key: cord-294270-do6i6ymq authors: Banu, Buyukaydin title: Pneumonia date: 2019-11-29 journal: Encyclopedia of Biomedical Gerontology DOI: 10.1016/b978-0-12-801238-3.62174-8 sha: doc_id: 294270 cord_uid: do6i6ymq Pneumonia remains the main cause of morbidity and mortality from infectious diseases in the world. The important reason for the increased global mortality is the impact of pneumonia on chronic diseases especially in the elderly population and the virulence factors of the causative microorganisms. Because elderly individuals present with comorbidities, particular attention should be paid for multidrug-resistant pathogens. Streptococcus pneumoniae remains the most frequently encountered pathogen. Enteric gram-negative rods, as well as anaerobes, should be considered in patients with aspiration pneumonia. Interventions for modifiable risk factors will reduce the risk of this infection. The adequacy of the initial antimicrobial therapy and determination of patients’ follow-up place is a key factor for prognosis. Also, vaccination is one of the most important preventive measures. In this section it was focused on several aspects, including the atypical presentation of pneumonia in the elderly, the methods to evaluate the severity of illness, the appropriate take care place and the management with prevention strategies. Pneumonia is defined as an acute respiratory infection that affects lung parenchyma. Despite the availability of antibiotic therapy and severity of illness assessments, pneumonia continues to be a leading cause of death worldwide. In the elderly population, the impact of pneumonia is greater than in other age groups. The mechanisms that increase the incidence and mortality rates in elderly pneumonia patients are not fully understood. The immunological changes that called immunosenescence are known to be responsible for the increased sensitivity of elderly people to infection diseases. The world population reached 7.6 billion and the people 60 years and over amounted 13% of the total, 962 million according to data United Nations World Population Prospects (Kaplan et al., 2002) . The annual incidence of pneumonia in the elderly is fourtimes that of the younger population. Older adults have also higher rates of hospitalization and mortality (Chong and Street, 2008) . Therefore, a better understanding of the pathophysiology, microbiology, treatment, and prevention of this common affliction is required. For proper diagnosis and treatment advice, pneumonia is classified as community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) along with the recent guidelines. In this section, the most recent data regarding the epidemiology, microbiology, diagnosis, classification, treatment, and prevention strategies are presented. The incidence of pneumonia varies according to geographical location, healthcare setting, and population. Including pneumonia, lower respiratory tract infections are the fourth most common cause of death all over the world. In a study carried out in the US, the annual incidence of pneumonia was observed as 24.8 cases/10,000 adults, with the highest rates among adults between 65 and 79 years of age; 63.0 cases/10,000 adults and in patients up to 80 years old; 164.3 cases/10000 adults (Konomura et al., 2017) . In terms of economic impact, two studies carried out in the Netherlands and Japan, sustained remarkable results. The majority of CAP episodes (64%) occurred among patients 50 years and older and these episodes incurred 76% of the costs. The second study included 29,619 patients with CAP aged 65 years and over and reported median treatment costs of US$ 346 per outpatient CAP and US$ 4851 per hospitalized CAP (Klausen et al., 2012; Kothe et al., 2008) . Mortality in elderly patients may be 25% higher than in the general population (10%). In this population group, hospitalization rates are five times more likely than other patients' groups also (Chong and Street, 2008) . Because of these negative impacts, several studies have attempted to identify risk factors. A population-based cohort study with 46,237 elderly patients found that immunosuppression, COPD, smoking, congestive heart failure, diabetes, malignancy, and previous hospitalizations for pneumonia are independent risk factors for developing the disease in this age group (Barlow et al., 2007) . For mortality risk, available data is useful. Comorbid illness (including cerebrovascular disease, congestive heart failure, and chronic liver disease), higher infection activity index and ineffective therapy were presented along with higher mortality risk in elderly. Other factors linked to increased mortality are accepted as bedridden status, delirium, the absence of fever, tachypnea, C-reactive protein levels greater than 100 mg/L, hypoalbuminemia, acute organ failure, suspicion of aspiration and swallowing disorders (Centers for Disease Control and Prevention (CDC), 2012). Identifying the causative agent can be useful for guiding antimicrobial therapy. Although the microbiological diagnosis is fundamental to ensure appropriate therapy, it is achieved in less than 50% of the cases. In order to avoid the delaying that associated with increased mortality, antimicrobial therapy should be administered empirically. Pathogens associated with communityacquired pneumonia in elderly patients are presented in Table 1 . In this age group, the possibility of obtaining a diagnostic sputum sample has been very low. Causative organisms are only identified in 5%-20% of the cases. Globally S. pneumoniae is accepted as being the most common pathogen. Also in elderly, this microorganism remains the single most common organism identified in hospitalized patients. The diagnosis of pneumococcal pneumonia has increased in recent years, due to the introduction of the pneumococcal urine antigen test. But the incidence has probably decreased because of pneumococcal vaccines along with the decreased rate of smoking (Garcia Vidal et al., 2010) . The differences in the chemical and antigenic composition of the pneumococcal capsule result in 93 different serotypes. Serotype 3 is the most common serotype associated with adult pneumococcal infection and with septic shock (Cilloniz et al., 2016) . Haemophilus influenzae was also frequently isolated accounting for 5%-14% in elderly. In patients with chronic obstructive lung disease, infection with this organism may be more common. Moraxella catarrhalis and Staphylococcus aureus (methicillin sensitive) have also been described as pathogens, with frequencies 4% and 7%, respectively (CDC, 2012) . Intracellular pathogens are one of the other frequent microorganisms (Donowitz and Cox, 2007) . The incidence is variable depending on the difficulties with microbiological cultures. They grow poorly in standard culture media and performing additional serologic tests on all patients is not common practice. Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Chlamydophila psittaci, and Coxiella burnetii are the well-established intracellular pathogens. No clinical features exist that make it possible to distinguish intracellular pathogens from classical ones. But extra-pulmonary manifestations are often associated with intracellular pathogens. Severe pneumonia caused by these pathogens accounts for 1%-7% of the cases. The major problem with these pathogens is that most antibiotics are unable to access intracellular spaces and to reach the optimal therapeutic concentrations is difficult. In those aged over 65 years, the atypical organisms are less frequently encountered but play a significant role in the clinical spectrum (Macfarlane et al., 1984) . Chlamydophila pneumoniae is the most common, with rates of 16%-28%, Mycoplasma pneumoniae is less frequently encountered (0%-13%) and Coxiella burnetii is a rare causative agent in elderly (CDC, 2012) . Although Legionella pneumophila is relatively uncommon in the elderly, it should be considered presenting with atypical symptoms for example, headache, altered mental status, gastrointestinal signs or bradycardia (Ruuskanen et al., 2011) . It appears to be reasonable to exclude this bacteria with urinary antigen testing in all elderly patients with pneumonia before atypical coverage is discontinued. Infections with Gram-negative bacteria are often related to comorbid illnesses. Excluding nursing-home residents and hospitalized patients, these infections are infrequent in the elderly. But in severely debilitated or chronically ill elderly patients from the community, especially in those who fail to improve on standard therapy, a high index of suspicion may be warranted for this bacteria (CDC, 2012) . Among other pathogens, respiratory viruses are considered responsible in one-third of the cases. Influenza viruses (A and B), Respiratory syncytial virus (RSV), parainfluenza viruses 1, 2, 3, coronaviruses and rhinoviruses, are the most commonly encountered ones. It is estimated that 100 million cases of viral pneumonia occur annually (Ruuskanen et al., 2011) . Influenza virus (A and B) is usually selflimiting, but severe complications like pneumonia can occur especially in high-risk patients like elderly with comorbidities along with increased mortality risk. Routine influenza screening appears reasonable in an elderly presenting with pneumonia-like complaints, but the sensitivity of available screening tests is poor and treatment decisions should not be based only the results of rapid flu testing. Aspiration pneumonia is another common cause of CAP. The most frequent microorganisms are anaerobic bacteria and microaerophilic streptococci from the oral flora. Aspiration pneumonia may be the second most common etiology of CAP in patients 80 years and older (Teramoto et al., 2015) . Approximately 6% of the CAP cases, a Multidrug-Resistant (MDR)-resistant to more than three classes of antibiotics-pathogen is an agent that most frequently being S. aureus and P. aeruginosa. In a recent European study, MDR pathogens were presented as 3.3% of the 7.6% CAP cases with most commonly presented with methicillin-resistant S. aureus (MRSA) . Community-associated methicillin-resistant S. aureus (CA-MRSA) raises concern for infection in elderly adults. The production of the toxin Panton-Valentine Leukocidin (PVL) is the main characteristic of CA-MRSA. This toxin causes leukocyte destruction and tissue necrosis. In elderly, CA-MRSA should be considered in presentation with influenza, such as prodromes, skin lesions, cavitary infiltrates, hemoptysis or rapidly progressing pneumonia. Table 1 Pathogens associated with community-acquired pneumonia in elderly patients Pseudomonas aeruginosa Endemic and Opportunistic infections P. aeruginosa is not a frequent pathogen in the CAP but severe CAP requiring intensive care unit (ICU) admission it was the causative agent in 1.8%-8.3% of the cases with the mortality rate of between 50% and 100% (Yoshimoto et al., 2005) . Prior antibiotic treatment is the only risk factor associated with CAP caused by MDR P. aeruginosa. Also, S. pneumoniae has increased its resistance to several antibiotics (cephalosporins, macrolides, and fluoroquinolones) in the last two decades. Between 20% and 30% of pneumococcus disease cases worldwide have MDR pattern. Nevertheless, the therapeutic failure involving b-lactams has not been reported because of pharmacodynamic properties (Draghi et al., 2006) . HAP is defined as pneumonia occurring 48 h or more after hospital admission. VAP is defined as pneumonia occurring > 48 h after endotracheal intubation. HAP is the second most frequent nosocomial infection and is considered the main cause of mortality for nosocomial infections. VAP is considered the main nosocomial infection in the ICU. HAP is divided into two groups according to the time of onset from admission. Early onset is defined when pneumonia development within the first 4 days of hospitalization. This presentation is associated with better clinical prognosis. Late onset is defined when pneumonia occurs after 5 days of hospitalization. The recently published guidelines propose that the presence of risk factors for MDR should take precedence rather than early or late onset pneumonia distinction (Kalil et al., 2016) . The top six pathogens causing 80% of the HAP cases are S. aureus, P. aeruginosa, Klebsiella spp., Escherichia coli, Acinetobacter spp., and Enterobacter spp. ( Table 2) . Gram-negative bacteria are the major agent with 50%-80% for HAP cases in ICU. The most frequent pathogens include P. aeruginosa, A. baumannii, H. influenzae, and Enterobacteriaceae spp. (K. pneumoniae, E. coli, Enterobacter species, Serratia species, Proteus species, etc.). The mortality increase to 42% with advanced age, increased disease score and inadequate initial antimicrobial treatment. An independent factor for predicting the mortality is the using of vasopressors in the case of VAP where P. aeruginosa is isolated (Micek et al., 2015) . Gram-positive pathogens account for 20%-30% of HAP cases. The most frequent microorganisms; Methicillin-resistant and methicillin-sensitive S. aureus, S. pneumonia, and Streptococcus spp. Pneumonia caused by more than two pathogenic microorganisms is defined as a polymicrobial infection. Approximately 30%-70% of VAP cases are considered to have polymicrobial etiology. Polymicrobial etiology generally did not influence the outcome when empiric antibiotic treatment was appropriate. MDR pathogens are a major problem for this group of patients. The 2016 Clinical Practice Guidelines summarize the following risk factors for MDR (Weiskopf et al., 2009 Elderly persons suffer from a variety of comorbidities. Associated factors predisposing patients to develop pneumonia are presented in Table 3 . Also, multimorbidity was associated with death, hospitalization or return to the emergency department within 90 days of discharge. In a recent study 80% of the cases presented with at least one comorbidity according to the aging group: 65-74 years old, 77.6%; 75-84 years old, 80.6% and > 85 years old, 80.8%.The most frequent comorbidity was presented as chronic pulmonary disease. Because of immunosenescence in elderly, the risk of misdiagnosis or delayed diagnosis is more frequent. Specific symptoms of pulmonary infection such as a cough, sputum, fever, chills, and chest pains may not be available. The complaints must be taken care of are altered mental status (i.e., delirium), falls, fatigue, lethargy, delirium, anorexia, tachypnea, tachycardia, and, less commonly, pleuritic pain, cough, and fever (Rockwood et al., 2005) . In elderly, pneumonia sometimes presents as an exacerbation or decompensation of previous comorbidities and also 30% of the cases the radiographic findings are inconclusive or difficult to interpret. Many biomarkers of infection such as leukocyte count, C-reactive protein (CRP), procalcitonin have been found to play a role in the early diagnosis, but in elderly with CAP, the reliability on these biomarkers is limited (Liu et al., 2013) . All patients should be screened by pulse oximetry, for unsuspected hypoxemia in patients with diagnosed pneumonia or to determine the presence of pneumonia without obvious signs. Since the microbiological diagnosis of pneumonia is important for a better clinical outcome, to follow national and international guidelines is recommended. These recommendations regarding samples and diagnostic tests are presented in Table 4 . Clinical indications for more extensive diagnostic testing should be decided on a clinical basis ( Table 5) . Some etiologic diagnoses have important epidemiologic implications and agents that should be reported to public health officials vary according to countries. In general, legionnaires disease, SARS (severe acute respiratory syndrome) psittacosis, avian influenza (H5N1), and possible agents of bioterrorism (plague, tularemia, and anthrax) are accepted as microorganisms to be notified. In low to mild cases of CAP, recommendations for the microbiological diagnostic test is optional. In the case of the severe CAP, to take blood cultures, sputum staining, sputum culture, urinary antigen test for Legionella and Pneumococcus are recommended. The main problems from these methods are the low yield, long turnaround time (48-72 h) and the effects of previous antibiotic use on microbiological results (Chastre and Fagon, 2002) . For all cases of HAP, microbiological tests should be performed on respiratory samples. Samples can obtain spontaneous expectoration, sputum induction, nasotracheal suctioning, and endotracheal aspiration in a patient with requires mechanical ventilation. For VAP cases noninvasive sampling with endotracheal aspiration cultures and blood culture is recommended (Kalil et al., 2016) . Blood and pleural cultures: Before antimicrobial treatment, performing blood culture have a high specificity but a low positivity (less than 20% of the cases). Blood cultures are optional but especially in patients with host defect, for example, asplenia, complement deficiencies, chronic liver disease or leukopenia is indicated along with in patients with HAP, the positivity of blood cultures varies from 8% to 20%. Because the spreading of the infection to the blood occurs in < 10% of VAP cases, blood cultures availability is limited. Approximately 40% of CAP cases have a pleural effusion. Patients with pleural effusions 15 cm in height on a lateral upright chest radiograph should undergo thoracentesis because of empyema is considered a risk factor for poor outcome. In pleural fluid samples, pneumococcal antigen or molecular detection are recommended also (Falguera et al., 2002) . Sputum gram stain and culture: Before antimicrobial therapy, sputum sample collection is performed. For diagnostic accuracy, an adequate collection and transport of the sample are recommended. The good quality sample is considered when the sputum sample contains less than 10 epithelial cells and more than 25 lymphocyte cells. The benefits of a sputum Gram stain; it broadens initial empirical therapy for a less common etiologies such as S. aureus and gram-negative organisms and it validates the subsequent sputum culture results. For pneumonia caused by S. pneumoniae, the sensitivity of the Gram stain is $ 80% and for S. aureus, it is 78% (Anevlavis et al., 2009) . The endotracheal aspirate is the equivalent of sputum in VAP cases. Gram stain and culture of the endotracheal aspirates are recommended for intubated patients. Both samples share the same criteria for quality. In VAP cases, for distinguishing colonization from infection, a threshold ! 10 5 colony forming units/mL is recommended (Cook and Mandell, 2000) . Antigen tests: Legionella serotype 1 and pneumococcus antigens are renally excreted and can be detected. Sensitivity for pneumococcus ranges from 50% to 80% with specificity from 70% to 90%. For pneumococcal pneumonia, disadvantages of this test are costing amount ($$30 per specimen) and false positive results with children and with chronic respiratory diseases who are colonized with S. pneumoniae (Navarro et al., 2004) . Along with Legionella serogroup 1, 70%-90% sensitivity and 99% specificity was reported. The problem is that the recommended empirical antibiotic regimens will cover both of these microorganisms and further researches are necessary to investigate the clinical usefulness of this method. The rapid antigen detection test for influenza can help for consideration of antiviral therapy. Although test performance varies according to patient age, the test used, sample type and duration of illness, 50%-70% sensitivity and $ 100% specificity was observed in adults. The disadvantages include cost ($$30 per specimen), high rates of false-negative results and false-positive results with adenovirus and not superiority according to physician judgment. In the last 10 years, for microbiological diagnosis of respiratory pathogens, molecular diagnostic tests are investigated. These tests provide identification of specific pathogens and differentiate bacterial and viral infection. Antibiotic susceptibility, response to antibiotic therapy, assessment for prognosis and disease surveillance is evaluated with these techniques. The methods are approved by the Food Drug Administration (FDA) (Gadsby et al., 2016) . Approximately 50% of the cases remain without microbiological identification. Conventional methods together with molecular testing will improve the microbiological diagnosis and clinical management of cases with pneumonia. A chest radiograph is required for the routine evaluation the patients who are likely to have pneumonia. Chest radiographs are sometimes useful for suggesting the etiologic agent, alternative diagnoses and associated conditions. Computerized tomography scans may be more sensitive when findings of radiography are negative or unclear. For patients who are hospitalized for suspected pneumonia but who have negative chest radiographic findings, it is advanced to treat presumptively with antibiotics and repeat the imaging in 24-48 h. When managing elderly patients who present with pneumonia, evaluation of severity and site-of-care decisions are critical. In elderly patients with CAP, several mortality predictors have been reported. Chronic comorbidities were the main predictors of mortality and readmission. The prognostic value of glucose levels was investigated and markedly elevated blood glucose levels on admission were associated with increased short-term and long-term mortality. In another study, the neutrophil-to-lymphocyte ratio was evaluated and presented better for prediction 30-day mortality according to the pneumonia severity index (PSI) and CURB-65 (Fine et al., 1997; Lim et al., 2003) . When a comparison is made in terms of mortality, between CRP, white blood cell (WBC) count and these indexes, PSI and CURB-65 are observed significantly associated with mortality and ICU admission. The PSI is based on 20 parameters that are evaluated at the time of clinical presentation as three demographics, five comorbid conditions five physical examination findings, and seven laboratory/imaging variables ( Table 6 ) (Fine et al., 1997) . The primary purpose of this score is to distinguish patients that could be safely treated in an outpatient setting versus inpatient observation and treatment. The major limitations of the PSI score are its focusing by age and comorbidity and not consider psychosocial variables, infrequent comorbidities, or patient preferences regarding treatment. The CURB-65 is a less complex scoring system only requires six variables to be evaluated at presentation (Table 7) . (Lim et al., 2003) . For severity assessment and hospitalization decision, the usefulness of these scores are presented in Table 8 . In CURB-65, age is an extremely significant variable. These scores highlight that elderly patients with pneumonia are at risk for higher severe disease and poorer clinical outcome, but the limitations of the CURB-65 score that not contain data such as hypoxemia, electrolyte disturbance or the inability to take oral medications. For prediction ICU admission and the risk of death in patients with severe CAP, several other tools have also been designed. The examples include the PS-CURXO80, SMART-COP, and CAP-PIRO scores. All of these guidelinesdexcept onedinclude age as one of the variables associated with poor outcomes. PS-CURXO80 uses age above 80 years old as one of the minor criterion for determining the severity of illness. The SMART-COP scoring system evaluates the need for respiratory and vasopressor support. In this score, age is not one of the severity markers but tachypnea and poor oxygenation are used as an adjustment tool. Rello and colleagues developed the CAP-PIRO score. This score evaluates predisposition, infection, response, and organ dysfunction variables (Espana et al., 2006; Charles et al., 2008; Rello et al., 2009) . Detailed information for all of these scores is presented in Table 9 . ICU admission is another important medical decision for these patients. Direct admission to an ICU is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation. Also, for patients with three of the minor criteria for severe CAP listed in Table 10 , direct admission to an ICU or high-level monitoring unit is recommended . But it must bear in mind that early recognition of sepsis in elderly compromised patients can be challenging. The classical criteria to define the systemic inflammatory response syndrome can be absent in anergic patients. In conclusion, in addition to objective criteria such as age, the clinician experience, and clinical judgment is always recommended for proper evaluation. CURB-65 is practical and functional in order to decide when to admit a patient to the hospital and IDSA/ ATS guidelines major and minor criteria are proper parameters to admit a patient to the ICU . Antimicrobials are the mainstay of treatment for elderly patients with CAP. Selection of antimicrobials for empirical therapy is based on the prediction of the most likely pathogen and knowledge of local susceptibility patterns. Unless outcome data clearly do not favor one drug, recommendations generally take place for a class of antibiotics. Overall efficacy remain the major factor for many classes of agents, other factors like pharmacokinetics/pharmacodynamics, compliance, safety, and cost must be into consideration. The most common pathogens of CAP are presented in Table 11 according to the severity of illness as judged by the site of care. In terms of analyzing the microbial etiology in elderly, a cohort study with 2149 CAP patients was shown that when patients divided by age, the microbiological diagnosis possibility decreases steadily with age; 65-74 years old, 44%; 75-84 years old, 41%; and 85 years and older, 31% (Cillóniz et al., 2013) . In this age group, to consider the substantial risk factors can help for prediction the responsible microorganisms and finally select the proper antimicrobial therapy (Table 12) . Current international guidelines for the treatment of CAP do not have specific recommendations for elderly patients. In this guidelines, evaluation, following, and treatment of the patients is taking place into three categories; outpatient treatment, inpatient-non ICU treatment and inpatient ICU treatment . The recommendations for outpatient treatment with the listed clinical risks: 1. Previously healthy and no use of antimicrobials within the previous 3 months A macrolide (azithromycin, clarithromycin, or erythromycin) (strong recommendation) Doxycycline (weak recommendation) 2. Presence of comorbidities such as chronic heart, lung, liver or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs; or use of antimicrobials within the previous 3 months A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg]) (strong recommendation) (1 point) ATS, American Thoracic Society; CAP, community-acquired pneumonia; ICU, ıntensive care unit; IDST, Infectious Diseases Society of America; PIRO, predisposition, infection, response and organ dysfunction score; PS CURXO80, pH, systolic blood pressure, confusion, urea nitrogen, respiratory rate, x-ray finding, oxygen arterial pressure and age of 80 years or more; SMART-COP, systolic blood pressure, multilobar chest radiography, albumin level, respiratory rate, tachycardia, confusion, oxygenation and pH; BUN, blood urea nitrogen; WBC, white blood cell. A b-lactam plus a macrolide (High-dose amoxicillin [e.g., 1 g three times daily] or amoxicillin-clavulanate [2 g two times daily] is preferred; alternatives include ceftriaxone, cefpodoxime, and cefuroxime [500 mg two times daily]; doxycycline is an alternative to the macrolide) (strong recommendation) 3. In regions with a high rate (> 25%) of infection with high-level (MIC > 16 mg/mL) macrolide-resistant S. pneumoniae, consider the use of alternative agents listed above in (2) for patients without comorbidities (moderate recommendation). The recommendations for hospital ward treatment with the listed clinical risks: 1. A respiratory fluoroquinolone (strong recommendation) 2. A b-lactam plus a macrolide (strong recommendation) Preferred b-lactam agents include cefotaxime, ceftriaxone, and ampicillin; Ertapenem for selected patients (patients with risks for infection with these pathogens and for patients who have recently received antibiotic therapy) with doxycyclinedas an alternative to the macrolide A respiratory fluoroquinolone should be used for penicillin-allergic patients. For most hospitals admitted patients, initial treatment should be given intravenously, but some without risk factors for severe pneumonia could receive oral therapy, especially with highly bioavailable agents such as fluoroquinolones. When an intravenous b-lactam is combined with coverage for atypical pathogens, a macrolide or doxycycline with oral therapy is appropriate for selected patients without severe pneumonia risk factors. The recommendations for ICU treatment with the listed clinical risks: Minimal recommended treatment is; 1. A b-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin or a fluoroquinolone (strong recommendation) For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam. The most common pathogens in the ICU population were (in descending order of frequency) S. pneumoniae, Legionella species, H. influenzae, Enterobacteriacea species, S. aureus and Pseudomonas species. The recommended standard empirical regimen should routinely cover the three most common pathogens, all of the atypical pathogens, and most of the relevant Enterobacteriaceae species. But for treatment of MRSA or P. aeruginosa infection, modification the standard empirical regimen is necessary. Along with suspicion of these pathogens, modification to the basic empirical treatment is; 1. For Pseudomonas infection, use an antipneumococcal, antipseudomonal b-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin (750-mg dose) or the above b-lactam plus an aminoglycoside and azithromycin or the above b-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone. For penicillin-allergic patients, substitute aztreonam for the b-lactam. Structural lung diseases, such as bronchiectasis, or repeated chronic lung disease exacerbations as well as prior antibiotic therapy are other clinical risk factors for infection with Pseudomonas species. Requiring for ICU admission is not routine with these pathogens. In patients with chronic alcoholism other serious gram-negative pathogens, such as K. pneumoniae or Acinetobacter species are important. Clinical risk factors for CAP with S. aureus include end-stage renal disease, injection drug abuse, rapid presentation and progression, associated skin lesions, prior influenza, and prior antibiotic therapy. For MSSA empirical combination therapy recommended above is adequate. Actually, vancomycin has never been specifically studied for CAP. Linezolid is detected superior to vancomycin in the retrospective analysis for nosocomial MRSA pneumonia. As newer presently available agents, daptomycin should not be used for CAP, and for tigecycline, there is no available data. Pathogen-Directed Therapy 1. The etiology of CAP has been identified with reliable microbiological methods, antimicrobial therapy should be oriented at that pathogen (moderate recommendation) Because of the benefit of combination therapy was also most pronounced in more severely ill patients, after results of cultures, discontinuation of combination therapy is most likely safe in only non-ICU patients (Cillóniz et al., 2013 ). 2. Early treatment (within 48 h of onset of symptoms) with oseltamivir or zanamivir is recommended for influenza A (strong recommendation). 3. Oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for > 48 h, but these drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia (moderate recommendation). 4. Parenteral acyclovir is indicated for varicella zoster or herpes simplex virus pneumonia. No antiviral treatment of proven value is available for other viral types of pneumonia. 5. An increasing greater than 10% is observed for Enterobacteriaceae with ESBL especially in patients with recent hospitalization or elderly. Ertapenem is a good therapeutic option with good sensitivity. 2. Patients should be switched from intravenous to oral therapy when they hemodynamically stable, are able to ingest medications, and have a normally functioning gastrointestinal tract (strong recommendation). 3. Patients should be discharged as soon as they are clinically stable, inpatient observation while receiving oral therapy is not necessary (moderate recommendation). Patients with higher PSI risk score take longer to reach clinical stability than do patients at lower risk, so elderly patients with multiple comorbidities generally recover more slowly. Appropriate follow-up and rehabilitation planning should be initiated early for these patients. In elderly presented with delirium, its resolution may represent a clinical marker of improvement. 1. Patients with CAP should be treated for a minimum of 5 days, should be afebrile for 48-72 h, and should have not clinical instability sign no more than one before discontinuation of therapy (moderate recommendation) (Waterer et al., 2001; Ramirez et al., 1995) . 2. If initial therapy was not active against the identified pathogen or if it was complicated by extrapulmonary infection, a longer duration of therapy may be needed (weak recommendation). Criteria for clinical stability is presented in Table 13 (Arnold et al., 2009 ). 3. Most patients with CAP have been treated for 7-10 days or longer, but few well-controlled studies evaluated the optimal duration of therapy. Short-duration may be suboptimal for patients with bacteremic S. aureus or Pseudomonas infection. The presence of cavities or other signs of tissue necrosis may require prolonged treatment. Other Important Treatment Considerations 1. Patients with CAP along with persistent septic shock despite adequate fluid resuscitation should be evaluated for therapy with drotrecogin alfa activated within 24 h of admission (weak recommendation)dAdvice patients' groups; patients with septic shock, sepsis-induced leukopenia and organ failure criteria. 2. Hypotensive, fluid-resuscitated patients with severe CAP should be screened for adrenal insufficiency (moderate recommendation). Stress-dose (200-300 mg of hydrocortisone per day or equivalent) steroid treatment improves outcomes of vasopressordependent patients with septic shock who have documented inadequate cortisol levels. 3. Patients with hypoxemia or respiratory distress should receive a cautious trial of noninvasive ventilation (NIV) unless they require immediate intubation (moderate recommendation). 4. Low-tidal-volume ventilation (6 cm 3 /kg of ideal body weight) should be used for patients undergoing ventilation who have diffuse bilateral pneumonia or ARDS (strong recommendation). 5. Other management protocols of severe sepsis and septic shock in patients with CAP do not appear to be different from those patients with other infections. Advice for Management of Nonresponding Pneumonia 1. 6%-15% of hospitalized patients with CAP do not respond to the initial antibiotic therapy. Mortality among nonresponding patients is increased several-fold according to responding patients. The using a systematic classification for possible causes is recommended (Table 14 ) (moderate recommendation). 2. Two patterns of undesirable response are seen in hospitalized patients: The first is progressive pneumonia or clinical deterioration, with acute respiratory failure requiring ventilatory support and/or septic shock, within the first 72 h of hospital admission. The second pattern is that of persistent or nonresponding pneumonia. 3. Nonresponding to antibiotics generally result in three patterns of clinical approachment (1) transferring of the patient to a higher level of care (2) further diagnostic testing, and (3) changing the treatment. Firstly, patients with nonresponding or deterioration are reevaluated for initial microbiological results and further history for risk factors for infection with unusual pathogens. Blood cultures should be repeated. In 44% of the patients with CAP, the etiology determined by bronchoscopy. Rapid urinary antigen test can remain positive for days after initiation of antibiotics and is considered in nonresponding patients an also concomitant or subsequent extrapulmonary infections, such as an intravascular catheter, urinary, abdominal, and skin infections must be kept in mind. 4. Other tests for selected patients with nonresponse: Chest CT, Bronchoscopy with lavage and transbronchial biopsies and thoracentesis. Current international guidelines for CAP do not provide specific recommendations for elderly patients but convenience to guidelines was associated with shorter time for clinical stability, shorter length of hospital stay, and lower in-hospital mortality (Egger et al., 2016 ). An international, multicenter observational study for elderly patients is reported that adherence to the 2007 IDSA/ATS guidelines for hospitalized non-ICU elderly patients was cost-effective but was not the most cost-effective strategy in ICU patients (Faverio et al., 2014) . In elderly patients, another important issue is age-related changes for antibiotic therapy that modify tolerability, metabolism, excretion of drugs and the risk of drug-drug interactions. In case of QT prolongation or concomitant medication that prolongs QT, using macrolides or fluoroquinolones is not suggested. In elderly, Achilles tendon rupture has been reported with fluoroquinolones. With aminoglycosides, nephro and ototoxicity must be kept in mind and presence and degree of renal and/or hepatic failure is always evaluated when choosing the antibiotic treatment (Faverio et al., 2014) . Another important risk in the elderly is the frequency of aspiration. Risk factors for aspiration pneumonia are age, male gender, neurologic impairment, Parkinson's disease, lung disease, diabetes mellitus, malnutrition, periodontal diseases, poor oral hygiene, vomiting, proven dysphagia, proton pump inhibitor, antipsychotic or sedative drug use. Diagnosing can be challenging, as a diagnostic tool, fiberoptic endoscopic evaluation of swallowing (FEES) can be performed at the bedside. The most common pathogens are oropharyngeal flora including anaerobes, Gram-positive cocci, and Gram-negative bacilli. Antibiotics against indigenous oral flora including anaerobes should be administered and both swallowing rehabilitation and oral healthcare management should be initiated. Percutaneous endoscopic gastrostomy (PEG) is often performed for preventing aspiration, but there is little evidence to indicate that it prevents pneumonia. A head-up position, by $ 30 degree and mosapride, a gastroprokinetic agent may be preventing gastroesophageal regurgitation and associated aspiration. Angiotensinconverting enzyme (ACE) inhibitors and cilostazol have been reported effective for prevention of pneumonia, because these medications increase substance P levels in the airways and plasma, improving both swallowing and cough reflexes. For prevention, also anticholinergic agents, tricyclic antidepressants, diuretics, and selective serotonin reuptake inhibitors that which cause dry mouth should be administered cautiously. In elderly patients with pneumonia, the development of cardiac complications was associated with a 60% increased mortality risk. Even only advanced age is associated with higher risk of long term-mortality. Other causes of death after following an episode were mainly related to comorbidities, malignancy, COPD and vascular diseases. As are cardiovascular and cerebrovascular events, to increase the rehabilitation and nutritional status after a CAP could ameliorate physical dysfunction in elderly. The effectiveness of pneumococcal polysaccharide vaccines for prevention of invasive infections among elderly individuals and younger adults have documented with epidemiologic studies. Currently, two types of vaccine are available: polyvalent pneumococcal polysaccharide vaccine (PPV23)d23 pneumococcal serotypes includeddand the pneumococcal conjugate vaccines (PCV13). The only difference of PCV13 is the capsular polysaccharides that conjugated to a carrier protein for enhancement the immunogenicity. Pneumococcal vaccine naïve > 65 years old persons should receive a single dose of PCV13 first, followed by a dose of PPV23 1 year later. Prior vaccination with PPV23 at age > 65 years should also receive a dose of PCV13 if they have not yet received one. A dose of PCV13 should be given > 1 year after of the most recent PPV23 dose. In patients who need to repeat PPV23, the period between administration of PCV13 and the new dose of PPV23 should be at least 1 and 5 years since the most recent dose of PPV23 . For influenza, chemoprophylaxis can be used as an adjunct treatment to vaccination. Oseltamivir and zanamivir are both approved for prophylaxis and may be useful for household exposure to influenza and those who work in institutions with an influenza outbreak (Hayden et al., 2004) . As other preventive measures, modifiable risk factors as reducing or cessation of alcohol consumption, smoking cessation, improving oral hygiene, ensuring good nutritional status, avoiding contact with lower respiratory infections were accepted. CAP is the fifth leading cause of death and the most common cause of death from infectious diseases in people aged 65 years and over. S. pneumoniae is still the most common pathogen. Elderly patients have a significant number of risk factors associated with higher risk for MDR pathogens. To establish supportive measures, systematic evaluation of cognitive, nutritional (hydration included) and functional status must be an important part of the clinical examination. Antimicrobial selection for elderly patients with CAP does not differ from that of younger adults. In clinical practice guidelines, early antibiotic administration and strict adherence to the regimes is recommended. It is not appropriate to restrict intensive care and ventilatory support only on the basis of chronologic age. There is no difference for management the patients with HAP and VAP in this age group. The long-term mortality rate after CAP hospitalization is really high in the elderly population. As prevention, immunization measures must be improved. Vaccination for pneumococcus and influenza and smoking cessation programs may help for decrease the incidence and severity of CAP, especially in this age group. choose the target specific antibiotics associated with HAP/VAP as narrowly as possible. Without risk factors for MDR organisms, empiric therapy should include one antibiotic (against P. aeruginosa, other gram-negative organisms, and methicillin-sensitive S. aureus) Suggested agents include piperacillin-tazobactam, cefepime, levofloxacin, imipenem In patients with risk factors for MRSA infection, empiric coverage should include vancomycin or linezolid HAP/VAP treatment should always include antipseudomonal coverage. Dual antipseudomonal agents from different classes are recommended for empiric therapy in patients with a risk factor for MDR gram-negative pathogens. Decisions about dual coverage should be individualized There is no difference in regard to mortality, treatment failure, recurrent pneumonia, or duration of mechanical ventilation. A longer duration may be appropriate where the patient may have a delayed clinical response The guidelines recommend that discontinuation of antibiotics be based on clinical criteria and procalcitonin testing Preventive Measures International guidelines recommend specific measures for preventing pneumonia Pneumococcal polysaccharide vaccine is recommended for persons > 65 years of age and for those with selected high-risk concurrent diseases (chronic cardiovascular, pulmonary, renal, or liver disease, diabetes mellitus, alcoholism, asplenia, immunocompromising conditions/medications, long-term care facility residents All persons > 50 years of age, others at risk for influenza complications; high-risk persons with household contacts and health care workers should receive inactivated influenza vaccine (strong recommendation). Influenza and pneumococcal vaccines can be given at the same time in different arms Vaccination status should be evaluated at hospital admission for all patients, especially those with medical illnesses (moderate recommendation) Vaccination may be performed either at hospital discharge or during outpatient status (moderate recommendation) Influenza vaccine should be offered to persons at hospital discharge or during outpatient therapy during the fall and winter (strong recommendation) Respiratory hygiene measures, including hand hygiene and respiratory masks, should be used in outpatient settings and in emergency departments (strong recommendation) Multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia A European perspective A prospective study of the diagnostic utility of sputum Gram stain in pneumonia Improving outcomes in elderly patients with community-acquired pneumonia by adhering to national guidelines: Community-Acquired Pneumonia Organization International Cohort. 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Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older United States Outcomes in elderly Danish citizens admitted with community-acquired pneumonia. 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The Hospital Infection Control Practices Advisory Committee Empirical antimicrobial therapy of septic shock patients: Adequacy and impact on the outcome Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: Guidelines for the prevention of antimicrobial resistance in hospitals Antibiotic use, hospital admissions, and mortality before and after implementing guidelines for nursing home-acquired pneumonia Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship Incidence, direct costs and duration of hospitalization of patients hospitalized with community-acquired pneumonia: A Nationwide Retrospective Claims Database Analysis