virus, Aspergillus spp) may be associated with worse outcomes in the setting of glucocorticoid use; given these concerns, we avoid adjunctive glucocorticoids if one of these pathogens is detected. (See 'Glucocorticoids' above.)
●We suggest that empiric antimicrobial treatment regimens be modified when results of diagnostic studies indicate a specific pathogen and if coinfection is unlikely based upon clinical or epidemiologic data (Grade 2B). (See 'Treatment regimens' above.)
●Patients should demonstrate some improvement in clinical parameters by 72 hours, although fever may persist with lobar pneumonia. Cough from pneumococcal pneumonia may not clear for a week; abnormal chest radiograph findings usually clear within four weeks but may persist for 12 weeks in older individuals and those with underlying pulmonary disease. (See 'Clinical response to therapy' above.)
●We suggest switching from intravenous to oral therapy when patients are hemodynamically stable, demonstrate some clinical improvement (in fever, respiratory status, white blood count), and are able to take oral medications (algorithm 1) (Grade 2A). (See 'Switch to oral therapy' above.)
●We suggest hospital discharge when the patient is clinically stable from the pneumonia, can take oral medication, has no other active medical problems, and has a safe environment for continued care; we suggest not keeping the patient overnight for observation following the switch (Grade 2B). (See 'Duration of hospitalization' above.)
●Patients with CAP who have a good clinical response within the first two to three days of therapy should generally be treated for five to seven days, but longer treatment is indicated if the initial therapy was not active against the subsequently identified pathogen, if extrapulmonary infection is identified (eg, meningitis or endocarditis) or if the patient has documented P. aeruginosa, S. aureus, or Legionella pneumonia, or pneumonia caused by some less common pathogens (algorithm 2). The duration of therapy in these patients should be individualized based upon the clinical response to treatment and patient comorbidities. For the treatment of MRSA pneumonia, we recommend a treatment duration of 7 to 21 days, depending upon the extent of infection and response to therapy; the shorter duration is recommended if the patient has a clear and early clinical response and no evidence of metastatic infection. (See 'Duration of therapy' above.)
●Routine follow-up chest radiographs for patients who are responding clinically within the first week are unnecessary. We suggest a follow-up chest radiograph at 7 to 12 weeks after treatment for patients who are over age 50 years to document resolution of the pneumonia and exclude underlying diseases, such as malignancy (Grade 2B). Follow-up chest radiograph is particularly important for males and smokers in this age group. (See 'Follow-up chest radiograph' above.)
●The most common cause of treatment failure is the lack of response by the host, despite appropriate antibiotics. Risk factors for treatment failure include neoplasia, aspiration pneumonia, neurologic disease, multilobar pneumonia, infection with MRSA, Legionella, or gram-negative bacilli, high Pneumonia Severity Index (PSI) (>90) (calculator 1), antibiotic-resistant pathogen, cavitation, pleural effusion, liver disease, and leukopenia. (See 'The nonresponding patient' above.)
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