Guidelines for the management of adult lower respiratory tract infections  Full version

This document is an update of Guidelines published in 2005 and now includes scientific publications through to May 2010. It provides evidence-based recommendations for the most common management questions occurring in routine clinical practice in the management of adult patients with LRTI. Topics include management outside hospital, management inside hospital (including community-acquired pneumonia (CAP), acute exacerbations of COPD (AECOPD), acute exacerbations of bronchiectasis) and prevention. Background sections and graded evidence tables are also included. The target audience for the Guideline is thus all those whose routine practice includes the management of adult LRTI.

# Introduction
In 2005 the European Respiratory Society (ERS), in collaboration with The European Society for Clinical Microbiology and Infectious Diseases (ESCMID), published guidelines on the management of lower respiratory tract infections (LRTI) in adults [bib_ref] Guidelines for the management of adult lower respiratory tract infections, Woodhead [/bib_ref]. This document was based on published scientific literature up to the end of 2002. We have now updated these guidelines to include publications to May 2010. The Taskforce responsible for guideline development has been sponsored by the ERS and ESCMID. Members of the Taskforce are members of the sponsoring ERS and/or ESCMID.
Our objective is to provide evidence-based recommendations for the most common management questions occurring in routine clinical practice in the management of adult patients with LRTI. The target audience for the guidelines is thus all those whose routine practice includes the management of adult LRTI. This document begins with definitions and background sections on microbial cause, resistance and pharmacokinetics/pharmacodynamics, with conventional referencing. The guideline section captures management outside hospital, management inside hospital (including community-acquired pneumonia (CAP), acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and acute exacerbations of bronchiectasis) and prevention. The guidelines are about the management of infection. This means that for conditions such as AECOPD, aspects of management that are unreleated to infection (e.g. use of steroids or bronchodilators) are not included. It contains the graded recommendations but also the background information for each recommendation, with details about each new cited reference and the evidence grades. Because this is an update, original data and publications have usually not been repeated and the reader is referred to the original publication [bib_ref] Guidelines for the management of adult lower respiratory tract infections, Woodhead [/bib_ref] for this. As this is an update using the same methodologies, the layout of the document, including text, recommendations and evidence tables, is the same as in 2005.

# Methods
Using the same search filter as for the 2005 document (this is described in detail in the previous publication [bib_ref] Guidelines for the management of adult lower respiratory tract infections, Woodhead [/bib_ref] and website documents-http://www.ersnet.org; http://www.escmid. org) we identified relevant manuscripts in PubMed published from July 2002 to May 2010. Thereby we retrieved titles and loaded them into an electronic database. From these, 1677 titles were identified as potentially relevant publications by the expert panel members. The same process of evidence appraisal and grading (Appendix 1) and recommendation development and grading (Appendix 2) as in the 2005 document was used.
The document takes each clinical question for which there was a recommendation in the 2005 guidelines and presents new information when available, followed by a new recommendation. In some circumstances, because of lack of new evidence, or sometimes even in the presence of new evidence, the recommendation is unchanged from 2005. Where this is the case it is indicated.
In some parts of the guidelines new questions and recommendations have been added to cover relevant areas not included in the 2005 guidelines (e.g. aspiration pneumonia).

## Lrti definitions
The guidelines are to be used to guide the management of adults with lower respiratory tract infection (LRTI). As will be seen in the following text, this diagnosis, and the other clinical syndromes within this grouping, can be difficult to identify accurately. In the absence of agreed definitions of these syndromes, these guidelines are to be used when, in the opinion of a clinician, an LRTI syndrome is present. The following are put forward as definitions to guide the clinician, but it will be seen in the ensuing text that some of these labels will always be inaccurate. These definitions are pragmatic and based on a synthesis of available studies. They are primarily meant to be simple to apply in clinical practice, and this might be at the expense of scientific accuracy. These definitions are not mutually exclusive, with lower respiratory tract infection being an umbrella term that includes all others, which can also be used for cases that cannot be classified into one of the other groups. No new evidence has been identified that would lead to a change in the clinical definitions, which are therefore unchanged from the 2005 publication.
Since the publication of the 2005 guidelines the term health care-associated pneumonia (HCAP) has been put forward to capture groups of patients with pneumonia, some acquired outside hospital, expected to be caused by similar pathogens, but different from those usually found in community-acquired LRTI. In the opinion of the taskforce members the evidence base does not support the use of this term as being clinically relevant in Europe at the present time. HCAP is therefore not covered further in this document [bib_ref] Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database..., Kollef [/bib_ref] [bib_ref] Health care-associated pneumonia and community-acquired pneumonia: a single-center experience, Micek [/bib_ref] [bib_ref] Indicators of potentially drug-resistant bacteria in severe nursing homeacquired pneumonia, El Solh [/bib_ref] [bib_ref] Microbiology of severe aspiration pneumonia in institutionalized elderly, El-Solh [/bib_ref] [bib_ref] Health care-associated pneumonia requiring hospital admission: epidemiology, antibiotic therapy, and clinical outcomes, Carratala [/bib_ref] [bib_ref] Differences in etiology of pneumonias in nursing home and community patients, Garb [/bib_ref] [bib_ref] A prospective comparison of nursing home acquired pneumonia with community acquired pneumonia, Lim [/bib_ref] [bib_ref] A comparison of nursing home-acquired pneumonia patients with patients with community-acquired pneumonia..., Marrie [/bib_ref] [bib_ref] Process of care performance, patient characteristics, and outcomes in elderly patients hospitalized..., Meehan [/bib_ref] [bib_ref] Antibiotic use, hospital admissions, and mortality before and after implementing guidelines for..., Naughton [/bib_ref] [bib_ref] Health-care-associated pneumonia among hospitalized patients in a Japanese community hospital, Shindo [/bib_ref] [bib_ref] Prediction of infection due to antibiotic-resistant bacteria by select risk factors for..., Shorr [/bib_ref] [bib_ref] Outcomes of patients hospitalized with community-acquired, health care-associated, and hospital-acquired pneumonia, Venditti [/bib_ref] [bib_ref] Health care-associated Staphylococcus aureus pneumonia, Webster [/bib_ref] [bib_ref] Antimicrobial therapy escalation and hospital mortality among patients with health-care-associated pneumonia: a..., Zilberberg [/bib_ref].

## Lower respiratory tract infection
An acute illness (present for 21 days or less), usually with cough as the main symptom, with at least one other lower respiratory tract symptom (sputum production, dyspnoea, wheeze or chest discomfort/pain) and no alternative explanation (e.g. sinusitis or asthma).
Definite community-acquired pneumonia As above, but supported by chest radiograph findings of lung shadowing that is likely to be new. In the elderly, the presence of chest radiograph shadowing accompanied by acute clinical illness (unspecified) without other obvious cause.

## Acute exacerbation of copd (aecopd)
An event in the natural course of the disease characterized by a worsening of the patient's baseline dyspnoea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management. If chest radiograph shadowing, consistent with infection, is present the patient is considered to have CAP.

## Acute exacerbation of bronchiectasis (aebx)
In a patient with features suggestive of bronchiectasis, an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, and/or cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management. If chest radiograph shadowing, consistent with infection, is present the patient is considered to have CAP.

# Background
What new information is available about the microbiological causes of LRTI?
Wide variations between studies regarding the frequency of each microorganism can be explained by several factors, including differences in studied populations (e.g. age range or other risk factors), geographical area, studied samples and microbiological methods; for example, some studies focused on bacterial agents and others on viruses and intracellular bacteria. Supplementing traditional diagnostic methods with new technology-based methods could achieve higher microbial yield [bib_ref] Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods, Johansson [/bib_ref]. [bib_ref] Guidelines for the management of adult lower respiratory tract infections, Woodhead [/bib_ref] In the majority of studies of LRTI there is a large proportion of cases with no pathogen identified, either because the appropriate tests were not performed (as is usually the rule in outpatients) or the organism was missed. Age >70 years, renal and cardiac co-morbid illnesses and non alveolar infiltrates were independently associated with a higher proportion of unknown aetiology in 204 patients hospitalized for CAP [bib_ref] Factors associated with unknown aetiology in patients with community-acquired pneumonia, Ewig [/bib_ref]. 2 On the other hand, multiple organisms may be found in adults, as already described in youngsters. Paediatric studies have found polymicrobial infections in CAP: dual viral infection is present in 0-14%, dual bacterial infection in 0-14%, and mixed viral-bacterial infection in 3-30% [bib_ref] Mixed microbial aetiology of community-acquired pneumonia in children, Korppi [/bib_ref].
In hospitalized adult non-immunocompromised patients, polymicrobial CAP occurred in 6-26% [bib_ref] Community-acquired pneumonia of mixed etiology: prevalence, clinical characteristics, and outcome, Gutierrez [/bib_ref] [bib_ref] Viral community-acquired pneumonia in nonimmunocompromised adults, De Roux [/bib_ref] [bib_ref] The role of viruses in the aetiology of community-acquired pneumonia in adults, Marcos [/bib_ref] [bib_ref] Etiology of community acquired pneumonia among adult patients requiring hospitalization in Taiwan, Lauderdale [/bib_ref] [bib_ref] Communityacquired pneumonia in southeast Asia: the microbial differences between ambulatory and hospitalized..., Wattanathum [/bib_ref] [bib_ref] Prospective multicenter study of the causative organisms of community-acquired pneumonia in adults..., Saito [/bib_ref] [bib_ref] Incidence and characteristics of viral community-acquired pneumonia in adults, Jennings [/bib_ref] [bib_ref] Epidemiology and clinical outcomes of community-acquired pneumonia in adult patients in Asian..., Song [/bib_ref]. Gutierrez et al. [bib_ref] Community-acquired pneumonia of mixed etiology: prevalence, clinical characteristics, and outcome, Gutierrez [/bib_ref] report two or more pathogens at all ages, and as well in inpatients and outpatients, the most frequent combinations being those of bacteria with an atypical organism (29%) and two bacteria (29%); patients with mixed pneumonia are likely to have more co-morbidities and a more altered outcome. Angeles Marcos et al. [bib_ref] The role of viruses in the aetiology of community-acquired pneumonia in adults, Marcos [/bib_ref] found that the most frequent co-pathogens were S. pneumoniae and C. pneumoniae, and the most frequent combinations S. pneumoniae and either influenza or parainfluenza virus, and influenza virus with C. pneumoniae. De Roux et al. [bib_ref] Mixed community-acquired pneumonia in hospitalised patients, De Roux [/bib_ref] reported that in the 10% of patients with mixed CAP, S. pneumoniae was the most prevalent microorganism; the most frequent combination was S. pneumoniae with H. influenzae; influenza virus A and S. pneumoniae was the most frequent association in the mixed pyogenic pneumonia group. Among the 17% of patients with mixed infections, Song et al. found 73% of patients with two different pathogens, 13% with three different pathogens and 13% with four different pathogens. The most frequent combination was S. pneumoniae with C. pneumoniae (15%). Mixed infections were found in 25% of patients with pneumococcal CAP [bib_ref] Epidemiology and clinical outcomes of community-acquired pneumonia in adult patients in Asian..., Song [/bib_ref]. Jennings et al. [bib_ref] Incidence and characteristics of viral community-acquired pneumonia in adults, Jennings [/bib_ref] found that polymicrobial infections involving bacterial and viral pathogens occurred in 15% of patients with CAP and might be associated with severe pneumonia. Johansson et al. found two or more pathogens in 35% of patients with CAP with a determined aetiology, most commonly S. pneumoniae together with a respiratory virus [bib_ref] Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods, Johansson [/bib_ref]. Evidence of concurrent bacterial infection was found in lung tissue specimens from 22 (29%) of the 77 US patients with fatal cases of confirmed 2009 pandemic influenza A (H1N1), including 13% caused by S. pneumoniae. [fig_ref] TABLE 1: Aetiology of lower respiratory tract infection in the community [/fig_ref] summarizes the microbiological aetiologies of LRTI in the community. Studies have investigated the microbiological causes of CAP in outpatients [fig_ref] TABLE 2: Aetiology of community-acquired pneumonia in the community [/fig_ref] and patients admitted to hospital [fig_ref] TABLE 3: Aetiology of community-acquired pneumonia in adults admitted to hospital [/fig_ref] or to the intensive care unit [fig_ref] TABLE 4: Aetiology of community-acquired pneumonia in adults admitted to an ICU [/fig_ref]. Most studies of mild infections suggest that microbial aetiologies in outpatients are similar to those in hospitalized patients .
In the community and on the regular ward, extracellular bacteria, especially Streptococcus pneumoniae (S. pneumoniae), are in first place, followed by Haemophilus influenzae (H. influenzae), Staphylococcus aureus (S. aureus) and Moraxella catarrhalis. Among intracellular bacilli, Mycoplasma pneumoniae (M. pneumoniae) is the most common, followed in frequency by Legionella and Chlamydia species, with viruses being involved in up to 60% of community-acquired LRTI and 30% of CAP. In the intensive care unit, S. aureus, Gram-negative bacilli and Legionella spp. might be more frequently encountered. Recurrence of CAP is more likely when Gram-negative bacteria are involved, and less likely if Legionella spp. are involved [bib_ref] Aetiology of, and risk factors for, recurrent community-acquired pneumonia, Garcia-Vidal [/bib_ref].
Originally a nosocomial pathogen, methicillin-resistant S. aureus (MRSA) disseminated during the last decade in the community (community-acquired MRSA, CA-MRSA). Methicillin resistance is mediated by the mecA gene that has been associated with the Panton-Valentine leukocidin (PVL) toxin, which creates lytic pores in the cell membranes of neutrophils and induces the release of neutrophil chemotactic factors that promote inflammation and tissue destruction. New PVL-positive clones may be arising and disseminating in the community [bib_ref] Predominance of staphylococcal cassette chromosome mec (SCCmec) type IV among methicillin-resistant Staphylococcus..., Berglund [/bib_ref]. MRSA has emerged as an infectious agent of increasing frequency associated with skin and soft-tissue infections in the community setting. However, CA-MRSA can also lead to severe pulmonary infections, including necrotizing and haemorrhagic pneumonia, pneumothorax, pneumopyothorax, empyema, ventilatory failure and septicaemia [bib_ref] Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly..., Gillet [/bib_ref] [bib_ref] Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season, Hageman [/bib_ref] [bib_ref] Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia, Lina [/bib_ref] [bib_ref] Epidemiology and outcomes of community-associated methicillin-resistant Staphylococcus aureus infection, Davis [/bib_ref].
Coxiella burnetii, a Gram-negative intracellular bacterium, and a potential bioterrorism agent, is responsible for Q fever, which may have a wide variety of clinical manifestations, including flu-like syndrome, pneumonia and long-lasting fatigue syndrome. C. burnetii is present worldwide, cattle, sheep and goats being the most common reservoirs. Q fever occurs as endemic cases or as outbreaks in endemic areas. Outbreaks have ocurred in Europe in recent decades including Switzerland, Spain, the UK, Germany and most recently, the Netherlands repeatedly since 2007, with more than 4000 notified cases [bib_ref] Q fever in the Netherlands: an update on the epidemiology and control..., Van Der [/bib_ref].
The importance of viruses as causal agents has been confirmed in LRTI [bib_ref] Aetiological role of viral and bacterial infections in acute adult lower respiratory..., Creer [/bib_ref] and CAP [bib_ref] Viral community-acquired pneumonia in nonimmunocompromised adults, De Roux [/bib_ref] [bib_ref] The role of viruses in the aetiology of community-acquired pneumonia in adults, Marcos [/bib_ref] [bib_ref] Viral lower respiratory tract infection in the elderly: a prospective in-hospital study, Flamaing [/bib_ref]. In the majority of aetiological CAP studies looking for viruses and bacteria, [bib_ref] Acute infections of the chest in general practice, Shaw [/bib_ref] 40 [bib_ref] Health care-associated Staphylococcus aureus pneumonia, Webster [/bib_ref] viruses are the most common aetiological agents after S. pneumoniae [bib_ref] The role of viruses in the aetiology of community-acquired pneumonia in adults, Marcos [/bib_ref] [bib_ref] Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation, Johnstone [/bib_ref]. Sporadic viral pneumonias that occurred in recent years were due to new virus, avian influenza virus, hantavirus and coronavirus. Avian influenza virus A/H5N1 infections increase the risk of a pandemic, are much more severe than routine seasonal influenza, and are associated with severe illness and a >50% mortality rate, especially in people aged 10-39 years [bib_ref] Avian influenza A (H5N1) infection in humans, Beigel [/bib_ref] [bib_ref] Human disease from influenza A (H5N1), Chotpitayasunondh [/bib_ref]. The hantavirus pulmonary syndrome was recognized in 1983, but was retrospectively identified using serological testing in patients who had a similar illness in 1959 [bib_ref] Community-acquired pneumonia: new facets of an old disease -Hantavirus pulmonary syndrome, Miedzinski [/bib_ref]. The syndrome can result from several hantaviruses, such as Sin Nombre virus. Avoidance of areas where infected rodents live is the only preventive measure. An outbreak of severe acute respiratory syndrome (SARS) was reported in 2002, mainly in Asian countries and Canada [bib_ref] An outbreak of human Coronavirus OC43 infection and serological cross-reactivity with SARS..., Patrick [/bib_ref] [bib_ref] Identification of a novel coronavirus in patients with severe acute respiratory syndrome, Drosten [/bib_ref]. New viruses belonging to the coronaviridae family were found to be responsible.
In the spring of 2009, an outbreak of severe pneumonia was reported in conjunction with the concurrent isolation of novel swine-origin influenza A (H1N1) subtype viruses, which have rarely predominated since the 1957 pandemic, with features of the epidemic similar to those of past influenza pandemics. The new influenza virus was affecting a younger population, suggesting relative protection for persons who were exposed to H1N1 strains during childhood before the 1957 pandemic [bib_ref] Severe respiratory disease concurrent with the circulation of H1N1 influenza, Chowell [/bib_ref]. Severe pneumonias were reported in conjunction with the novel influenza A (H1N1) subtype virus. Pneumonias were due to the virus and to superinfection by S. pneumoniae or Staphylococcus. Microorganisms isolated in hospitalized elderly patients with CAP are shown in [fig_ref] TABLE 5: Microorganisms isolated in hospitalized elderly patients with community-acquired pneumonia [/fig_ref]. There are large variations, depending on the elderly threshold, where patients live and comorbidities. However, Gutierez et al. [bib_ref] The influence of age and gender on the population-based incidence of community-acquired..., Gutierrez [/bib_ref] found that age has a strong influence on the incidence of CAP caused by the main microbial pathogens; ageing is associated with a higher risk of acquiring pneumonia by S. pneumoniae, influenza virus and Chlamydia species. Ingarfield et al. [bib_ref] The bacteriology of pneumonia diagnosed in Western Australian emergency departments, Ingarfield [/bib_ref] emphasize that enterobacteriacae accounted for more than 25% of isolates in patients older than 65 years. [fig_ref] TABLE 6: Aetiology of exacerbations in patients with COPD [/fig_ref] provides microbiological aetiologies of airway infection in patients with COPD exacerbation, as found in studies using various methods. Recent studies of the microbiology of acute exacerbations of chronic bronchitis found an influence of the baseline level of lung function on pathogens (typical and atypical bacteria and/or virus) found in respiratory secretion samples [bib_ref] Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function, Eller [/bib_ref] [bib_ref] Relationship between bacterial flora in sputum and functional impairment in patients with..., Miravitlles [/bib_ref] [bib_ref] Bacterial infection and risk factors in outpatients with acute exacerbation of chronic..., Alamoudi [/bib_ref] [bib_ref] Respiratory viral infection in exacerbations of COPD, Mcmanus [/bib_ref] [bib_ref] Yield of sputum microbiological examination in patients hospitalized for exacerbations of chronic..., Roche [/bib_ref] [bib_ref] A communitybased, time-matched, case-control study of respiratory viruses and exacerbations of COPD, Hutchinson [/bib_ref] [bib_ref] The role of atypical respiratory pathogens in exacerbations of chronic obstructive pulmonary..., Diederen [/bib_ref] [bib_ref] A 1-year prospective study of the infectious etiology in patients hospitalized with..., Ko [/bib_ref]. P. aeruginosa should be suspected in patients who have been treated with antibiotics and in those not vaccinated against influenza [bib_ref] Bacterial infection in exacerbated COPD with changes in sputum characteristics, Monso [/bib_ref]. Both short-term colonization followed by clearance and long-term persistence of P. aeruginosa are observed. While serum antibody responses do not mediate clearance of P. aeruginosa, mucoid strains persist in the airways [bib_ref] Pseudomonas aeruginosa in chronic obstructive pulmonary disease, Murphy [/bib_ref]. The microbiological pattern of airway infection may also differ between pneumonic and non-pneumonic hospitalized exacerbations of COPD, as shown in a prospective study of 240 patients. Identification of a pathogen was more frequent in pneumonic cases (96% vs. 71%), in which S. pneumoniae and viruses were more frequent (43% and 78% vs. 18% and 46%, respectively) [bib_ref] Pneumonic vs nonpneumonic acute exacerbations of COPD, Lieberman [/bib_ref]. Respiratory viruses are more frequently found in induced sputum of hospitalized patients with COPD exacerbations than in control stable COPD subjects (47% vs. 10%), the most frequent viruses being rhinovirus, influenza, parainfuenza and RSV. However, if exacerbations of chronic bronchitis and/or COPD may be due to viral and/or bacterial infection, such infections may occur without exacerbation [bib_ref] Infections with viruses and Mycoplasma pneumoniae during exacerbations of chronic bronchitis, Buscho [/bib_ref]. Finally, bacterial exacerbations of COPD could be related to the appearance of new strains of S. pneumoniae, H. influenzae or M. catarrhalis in the colonized airways [bib_ref] New strains of bacteria and exacerbations of chronic obstructive pulmonary disease, Sethi [/bib_ref].
Only a few studies assessed the microbiological pattern of airway colonization in bronchiectasis, and no study has investigated the microbiological aetiology of exacerbations. The main results for steady state bronchiectasis are provided in [fig_ref] TABLE 7: Microorganisms isolated in inpatients with non-cystic fibrosis bronchiectasis [/fig_ref] ; they highlight the high frequency of Pseudomonas infection, particularly in the case of impaired lung function.
In a 2-year prospective study of 77 patients with clinically stable bronchiectasis, multivariate analysis found that early diagnosis of the disease (before 14 years of age), reduced FEV 1 (<80% predicted) and varicose-cystic bronchiectasis are risk factors for bronchial colonization with pathogenic bacteria, mainly H. influenzae and P. aeruginosa (odds ratio: 3.92, 3.91 and 4.80, respectively) [bib_ref] Bacterial colonisation in patients with bronchiectasis: microbiological pattern and risk factors, Angrill [/bib_ref]. In a study of 100 patients with steady-state bronchiectasis, the presence of P. aeruginosa in the sputum was associated with a lower FEV 1 /FVC ratio (60% vs. 72% in the absence of a pathogenic microorganism) and higher volume of daily sputum production (1-6 score: 3 vs. 1) [bib_ref] The effect of Pseudomonas aeruginosa infection on clinical parameters in steady-state bronchiectasis, Ho [/bib_ref]. In that study, FEV 1 /FVC <60% and high sputum output were independently associated with an increased risk of sputum isolation of P. aeruginosa (odds ratio: 3.1 and 4.7, respectively).

# Conclusion
There has been no major change in causative pathogens for LRTI. More information is available about the frequency of polymicrobial infections, including viral infections. PVL-producing Staphylococcus aureus has emerged as a new cause, often of severe CAP, but currently remains uncommon.
What information is available about the frequency of antimicrobial resistance in these settings Streptococcus pneumoniae. Beta-lactams: The prevalence of resistance to penicillin and other drugs among pneumococci has considerably complicated the empirical treatment of respiratory tract infections. Worryingly, the majority of resistant isolates are resistant to multiple classes of antimicrobials, which has a serious impact on many first-line antimicrobial therapies. The mechanism of resistance to penicillin and other b-lactams is due to alterations of penicillin-binding proteins (PBP). PBPs interact with b-lactams enzymatically by forming a covalent complex via the active-site serine. The loss of affinity for the PBPs affects all b-lactams, although this may vary substantially depending on the drug. The affinity for a given b-lactam is different for different PBPs, and conversely, one PBP has distinct affinities for different b-lactams. Therefore point mutations reducing the affinity for one b-lactam do not necessarily affect the affinity for another compound [bib_ref] Penicillin-binding proteins and cell shape in E. coli, Spratt [/bib_ref]. However, National Committee for Clinical Laboratory Standards (NCCLS) guidelines state that a pneumococcal isolate that is susceptible to penicillin can be considered susceptible to other b-lactams. It is generally accepted that the MICs of amoxicillin and extended-spectrum cephalosporins are usually equal to or two to four times lower than the MIC of benzylpenicillin. However, pneumococci resistant to amoxicillin and or extended-spectrum cephalosporins with the MICs of these agents equal to or 1 dilution higher than the MIC of penicillin have been identified [bib_ref] Emergence in france of multiple clones of clinical Streptococcus pneumoniae isolates with..., Doit [/bib_ref].
Pneumococci with decreased susceptibility to penicillin have a much higher rate of resistance to other classes of antibiotics, as has been mentioned above. Carbapenems, imipenem, meropenem and ertapenem, are the most active b-lactams available against PRSP. Among parenteral cephalosporins, those with good activity are cefotaxime, ceftriaxone, cefepime and cefpirome. It is important to note that other parenteral third-generation cephalosporins are considerably less active, for example ceftizoxime and ceftazidime; the latter has been linked to a poor clinical response [bib_ref] Treatment of penicillin-resistant pneumococcal bacteremia in neutropenic patients with cancer, Carratala [/bib_ref].
Amoxicillin remains the most active of all oral b-lactams, and among cephalosporins, cefditoren and cefpodoxime are most active, then cefuroxime and cefprozil. The use of cefuroxime in cases of bacteraemic pneumococcal pneumonia caused by penicillin non-susceptible strains has been linked to an increased mortality [bib_ref] An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance,..., Yu [/bib_ref].
The prevalence of penicillin-resistant Streptococcus pneumoniae (PRSP) and multidrug-resistant SP varies between regions. Data on the prevalence of antibiotic resistance among Streptococcus pneumoniae has been regularly produced by the EARSS project, a European-wide network of national surveillance systems, providing reference data on antimicrobial resistance for public health purposes. This network receives funding from the European Commission (http://www.earss.rivm.nl).
In 2008, 1152 (10%) of the 11 584 invasive S. pneumoniae isolates reported by 32 countries were non-susceptible to penicillin [fig_ref] FIG. 1: Streptococcus pneumoniae [/fig_ref]. Penicillin non-susceptible S. pneumoniae (PNSP) shows a heterogeneous picture in Europe. Most northern European countries had levels of non-susceptibility below 5%, but Finland (11%, n = 642) and Ireland (23%, n = 441) reported relatively high levels. High levels of PNSP, above 25%, were mainly reported from southern and eastern Europe, Cyprus (43%, n = 14), France (30%, n = 557), Hungary (27%, n = 166), Malta (47%, n = 17) and Turkey (34%, n = 97). The level of penicillin non-susceptibility in Fin- land and Ireland has risen significantly from 2005. The two countries with the highest levels of PNSP in 2007 (France and Israel) showed significant decreasing rates of PNSP during the past years. Lithuania and Norway (the latter only significantly for the laboratories reporting consistently in the last 4 years) also showed decreasing trends for PNSP. In Belgium, the proportions of PNSP as well as PRSP continued to decrease significantly in 2008. In Croatia, Hungary, Ireland and Turkey a significant increase was also observed, but only for the percentage of fully resistant isolates (see [fig_ref] FIG. 1: Streptococcus pneumoniae [/fig_ref].
The changes in the distribution of serotypes compared with 2007 were small. Serogroups 1 and 19 were still the most prevalent ones, whereas serogroup 7 and serogroup 3 became slightly more prevalent, and serogroup 14 became less prevalent in the population. The highest resistance proportions were identified in serogroups 1, , of which all but 1 and 33 are included in the seven-conjugate vaccine.
Another recent survey of interest was performed in eastern and southern Mediterranean countries. Over a 36-month period, from 2003 to 2005, the ARMed project collected 1298 susceptibility test results of invasive isolates of S. pneumoniae from blood and spinal fluid cultures routinely processed within 59 participating laboratories situated in Algeria, Cyprus, Egypt, Jordan, Lebanon, Malta, Morocco, Tunisia and Turkey. Overall, 26% (335) of isolates were reported as non-susceptible to penicillin, with the highest proportions being reported from Algeria (44%) and Lebanon (40%) [bib_ref] Prevalence of penicillin and erythromycin resistance among invasive Streptococcus pneumoniae isolates reported..., Borg [/bib_ref].
In the US, the incidence of invasive pneumococcal disease due to penicillin-resistant 19A isolates increased from 6.7% to 35% between 1998 and 2005 (p <0.0001). Of 151 penicillin-resistant 19A isolates, 111 (73.5%) belonged to the rapidly emerging clonal complex 320, which is related to multidrug-resistant Taiwan (19F)-14 [bib_ref] Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, Moore [/bib_ref]. The importance of these findings is the high levels of penicillin resistance among strains with this serotype (amoxicillin MIC, 4 mg/L; cefotaxime MIC, 2 mg/L), and their frequent multiresistance, precluding the use of any oral b-lactam for the treatment of infections caused by these resistant strains.
Of special concern, is the increase in some European countries of MDR strains of serotype 19A, particularly in Spain and France [bib_ref] Emergence of a multidrug-resistant clone (ST320) among invasive serotype 19A pneumococci in..., Ardanuy [/bib_ref].
The new susceptibility breakpoints for S. pneumoniae, published by the Clinical and Laboratory Standards Institute (CLSI) in January 2008, were the result of a re-evaluation that showed clinical response to penicillin was being preserved in clinical studies of pneumococcal infection, despite reduced susceptibility response in vitro. Antimicrobial susceptibility breakpoints are currently established based on (i) the pharmacokinetic and pharmacodynamic properties of an antimicrobial agent and (ii) data correlating individual MIC results with patient outcomes. Under the former criteria, susceptible, intermediate and resistant MIC breakpoints for penicillin were 0.06, 0.12-1 and 2 mg/L, respectively, for all pneumococcal isolates, regardless of clinical syndrome or route of penicillin administration. Those breakpoints remain unchanged for patients without meningitis who can be treated with oral penicillin (e.g. for outpatient pneumonia). For patients without meningitis who are treated with intravenous penicillin, the new breakpoints are 2, 4 and 8 mg/L, respectively.
The changes in penicillin breakpoints for S. pneumoniae have the potential to allow clinicians to increase use of penicillin to treat penicillin-susceptible non-meningitis pneumococcal infections, instead of using broader-spectrum antimicrobials. Its use is encouraged to prevent the spread of antimicrobial-resistant S. pneumoniae and also the spread of methicillin-resistant Staphylococcus aureus and Clostridium difficile, which can result from use of broader-spectrum antimicrobials. In accordance with the penicillin breakpoints, the doses of suitable b-lactam agents for the treatment of hospitalized patients with pneumonia when Streptococcus pneumoniae is suspected are: penicillin G 2 g (3.2 mU) i.v. Q4 h should be adequate for strains with a penicillin MIC of 8 mg/L; dose to be adjusted for renal impairment; ceftriaxone 1 g i.v. or i.m. Q 12 h or cefotaxime 2 g i.v. Q6 h, should be adequate for strains with a MIC of 8 mg/L [bib_ref] Penicillins for treatment of pneumococcal pneumonia: does in vitro resistance really matter?, Peterson [/bib_ref].
The new formulation of amoxicillin-clavulanic acid (2 g/125 q12 h) available in some European countries, is able to eradicate amoxicillin-resistant strains (MICs, 4-8 mg/L), as shown in two recent randomized clinical trials (RCTs) [bib_ref] Efficacy of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2000/125 mg) in..., File [/bib_ref].
Macrolides: In the EARSS database 10 982 (95%) invasive S. pneumoniae isolates had susceptibility results for erythromycin in 2008. From the 32 countries reporting data, 1655

## Cmi
(15%) isolates were reported as non-susceptible to erythromycin. Three countries reported erythromycin non-susceptibility below 5% (Czech Republic (n = 243), Estonia (n = 53) and Bulgaria (n = 24)). On the other hand, five countries reported non-susceptibility proportions above 25%, namely Italy (27%, n = 154), Turkey (29%, n = 97), France (31%, n = 557), Hungary (32%, n = 158) and Cyprus (29%, n = 14). A very pronounced increase of erythromycin resistance was reported from Turkey (10% in 2005 vs.29% in 2008) and from Ireland, only significant for the selected laboratories. The proportion of isolates non-susceptible to erythromycin in Belgium, France and the UK continued to decrease, and now also Germany, the Netherlands and Norway have reported significant decreasing rates with respect to this (see [fig_ref] FIG. 2: Streptococcus pneumoniae [/fig_ref].
In another survey, during the same time period, the highest proportions of pneumococci that were not susceptible to erythromycin were reported from Malta (46%) and Tunisia (39%) [bib_ref] Prevalence of penicillin and erythromycin resistance among invasive Streptococcus pneumoniae isolates reported..., Borg [/bib_ref].
Macrolide resistance in S. pneumoniae occurs by two main mechanisms: target-site modification or efflux of the drug out of the cell. The most common form of target-site modification is a specific adenine residue on the 23S rRNA (A2058) that is dimethylated by an rRNA methylase. The predominant methylase responsible for macrolide resistance in S. pneumoniae is encoded by erm (B). This methylation is thought to lead to conformational changes in the ribosome, resulting in decreased binding of all macrolide, lincosamide and streptogramin antibacterials (the so-called MLSB phenotype). The pneumococci harbouring erm (B) gene exhibits highs to very high levels of resistance to all macrolides, with a MIC90 of both clarithromycin and azithromycin of 256 mg/ L or more [bib_ref] Erythromycin resistance by ribosome modification, Weisblum [/bib_ref] [bib_ref] Identification of an erm(A) erythromycin resistance methylase gene in Streptococcus pneumoniae isolated..., Syrogiannopoulos [/bib_ref].
Macrolide efflux is mediated by the product of the mef (A) gene, which usually causes MICs lower than the erm (B) isolates (MICs of 1-32 mg/L) and retains susceptibility to clindamycin (the so-called M-phenotype) [bib_ref] Prevalence and characterization of the mechanisms of macrolide, lincosamide, and streptogramin resistance..., Johnston [/bib_ref]. Much more rarely, mutations at different positions in domains V and II of 23S rRNA and in genes that encode the ribosomal proteins L4 and L22 have been identified as a cause of macrolide resistance [bib_ref] Macrolide resistance by ribosomal mutation in clinical isolates of Streptococcus pneumoniae from..., Farrell [/bib_ref].
Although it is not surprising that highly resistant strains (MIC, 16 mg/mL) may lead to clinical failure, the relevance of low-level resistance (MIC, 0.5-8 mg/mL) has been brought into question. Early this decade, a matched case-control study of patients with bacteraemic pneumococcal infections showed that breakthrough bacteraemia with an erythromycin-resistant isolate occurred in 18 (24%) of 76 patients taking a macrolide compared with none of the 136 matched patients with bacteraemia with an erythromycin-susceptible isolate [bib_ref] Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant..., Lonks [/bib_ref]. These results established that macrolide resistance among pneumococci, including low level erythromycin-resistant isolates (M phenotype), is a cause of failure of outpatient pneumonia therapy. A more recent population-based case-control study from Toronto has confirmed these results [bib_ref] Macrolide resistance in bacteremic pneumococcal disease: implications for patient management, Daneman [/bib_ref].
Macrolide resistance contributes to an increased risk of macrolide failure, irrespective of the underlying resistance mechanism or the degree of elevation in erythromycin MIC. Therefore, it would be wise to avoid empirical macrolide therapy when a patient is at risk of being infected with a macrolide-resistant pathogen, either as a result of patient-specific characteristics or the overall rate of resistance in the community. Clinical parameters associated with macrolide resistance among pneumococci include macrolide exposure within the previous 3 months, recent use of a penicillin or trimethroprim-sulphamethoxazole, extremes of age, HIV infection and exposure to siblings colonized with resistant isolates [bib_ref] Macrolide and ketolide resistance with Streptococcus pneumoniae, Doern [/bib_ref].
The issue of whether the outcome of bacteraemic pneumococcal pneumonia is improved with the use of combination antibiotic therapy vs. monotherapy is still not resolved. The mechanism for the potential benefit of combining a macrolide with a b-lactam is uncertain, and may be multifactorial, such as providing cover for atypical pathogens, unrecognized polymicrobial infection, and/or additional cover for drugresistant infections, synergy between these two classes of agents, and immunomodulatory properties of the macrolides. Macrolides, at sub-MICs, but not other classes of antibiotic, subvert the production of pneumolysin, even in the presence of (and irrespective of the mechanism of) macrolide resistance in S. pneumoniae [bib_ref] Comparison of the effects of macrolides, amoxicillin, ceftriaxone, doxycycline, tobramycin and fluoroquinolones,..., Anderson [/bib_ref].
Fluoroquinolones: Resistance to quinolones occurs in a stepwise fashion, with mutations being observed first in

## E10
Clinical Microbiology and Infection, Volume 17 Supplement 6, November 2011 either parC or gyrA leading to decreased fluoroquinolone susceptibility. Strains usually become fully resistant with the addition of a mutation in the other target gene (either gyrA or parC) [bib_ref] Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus..., Pan [/bib_ref]. Mutations in parE and gyrB and efflux pump are less important mechanisms of resistance. Emergence of resistance during the course of antimicrobial therapy is most likely to develop from strains that already carry one quinolone resistance determining region (QRDR) as they require only one additional mutation in one of the other target genes to become resistant. The concept of mutant prevention concentration reflects the concentration that prevents the growth of first-step mutants. Based on their potential for restricting the selection of resistant mutants, not all fluoroquinolones are equal and can be classified accordingly; their ability to prevent the selection of mutants is in descending order: moxifloxacin, trovafloxacin, gatifloxacin, grepafloxacin and levofloxacin [bib_ref] Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae, Blondeau [/bib_ref].
Fluoroquinolone resistance among S. pneumoniae remains rare in Europe. The use of older agents and incorrect dosing are the main drivers of resistance. The Alexander Project reported fluoroquinolone resistance among pneumococci of <1% in 2001 in northern and southern Europe (http:// www.alexandernetwork.com). The PROTEKT study identified no quinolone-resistant isolates in northern Europe and only 1.3% of S. pneumoniae from southern Europe were resistant to levofloxacin (http://www.protekt.org.). However, the prevalence of first-step mutants is largely unknown. More recent surveys suggest that the prevalence of resistance to levofloxacin and 8-methoxi fluoroquinolones (moxifloxacin, gatifloxacin) in southern Europe, specifically in Italy and Spain, appears to be around 2-3% [bib_ref] Changes in fluoroquinolone-resistant Streptococcus pneumoniae after 7-valent conjugate vaccination, De La Campa [/bib_ref].
Tetracyclines and other agents: In many countries of the world chloramphenicol, co-trimoxazole and tetracyclines have reached such a level and prevalence of resistance that they are no longer a good option for empirical therapy in RTI of pneumococcal aetiology. Thus, resistance to trimethoprim-sulphamethoxazole is reported in approximately 35% of isolates. Tetracycline resistance in pneumococi remains relatively high in some European countries. However, no recent comprehensive surveillance data on tetracycline resistance are available. Early this decade, among invasive isolates, up to 11.5% were reported to be resistant to tetracycline, and among non-invasive isolates, the prevalence of tetracycline resistance can be as high as 42% in southern Europe. In other European countries, recent studies have shown low resistant rates of tetracycline resistance. Thus, in the UK and Ireland, out of 1388 invasive isolates, only 4% were resistant, and among 5810 respiratory isolates, 7.6% were resistant [bib_ref] Non-susceptibility trends and serotype distributions among Streptococcus pneumoniae from community-acquired respiratory tract..., Farrell [/bib_ref].
Haemophilus influenzae. Beta-lactams: b-Lactamase production is the primary mechanism of resistance among H. influenzae and is a well-known predictor of treatment failure in community-acquired respiratory tract infections. This can be overcome with the use of b-lactamase-stable cephalosporins or b-lactam plus b-lactamase-inhibitor combinations. In addition, H. influenzae isolates carrying amino acid substitutions in the ftsI gene (encoding PBP 3) are phenotypically recognized as b-lactamase negative ampicillin resistant (BLNAR), which leads to the loss of susceptibility to aminopenicillin and some cephalosporins.
In Europe, resistance rates of Haemophilus influenzae against b-lactams, in spite of large inter-regional differences, seem to decline due to a decreasing number of BL-producing strains. In a recent surveillance study of antibiotic resistance in H. influenzae, the mean prevalence of b-lactam producers was 7.6%, with a range of 0.7-17.6% [bib_ref] Longitudinal European surveillance study of antibiotic resistance of Haemophilus influenzae, Jansen [/bib_ref]. Although rare, blactamase-negative ampicillin-resistant (BLNAR) and b-lactamase-positive amoxicillin/clavulanate-resistant (BLPACR) H. influenzae are of concern where they exist.
Macrolides: Azithromycin is the most active of these agents against H. influenzae, with a MIC four-to eightfold lower than erythromycin (azithromycin MICs, <0.25-4 mg/L). On the other hand, the existence of efflux pumps leads to loss of susceptibility to macrolides in more than 98% of H. influenzae strains [bib_ref] Effects of an efflux mechanism and ribosomal mutations on macrolide susceptibility of..., Peric [/bib_ref]. It appears that the vast majority (>98%) of H. influenzae strains have a macrolide efflux mechanism, with a few of these being hyper-resistant (1.3%; azithromycin MICs >4 mg/L) due to one or several ribosomal mutations. Occasional hypersusceptible strains (1.8%; azithromycin MICs <0.25 mg/L) are found without any underlying mechanism of resistance and appear to be the only truly macrolide-susceptible variants of H. influenzae.
The prevalence of resistance is based on the use of pharmacokinetic/pharmacodynamic breakpoints; large discrepancies are observed in terms of susceptibility, by use of CLSI breakpoints. So, for instance, the rate of susceptibility to clarithromycin can shift from >99% to 5% (by use of the PK/PD breakpoints).
Fluoroquinolones and other agents: Fluoroquinolone resistance remains rare with H. Influenzae.
Prevalence of tetracycline resistance: few recent data are available. A survey in the UK and Ireland showed a significant though slow downward trend (p <0.00008) in tetracycline non-susceptibility, which reduced from 3.5% in 1999/2000 to 1.2% in 2006/2007 and dipped as low as 0.9% in 2004/2005 [bib_ref] Non-susceptibility trends among Haemophilus influenzae and Moraxella catarrhalis from community-acquired respiratory tract..., Morrissey [/bib_ref].
In Greece, resistance to tetracycline increased from 1.6% in 1996 to 38% in 2005 [bib_ref] Antimicrobial susceptibilities of 930 Haemophilus influenzae clinical strains isolated from the island..., Kofteridis [/bib_ref].
Resistance to other orally administered agents, such as trimethoprim-sulphamethoxazole (TMP-SMX) and chloramphenicol, is well known. The overall frequencies of resistance to TMP-SMX remain around 18% in a recent survey in the US [bib_ref] National and regional assessment of antimicrobial resistance among community-acquired respiratory tract pathogens..., Critchley [/bib_ref].
Moraxella catarrhalis. The susceptibility of M. catarrhalis has changed little since 1999. It is interesting to note that, despite almost universal b-lactamase prevalence, resistance to other antibacterial agents has not developed in M. catarrhalis. Clinicians should assume that all isolates of M. catarrhalis are resistant to amoxicillin, ampicillin, piperacillin and penicillin. Two types of b-lactamases can be found that are phenotypically identical: the BRO-1 and BRO-2 types. Both enzymes are readily inactivated by b-lactamase inhibitors, and all isolates are still susceptible to amoxicillin in combination with clavulanic acid. Other enzyme-stable b-lactams, macrolides and tetracyclines are still very active against M. catarrhalis, but rates of TMP-SMX resistance as high as 50% have been occasionally reported.
Mycoplasma pneumoniae. M. pneumoniae is inhibited by tetracyclines, macrolides, ketolides and fluoroquinolones, with little variation in MICs among clinical isolates [bib_ref] In vitro susceptibilities to and bactericidal activities of garenoxacin (BMS-284756) and other..., Waites [/bib_ref] [bib_ref] In vitro activities of ABT-773 and other antimicrobials against human mycoplasmas, Waites [/bib_ref]. Other agents that are active at the bacterial ribosome, such as streptogramins, chloramphenicol and aminoglycosides, may also show in vitro inhibitory activity against M. pneumoniae but are not normally used for therapeutic purposes against this organism. Clindamycin is active in vitro but its in vivo activity has never been demonstrated. Due to the lack of a cell wall, mycoplasmas are resistant to all b-lactams and glycopeptides. Sulphonamides, trimethoprim, polymixins, nalidixic acid and rifampin are also inactive [bib_ref] Mycoplasma pneumoniae and its role as a human pathogen, Waites [/bib_ref]. As tetracyclines and fluoroquinolones are not approved for use in children, macrolides are generally considered the treatment of choice for M. pneumoniae infections in both adults and children.
Since 2000, the emergence of macrolide resistance has been reported mainly in Asia. In Japan, several recent studies reported that macrolide-resistant M. pneumoniae isolates have been spreading since 2000, with prevalence increasing up to 30.6% according to these studies [bib_ref] Characterization and molecular analysis of macrolide-resistant Mycoplasma pneumoniae clinical isolates obtained in..., Matsuoka [/bib_ref] [bib_ref] Emergence of macrolide-resistant Mycoplasma pneumoniae with a 23S rRNA gene mutation, Morozumi [/bib_ref] [bib_ref] Increased macrolide resistance of Mycoplasma pneumoniae in pediatric patients with community-acquired pneumonia, Morozumi [/bib_ref]. The A2058G mutation in domain V of 23S rRNA is the most frequent substitution associated with macrolide resistance in clinical isolates.
Data regarding current resistance patterns for M. pneumoniae in European adult and adolescent patients with CAP are limited. Macrolide resistance rates of 3.0% in Germany have been recently reported [bib_ref] Occurrence of macrolideresistant Mycoplasma pneumoniae strains in Germany, Dumke [/bib_ref]. In France, among M. pneumo-niae-positive specimens collected before 2005, no macrolideresistant M. pneumoniae isolate was detected. In contrast, among 51 samples collected between 2005 and 2007, five (9.8%) yielded a resistant genotype, suggesting a recent increase in macrolide-resistant M. pneumoniae isolates in France [bib_ref] Increased macrolide resistance of Mycoplasma pneumoniae in France directly detected in clinical..., Peuchant [/bib_ref]. These emerging data suggest that the epidemiological monitoring of macrolide resistance in this species has become necessary in Europe.
Staphylococcus aureus. In the European setting, S. aureus remains an unusual primary cause of CAP [bib_ref] Staphylococcus aureus in community-acquired pneumonia, Stralin [/bib_ref] , although it is an important cause of pneumonia and death following influenza [bib_ref] Predominant role of bacterial pneumonia as a cause of death in pandemic..., Morens [/bib_ref]. The role of CA-MRSA is even more poorly defined, although emergent in Europe [bib_ref] Guidelines for UK practice for the diagnosis and management of methicillin-resistant Staphylococcus..., Nathwani [/bib_ref]. Infections due to CA-MRSA have symptom onset before or within 48 h of admission to hospital and patients have no significant previous healthcare contact. CAP, which is due to CA-MRSA, classically presents in a young, previously healthy, individual with rapidly progressive, severe respiratory disease. The aggressive nature of CA-MRSA, due to toxin production, causes massive destruction in previously normal lungs.
CA-MRSA is usually only resistant to the b-lactams and susceptible to most other antibiotic classes. This difference in the laboratory findings may indicate that the patient has a CA-MRSA isolate as opposed to an HA-MRSA isolate. However, with time, CA-MRSA is likely to acquire the resistance genes that will make it more difficult to differentiate from HA-MRSA by routine antimicrobial susceptibility testing.
Because S. aureus is an uncommon cause of CAP, it does not need to be covered routinely by the empirical CAP treatment. However, the severity associated with S. aureus pneumonia reinforces the importance of performing routine blood and respiratory cultures in pneumonia patients.
Clindamycin and linezolid markedly suppress the formation of PVL, a-haemolysin and toxic shock syndrome toxin 1 by suppressing translation but not transcription. Nafcillin, on the other hand, stimulates toxin production, whereas toxin levels with use of vancomycin are comparable to those in control samples not exposed to antibiotics.
As suppression of toxin production may correlate with improved outcome, vancomycin alone may not be the optimal treatment for pneumonia caused by toxin-producing CA-MRSA. Although it has not been established that the combination of a bactericidal agent with a toxin-suppressing agent, such as clindamycin or linezolid, is associated with improved outcome, it is the general feeling that vancomycin should not be used as a single agent in the treatment of CA-MRSA CAP.
In severe infections there are limited trial data to support the use of one regimen over another and recommendations are largely based on expert advice. Adjunctive therapy, such as intravenous immunoglobulin, has been successful in some case reports, but its real contribution is unknown.
What new information is available about the clinical relevance of antimicrobial resistance in this setting?
The pattern of antimicrobial resistance varies between European countries. Changes in the prevalence of antibiotic resistance among the main respiratory pathogens in Europe have been reported; continued surveillance of antimicrobial resistance in all common pathogens is essential.
1 In pneumococci, erythromycin MICs >0.5 mg/L predict clinical failure. The prevalence of resistance in many countries compromises the efficacy of macrolides in the treatment of pneumococcal infection. The prevalence of resistance will dictate the need to reassess current recommendations for the treatment of CAP. 7 The role of CA-MRSA in CAP is poorly defined, although emergent in Europe. CA-MRSA is usually only resistant to the b-lactams and susceptible to most other antibiotic classes. The antibiotic treatment of CA-MRSA pneumonia is not known. As suppression of toxin production may correlate with improved outcome, vancomycin alone may not be the optimal treatment for pneumonia. Thus, the combination of a bactericidal agent with a toxin-suppressing agent, such a clindamycin or linezolid, has been suggested as the optimal choice. 8 In vivo selection of resistance means that proper use of antimicrobials is essential.

## What new information is available about antimicrobial pharmacokinetics and pharmacodynamics
The only new information is about the need for high levofloxacin doses (750 mg OD) in the treatment of Pseudomonas and Klebsiella [bib_ref] Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and..., Drusano [/bib_ref] [bib_ref] In vivo measurement of levofloxacin penetration into lung tissue after cardiac surgery, Hutschala [/bib_ref]. Two other new studies do now alter the current guideline recommendations [bib_ref] Intrapulmonary pharmacodynamics of high-dose levofloxacin in subjects with chronic bronchitis or chronic..., Conte [/bib_ref] [bib_ref] Pharmacokinetics-pharmacodynamics of quinolones against Streptococcus pneumoniae in patients with communityacquired pneumonia, Bhavnani [/bib_ref].

## Management outside hospital introduction
Lower respiratory tract infection is a broad description of a group of disease entities, encompassing acute bronchitis, pneumonia and exacerbations of chronic lung disease. In primary care it is very difficult to differentiate between those different diseases without doing extensive additional diagnostic tests. Patients can present with cough, dyspnoea, tachypnoea, fever, pain in the chest, wheezing and auscultatory abnormalities. There is huge overlap in presentation between the different lower respiratory diseases mentioned above and it is neither feasible nor cost-efficient to do a full diagnostic work-up in all patients. Therefore an empirical and pragmatic approach is warranted. The statements and recommendations below are based on primary care studies, expert opinion and consensus among members of the working group.

## Diagnosis
When should aspiration pneumonia be considered? Recommendation: Aspiration pneumonia should be considered in patients with difficulties with swallowing who show signs of an acute LRTI. In these patients a chest X-ray should be performed .
No new information. Recommendation not changed.
When should left ventricular failure be considered?
Recommendation: Left ventricular failure should be considered in patients above 65, with either orthopnoea, displaced apex beat and/or a history of myocardial infarction, hypertension or atrial fibrillation. Low serum levels of atrial natriuretic peptide (Brain Natriucetic Peptide <40 pg/mL) or N-terminal pro-BNP <150 pg/mg) make the presence of left ventricular failure unlikely [C3].
New information. Recommendation not changed.
A number of new studies on the diagnosis of cardiac failure in primary care were found, but none involving patients with a cough. The presence of hypertension and atrial fibrillation is associated with cardiac failure, and levels of BNP and NT-proBNP were found to have diagnostic value for detecting cardiac failure [bib_ref] Early diagnosis of congestive heart failure: clinical utility of B-type natriuretic peptide..., Aspromonte [/bib_ref] [bib_ref] Neurohormonal activation and diagnostic value of cardiac peptides in patients with suspected..., Mikkelsen [/bib_ref] [bib_ref] The diagnostic accuracy and utility of a B-type natriuretic peptide test in..., Fuat [/bib_ref].
Evidence To assess diagnostic accuracy of cardiac peptides in detecting any left ventricular dysfunction (LVD) in patients referred from primary care with suspected HF before institution of medical therapy

## Css 4a+
Fuat et al. [bib_ref] The diagnostic accuracy and utility of a B-type natriuretic peptide test in..., Fuat [/bib_ref] To test and compare the diagnostic accuracy and utility of B-type natriuretic peptide (BNP) and N-terminal B-type natriuretic peptide (NT proBNP) in diagnosing heart failure due to left ventricular systolic dysfunction in patients with suspected heart failure referred by GPs to one-stop diagnostic clinics

## Css 4a+
When should pulmonary embolism be considered? Recommendation: Pulmonary embolism should be considered in patients with one of the following characteristics: a history of DVT or pulmonary embolism, immobilization in the past 4 weeks, or malignant disease [C3].
No new information. Recommendation not changed.
When should chronic airway disease be considered? Recommendation: In patients with a persistent cough and at least two of the following, wheezing (either as sign or as symptom), previous consultations for wheezing or cough, dyspnoea, prolonged expiration, a smoking history and symptoms of allergy, lung-function tests should be considered to assess the presence of chronic airway disease. In elderly patients who smoke and present with a cough, COPD should be considered [B1].
One relevant study indicated that smoking and age >60 years in combination with a cough is clearly related to the presence of COPD [bib_ref] Detecting patients at a high risk of developing chronic obstructive pulmonary disease..., Van Schayck [/bib_ref]. One literature review was recently published that gave a critical report on six studies on the detection of COPD. The following signs and symptoms were mentioned at least three times in those studies: dyspnoea, wheezing (complaint), previous consultation for wheezing or cough, self-reported COPD, age, smoking, wheezing (sign), prolonged expirium and forced expiration time. The review concluded that variation and weaknesses in study designs warranted further studies [bib_ref] The diagnostic value of history and physical examination for COPD in suspected..., Broekhuizen [/bib_ref].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review

## Reference
Objective Design Evidence
Van Schayck et al. [bib_ref] Detecting patients at a high risk of developing chronic obstructive pulmonary disease..., Van Schayck [/bib_ref] To investigate the effectiveness of case finding of patients at risk of developing chronic obstructive pulmonary disease

## Css 4a+
Broekhuizen et al. [bib_ref] The diagnostic value of history and physical examination for COPD in suspected..., Broekhuizen [/bib_ref] To review the literature on detection of COPD in patients with cough in primary care MA 1C?
How to differentiate between pneumonia and other respiratory tract infections Recommendation: A patient should be suspected of having pneumonia when one of the following signs and symptoms are present: new focal chest signs, dyspnoea, tachypnoea, pulse rate >100, fever >4 days. In patients with a suspected pneumonia a test for serum-level of C-reactive protein (CRP) can be done. A CRP level of <20 mg/L at presentation, with symptoms for >24 h, makes the presence of pneumonia highly unlikely, a level of >100 mg/L makes pneumonia likely.
In the case of persisting doubt after CRP testing, a chest X-ray should be considered to confirm or reject the diagno-
[formula] sis [B1]. [/formula]
Two new studies on the diagnostic value of signs, symptoms and CRP [bib_ref] Contributions of symptoms, signs, erythrocyte sedimentation rate, and C-reactive protein to a..., Hopstaken [/bib_ref] [bib_ref] Can history and exam alone reliably predict pneumonia?, Graffelman [/bib_ref] both showed that a combination of signs, symptoms and CRP does have diagnostic value in detecting and mainly ruling out pneumonia. Two new studies on the isolated diagnostic value of CRP confirmed the diagnostic value of CRP [bib_ref] Performance of a bedside C-reactive protein test in the diagnosis of community-acquired..., Flanders [/bib_ref] [bib_ref] Procalcitonin versus C-reactive protein for predicting pneumonia in adults with lower respiratory..., Holm [/bib_ref].
On the other hand, two reviews on the value of CRP in this field conclude that CRP has no clear diagnostic value in primary care. The review by van der Meer et al., however, found excellent positive and negative predictive values, with a ROC curve with area under the curve of 0.80. Falk et al.
concluded in their review that the isolated use of CRP will not be very useful in primary care but state nevertheless in their discussion that when a physician is in doubt about the presence of pneumonia, CRP could be helpful to rule out the disease [bib_ref] C-reactive protein and community-acquired pneumonia in ambulatory care: systematic review of diagnostic..., Falk [/bib_ref].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review To evaluate the diagnostic accuracy of C-reactive protein in detecting radiologically proved pneumonia and to evaluate how well it can discriminate between bacterial and viral infections of the lower respiratory tract.

## Ma
1A?
Graffelman et al. [bib_ref] Can history and exam alone reliably predict pneumonia?, Graffelman [/bib_ref] To assess the diagnostic value of signs, symptoms and CRP in detecting pneumonia

## Pcs 3b+
Holm et al. [bib_ref] Procalcitonin versus C-reactive protein for predicting pneumonia in adults with lower respiratory..., Holm [/bib_ref] To evaluate the diagnostic value of CRP and procalcitonine in detecting pneumonia

## Pcs 3a+
Falk and Fahey [bib_ref] C-reactive protein and community-acquired pneumonia in ambulatory care: systematic review of diagnostic..., Falk [/bib_ref] To One new updated Cochrane review on cough medication concluded that there is no clear benefit from interventionsSome of the studies in this review did report some beneficial effects from expectorants and antitusive agents, but these studies were small and suffered from methodological flaws. The Cochrane review on the use of bronchodilators in acute cough showed no beneficial effects. One new RCT on the effects of inhaled fluticasone in patients with acute cough showed a small effect on symptom severity in the second week of disease. The clinical relevance of this small effect is, however, doubtful [bib_ref] Efficacy of fluticasone on cough: a randomised controlled trial, Ponsioen [/bib_ref].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review Reference Objective Design Evidence
Smith et al.To assess the effects of oral over-the-counter cough preparations for acute cough.

## Ma 1a)
Smucny et al.To determine whether beta2-agonists improve the symptoms of acute bronchitis in patients who do not have underlying pulmonary disease.

## Ma 1a+
Ponsioen et al. [bib_ref] Efficacy of fluticasone on cough: a randomised controlled trial, Ponsioen [/bib_ref] To investigate the short-term effects of an inhaled steroid (fluticasone propionate (FP)) on cough

## Rct 2a+
When should antibiotic treatment be considered in patients with LRTI?
Recommendation: Antibiotic treatment should be prescribed in patients with suspected or definite pneumonia (see How to differentiate between pneumonia and other respiratory tract infections?) [C1]. Antibiotic treatment should be considered for patients with LRTI and serious co-morbidity such as: There is one new update of a Cochrane review on the effects of antibiotics in acute bronchitis, including one large new trial on the effects of antimicrobial therapy: no new conclusions on the overall effects on the average adult patient with acute bronchitis [bib_ref] Information leaflet and antibiotic prescribing strategies for acute lower respiratory tract infection:..., Little [/bib_ref]. Recommendations for subgroups are based on consensus.
Evidence To estimate the effectiveness of three prescribing strategies and an information leaflet for acute lower respiratory tract infection RCT 2A+
SmithTo assess the effects of antibiotic treatment for patients with a clinical diagnosis of acute bronchitis

## Ma 1a+
What are the indications for antibiotic treatment of acute exacerbations of chronic obstructive lung disease (COPD)?
Recommendation: An antibiotic should be given in exacerbations of COPD in patients with all three of the following symptoms: increased dyspnoea, sputum volume and sputum purulence. In addition, antibiotics should be considered for exacerbations in patients with severe COPD [C1]. New information. Recommendation not changed.
A new Cochrane review concluded that antibiotic treatment has beneficial effects in moderately and severely ill patients with increased cough and purulence of sputum. However, the authors state that their conclusions are somewhat weakened by the considerable differences in methodology and settings between studies. The three studies in outpatients indicate that there is only a potentially beneficial effect in patients with three Anthonisen criteria [bib_ref] Antibiotics for exacerbations of chronic obstructive pulmonary disease, Ram [/bib_ref].
Evidence Which antibiotics should be used in patients with LRTI?
Recommendation: Amoxicillin or tetracycline should be used as antibiotic of first choice based on least chance of harm and wide experience in clinical practice. In case of hypersensitivity a tetracycline or macrolide such as azithromycin, clarithromycin, erythromycin or roxithromycin is a good alternative in countries with low pneumococcal macrolide resistance. National/local resistance rates should be considered when choosing a particular antibiotic. When there are clinically relevant bacterial resistance rates against all first-choice agents, treatment with levofloxacin or moxifloxacin may be considered .
No clear preferences between available antibiotics can be given based on short-term benefits or frequency of sideeffects. Clinical trials assessing the effects of antibiotics in primary care do vary considerably both in quality and methods regarding their reports on side-effects and adverse events in subjects. Equally, it is not really possible to compare tendencies to evoke bacterial resistance or rare, but important, side-effects. All available antibiotic agents that are active against respiratory pathogens do cause bacterial resistance. In the following recommendations the newer broad-spectrum antibiotics are reserved for second-choice escape medication when the traditional well-known agents cannot be used. Two new reviews support these recommendations [bib_ref] Antibiotics for community acquired pneumonia in adult outpatients, Bjerre [/bib_ref] [bib_ref] Effectiveness of beta lactam antibiotics compared with antibiotics active against atypical pathogens..., Mills [/bib_ref].
Evidence Most recent publications have shown that the CURB-score and its modifications (particularly CRB-65 score) are comparable to the Pneumonia Severity Index index in terms of prediction of death from pneumonia in both outpatients and inpatients [bib_ref] CRB-65 predicts death from community-acquired pneumonia, Bauer [/bib_ref] [bib_ref] Defining community acquired pneumonia severity on presentation to hospital: an international derivation..., Lim [/bib_ref] [bib_ref] Validation of predictive rules and indices of severity for community acquired pneumonia, Ewig [/bib_ref] [bib_ref] New perspectives on community-acquired pneumonia in 388 406 patients. Results from a..., Ewig [/bib_ref] [bib_ref] Reasons why emergency department providers do not rely on the pneumonia severity..., Aujesky [/bib_ref] [bib_ref] Validation of a predictive rule for the management of community-acquired pneumonia, Capelastegui [/bib_ref] [bib_ref] A prospective comparison of severity scores for identifying patients with severe community..., Buising [/bib_ref] [bib_ref] Prospective comparison of three predictive rules for assessing severity of community-acquired pneumonia..., Man [/bib_ref] [bib_ref] Severity assessment criteria recommended by the British Thoracic Society (BTS) for community-acquired..., Myint [/bib_ref]. Moreover, the CURB-65 has been shown to outperform generic sepsis and early warning scores [bib_ref] The CURB65 pneumonia severity score outperforms generic sepsis and early warning scores..., Barlow [/bib_ref]. In view of its simplicity and the absence of any laboratory and radiographic criterion, which may not be easily available in general practice, the CRB-65 score is recommended as tool of choice in the assessment of pneumonia severity. Systolic blood pressure is the best haemodynamic predictor; diastolic pressure may be neglected [bib_ref] Systolic blood pressure is superior to other haemodynamic predictors of outcome in..., Chalmers [/bib_ref]. The priority of clinical judgement and the need to consider non-clinical factors for decision making about treatment settings is reinforced [bib_ref] Factors associated with the hospitalization of low-risk patients with community-acquired pneumonia in..., Labarere [/bib_ref] [bib_ref] Admission is not always necessary for patients with community-acquired pneumonia in risk..., Marrie [/bib_ref] [bib_ref] Clinical judgment versus the Pneumonia Severity Index in making the admission decision, Seymann [/bib_ref]. In patients residing in nursing homes, a predefined clinical pathway can help to reduce hospitalization by about 50%, with comparable clinical outcomes [bib_ref] Effect of a clinical pathway to reduce hospitalizations in nursing home residents..., Loeb [/bib_ref].
Biomarkers (C-reactive protein (CRP)) [bib_ref] Procalcitonin versus C-reactive protein for predicting pneumonia in adults with lower respiratory..., Holm [/bib_ref] [bib_ref] Comparison of usefulness of plasma procalcitonin and C-reactive protein measurements for estimation..., Hirakata [/bib_ref] [bib_ref] Utility of C-reactive protein in assessing the disease severity and complications of..., Hohenthal [/bib_ref] [bib_ref] Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia, Menendez [/bib_ref] [bib_ref] C-reactive protein, severity of pneumonia and mortality in elderly, hospitalised patients with..., Thiem [/bib_ref] , procalcitonin (PCT) [bib_ref] Procalcitonin versus C-reactive protein for predicting pneumonia in adults with lower respiratory..., Holm [/bib_ref] [bib_ref] Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia, Menendez [/bib_ref] [bib_ref] Procalcitonin and severity of community-acquired pneumonia, Okimoto [/bib_ref] [bib_ref] Pro-atrial natriuretic peptide and pro-vasopressin to predict severity and prognosis in community-acquired..., Kruger [/bib_ref] , D-dimer, carboxy-terminal provasopressin (CT-proAVO, copeptin) [bib_ref] C-terminal provasopressin (copeptin) in patients with community-acquired pneumonia -influence of antibiotic pre-treatment:..., Kruger [/bib_ref] , midregional proatrial natriuretic peptide (MR-pro-ANP) [bib_ref] Pro-atrial natriuretic peptide and pro-vasopressin to predict severity and prognosis in community-acquired..., Kruger [/bib_ref] [bib_ref] Use of B-type natriuretic peptide in the risk stratification of community-acquired pneumonia, Christ-Crain [/bib_ref] [bib_ref] Midregional pro-atrial natriuretic peptide as a prognostic marker in pneumonia, Prat [/bib_ref] , midregional proadrenomedullin (MR-ADM) [bib_ref] Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia, Huang [/bib_ref] , and triggering receptor expressed on myeloid cells (TREM-1) [bib_ref] Prognosis of community acquired pneumonia (CAP): value of triggering receptor expressed on..., Tejera [/bib_ref] , as well as the adrenal response [bib_ref] Free and total cortisol levels as predictors of severity and outcome in..., Christ-Crain [/bib_ref] [bib_ref] Adrenal response in severe community-acquired pneumonia: impact on outcomes and disease severity, Salluh [/bib_ref] , as an alternative or additional tool for the assessment of pneumonia severity, have recently gained much attention. It appears that all of them seem to have a significant potential to predict mortality. Some data suggest that predictive tools and biomarkers do not reflect identical processes and that biomarkers may improve predictions based on clinical parameters [bib_ref] Procalcitonin predicts patients at low risk of death from community-acquired pneumonia across..., Kruger [/bib_ref] [bib_ref] Risk prediction with procalcitonin and clinical rules in community-acquired pneumonia, Huang [/bib_ref]. However, the optimal use of clinical assessment, including severity scores and biomarkers, remains to be established. Currently, CRP and PCT are best available and may be implemented as an additional severity tool; however, the evidence is still limited. Among all biomarkers investigated, pro-ADM seems most promising [bib_ref] Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia, Huang [/bib_ref].
Evidence Admission D-dimer can identify low-risk patients with community-acquired pneumonia PCS 3A+
Christ-Crain et al.Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia PCS 3A+
Christ-Crain et al. [bib_ref] Free and total cortisol levels as predictors of severity and outcome in..., Christ-Crain [/bib_ref] Free and total cortisol levels as predictors of severity and outcome in community-acquired pneumonia PCS 3B+
Christ-Crain et al. [bib_ref] Use of B-type natriuretic peptide in the risk stratification of community-acquired pneumonia, Christ-Crain [/bib_ref] Use of B-type natriuretic peptide in the risk stratification of community-acquired pneumonia PCS 3B+
Hirakata et al. [bib_ref] Comparison of usefulness of plasma procalcitonin and C-reactive protein measurements for estimation..., Hirakata [/bib_ref] Comparison of usefulness of plasma procalcitonin and C-reactive protein measurements for estimation of severity in adults with community-acquired pneumonia RCS 4C)
Hohenthal et al. [bib_ref] Utility of C-reactive protein in assessing the disease severity and complications of..., Hohenthal [/bib_ref] Utility of C-reactive protein in assessing the disease severity and complications of community-acquired pneumonia

## Rcs 4b+
Holm et al. [bib_ref] Procalcitonin versus C-reactive protein for predicting pneumonia in adults with lower respiratory..., Holm [/bib_ref] Procalcitonin vs. C-reactive protein for predicting pneumonia in adults with lower respiratory tract infection in primary care

## Pcs 3b+
Huang et al. [bib_ref] Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia, Huang [/bib_ref] Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia PCS 3A+
Menendez et al. [bib_ref] Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia, Menendez [/bib_ref] Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia

## Pcs 3a+
Okimoto et al. [bib_ref] Procalcitonin and severity of community-acquired pneumonia, Okimoto [/bib_ref] Procalcitonin and severity of community-acquired pneumonia

## Rcs 4c)
Kruger et al. [bib_ref] Pro-atrial natriuretic peptide and pro-vasopressin to predict severity and prognosis in community-acquired..., Kruger [/bib_ref] Pro-atrial natriuretic peptide and pro-vasopressin to predict severity and prognosis in community-acquired pneumonia: results from the German competence network CAPNETZ

## Pcs 3a+
Kruger et al. [bib_ref] Procalcitonin predicts patients at low risk of death from community-acquired pneumonia across..., Kruger [/bib_ref] Procalcitonin The predictive potential of rules for the prediction of ICU admission depends on local facilities. Therefore, it appears that severity criteria should be used to indicate the need for intensive care treatment rather than care in a special unit.
The presence of at least two of systolic blood pressure <90 mmHg, severe respiratory failure (PaO 2 /F I O 2 < 250), involvement of >two lobes on chest radiograph (multilobar involvement), or one of requirement for mechanical ventilation or requirement for vasopressors >4 h (septic shock), indicates severe CAP. Alternatively, the presence of several minor criteria as provided in the last IDSA/ATS update may indicate severe CAP [A3].
Both rules should increase the attention given to the recognition of patients with unstable courses of pneumonia in order to avoid delayed transfer to the ICU.
External validation of the modified ATS rule as well as other rules (e.g. the IDSA/ATS rule [bib_ref] Validation and clinical implications of the IDSA/ATS minor criteria for severe community-acquired..., Phua [/bib_ref] and SMART-COP rule [bib_ref] SMART-COP: a tool for predicting the need for intensive respiratory or vasopressor..., Charles [/bib_ref] [bib_ref] Predicting the need for mechanical ventilation and/or inotropic support for young adults..., Chalmers [/bib_ref] has resulted in two important insights. First, no rule is able to account for all important severity criteria, which could justify ICU admission without substantial loss of specificity. Second, the decision to admit to the ICU is usually not exclusively based on clinical criteria but also depends on the local settings and facilities [bib_ref] SMART-COP: a tool for predicting the need for intensive respiratory or vasopressor..., Charles [/bib_ref] [bib_ref] Validation of the Infectious Disease Society of America/American Thoracic Society 2007 guidelines..., Brown [/bib_ref] [bib_ref] Community-acquired pneumonia requiring admission to an intensive care unit: a descriptive study, Marrie [/bib_ref] [bib_ref] criteria for severe community-acquired pneumonia, Riley [/bib_ref]. Therefore, it appears that criteria for ICU admission should be used as indicators for the need for intensified treatment (i.e. monitoring and treatment for acute respiratory failure and/or severe sepsis) rather than as advice for ICU admission.
Whereas no score has been shown to be consistently superior to others, scores relying on so-called 'minor criteria' should be preferred, at least for clinical use, because they avoid relying on tautological 'major criteria'. Pneumonia severity rules such as CRB-65/CURB-65 and PSI are not useful for identifying patients with severe pneumonia.
In view of a worse prognosis in patients with a delayed transfer to the ICU as compared with direct transfer patients, close monitoring within intensified treatment should be offered to patients at risk of progressive disease. However, there is still a major need for predictors of patients who will deteriorate. The recently developed REA-ICU index still awaits validation in independent cohorts and different settings [bib_ref] Association between timing of intensive care unit admission and outcomes for emergency..., Renaud [/bib_ref]. Currently, close monitoring of patients at risk within intensified treatment is the best measure to identify those patients.
Consecutive measurements of CRP and assessment of oxygenation may be used during follow-up to assess treatment response [bib_ref] Usefulness of consecutive C-reactive protein measurements in follow-up of severe community-acquired pneumonia, Bruns [/bib_ref] [bib_ref] Early evolution of arterial oxygenation in severe community-acquired pneumonia: a prospective observational..., Wu [/bib_ref]. [bib_ref] Community-acquired pneumonia requiring hospitalization: 5-year prospective study, Marrie [/bib_ref] [bib_ref] Sputum gram stain assessment in community-acquired bacteremic pneumonia, Gleckman [/bib_ref] and Haemophilus influenzae in various percentages from 2% to 13%. Other organisms are recovered in diminishing order of frequency from 14% to 2% and 1%: Gram-negative aerobes, streptococci (S. pyogenes and other), Staphylococcus aureus and mixtures of organisms [bib_ref] Community-acquired pneumonia requiring hospitalization: 5-year prospective study, Marrie [/bib_ref]. For most of the latter it is difficult to decide whether they were present in the bloodstream or are skin contaminants.

## Evidence
In a retrospective observational cohort study of 684 hospitalized patients admitted via the Emergency Department for treatment of pneumonia [bib_ref] Selective use of blood cultures in emergency department pneumonia patients, Benenson [/bib_ref] , only 3.4% had true positive blood cultures. Combining the results of this study with six other studies, only 2.2% of >3000 patients had antibiotics changed based on positive blood cultures. This study demonstrates the limited utility of blood cultures in CAP patients. However, it did not include many patients at risk of multidrug-resistant pathogens.
From a systematic review of 15 studies with a total of 3898 adult patients admitted with CAP, it was concluded that blood cultures rarely alter empirical antibiotic therapy, and even when there is a change, it is mostly not likely to impact patient outcome [bib_ref] Blood cultures for community-acquired pneumonia: are they worthy of two quality measures?..., Afshar [/bib_ref]. The findings of this systematic review do not support obtaining blood cultures in all adults hospitalized with CAP.
However, also in this systematic review, most investigations excluded immunocompromized or other high-risk groups, which could have biased results against blood culture utility. It would be prudent therefore not to generalize the findings.
In addition, all 15 studies included in this review were observational. Most did not prospectively require blood cultures in all patients admitted with CAP. Several studies did not explicitly require two sets of blood cultures or that blood cultures be done prior to antibiotics, so they may not have revealed the maximum utility of blood cultures. Methicilin-resistant Staphylococcus aureus (MRSA) previously confined to nosocomial infections has become more prevalent in the community, causing community-associated MRSA infections, including CAP [bib_ref] Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season, Hageman [/bib_ref] [bib_ref] Staphylococcus aureus pneumonia: emergence of MRSA in the community, Bradley [/bib_ref]. During recent years healthy young people without traditional risk factors for S. aureus disease present increasingly with severe MRSA CAP associated with high mortality. Many strains contain toxin and Panton-Valentine leucocidine genes. Specimens including blood cultures should be obtained for diagnostic and antimicrobial drug susceptibility testing in order to target therapy. New information. Recommendation not changed. El Sohl studied nursing home patients requiring mechanical ventilation for suspected pneumonia and evaluated quantitative endotracheal aspirates in comparison with PSB and BAL specimens [bib_ref] Diagnostic yield of quantitative endotracheal aspirates in patients with severe nursing home-acquired..., El Solh [/bib_ref]. This study shows that QEA correlate well with quantitative bronchoscopic PSB and BAL. Diagnostic accuracy was most favourable at 10 4 CFU/mL and may be a reliable alternative to PSB or BAL in patients admitted from nursing homes requiring ventilation when bronchoscopic procedures are not feasible or available. Acceptable sputum specimens can be obtained with some effort from approximately 25% of patients after inhalation of hypertonic saline to induce secretion and cough [bib_ref] Sputum specimens can be obtained from patients with community-acquired pneumonia in primary..., Lagerstrom [/bib_ref].

## Evidence

## Evidence
The value of the Gram stain of acceptable sputum specimens depends on the presence of a predominant bacterial morphotype [bib_ref] Assessment of the usefulness of sputum culture for diagnosis of community-acquired pneumonia..., Garcia-Vazquez [/bib_ref] [bib_ref] Value of intensive diagnostic microbiological investigation in low-and high-risk patients with community-acquired..., Van Der Eerden [/bib_ref] [bib_ref] Diagnostic value of microscopic examination of Gram-stained sputum and sputum cultures in..., Musher [/bib_ref]. In a retrospective cohort study [bib_ref] Sputum examination in the clinical management of community-acquired pneumonia, Signori [/bib_ref] , sputum examination was used as a diagnostic tool in a minority of the patients, without noticeable benefit in the clinical management of CAP inpatients.
The study of Anevlavis is the first reported study to have such an amount of information concerning operating characteristics and the diagnostic value of sputum Gram stain in 1390 patients with bacteraemic CAP [bib_ref] A prospective study of the diagnostic utility of sputum Gram stain in..., Anevlavis [/bib_ref]. The sensitivity of sputum Gram stain was 82% for pneumococcal pneumonia, 76% for staphylococcal pneumonia and 79% for Haemophilus influenzae pneumonia, with specificities ranging from 93% to 96%. Data from this study suggest that a properly collected and read Gram stain provides a simple, readily available, rapid and inexpensive test result and can be a dependable test for the early aetiological diagnosis of bacterial pneumonia in bacteraemic patients.
Infection by Aspergillus spp. can be distinguished from colonization by the presence of hyphae in respiratory specimens but the diagnosis of aspergillosis is still based on the detection of circulating antigens in serum [bib_ref] Significance of Aspergillus fumigatus isolation from respiratory specimens of nongranulocytopenic patients, Uffredi [/bib_ref].
Evidence Recommendation: Culture: a culture from a purulent sputum specimen of a bacterial species compatible with the morphotype observed in the Gram stain, which is processed correctly, should be considered for confirmation of the species identification and antibiotic susceptibility testing .
No new information. Recommendation not changed. Sensitivity and specificity of sputum cultures are reduced by contamination with flora colonizing the upper respiratory tract. The value of sputum cultures in establishing a bacterial cause of LRTI depends on how the specimens are collected and processed and on whether a predominant bacterial morphotype has been observed in the Gram stain.
What can antigen tests offer in the diagnosis of communityacquired pneumonia? Recommendation: The immunochromatographic urinary antigen test for S. pneumoniae should be performed in patients admitted to the hospital for reasons of illness severity. This test should also be considered whenever a pleural fluid sample is obtained in the setting of a parapneumonic effusion [A3].
Urine L. pneumophila serogroup 1 antigen detection should be performed in patients admitted to the hospital for reasons of severity and in other patients where this infection is clinically or epidemiologically suspected [A3]. L. pneumophila serogroup 1 antigen detection in urine is the most rapid method for diagnosing or excluding the infection. A negative test makes legionella unlikely, but does not exclude legionella infection .
The value of the S. pneumoniae urinary antigen test in adults has a sensitivity of 65-100% and a specificity of 94%; however, weak positive results should be interpreted with caution. There is a relationship between the degree of the S. pneumoniae urinary antigen test positivity and the pneumonic severity index [bib_ref] Utility of a pneumonia severity index in the optimization of the diagnostic..., Ortega [/bib_ref]. Therefore and for cost saving, the test could be applied in a sequential manner with reservation of the test for high-risk patients for whom demonstrative results of a sputum Gram stain are unavailable [bib_ref] Evaluation of the immunochromatographic Binax NOW assay for detection of Streptococcus pneumoniae..., Gutierrez [/bib_ref] [bib_ref] Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic..., Smith [/bib_ref] [bib_ref] Rapid urinary antigen test for diagnosis of pneumococcal communityacquired pneumonia in adults, Marcos [/bib_ref] [bib_ref] Contribution of a urinary antigen assay (Binax NOW) to the early diagnosis..., Roson [/bib_ref] [bib_ref] A 3-year prospective study of a urinary antigen-detection test for Streptococcus pneumoniae..., Ishida [/bib_ref] [bib_ref] Comparison of two urinary antigen tests for establishment of pneumococcal etiology of..., Stralin [/bib_ref] [bib_ref] Usefulness of pneumococcal antigen detection in pleural fluid samples by immunochromatographic assay..., Andreo [/bib_ref] [bib_ref] Validation of urinary antigen test for Streptococcus pneumoniae in patients with pneumococcal..., Ercis [/bib_ref] [bib_ref] Analysis of factors that contribute to treatment failure in patients with communityacquired..., Genne [/bib_ref] [bib_ref] Evaluation of the Binax NOW Streptococcus pneumoniae urinary antigen assay in intensive..., Lasocki [/bib_ref]. An S. pneumoniae type specific urinary antigen identifies the serotype involved [bib_ref] Diagnosis of invasive pneumococcal infection by serotype-specific urinary antigen detection, Leeming [/bib_ref].
Also in the prospective cohort study reported by Kobashi the pneumococcal urinary immunochromatographic test (ICT) [bib_ref] Evaluating the use of a Streptococcus pneumoniae urinary antigen detection kit for..., Kobashi [/bib_ref] increased the diagnostic yield for pneumococcal pneumonia in patients with CAP and was particularly useful for diagnosing patients with poor quality sputum in whom antibiotic treatment nevertheless had to be selected. In this study, the authors were able to establish the clinical impact of the rapidity and simplicity of the ICT test for pneumococcal pneumonia. Pneumonia caused by S. pneumoniae also appeared to be treated safely and effectively with high-dose penicillin based on positive results of the urinary antigen test in the retrospective study reported by Oka [bib_ref] The efficacy of high-dose penicillin for community-acquired pneumonia diagnosed by pneumococcal urine..., Oka [/bib_ref]. Even compared with PCR on blood samples the Binax NOW S. pneumonia urinary antigen test is a more sensitive and rapid test for the early diagnosis of bacteraemic pneumococcal pneumonia [bib_ref] Diagnosis of Streptococcus pneumoniae infections in adults with bacteremia and communityacquired pneumonia:..., Smith [/bib_ref]. Persistence of S. pneumoniae antigenuria following diagnosis of pneumococcal pneumonia is normal and can be prolonged, especially if concentrated urine is used [bib_ref] Persistence of Streptococcus pneumoniae urinary antigen excretion after pneumococcal pneumonia, Andreo [/bib_ref].
The effect of pretreatment with antibiotics resulted in contradictory reports: a lower detection rate in one study [bib_ref] Value of intensive diagnostic microbiological investigation in low-and high-risk patients with community-acquired..., Van Der Eerden [/bib_ref] and an increased detection rate if the test is performed 24-48 h after initiation of antibiotic treatment [bib_ref] Antibiotic treatment and the diagnosis of Streptococcus pneumoniae in lower respiratory tract..., Korsgaard [/bib_ref]. The urinary antigen test may also be carried out on pleural fluid with a sensitivity and specificity of 79% and 94%, respectively [bib_ref] Usefulness of pneumococcal antigen detection in pleural fluid samples by immunochromatographic assay..., Andreo [/bib_ref] , and on serum samples with a sensitivity of 50% in bacteraemic patients and 40% in non-bacteraemic patients [bib_ref] Rapid detection of pneumococcal antigen in serum samples for diagnosing pneumococcal pneumonia, Dominguez [/bib_ref]. The ICT test performed on pleural fluid samples augments the standard diagnostic methods of blood and pleural fluid cultures, even in the case of prior antibiotic therapy, and enhances the ICT urinary antigen test: it may provide additional information beyond that obtained by the measurement of urine samples alone and vice versa [bib_ref] Contribution of a pleural antigen assay (Binax NOW) to the diagnosis of..., Porcel [/bib_ref]. Therefore this test should be considered whenever a pleural fluid sample is obtained in the setting of a parapneumonic effusion, particularly when the urinary antigen test is not contributory.
Vaccination does not result in a positive urinary antigen test [bib_ref] Respiratory viral infections in hospital patients with chronic bronchitis. Observations during periods..., Lamy [/bib_ref]. Urinary antigen detection is currently the most helpful rapid test for the diagnosis of Legionella infection. The immunochromatographic format is better suited for single specimens, and produces a result within minutes. In one report different urinary antigen tests have an identical sensitivity [bib_ref] Comparison of three Legionella urinary antigen assays during an outbreak of legionellosis..., Dirven [/bib_ref] ; in a second report the results of the tests differ when performed on unconcentrated urine samples but are identical when performed on concentrated urine specimens [bib_ref] Comparison of diagnostic sensitivities of three assays (Bartels enzyme immunoassay [EIA], Biotest..., Guerrero [/bib_ref]. In the study by Olsen, the Binax test had a significantly higher sensitivity than the Biotest kit both for L. pneumophila serogroup one species and for non-L. pneumophila species or non-serogroup 1 L. pneumophila [bib_ref] Comparison of the sensitivity of the Legionella urinary antigen EIA kits from..., Olsen [/bib_ref]. New Legionella antigen tests have been developed and are becoming available. They show performances comparable to that of the Binax NOW test and could be an alternative for the detection of L. pneumophila antigen in urine from patients suspected of having a Legionella pneumonia [bib_ref] Detection of Legionella antigen in nonconcentrated and concentrated urine samples by a..., Blanco [/bib_ref] [bib_ref] Evaluation of the Oxoid Xpect Legionella test kit for detection of Legionella..., Diederen [/bib_ref].
Since the urinary antigen test has been introduced, early diagnosis and treatment has helped to improve the outcomes and case fatality rate of cases involved in outbreaks of Legionellosis [bib_ref] Impact of the Legionella urinary antigen test on epidemiological trends in community..., Alvarez [/bib_ref].
In Legionella infection there also exists a relationship between the degree of positivity of the urinary antigen test and the severity of the disease [bib_ref] Sensitivity of urinary antigen test in relation to clinical severity in a..., Blazquez [/bib_ref]. A positive result of the urinary antigen test, as demonstrated in the CAPNETZ study [bib_ref] Community-acquired Legionella pneumonia: new insights from the German competence network for community..., Von [/bib_ref] , is associated with a more severe clinical course and leads to a potential relevant under-recognition of species other than L. pneumophila.
Rapid antigen tests on respiratory specimens for the diagnosis of influenza virus infection in adult patients are too insensitive and consequently of limited value for confirming

## E22
Clinical Microbiology and Infection, Volume 17 Supplement 6, November 2011 the diagnosis when influenza is clinically suspected in adults, according to one study [bib_ref] Near-patient assays for diagnosis of influenza virus infection in adult patients, Steininger [/bib_ref]. However, the study by Falsey [bib_ref] Respiratory syncytial virus infection in adults, Falsey [/bib_ref] clearly showed that rapid influenza testing leads to reduction in antibiotic use in hospitalized adults.
Evidence [bib_ref] Evaluation of 12 commercial tests and the complement fixation test for Mycoplasma..., Beersma [/bib_ref] [bib_ref] Analysis of eight commercial enzyme immunoassay tests for detection of antibodies to..., Talkington [/bib_ref] [bib_ref] Evaluation of eight commercial tests for Mycoplasma pneumoniae antibodies in the absence..., Nir-Paz [/bib_ref]. In one study 6/12 and 9/12 of PCR-documented M. pneumoniae infections were diagnosed in acute and convalescent phase sera, respectively [bib_ref] Comparison and evaluation of real-time PCR, real-time nucleic acid sequencebased amplification, conventional..., Templeton [/bib_ref]. In another study anti-M. pneumoniae IgM antibodies were detected in 7-25% (depending on the test applied) of acute sera and IgG antibodies in 41-63% of convalescent sera [bib_ref] Evaluation of 12 commercial tests and the complement fixation test for Mycoplasma..., Beersma [/bib_ref]. Although IgM detection in the acute phase shows a moderate sensitivity, provided a specific test is used, a combination of IgM antibody detection and PCR may be the most sensitive approach to diagnose Mycoplasma pneumoniae infections, as demonstrated in the study by Martinez [bib_ref] Detection of Mycoplasma pneumoniae in adult community-acquired pneumonia by PCR and serology, Martinez [/bib_ref] and in the CAPNETZ study [bib_ref] Mycoplasma pneumoniae pneumonia revisited within the German Competence Network for Community-acquired pneumonia..., Von [/bib_ref]. Also for acute LRTI due to C. pneumoniae a combination of PCR detection and specific single serum IgM measurement seems recommended [bib_ref] Chlamydophila pneumoniae diagnostics: importance of methodology in relation to timing of sampling, Hvidsten [/bib_ref].
Also the recent study on Legionella antibody detection confirms that the diagnosis cannot be based on one serum sample from the patient. As serology based on paired sera in most cases cannot be confirmed until rather late in the course of the disease, it is advisable to use other diagnostic tests in combination with serology [bib_ref] Comparison and evaluation of four commercial kits relative to an in-house immunofluorescence..., Elverdal [/bib_ref]. Comparison and evaluation of four commercial kits relative to an in-house immunofluorescence test for detection of antibodies against Legionella pneumophila

## Evidence

## Rcs 4a+
Are amplification tests useful for the diagnosis of LRTI? Recommendation: Where available, application of quantitative molecular tests for the detection of Streptococcus pneumoniae, both in sputum and in blood, may be valuable in CAP patients in whom antibiotic therapy has been initiated and may be a useful tool for severity assessment Application of molecular tests for the detection of influenza and RSV should be considered during the winter season and for the detection of atypical pathogens, provided the tests are validated and the results can be obtained sufficiently rapidly to be therapeutically relevant [A3]. Qualitative Nucleic Acid Amplification Tests (NAATs) for S. pneumoniae on pleural fluid, peripheral blood or sputum add little to the existing diagnostic tests in sputum and are unable to distinguish colonization from infection.
In a recent prospective study, real-time quantitative PCR (RQ-PCR) was evaluated on sputum samples from patients with CAP admitted to the hospital: the yield from RQ-PCR was almost twice as high as that from sputum culture in patients with proven pneumococcal aetiology. These figures suggest that in hospital-treated CAP patients, sputum PCR is a more sensitive method for detecting S. pneumoniae than sputum culture and the previously chosen cut-off level corresponding to 10 5 CFU/mL is confirmed [bib_ref] Quantitative detection of Streptococcus pneumoniae from sputum samples with real-time quantitative polymerase..., Johansson [/bib_ref]. Especially when antibiotic treatment has been initiated, RQ-PCR, together with urine antigen detection, was the best method for identifying S. pneumoniae.
The detection of S. pneumoniae specific targets by real-time PCR assays, such as Spn9802 or lytA in plasma, is also useful for the rapid detection of bacteraemic pneumococcal pneumonia [bib_ref] Usefulness of real-time PCR for lytA, ply, and Spn9802 on plasma samples..., Abdeldaim [/bib_ref]. Detection of bacterial DNA load in whole blood supports the diagnosis of S. pneumoniae infection in patients with CAP [bib_ref] Streptococcus pneumoniae DNA load in blood as a marker of infection in..., Peters [/bib_ref]. Bacterial load is associated with the likelihood of death, the risk of septic shock, and the need for mechanical ventilation. High genomic bacterial load for S. pneumoniae may be a useful tool for severity assessment [bib_ref] Severity of pneumococcal pneumonia associated with genomic bacterial load, Rello [/bib_ref].
The ompP6-based real-time PCR for the detection of Haemophilus influenzae is both sensitive and specific for the detection of Haemophilus influenzae in respiratory secretions. Quantification facilitates discrimination between disease-causing H. influenzae strains and commensal colonization [bib_ref] Detection of Haemophilus influenzae in respiratory secretions from pneumonia patients by quantitative..., Abdeldaim [/bib_ref].
Quantitative PCR assays have also been shown to be useful in the diagnosis of CAP cases caused by L. pneumophila, although they had lower sensitivity than the urinary antigen test. Both RQ-PCR and antigen testing should be considered complementary in the diagnostic armamentarium for Legionellosis. High bacterial loads determined by RQ-PCR in LRT samples were useful for predicting disease severity, which may be an advantage of these techniques and therefore warrant further investigation [bib_ref] Quantitative real-time PCR tests for diagnostic and prognostic purposes in cases of..., Maurin [/bib_ref].
NAATs for M. pneumoniae, C. pneumoniae, L. pneumophila and B. pertussis, preferably in sputum, have been further validated [bib_ref] Comparison and evaluation of real-time PCR, real-time nucleic acid sequencebased amplification, conventional..., Templeton [/bib_ref] [bib_ref] Sample type is crucial to the diagnosis of Mycoplasma pneumoniae pneumonia by..., Raty [/bib_ref].
The addition of an L. pneumophila-specific PCR to a urinary antigen test is useful in patients with suspected Legionnaires' disease who produce sputum and might allow the early detection of a significant number of additional patients [bib_ref] Utility of real-time PCR for diagnosis of Legionnaires' disease in routine clinical..., Diederen [/bib_ref].
For the detection of M. pneumoniae CAP or LRTI cases, PCR was less sensitive than serology in one study [bib_ref] Detection of Mycoplasma pneumoniae in adult community-acquired pneumonia by PCR and serology, Martinez [/bib_ref] but superior to serology, especially during the early phases of infection, in another study [bib_ref] Polymerase chain reaction is superior to serology for the diagnosis of acute..., Nilsson [/bib_ref]. Data analysis of different studies indicates that no single available test was reliable for the identification of M. pneumoniae in CAP. A combination of serology and PCR proved to be the most reliable approach for identification of M. pneumoniae [bib_ref] Detection of Mycoplasma pneumoniae in adult community-acquired pneumonia by PCR and serology, Martinez [/bib_ref] [bib_ref] Mycoplasma pneumoniae pneumonia revisited within the German Competence Network for Community-acquired pneumonia..., Von [/bib_ref] [bib_ref] Comparison of laboratory diagnostic procedures for detection of Mycoplasma pneumoniae in community..., Thurman [/bib_ref].
Also for acute LRTI caused by C. pneumoniae a combination of PCR detection and specific single serum IgM measurement seems recommended [bib_ref] Chlamydophila pneumoniae diagnostics: importance of methodology in relation to timing of sampling, Hvidsten [/bib_ref].
The use of a Bordetella pertussis specific PCR in combination with single-serum serology [bib_ref] Comparison of serological and real-time PCR assays to diagnose Bordetella pertussis infection..., Andre [/bib_ref] or the combination of culture and PCR increases the sensitivity for pertussis diagnosis [bib_ref] Evaluation of polymerase chain reaction and culture for diagnosis of pertussis in..., Sotir [/bib_ref].

## E24
Clinical Microbiology and Infection, Volume 17 Supplement 6, November 2011
The results of a recent study confirm previous findings that the addition of PCR-based methods to the conventional microbial techniques improves the yield of aetiological agents significantly and indicate that PCR is not only more rapid than conventional methods, but also more sensitive, both in aetiological diagnosis of CAP [bib_ref] Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods, Johansson [/bib_ref] and for the detection of respiratory viruses in LRTI [bib_ref] Development of a respiratory virus panel test for detection of twenty human..., Mahony [/bib_ref] [bib_ref] Increased detection of respiratory syncytial virus, influenza viruses, parainfluenza viruses, and adenoviruses..., Van De Pol [/bib_ref] [bib_ref] Evaluation of multiple test methods for the detection of the novel 2009..., Ginocchio [/bib_ref] [bib_ref] Respiratory syncytial virus outbreak in a long-term care facility detected using reverse..., Caram [/bib_ref] , allowing clinicians to initiate optimal symptomatic treatment and rational use of antibiotics, adequate antiviral therapy where indicated and optimal infection control.
Previously unknown viruses have been discovered: several coronaviruses, human metapneumovirus and bocavirus. They are detected in CAP by NAATs. Reports on infection by a mixture of several viruses or infection by a mixture of viruses and bacteria exist. Systematic comprehensive studies are awaited to define the clinical importance of these viral and mixed infections. Respiratory syncytial virus outbreak in a long-term care facility detected using reverse transcriptase polymerase chain reaction: an argument for real-time detection methods

## Evidence

## Pcs 3a+
What classification should be used for treatment? Recommendation: Antimicrobial treatment has to be empirical and should follow an approach according to the individual risk of mortality. The assessment of severity according to mild, moderate and severe pneumonia implies a decision about the most appropriate treatment setting (ambulatory, hospital ward or ICU) [A4]. Antimicrobial treatment should be initiated as soon as possible [A3]. The guidance for empirical initial antimicrobial treatment should follow three basic considerations and overall ten criteria.
(A) Prognostic assessment (1) The assessment of age: patients aged 65 years are subdivided into those with moderate/good ability and those who are severely disabled. Ideally, this assessment should follow an established score (e.g. ADL score). Roughly, severely disabled patients may be defined as bedridden.
(2) The assessment of general prognosis: patients with pneumonia as an expected terminal event of severe co-morbidity should be managed along principles of palliative medicine.
(B) Assessment of correct grouping (3) Previous hospitalizations and antimicrobial treatment: patients with hospitalizations <3 months ago and those with repeated recent antimicrobial treatments should be classified as nosocomial pneumonia and treated accordingly.
(4) Risk factors for severe immunosuppression (i.e. at risk of opportunistic pathogens): these patients should be managed following the guidelines for immunocompromised patients.
(C) Assessment of factors determining selection of antimicrobial treatment.
(5) Severity: although severity has only a minor impact on microbial patterns, broad combination treatment is mandatory in order to cover all potential pathogens and prevent excess mortality due to treatment failure.
(6) Co-morbidity: co-morbidities may have an independent bearing on potential underlying pathogens.
(7) Residence: nursing home residence as such may not alter microbial patterns. Such risk should be assessed individually.
(8) Aspiration: may be witnessed or suspected; may correspond to gross or silent aspiration.
(9) Regional and local patterns of microbial prevalence and resistance.
(10) Considerations of tolerability and toxicity of antimicrobial agents in the individual patient.
When should antibiotics be administered after diagnosis of pneumonia? Recommendation: Antibiotic treatment should be initiated immediately after diagnosis of CAP [C3]. In patients with CAP and septic shock, delay must not be more than 1 h after diagnosis [A1].
As a consequence of studies suggesting an adverse prognostic effect of delayed antimicrobial treatment, immediate timely administration of antibiotics has been advocated in patients with CAP and suggested as an indicator of quality. Although early antibiotic treatment has been confirmed as advantageous by some authors [bib_ref] Treatment and outcomes for patients with bacteremic pneumococcal pneumonia, Berjohn [/bib_ref] , it has been heavily challenged. Some studies failed to confirm such a disadvantage of delayed antibiotic treatment [bib_ref] Delayed administration of antibiotics and mortality in patients with community-acquired pneumonia 89, Cheng [/bib_ref] [bib_ref] Time for first antibiotic dose is not predictive for the early clinical..., Bruns [/bib_ref] ; others have questioned this practice in view of the questionable feasibility of such a policy [bib_ref] Identification of 90% of patients ultimately diagnosed with community-acquired pneumonia within four..., Fee [/bib_ref] , a high rate of misdiagnosis and overtreatment [bib_ref] Reporting hospitals' antibiotic timing in pneumonia: adverse consequences for patients?, Friedberg [/bib_ref] [bib_ref] Misdiagnosis of community-acquired pneumonia and inappropriate utilization of antibiotics: side effects of..., Kanwar [/bib_ref]. The American Academy of Emergency Medicine recommended that measurement of time to first antibiotic dose in CAP be discontinued [bib_ref] The measurement of time to first antibiotic dose for pneumonia in the..., Pines [/bib_ref]. Not all authors confirm misdiagnosis and overtreatment along with reporting antibiotic timing [bib_ref] Reporting hospitals' antibiotic timing in pneumonia: adverse consequences for patients?, Friedberg [/bib_ref].
A distinct diagnosis of pneumonia seems mandatory before initiation of antibiotic treatment. It appears that the prognostic relevance of antibiotic timing is highest in patients at a higher risk of death. Aminopenicillin  macrolide a,b Aminopenicillin/b-lactamase inhibitor a  macrolide b Non-antipseudomonal cephalosporin Cefotaxime or ceftriaxone  macrolide b Levofloxacin a Moxifloxacin a,c Penicillin G  macrolide a Can be applied as sequential treatment using the same drug. b New macrolides preferred to erythromycin. c Within the fluoroquinolones, moxifloxacin has the highest antipneumococcal activity. In patients at risk of GNEB, particularly strains with ESBL, but without risk (or after exclusion of) of P. aeruginosa, ertapenem may be used.

## Evidence
Several publications have demonstrated that low-level pneumococcal resistance to penicillin is not associated with adverse outcomes in the treatment of patients with community-acquired pneumonia. Resistance to macrolides may be relevant in patients with moderate to severe pneumonia [bib_ref] A case series of macrolide treatment failures in community acquired pneumonia, Iannini [/bib_ref] [bib_ref] Comparison of beta-lactam and macrolide combination therapy versus fluoroquinolone monotherapy in hospitalized..., Rzeszutek [/bib_ref]. Therefore, the choice of antimicrobial agents should be based on considerations of allergy, intolerance, previous use of penicillins, macrolides or quinolones, cost and potential adverse effects rather than pencillin resistance.

## E26
Clinical Microbiology and Infection, Volume 17 Supplement 6, November 2011
Several retrospective studies suggest the superiority of a b-lactam-macrolide combination therapy in hospitalized patients, particularly those with more severe disease [bib_ref] Antibiotics for bacteremic pneumonia: improved outcomes with macrolides but not fluoroquinolones, Metersky [/bib_ref] [bib_ref] Impact of intravenous {beta}-lactam/macrolide versus {beta}-lactam monotherapy on mortality in hospitalized patients..., Tessmer [/bib_ref]. However, definite conclusions cannot be made from the present data [bib_ref] The need for macrolides in hospitalised community-acquired pneumonia: propensity analysis, Paul [/bib_ref]. Therefore, it appears that combination treatment should be restricted to patients with higher risk classes. As a rule of thumb, the more severely the patient presents, the stronger is the recommendation for such combination treatment.
There is a new formulation of amoxicillin-clavulanic acid available (2000/125 instead of 875-1000/125), which offers the advantage of higher penicillin dosing [bib_ref] Efficacy of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2000/125 mg) in..., File [/bib_ref] [bib_ref] The development of pharmacokinetically enhanced amoxicillin/clavulanate for the management of respiratory tract..., File [/bib_ref] [bib_ref] The efficacy and safety of oral pharmacokinetically enhanced amoxycillin-clavulanate 2000/125 mg, twice..., Petitpretz [/bib_ref] [bib_ref] Efficacy and safety of twice-daily pharmacokinetically enhanced amoxicillin/ clavulanate (2000/125 mg) in..., Siquier [/bib_ref]. This may be particularly advantageous in patients with pneumococcal pneumonia resistant (low-level) to penicillin [bib_ref] Efficacy of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2000/125 mg) in..., File [/bib_ref].
Respiratory quinolones are now established treatment options [363, [bib_ref] Tigecycline versus levofloxacin for the treatment of community-acquired pneumonia: European experience, Dartois [/bib_ref] [bib_ref] An open-label, randomized comparison of levofloxacin and amoxicillin/clavulanate plus clarithromycin for the..., Lin [/bib_ref] [bib_ref] Moxifloxacin monotherapy compared to amoxicillin-clavulanate plus roxithromycin for nonsevere community-acquired pneumonia in..., Portier [/bib_ref] [bib_ref] Levofloxacin versus ceftriaxone plus clarithromycin in the treatment of adults with community-acquired..., Querol-Ribelles [/bib_ref] [bib_ref] Fluoroquinolone treatment of community-acquired pneumonia: a meta-analysis, Salkind [/bib_ref] [bib_ref] A comparison of levofloxacin and moxifloxacin use in hospitalized community-acquired pneumonia (CAP)..., Schein [/bib_ref] [bib_ref] Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in..., Tanaseanu [/bib_ref] [bib_ref] Efficacy and safety of tigecycline versus levofloxacin for community-acquired pneumonia, Tanaseanu [/bib_ref] [bib_ref] Effectiveness of oral moxifloxacin in standard first-line therapy in community-acquired pneumonia, Torres [/bib_ref] [bib_ref] Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized..., Vardakas [/bib_ref]. However, the potential small superiority of respiratory quinolones as compared with penicillin and macrolides must be balanced against concerns of selection pressure and cost [bib_ref] Fluoroquinolone treatment of community-acquired pneumonia: a meta-analysis, Salkind [/bib_ref]. Of note, because of the absence of pneumococcal coverage, ciprofloxacin is contraindicated in the treatment of community-acquired pneumonia.
The EMEA has limited the use of oral moxifloxacin. Although it was stated that 'the benefits continue to outweigh its risks', it is stated that it should only be prescribed when other antibiotics cannot be used or have failed. This recommendation was made mainly in view of an increased risk of adverse hepatic reactions. There is no evidence from the literature that moxifloxacin should be considered differently to levofloxacin in this regard. Moreover, there is evidence that liver toxicity is higher in amoxicillin-clavulanic acid than in respiratory quinolones [bib_ref] Safety profile of the respiratory fluoroquinolone moxifloxacin: comparison with other fluoroquinolones and..., Van [/bib_ref].
Two additional agents have been investigated in patients with CAP: tigecycline [bib_ref] Tigecycline versus levofloxacin for the treatment of community-acquired pneumonia: European experience, Dartois [/bib_ref] [bib_ref] Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in..., Tanaseanu [/bib_ref] [bib_ref] Efficacy and safety of tigecycline versus levofloxacin for community-acquired pneumonia, Tanaseanu [/bib_ref] [bib_ref] Safety and efficacy of intravenous tigecycline in treatment of community-acquired pneumonia: results..., Bergallo [/bib_ref] and ertapenem [bib_ref] Ertapenem versus ceftriaxone for the treatment of communityacquired pneumonia in adults: combined..., Ortiz-Ruiz [/bib_ref] [bib_ref] A prospective, randomized, double-blind multicenter comparison of parenteral ertapenem and ceftriaxone for..., Vetter [/bib_ref] [bib_ref] Ertapenem versus cefepime for initial empirical treatment of pneumonia acquired in skilled-care..., Yakovlev [/bib_ref]. However, there are concerns about low serum levels of tigecycline at standard dosage, which might be hazardous in bacteraemic pneumonia. Ertapenem seems to be an attractive choice in patients at risk of Gram-negative enterobacteriaceae (GNEB) infection, particularly with ESBLproducing strains, but not in those at risk of Pseudomonas aeruginosa infection [bib_ref] Outcome of community-acquired pneumonia: influence of age, residence status and antimicrobial treatment, Kothe [/bib_ref] [bib_ref] Clinical response to ertapenem in severe community-acquired pneumonia: a retrospective series in..., Murcia [/bib_ref] [bib_ref] Once-daily cefepime versus ceftriaxone for nursing home-acquired pneumonia, Paladino [/bib_ref] [bib_ref] Community-acquired pneumonia through Enterobacteriaceae and Pseudomonas aeruginosa: diagnosis, incidence and predictors, Von [/bib_ref].
Regular coverage of atypical pathogens may not be necessary in non-severe hospitalized patients [bib_ref] Effectiveness of beta lactam antibiotics compared with antibiotics active against atypical pathogens..., Mills [/bib_ref] [bib_ref] Impact of atypical coverage for patients with community-acquired pneumonia managed on the..., Frei [/bib_ref] [bib_ref] Role of 'atypical pathogens' among adult hospitalized patients with community-acquired pneumonia, Lui [/bib_ref] [bib_ref] Empiric antibiotic coverage of atypical pathogens for community acquired pneumonia in hospitalized..., Shefet [/bib_ref].
Treatment options for patients with severe community-acquired pneumonia [c4] (ICU or intermediate care):

## Recommendation:
No risk factors for P. aeruginosa Non-antipseudomonal cephalosporin III + macrolide a or moxifloxacin or levofloxacin  non-antipseudomonal cephalosporin III Risk factors for P. aeruginosa Antipseudomonal cephalosporin b or acylureidopenicillin/b-lactamase inhibitor or carbapenem (meropenem preferred, up to 6 g possible, 3  2 in 3-h infusion) PLUS Ciprofloxacin c OR PLUS Macrolide a + aminoglycoside (gentamicin, tobramycin or amikacin) a New macrolides preferred to erythromycin. b Ceftazidime has to be combined with penicillin G for coverage of S. pneumoniae. c Levofloxacin 750 mg/24 h or 500 mg twice daily is an alternative and also covers Gram-positive bacteria if treatment is empirical.
No controlled trials are available for patients treated in the ICU or meeting predictive rules for severe CAP.
Combination treatment offers an advantage over monotherapy by expanding the antimicrobial coverage [bib_ref] Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus..., Garcia [/bib_ref] [bib_ref] Monotherapy versus dual therapy for communityacquired pneumonia in hospitalized patients, Martinez [/bib_ref] [bib_ref] Clinical characteristics at initial presentation and impact of dual therapy on the..., Weiss [/bib_ref] and probably by immunomodulation (macrolides, quinolones). Therefore, it should be the treatment of choice. However, respiratory quinolones may be used as monotherapy in severe pneumonia without septic shock [bib_ref] Clinical experience with levofloxacin in the treatment of pneumonia in ICU patients, Alvarez [/bib_ref] [bib_ref] Fullcourse oral levofloxacin for treatment of hospitalized patients with community-acquired pneumonia, Erard [/bib_ref] [bib_ref] Safety and efficacy of sequential i.v. to p.o. moxifloxacin versus conventional combination..., Katz [/bib_ref] [bib_ref] Sequential IV/PO moxifloxacin treatment of patients with severe community-acquired pneumonia, Lode [/bib_ref] [bib_ref] Combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock, Rodriguez [/bib_ref] [bib_ref] Moxifloxacin monotherapy is effective in hospitalized patients with community-acquired pneumonia: the MOTIV..., Torres [/bib_ref] [bib_ref] Costeffectiveness of full-course oral levofloxacin in severe communityacquired pneumonia, Wasserfallen [/bib_ref].
The incidence of CAP through P. aeruginosa seems to be low [bib_ref] Community-acquired pneumonia through Enterobacteriaceae and Pseudomonas aeruginosa: diagnosis, incidence and predictors, Von [/bib_ref]. In patients with risk factors for P. aeruginosa, meropenem offers advantages over imipenem because of the option to increase the dose significantly up to 3  2 g [bib_ref] Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients:..., Romanelli [/bib_ref]. Patients at risk of CAP through P. aeruginosa always should be treated by two antipseudomonal drugs in order to reduce the chance of inadequate treatment. After pathogen isolation and susceptibility testing, combination treatment may be deescalated to monotherapy. Addition of a macrolide to a betalactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteraemic pneumococcal pneumonia

## Evidence

## Rcs 4c)
Romanelli et al. [bib_ref] Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients:..., Romanelli [/bib_ref] Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients: a comparative study against standard therapy

## Pcs 3a+
Rzeszutek et al. [bib_ref] Comparison of beta-lactam and macrolide combination therapy versus fluoroquinolone monotherapy in hospitalized..., Rzeszutek [/bib_ref] A review of clinical failures associated with macrolide-resistant Streptococcus pneumoniae

## Ma 1a+
Shefet et al. [bib_ref] Empiric antibiotic coverage of atypical pathogens for community acquired pneumonia in hospitalized..., Shefet [/bib_ref] Empirical antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults

## Ma 1a+
Wasserfallen et al. [bib_ref] Costeffectiveness of full-course oral levofloxacin in severe communityacquired pneumonia, Wasserfallen [/bib_ref] Cost-effectiveness of full-course oral levofloxacin in severe communityacquired pneumonia

## Rct 2a+
Weiss and Tillotson [bib_ref] The controversy of combination vs monotherapy in the treatment of hospitalized community-acquired..., Weiss [/bib_ref] The controversy of combination vs. monotherapy in the treatment of hospitalized community-acquired pneumonia There is still no convincing evidence that discordant treatment of penicillin-resistant pneumococci negatively affects clinical outcome [bib_ref] Penicillins for treatment of pneumococcal pneumonia: does in vitro resistance really matter?, Peterson [/bib_ref] [bib_ref] Drug-resistant pneumococcal pneumonia: clinical relevance and related factors, Aspa [/bib_ref] [bib_ref] Community-acquired bacteraemic pneumococcal pneumonia in adults: effect of diminished penicillin susceptibility on..., Bonnard [/bib_ref] [bib_ref] Influence of penicillin resistance on outcome in adult patients with invasive pneumococcal..., Falco [/bib_ref] [bib_ref] Prospective observational study of bacteremic pneumococcal pneumonia: effect of discordant therapy on..., Lujan [/bib_ref]. Thus, pencillin may still be used as a targeted treatment in pneumococci resistant up to MIC 4 mg/L.
Recent publications have confirmed that respiratory quinolones, particularly levofloxacin, offer advantages over macrolide treatment for Legionella infection. If a macrolide is used, azithromycin is the preferred drug. The superiority of levofloxacin and azithromycin is most relevant in patients with severe Legionellosis [bib_ref] Azithromycin in the treatment of Legionella pneumonia requiring hospitalization, Plouffe [/bib_ref] [bib_ref] Fluoroquinolones vs macrolides in the treatment of Legionnaires disease, Sabria [/bib_ref] [bib_ref] Levofloxacin efficacy in the treatment of community-acquired legionellosis, Yu [/bib_ref].
Evidence The focus of recent studies dealing with treatment duration has been the assessment of post-discharge outcomes. European authors report a declining duration of hospitalization (and therefore i.v. treatment) [bib_ref] Declining length of hospital stay for pneumonia and postdischarge outcomes, Capelastegui [/bib_ref]. Co-morbidity, particularly cardiopulmonary and neurological conditions, has been associated with rehospitalizations but not treatment failures due to inadequately short (i.v.) treatment duration [bib_ref] Causes and risk factors for rehospitalization of patients hospitalized with community-acquired pneumonia, Jasti [/bib_ref]. On the other hand, ongoing clinical inflammation despite clinical recovery has been described [bib_ref] Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis, Yende [/bib_ref]. However, it is improbable that the level of inflammation can be influenced by prolonged treatment duration.
Most patients with hospitalized non-severe pneumonia are appropriately treated with 7 days of antibiotics. Although there is only one study addressing treatment duration in nosocomial pneumonia, it appears reasonable to believe that treatment duration for severe pneumonia should not be different from nosocomial pneumonia. According to this study, 8 days appears to be comparable to 15 days of treatment. However, in the presence of P. aeruginosa and other non-fermenters, clinicians must be aware of an increased risk of relapses [bib_ref] Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia..., Chastre [/bib_ref].
Recently, biomarkers have been described as useful tools to safely reduce antibiotic treatment duration. Biomarkers can guide treatment duration by the application of predefined stopping rules for antibiotics [bib_ref] Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial, Christ-Crain [/bib_ref] [bib_ref] Antibiotic treatment interruption of suspected lower respiratory tract infections based on a..., Kristoffersen [/bib_ref] [bib_ref] Effect of procalcitoninbased guidelines vs standard guidelines on antibiotic use in lower..., Schuetz [/bib_ref]. It has been shown that such rules work even in most severe cases, including pneumonia with septic shock, and even if clinicians are allowed to overrule the predefined stopping rule [bib_ref] Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care..., Bouadma [/bib_ref] [bib_ref] Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a..., Nobre [/bib_ref]. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial

## Evidence

## Rct 2b+
El Moussaoui et al. [bib_ref] Effectiveness of discontinuing antibiotic treatment after three days versus eight days in..., El Moussaoui [/bib_ref] Comparison of 3 days with 8 days of intravenous amoxicillin

## Rct 2a+
Jasti et al. [bib_ref] Causes and risk factors for rehospitalization of patients hospitalized with community-acquired pneumonia, Jasti [/bib_ref] Causes and risk factors for rehospitalization of patients hospitalized with community-acquired pneumonia

## Pcs 3a+
Kristoffersen et al. [bib_ref] Antibiotic treatment interruption of suspected lower respiratory tract infections based on a..., Kristoffersen [/bib_ref] Antibiotic treatment interruption of suspected lower respiratory tract infections based on a single procalcitonin measurement at hospital admission-a randomized trial

## Rct 2a+
Nobre et al. [bib_ref] Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a..., Nobre [/bib_ref] Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial

## Rct 2a+
Schuetz et al. [bib_ref] Effect of procalcitoninbased guidelines vs standard guidelines on antibiotic use in lower..., Schuetz [/bib_ref] Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial

## Rct 2a+
Yende et al. [bib_ref] Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis, Yende [/bib_ref] Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis

## Pcs 3a+
When should i.v. treatment be used and when should the switch to oral occur? Recommendation: In ambulatory pneumonia, treatment can be applied orally from the beginning [A3]. Some carefully selected hospital inpatients may also be candidates for exclusively oral treatment.
In hospitalized patients, sequential treatment should be considered in all patients except the most severely ill. The optimal time to switch to oral treatment is also unknown; this decision should be guided by the resolution of the most prominent clinical features at admission [A3]. In most patients it is probably not necessary to observe patients in hospital after having switched to oral treatment [A3]. Switch to oral treatment after reaching clinical stability is also safe in patients with severe pneumonia [A2].
The efficacy and safety of early switch therapy has been confirmed by several studies and meta-analyses [bib_ref] Early switch to oral treatment in patients with moderate to severe communityacquired..., Athanassa [/bib_ref] [bib_ref] Early switch to oral antibiotics and early discharge guidelines in the management..., Lee [/bib_ref]. Hospitalized patients with non-severe pneumonia, no sepsis and no reason for impaired intestinal absorption are candidates for oral treatment from the beginning [bib_ref] Efficacy of exclusively oral antibiotic therapy in patients hospitalized with nonsevere community-acquired..., Marras [/bib_ref]. Switch therapy is safe and may be guided by an algorithm [bib_ref] Evaluation of an algorithm for switching from IV to PO therapy in..., Van Der Eerden [/bib_ref] or pathway [bib_ref] Implication of clinical pathway care for community-acquired pneumonia in a community hospital:..., Shindo [/bib_ref]. The routine practice of in-hospital observation after the switch from i.v. to oral antibiotics for patients with CAP may be avoided [bib_ref] Weingarten SR. In-hospital observation after antibiotic switch in pneumonia: a national evaluation, Nathan [/bib_ref]. Also in patients with severe pneumonia, switch to oral antimicrobial treatment after 3 days of intravenous treatment and treatment response is safe [bib_ref] Effectiveness of early switch from intravenous to oral antibiotics in severe community..., Oosterheert [/bib_ref].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review Reference Objective Design Evidence
Athanassa et al. [bib_ref] Early switch to oral treatment in patients with moderate to severe communityacquired..., Athanassa [/bib_ref] Early switch to oral treatment in patients with moderate to severe communityacquired pneumonia: a meta-analysis

## Ma 1a+
Lee and Lindstrom [bib_ref] Early switch to oral antibiotics and early discharge guidelines in the management..., Lee [/bib_ref] Early switch to oral antibiotics and early discharge guidelines in the management of community-acquired pneumonia

## Pcs 3b+
Marras et al. [bib_ref] Efficacy of exclusively oral antibiotic therapy in patients hospitalized with nonsevere community-acquired..., Marras [/bib_ref] Efficacy of exclusively oral antibiotic therapy in patients hospitalized with non-severe community-acquired pneumonia: a retrospective study and meta-analysis
[formula] RCS + MA 4B + 1B+ [/formula]
Nathan et al. [bib_ref] Weingarten SR. In-hospital observation after antibiotic switch in pneumonia: a national evaluation, Nathan [/bib_ref] In-hospital observation after antibiotic switch in pneumonia: a national evaluation. The treatment of severe sepsis and septic shock is confined to supportive measures [A3].
Steroids are not recommended in the treatment of pneumonia [A3].
Early mobilization has been shown to be associated with better outcome. For the purpose of the study, early mobilization was defined as movement out of bed with change from horizontal to upright position for at least 20 min during the first 24 h of hospitalization, with progressive movement each subsequent day during hospitalization [bib_ref] Early mobilization of patients hospitalized with community-acquired pneumonia, Mundy [/bib_ref].
Several studies indicate that non-invasive ventilation (NIV) may also work in patients with pneumonia, particularly in patients with COPD [bib_ref] Acute respiratory failure in patients with severe community-acquired pneumonia. A prospective randomized..., Confalonieri [/bib_ref] [bib_ref] Noninvasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial, Ferrer [/bib_ref]. Non-invasive ventilation has been shown to reduce intubation in patients with ARDS in 54% of treated cases [bib_ref] A multiple-center survey on the use in clinical practice of noninvasive ventilation..., Antonelli [/bib_ref]. It may be feasible and also effective in do-not-intubate patients [bib_ref] Non-invasive ventilation in do-not-intubate patients: five-year follow-up on a two-year prospective, consecutive..., Bulow [/bib_ref] and, therefore, may be an option even in palliative care.
Despite one promising controlled trial [bib_ref] Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study, Confalonieri [/bib_ref] , two metaanalyses show that at present steroids cannot be recommended in the treatment of patients with CAP [bib_ref] Corticosteroid treatment of severe community-acquired pneumonia, Gorman [/bib_ref] [bib_ref] The role of corticosteroids in severe communityacquired pneumonia: a systematic review, Salluh [/bib_ref].
One meta-analysis failed to find an effect for the following interventions: activated protein C, non-invasive mechanical ventilation, anticoagulants, immunoglobulin, granulocyte-colony-stimulating factor, statins, probiotics, chest physiotherapy, antiplatelet drugs, over-the-counter cough medications, beta(2)-agonists, inhaled nitric oxide and angiotensin-converting enzyme inhibitors [bib_ref] Adjunctive therapies for community-acquired pneumonia: a systematic review, Siempos [/bib_ref].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review Reference Objective Design Evidence
Antonelli et al. [bib_ref] A multiple-center survey on the use in clinical practice of noninvasive ventilation..., Antonelli [/bib_ref] A multiple-centre survey on the use in clinical practice of non-invasive ventilation as a first-line intervention for acute respiratory distress syndrome

## Pcs 3a+
Bulow and Thorsager [bib_ref] Non-invasive ventilation in do-not-intubate patients: five-year follow-up on a two-year prospective, consecutive..., Bulow [/bib_ref] Non-invasive ventilation in do-not-intubate patients: 5-year follow-up on a 2-year prospective, consecutive cohort study

## Rcs 4b+
Confalonieri et al. [bib_ref] Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study, Confalonieri [/bib_ref] Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study RCT 2C)
Confalonieri et al. [bib_ref] Acute respiratory failure in patients with severe community-acquired pneumonia. A prospective randomized..., Confalonieri [/bib_ref] Acute respiratory failure in patients with severe community-acquired pneumonia. A prospective randomized evaluation of non-invasive ventilation

## Rct 2b+
Ferrer et al. [bib_ref] Noninvasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial, Ferrer [/bib_ref] Non-invasive ventilation in severe hypoxaemic respiratory failure: a randomized clinical trial

## Rct 2b+
Gorman et al. [bib_ref] Corticosteroid treatment of severe community-acquired pneumonia, Gorman [/bib_ref] Corticosteroid treatment of severe community-acquired pneumonia.

## Ma 1a+
Mundy et al. [bib_ref] Early mobilization of patients hospitalized with community-acquired pneumonia, Mundy [/bib_ref] Early mobilization of patients hospitalized with community-acquired pneumonia. The role of corticosteroids in severe community-acquired pneumonia: a systematic review

## Ma 1a+
Siempos et al. [bib_ref] Adjunctive therapies for community-acquired pneumonia: a systematic review, Siempos [/bib_ref] Adjunctive therapies for communityacquired pneumonia: a systematic review

## Ma 1a+
When should aspiration pneumonia be suspected? Recommendation: There is no agreed definition. Aspiration pneumonia should be suspected in those with CAP which either:
1 follows an episode of witnessed aspiration; or 2 occurs in the presence of risk factors for aspiration, including reduced consciousness level and dysphagia due to mechanical or neurological upper digestive tract dysfunction [C3].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review), RCT, randomized controlled trial, PCS, prospective cohort study, RCS, retrospective cohort study, CCS, case-control study, CSS, cross-sectional study, SR, systematic review To compare features of aspiration pneumonia (AP) with aspiration pneumonitis

## Rcs 4a+
Reza et al. [bib_ref] Differences in the features of aspiration pneumonia according to site of acquisition:..., Reza [/bib_ref] To compare features of AP in patients from long-term care facilities and the community

## Rcs 4a+
Teramoto et al. [bib_ref] High incidence of aspiration pneumonia in community-and hospitalacquired pneumonia in hospitalized patients:..., Teramoto [/bib_ref] To identify frequency of aspiration pneumonia in hospitalized adults with CAP PCS 3B?
What empirical antibiotic treatment is recommended for aspiration pneumonia? Recommendation: Studies (mainly of clindamycin vs. a comparator antibiotic) have mainly included only small numbers of patients (<40 per treatment arm) and do not reach consistent conclusions regarding the superiority of one antibiotic regime over another [bib_ref] Reappraisal of clindamycin IV monotherapy for treatment of mild-to-moderate aspiration pneumonia in..., Kadowaki [/bib_ref] [bib_ref] Ampicillin + sulbactam vs clindamycin +/) cephalosporin for the treatment of aspiration..., Allewelt [/bib_ref] [bib_ref] Treatment of aspiration pneumonia and primary lung abscess. Penicillin G vs clindamycin, Bartlett [/bib_ref] [bib_ref] Efficacy and safety of sequential amoxicillin-clavulanate in the treatment of anaerobic lung..., Fernandez-Sabe [/bib_ref] [bib_ref] Clindamycin vs penicillin for anaerobic lung infections. High rate of penicillin failures..., Gudiol [/bib_ref] [bib_ref] Metronidazole vs clindamycin treatment of anerobic pulmonary infection. Failure of metronidazole therapy, Perlino [/bib_ref]. In one larger open RCT, clinical response was identical in those treated with moxifloxacin and those treated with ampicillin-sulbactam, but a significant difference could have been missed due to lack of blinding and because target recruitment was not achieved [bib_ref] Moxifloxacin vs ampicillin/sulbactam in aspiration pneumonia and primary lung abscess, Ott [/bib_ref]. Our recommendation is based on knowledge of likely causative pathogens [bib_ref] Microbiology of severe aspiration pneumonia in institutionalized elderly, El-Solh [/bib_ref] [bib_ref] Community-acquired aspiration pneumonia in intensive care units. Epidemiological and prognosis data, Leroy [/bib_ref] [bib_ref] Is penicillin G an adequate initial treatment for aspiration pneumonia? A prospective..., Mier [/bib_ref] and the antibiotic regimes used in these studies.
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review Repeated daily measurement of the PSI found a rising PSI to be related to mortality in one study, but is not practical in routine practice [bib_ref] Repeated pneumonia severity index measurement after admission increases its predictive value for..., Chen [/bib_ref].
A number of studies have used C-reactive protein levels on admission [bib_ref] Markers of treatment failure in hospitalised community acquired pneumonia, Menendez [/bib_ref] and repeated measurements after admission, both for all admissions [bib_ref] Utility of C-reactive protein in assessing the disease severity and complications of..., Hohenthal [/bib_ref] [bib_ref] Usefulness of consecutive C-reactive protein measurements in follow-up of severe community-acquired pneumonia, Bruns [/bib_ref] [bib_ref] Markers of treatment failure in hospitalised community acquired pneumonia, Menendez [/bib_ref] [bib_ref] C-reactive protein is an independent predictor of severity in community-acquired pneumonia, Chalmers [/bib_ref] and those admitted to the ICU [bib_ref] Usefulness of C-reactive protein in monitoring the severe community-acquired pneumonia clinical course, Coelho [/bib_ref] , to predict clinical outcome. Measurement of CRP on day 3 [bib_ref] Usefulness of consecutive C-reactive protein measurements in follow-up of severe community-acquired pneumonia, Bruns [/bib_ref] [bib_ref] Markers of treatment failure in hospitalised community acquired pneumonia, Menendez [/bib_ref] or day 4 [bib_ref] Utility of C-reactive protein in assessing the disease severity and complications of..., Hohenthal [/bib_ref] [bib_ref] C-reactive protein is an independent predictor of severity in community-acquired pneumonia, Chalmers [/bib_ref] appears to be most useful. Failure of CRP to fall by 50% by day 4 was associated with fivefold increase in mortality, ventilation and complications [bib_ref] C-reactive protein is an independent predictor of severity in community-acquired pneumonia, Chalmers [/bib_ref].
Procalcitonin may also be useful but has not been sufficiently studied to make a recommendation [bib_ref] Markers of treatment failure in hospitalised community acquired pneumonia, Menendez [/bib_ref].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review Reference Objective Design Evidence
Bruns et al. [bib_ref] Usefulness of consecutive C-reactive protein measurements in follow-up of severe community-acquired pneumonia, Bruns [/bib_ref] To study relation between day 3 and 7 CRP levels and inappropriate antibiotic therapy

## Pcs 3c+
Chalmers et al. [bib_ref] C-reactive protein is an independent predictor of severity in community-acquired pneumonia, Chalmers [/bib_ref] To study CRP as severity predictor in CAP PCS 3A+
Chen et al. [bib_ref] Repeated pneumonia severity index measurement after admission increases its predictive value for..., Chen [/bib_ref] To assess value of repeated PSI measurement as mortality predictor

## Pcs 3a+
Coelho et al. [bib_ref] Usefulness of C-reactive protein in monitoring the severe community-acquired pneumonia clinical course, Coelho [/bib_ref] To study relationship between CRP and clinical course of CAP on the ICU

## Pcs 3a+
Hohenthal et al. [bib_ref] Utility of C-reactive protein in assessing the disease severity and complications of..., Hohenthal [/bib_ref] To study relationship between daily CRP and complications in CAP PCS 3A+
Menendez et al. [bib_ref] Markers of treatment failure in hospitalised community acquired pneumonia, Menendez [/bib_ref] Study of relationship between cytokines and treatment failure

## Pcs 3a+
How should the non-responding patient be assessed? Recommendation: Two types of treatment failures, nonresponding pneumonia and slowly resolving pneumonia, should be differentiated [A3]. Non-responding pneumonia occurring in the first 72 h of admission is usually due to antimicrobial resistance or an unusually virulent organism or a host defence defect. Non-response after 72 h is usually due to a complication. The evaluation of non-responding pneumonia depends on the clinical condition. There are no trials of different approaches to the non-responding patient to guide this recommendation. In unstable patients, full reinvestigation followed by a second empirical antimicrobial treatment regimen should be carried out. The latter may be withheld in stable patients. Slowly resolving pneumonia should be reinvestigated according to clinical needs, the condition of the patient and his/her individual risk factors [C3].

## Exacerbations of chronic obstructive pulmonary disease
Which hospitalized patients with COPD exacerbations should receive antibiotics? Recommendation: Fever is not observed in 30% of exacerbations [bib_ref] Prevalence and clinical significance of fever in acute exacerbations of chronic obstructive..., Lieberman [/bib_ref]. The relationship between purulence and bacterial growth is confirmed in one study [bib_ref] Sputum color as a marker of acute bacterial exacerbations of chronic obstructive..., Allegra [/bib_ref]. In addition, a bronchoscopic study found that referred purulence by the patient had a sensitivity of 89.5%, a specificity of 76%, a predictive positive value of 77% and a negative predictive value of 89% to detect bacteria in protected specimen brush bronchoscopic samples in COPD hospitalized patients with exacerbation [bib_ref] Bronchoscopic validation of the significance of sputum purulence in severe exacerbations of..., Soler [/bib_ref].
However, small studies found a weak association between sputum purulence and bacterial load [bib_ref] Relation of sputum colour to bacterial load in acute exacerbations of COPD, Brusse-Keizer [/bib_ref] or bacterial growth [bib_ref] Indicators of bacterial infection in patients with acute exacerbation of chronic bronchitis..., Burley [/bib_ref]. In this later study Gram stain of sputum was the best indicator of bacterial infection. Randomized-controlled trials are needed to clarify which COPD exacerbated patients requiring hospitalization would benefit from antibiotics. Biomarkers such as procalcitonin may help to detect those exacerbations requiring antibiotics but the information available comes from a single-centre randomized study [bib_ref] Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance..., Stolz [/bib_ref].
In one case-control study of AECOPD, viruses were found in an important percentage of AECOPD patients requiring hospitalization [bib_ref] Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a..., Rohde [/bib_ref]. In one study focusing on Mycoplasma pneumoniae, this microorganism was involved in 32% of hospitalizations [bib_ref] Serological evidence of Mycoplasma pneumoniae infection in acute exacerbation of COPD, Lieberman [/bib_ref].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review Reference Objective Design Evidence Allegra et al. [bib_ref] Sputum color as a marker of acute bacterial exacerbations of chronic obstructive..., Allegra [/bib_ref] To study the relationship between objective purulence and the presence of bacteria

## Pcs 3b+
Lieberman et al. [bib_ref] Prevalence and clinical significance of fever in acute exacerbations of chronic obstructive..., Lieberman [/bib_ref] To study the frequency of fever in exacerbations PCS 3C+
Rohde et al. [bib_ref] Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a..., Rohde [/bib_ref] A case control study to investigate the role of different viruses on acute exacerbations of chronic obstructive pulmonary disease (AECOPD)

## Ccs 3c+
Lieberman et al. [bib_ref] Serological evidence of Mycoplasma pneumoniae infection in acute exacerbation of COPD, Lieberman [/bib_ref] To study the role of Mycoplasma pneumoniae in hospitalized patients with AECOPD

## Pcs 2c+
Soler et al. [bib_ref] Bronchoscopic validation of the significance of sputum purulence in severe exacerbations of..., Soler [/bib_ref] To study the association between purulence and bacterial bronchoscopic samples

## Pcs 3a+
Brusse-Keizer et al. [bib_ref] Relation of sputum colour to bacterial load in acute exacerbations of COPD, Brusse-Keizer [/bib_ref] To study the association between sputum colour and sputum bacterial load
[formula] PCS 3C) [/formula]
Burley et al. [bib_ref] Indicators of bacterial infection in patients with acute exacerbation of chronic bronchitis..., Burley [/bib_ref] To study the association between symptoms and Gram stain and sputum bacterial growth

## Pcs 3b+
Stolz et al. [bib_ref] Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance..., Stolz [/bib_ref] To study the value of procalcitonin to decrease the use of antibiotics in exacerbated COPD

## Rct 2a+
What stratification of patients with COPD exacerbation is recommended in order to direct treatment? Recommendation: New information. Recommendation reworded, but not changed. It is confirmed that P. aeruginosa is associated with a small percentage of exacerbations that need hospitalization [bib_ref] Bacterial infections in patients requiring admission for an acute exacerbation of COPD;..., Groenewegen [/bib_ref] [bib_ref] Sputum bacteriology in patients with acute exacerbations of COPD in Hong Kong, Ko [/bib_ref]. P. aeruginosa exacerbations seem to be independent of the bronchial bacterial load [bib_ref] Microbiologic determinants of exacerbation in chronic obstructive pulmonary disease, Rosell [/bib_ref]. P. aeruginosa represented the 17% of isolated microorganisms in 328 out of 494 episodes in Taiwan. The isolation of P. aeruginosa was associated with poorer outcome [bib_ref] Sputum bacteriology in hospitalized patients with acute exacerbation of chronic obstructive pulmonary..., Lin [/bib_ref]. In a case-control study the isolation of multidrug-resistant microorganisms in AECOPD, including P. aeruginosa, was associated with higher mortality [bib_ref] Mortality of COPD patients infected with multi-resistant Pseudomonas aeruginosa: a case and..., Montero [/bib_ref].
Evidence To study bacterial infections in COPD exacerbated patients that need hospitalization

## Pcs 3c+
Ko et al. [bib_ref] Sputum bacteriology in patients with acute exacerbations of COPD in Hong Kong, Ko [/bib_ref] To study sputum microbiology in AECOPD

## Pcs 4c+
Rosell et al. [bib_ref] Microbiologic determinants of exacerbation in chronic obstructive pulmonary disease, Rosell [/bib_ref] To study the microbiological determinants of AECOPD

## Ma 1a+
Lin et al. [bib_ref] Sputum bacteriology in hospitalized patients with acute exacerbation of chronic obstructive pulmonary..., Lin [/bib_ref] To study the microbiology of AECOPD

## Pcs 3b+
Montero et al. [bib_ref] Mortality of COPD patients infected with multi-resistant Pseudomonas aeruginosa: a case and..., Montero [/bib_ref] To study the association between multi-resistant P. aeruginosa and outcome of AECOPD

## Ccs 4b+
What are the risk factors for P. aeruginosa? Recommendation: P. aeruginosa should be considered in the presence of at least two of the following. One study has investigated [bib_ref] Bacterial infection in exacerbated COPD with changes in sputum characteristics, Monso [/bib_ref] the risk factors for P. aeruginosa. Prior use of antibiotics was a risk factor for P. aeruginosa infection (OR 6.06). Influenza vaccination was a protective factor (OR 0.15). We do not know the negative predictive value of this finding. A study of 193 patients with acute exacerbation identified the following variables as independent predictors of Gram-negative bacilli and P. aeruginosa infection: FEV 1 < 35% of predicted value, systemic steroid use and prior antibiotic therapy within the preceding 3 months. The negative predictive value of this rule was 89% [bib_ref] A prediction model for bacterial etiology in acute exacerbations of COPD, Lode [/bib_ref]. A recent study from Garcia Vidal et al. [bib_ref] Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation: a prospective study, Garcia-Vidal [/bib_ref] found that the risk factors for P. aeruginosa in the initial sputum were the BODE index, admissions in the previous year, systemic steroid treatment and previous isolation of P. aeruginosa. However, in a very large retrospective study P. aeruginosa was found independently of the severity (uncomplicated AE-COPD vs. complicated AECOPD; 6% vs. 9.4%) [bib_ref] Study entry microbiology in patients with acute bacterial exacerbation of chronic bronchitis..., Kahn [/bib_ref].
Despite the fact that recommendations for treating Pseudomonas aeruginosa remain unchanged in these guidelines, some members of the panel disagreed about covering Pseudomonas aeruginosa as initial empirical treatment in patients at risk. The rationale behind this disagreement lies in the studies that consider that P. aeruginosa is a colonizer and not a pathogen.
Evidence To study the risk factors for bacterial exacerbations

## Pcs 3c+
Lode et al. [bib_ref] A prediction model for bacterial etiology in acute exacerbations of COPD, Lode [/bib_ref] To study the risk factors for bacterial aetiology in AECOPD PCS 3B+
Garcia-Vidal et al. [bib_ref] Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation: a prospective study, Garcia-Vidal [/bib_ref] To study the risk factors for P. aeruginosa isolation in AECOPD

## Pcs 3b+
Kahn et al. [bib_ref] Study entry microbiology in patients with acute bacterial exacerbation of chronic bronchitis..., Kahn [/bib_ref] To study the entry microbiological criteria in antibiotic trials of AECOPD

## Rct 4b+
Which microbiological investigations are recommended for the hospitalized patient with COPD exacerbation? Recommendation: Sputum cultures or endotracheal aspirates (in mechanically ventilated patients) should be obtained and are a good alternative to bronchoscopic procedures for evaluation of the bacterial burden by potential pathogenic microorganisms [A3]. Recommendation modified.
Is there new information about pathogens associated with COPD? Most bacterial isolates from patients with COPD are Streptococcus pneumoniae and Haemophilus influenzae, but Moraxella catarrhalis has recently been shown to be associated with approximately 10% of all exacerbations of COPD [bib_ref] Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune..., Murphy [/bib_ref]. In the case of H. influenzae, it is now clear that patients can be colonized by an identical strain of H. influenzae over extended periods of time despite intermittent cultures being negative for the colonizing (or any other) H. influenzae strain [bib_ref] Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease, Murphy [/bib_ref]. Over the course of the lifetime of a COPD patient, the flora associated with exacerbations does change. In severe cases with FEV 1 < 50% of normal, Gram-negative flora, including P. aeruginosa, become increasingly important as associated pathogens [bib_ref] Sputum color as a marker of acute bacterial exacerbations of chronic obstructive..., Allegra [/bib_ref]. Acquisition of a new strain of P. aeruginosa is associated with exacerbations [bib_ref] Pseudomonas aeruginosa in chronic obstructive pulmonary disease, Murphy [/bib_ref] [bib_ref] Sputum color as a marker of acute bacterial exacerbations of chronic obstructive..., Allegra [/bib_ref].
Is there a causal relationship between infections and exacerbations of COPD? Purulent sputum is almost always associated with significantly positive cultures [bib_ref] Sputum color as a marker of acute bacterial exacerbations of chronic obstructive..., Allegra [/bib_ref]. A causal relationship between infections and exacerbations of COPD has not been established but the association between the two is very strong. In a prospective analysis of COPD patients with exacerbations requiring hospitalization, Papi et al. [bib_ref] Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations, Papi [/bib_ref] showed that the frequency of isolation from sputum of bacteria and viruses was much higher during exacerbations than during stable periods, and that eosinophilia within sputum was higher in viral infections. Furthermore, in a longitudinal study of bacterial load in sputum amongst patients with COPD, the FEV 1 decline was mirrored by an increase in sputum bacterial load [bib_ref] Airway bacterial load and FEV1 decline in patients with chronic obstructive pulmonary..., Wilkinson [/bib_ref]. A recent detailed longitudinal study found that quantitative counts of established sputum flora do not greatly change between stable and exacerbation periods in COPD patients [bib_ref] Airway bacterial concentrations and exacerbations of chronic obstructive pulmonary disease, Sethi [/bib_ref]. Sethi et al. [bib_ref] Strain-specific immune response to Haemophilus influenzae in chronic obstructive pulmonary disease, Sethi [/bib_ref] have demonstrated that during exacerbations of COPD caused by H. influenzae there is a specific immune response to the infecting strain of H. influenzae.
Does PSI sampling increase the diagnostic yield over other respiratory tract samples? In patients with cystic fibrosis, PSI sampling does not increase the culturable yield of P. aeruginosa over regular sputum sampling [bib_ref] Sputum versus bronchoscopy for diagnosis of Pseudomonas aeruginosa biofilms in cystic fibrosis, Aaron [/bib_ref].
Evidence Oral gemifloxacin and levofloxacin (750 mg/24 h) over 5 days may be used to effectively treat AECOPD patients that require hospitalization [bib_ref] Oral gemifloxacin once daily for 5 days compared with sequential therapy with..., Wilson [/bib_ref] [bib_ref] Patient stratification in the management of acute bacterial exacerbation of chronic bronchitis:..., Martinez [/bib_ref]. This information comes from two randomized clinical trials that compare these two quinolones with standard treatments (10 days) in hospitalized and non-hospitalized patients with AECB.
A meta-analysis of randomized controlled-trials (including six studies on hospitalized AECOPD patients), comparing what they called first-line (amoxicillin, ampicillin, trimetroprim-sulphamethoxazol) with second-line antibiotics (amoxicillin-clavulanic acid, macrolides, second-or third-generation cephalosporins) for AECOPD, showed that first-line antibiotics were associated with lower treatment success compared with second-line antibiotics (mainly macrolides and amoxicillin-clavulanate; OR., 0.51) [bib_ref] Comparison of first-line with second-line antibiotics for acute exacerbations of chronic bronchitis:..., Dimopoulos [/bib_ref] New information. Recommendation not changed. The combination of ciprofloxacin and inhaled tobramycin may improve microbiological and clinical outcome. However, in 50% of patients treated with inhaled tobramycin wheezing was observed [bib_ref] Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa..., Bilton [/bib_ref].
Prolonged antibiotic therapy has shown small benefit in modifying the outcome of purulent bronchiectasis [bib_ref] Prolonged antibiotics for purulent bronchiectasis, Evans [/bib_ref] [B2].
What antibiotics are recommended for exacerbations of bronchiectasis? . The risk of P. aeruginosa infection should be considered. No validated risk factors are available; however, risk appears to be related to recent antibiotic therapy or hospitalization, serious disease or prior isolation of Pseudomonas species [bib_ref] Bacterial colonisation in patients with bronchiectasis: microbiological pattern and risk factors, Angrill [/bib_ref] Recommendation: New information [bib_ref] Prophylactic antibiotic therapy for chronic bronchitis, Black [/bib_ref] [bib_ref] Antibiotics for acute bronchitis, Smucny [/bib_ref]. The PULSE study investigated whether a pulsed therapy with moxifloxacin every 8 weeks for 5 days over a 6-month period was able to prolong the time to the next exacerbation in COPD patients in comparison to placebo. The study was negative, although there was some trend that patients with purulent sputum showed a prolongation of the time to the next acute exacerbation [bib_ref] Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease:..., Sethi [/bib_ref].
Recommendation not changed.
Evidence What is the role of prophylactic antibiotic therapy in patients with COPD or bronchiectasis? (a) COPD Recommendation: The use of nebulized antibiotics or intermittent long-term macrolide therapy is not recommended in COPD patients in general [C4].
The use of nebulized antibiotics for the prevention of LRTI has only been studied in small groups of patients with COPD.
One randomized clinical trial has investigated the use of erythromycin (2  250 mg/day) over 12 months in COPD patients, with the aim of reducing moderate to severe exacerbations in these patients [bib_ref] Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations..., Seemungal [/bib_ref]. In total, 109 outpatients have been included in the trial: 69 (63%) male; 52 (48%) current smokers; mean (SD) age, 67.2 (8.6) years; FEV 1 , 1.32 (0.53) L; FEV 1 % predicted, 50 (18%). Thirty-eight (35%) of the patients had three or more exacerbations in the year before recruitment, with no differences between treatment groups. There was a total of 206 moderate to severe exacerbations; 125 occurred in the placebo arm. Ten in the placebo group and nine in the macrolide group withdrew. Generalized linear modelling showed that the rate ratio for exacerbations for the macrolide-treated patients compared with placebo-treated patients was 0.648 (95% confidence interval, 0.489, 0.859; p 0.003) and that these patients had shorter-duration exacerbations compared with those on placebo.
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review et al. [bib_ref] Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations..., Seemungal [/bib_ref] To study the efficacy of adding 2  250 mg erythromycin to the existing treatment regimen in patients with COPD

## Rct 2a+
(b) Bronchiectasis-nebulized antibiotics Recommendation: There is not enough evidence to recommend the use of nebulized antibiotics (tobramycin) in non-CF-bronchiectasis [C2].
Nebulized tobramycin has been used with some success in cystic fibrosis patients. In non-CF-bronchiectasis patients, only small studies have been done. One found no effect [bib_ref] Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection..., Drobnic [/bib_ref] and one [bib_ref] Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis, Barker [/bib_ref] found a decrease of hospital admission and some clinical improvement. Clear evidence for a recommendation to use inhaled tobramycin could not be drawn from these studies.
Evidence (c) Bronchiectasis-macrolides
Recommendation: There is not enough evidence to recommend the use of intermittent long-term macrolide therapy in non-CF-bronchiectasis in general [C2].
Use of intermittent macrolide therapy has been successful in patients with CF and patients following lung transplantation. The number of studies investigating non-CF-bronchiectasis patients is low. Besides some letters, case reports and very small studies [bib_ref] The disease-modifying effects of twice-weekly oral azithromycin in patients with bronchiectasis, Cymbala [/bib_ref] , one retrospective study has been published. This study investigated prophylaxis with 3 azithromycin/week in bronchiectasis patients. A reduction of acute exacerbations of 50% has been observed, as well as an increase of FEV 1 [bib_ref] Effects of long-term low-dose azithromycin in patients with non-CF bronchiectasis 232, Anwar [/bib_ref]. MA, meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review Are oral mucolytics useful for the prevention of LRTI? Recommendation:

## Evidence
In patients with bronchiectasis, oral mucolytics should not be used for prevention of LRTI [B1]. Prescription of oral mucolytics through the winter months should be considered for those who have frequent or prolonged exacerbations, or those who are repeatedly admitted to hospital with exacerbations of COPD and for whom inhaled corticosteroids (ICS) are not prescribed [B1].
Although it has been shown that oral mucolytics prevent acute exacerbations in patients with chronic bronchitis (1A+), it has not been shown that these substances prevent infection in the general population. However, there is some evidence that individuals who have frequent or prolonged exacerbations, or those who are repeatedly admitted to hospital with exacerbations of COPD and for whom inhaled corticosteroids (ICS) are not prescribed, may benefit from a prescription of oral mucolytics through the winter months (1A+).
A third systematic review in a row has shown at least some effect of oral mucolytics in selected patients (severe COPD, frequent exacerbations, no ICS) [bib_ref] Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease, Poole [/bib_ref]. Barrett et al. [bib_ref] Treatment of the common cold with unrefined echinacea. A randomized, double-blind, placebo-controlled..., Barrett [/bib_ref] Ecchinacea for common cold RCT 2A)

## Evidence
McElhaney et al. [bib_ref] Efficacy of COLD-fX in the prevention of respiratory symptoms in community-dwelling adults:..., Mcelhaney [/bib_ref] Extract of the roots of North American ginseng (Panax quinquefolium)

## Rct 2a+
Heimer et al. [bib_ref] Examining the evidence for the use of vitamin C in the prophylaxis..., Heimer [/bib_ref] Vitamin C to prevent common cold MA 1B)
Oral care in nursing homes.
Recommendation: Intensified oral care in nursing home residents should be considered as a preventive measure to reduce the incidence of pneumonia and the risk of death from pneumonia in these patients .
Since the last version of these recommendations one meta-analysis and two intervention trials have investigated the question of intensified oral care in nursing home patients in relation to the prevention of LRTI or pneumonia.
Evidence To study the risk of death from pneumonia in relation to dental status

## Ccs 4c+
Bassim et al. [bib_ref] Modification of the risk of mortality from pneumonia with oral hygiene care, Bassim [/bib_ref] To study the risk of mortality from pneumonia with oral hygiene care

## Ccs 3b+
Are there commonly used medications decreasing the risk of LRTI or CAP? Since the last version of these recommendations a variety of commonly used drugs has been investigated with regard to their potential to decrease the risk of LRTI or CAP. These drugs are: inhaled steroids in COPD patients, and ACE-inhibitors or statins in the general population.
Inhaled steroids in COPD patients: Inhaled steroids might decrease the risk of acute exacerbation in subgroups of COPD patients, but they do not decrease the risk of LRTI. In fact they seem to increase the risk of LTRI/CAP in COPD patients. Statin use in the general population and the risk of CAP and death from CAP: The use of statins and/or ACE inhibitors in the general population has been investigated with regard to their potential to decrease the risk of CAP or CAP-related death.

## Evidence
The use of statins and/or ACE inhibitors might decrease the risk of CAP or CAP-related death in the general population. There are many more data for statins then for ACE inhibitors.
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review. To study mortality in pneumonia in current statin users

## Ccs 4b+
Tleyjeh et al. [bib_ref] Statins for the prevention and treatment of infections: a systematic review and..., Tleyjeh [/bib_ref] To study statin use to prevent infection SR 1A+

## Recommendations for influenza vaccination
Should influenza vaccine be used to prevent LRTI?
Recommendation:
1 Influenza vaccine should be given yearly to persons at increased risk of complications due to influenza [A2].
Vaccination should be given to immunocompetent adults belonging to one, or more, of the following categories: age >65 years, institutionalization, chronic cardiac diseases, chronic pulmonary diseases, diabetes mellitus, chronic renal diseases, haemoglobinopathies, and women who will be in the second or third trimester of pregnancy during the influenza season [bib_ref] Microbiology of severe aspiration pneumonia in institutionalized elderly, El-Solh [/bib_ref]. In the elderly (>65 years of age) and in high-risk adults, irrespective of age, new studies have confirmed that seasonal influenza vaccination is effective in prevention of severe complications or death due to influenza [bib_ref] Clinical effectiveness of influenza vaccination in persons younger than 65 years with..., Hak [/bib_ref] [bib_ref] Conventional influenza vaccination is not associated with complications in working-age patients with..., Hak [/bib_ref] [bib_ref] Influenza but not pneumococcal vaccination protects against all-cause mortality in patients with..., Schembri [/bib_ref] [bib_ref] Influenza vaccination and mortality: prospective cohort study of the elderly in a..., Ortqvist [/bib_ref]. As most of these results are based on non-controlled studies, they may result in either a too pessimistic or too optimistic view of the effectiveness of vaccination. The latter, based on 'healthy user biases', has been shown in several recent studies [bib_ref] Influenza vaccination and mortality: prospective cohort study of the elderly in a..., Ortqvist [/bib_ref] [bib_ref] Evidence of bias in estimates of influenza vaccine effectiveness in seniors, Jackson [/bib_ref] [bib_ref] Mortality reduction with influenza vaccine in patients with pneumonia outside ''flu'' season:..., Eurich [/bib_ref] [bib_ref] Influenza vaccination and risk of community-acquired pneumonia in immunocompetent elderly people: a..., Jackson [/bib_ref].
A recent Cochrane analysis was unable to reach clear conclusions about the effects of the influenza vaccine in the elderly [bib_ref] Vaccines for preventing influenza in the elderly, Jefferson [/bib_ref] , but it must be emphasized that a lack of evidence does not equal a lack of effectiveness. So far, there is unfortunately only one randomized controlled study of high quality [bib_ref] The efficacy of influenza vaccination in elderly individuals. A randomized double-blind placebo-controlled..., Govaert [/bib_ref]. This study clearly demonstrated that the vaccine was effective in prevention of clinical and laboratory verified influenza in the elderly, but was not powered to detect effects on complications. However, based on that study it is reasonable to assume that the vaccine will also prevent severe influenza and its complications, which is in accordance with the findings of a large majority of well-performed observational studies.
The specific age-limit of 65 years of age for recommendation of general seasonal influenza vaccination used in these guidelines is based on the fact that most trials have used this cut-off for the inclusion of patients and/or the analysis of the results. In some countries general vaccination is recommended also for some age groups below 65 years (e.g. in the USA, where vaccination is recommended for all persons aged 50-64 years because persons in this age group have an increased prevalence of high-risk conditions and low vaccination rates) [bib_ref] Prevention and control of influenza, Fiore [/bib_ref].
Yearly vaccinations with the seasonal influenza vaccine do not lead to a decreasing immune response or protection, or to more frequent effects than those seen after primary vaccination. Two new studies have confirmed that the inactivated injectable influenza vaccine is superior to the live attenuated vaccine in healthy adults [bib_ref] Live attenuated or inactivated influenza vaccines and medical encounters for respiratory illnesses..., Wang [/bib_ref] [bib_ref] Comparative efficacy of inactivated and live attenuated influenza vaccines, Monto [/bib_ref] However, although the seasonal influenza vaccine prevents respiratory illnesses in healthy adults [bib_ref] Comparative efficacy of inactivated and live attenuated influenza vaccines, Monto [/bib_ref] [bib_ref] Influenza vaccination among college and university students: impact on influenzalike illness, health..., Nichol [/bib_ref] , a revision of the Cochrane analysis by Demicheli et al. [bib_ref] Vaccines for preventing influenza in healthy adults, Demicheli [/bib_ref] indicates that vaccination is of only limited clinical value in this group of patients.
Systematic reviews indicate that vaccination of health care personnel against influenza may reduce influenza-like illness and all-cause mortality of elderly people in long-term hospitals, but have not demonstrated an effect on specific outcomes, such as laboratory-proven influenza, pneumonia or deaths from pneumonia [bib_ref] Influenza vaccination for healthcare workers who work with the elderly, Thomas [/bib_ref] [bib_ref] Influenza vaccination for healthcare workers who work with the elderly, Thomas [/bib_ref].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review. To study the effectiveness of influenza vaccination in adults 18-64 with COPD

## Ccs 4a+
Jackson et al. [bib_ref] Evidence of bias in estimates of influenza vaccine effectiveness in seniors, Jackson [/bib_ref] To study the effectiveness of influenza vaccination in elderly persons

## Rcs 4a+
Thomas et al. [bib_ref] Influenza vaccination for healthcare workers who work with the elderly, Thomas [/bib_ref] To study the effectiveness of influenza vaccination of health-care workers in order to protect elderly persons SR 1A)
Squarcione et al. [bib_ref] Comparison of the reactogenicity and immunogenicity of a split and a subunit-adjuvanted..., Squarcione [/bib_ref] To study the immunogenicity and reactogenicity of inactivated influenza vaccine in older persons RCT 2C)
Wang et al. [bib_ref] Live attenuated or inactivated influenza vaccines and medical encounters for respiratory illnesses..., Wang [/bib_ref] To study live attenuated vs. inactivated influenza vaccines and medical encounters for respiratory illnesses among US military personnel

## Pcs 3b+
Monto et al. [bib_ref] Comparative efficacy of inactivated and live attenuated influenza vaccines, Monto [/bib_ref] Comparative efficacy of inactivated and live attenuated influenza vaccines in healthy adults

## Rct 2a+
Nichol et al. [bib_ref] Influenza vaccination among college and university students: impact on influenzalike illness, health..., Nichol [/bib_ref] To study the effectiveness of influenza vaccination in prevention of influenza-like illness

## Pcs 3b+
Schembri et al. [bib_ref] Influenza but not pneumococcal vaccination protects against all-cause mortality in patients with..., Schembri [/bib_ref] To study the effectiveness of influenza vaccination in prevention of all-cause mortality in elderly persons

## Rcs 4a+
O rtqvist et al. [bib_ref] Influenza vaccination and mortality: prospective cohort study of the elderly in a..., Ortqvist [/bib_ref] To study the effectiveness of influenza vaccination in prevention of all-cause mortality in elderly persons

## Pcs 3a+
Eurich et al. [bib_ref] Mortality reduction with influenza vaccine in patients with pneumonia outside ''flu'' season:..., Eurich [/bib_ref] To study the effectiveness of influenza vaccination in prevention of all-cause mortality in elderly persons

## Pcs 3a+
Jackson et al. [bib_ref] Influenza vaccination and risk of community-acquired pneumonia in immunocompetent elderly people: a..., Jackson [/bib_ref] To study the effectiveness of influenza vaccination in prevention of communityacquired pneumonia in immunocompetent elderly people

## Ccs 4a+
Jefferson et al. [bib_ref] Vaccines for preventing influenza in the elderly, Jefferson [/bib_ref] To study vaccines for preventing influenza in the elderly SR 1B)
Thomas et al. [bib_ref] Influenza vaccination for healthcare workers who work with the elderly, Thomas [/bib_ref] To study the effect of influenza vaccination for healthcare workers who work with the elderly

## Recommendations for pneumococcal vaccination
Should pneumococcal vaccine be used to prevent LRTI? Recommendation:
1 The 23-valent polysaccharide pneumococcal vaccine prevents invasive pneumococcal disease in older persons and in other high-risk groups and should be given to all adult persons at risk of pneumococcal disease [A1]. 2 Risk factors for pneumococcal disease are: age >65 years, institutionalization, dementia, seizure disorders, congestive heart failure, cerebrovascular disease, chronic obstructive pulmonary disease, history of a previous pneumonia, chronic liver disease, diabetes mellitus, functional or anatomical asplenia, and chronic cerebrospinal fluid leakage [B3]. Although smoking seems to be a significant risk factor in otherwise healthy younger adults, measures aimed at reducing smoking and exposure to environmental tobacco smoke should be preferred in this group. 3 Revaccination, once, and not earlier than 5 years after primary vaccination, should be performed in asplenic patients and can be considered in the elderly and other high-risk groups [B3]. 4 There are not enough data to give any recommendations concerning the use of conjugate pneumococcal vaccine in adults.
The immunogenicity of the 23-valent polysaccharide pneumococcal vaccine (PPV) is generally good, but may be poor in some elderly patients or in persons with some underlying illnesses (e.g. bronchiectasis) [bib_ref] Impaired pneumococcal antibody response in bronchiectasis of unknown aetiology, Van Kessel [/bib_ref]. It is also important to stress that the PPV includes 23 antigens and that a person can develop a pneumococcal disease from one of these serotypes, despite responding to all the others [bib_ref] Non-response to specific serotypes likely cause for failure to 23-valent pneumococcal polysaccharide..., Ortqvist [/bib_ref]. Previously, there have been conflicting data concerning whether a pneumococcal conjugate vaccine (PCV) could result in a superior immune response in elderly patients or high-risk adults, compared with PPV [bib_ref] Review of pneumococcal conjugate vaccine in adults: implications on clinical development, Abraham-Van Parijs [/bib_ref] , but a couple of recent studies do indicate that this may be the case [bib_ref] Initial and subsequent response to pneumococcal polysaccharide and protein-conjugate vaccines administered sequentially..., Musher [/bib_ref] [bib_ref] Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults:..., De Roux [/bib_ref]. The drawbacks of PCV, however, are the limited number of serotypes, the much higher price, and the lack of data on efficacy (although a large RCT is underway).
Vaccination of children with PCV may be of benefit also for adults. Since the start of vaccination of children with PCV in the USA in 2000 a marked reduction of IPD has been noted both in the vaccinated cohorts and in adults [bib_ref] Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae, Kyaw [/bib_ref] [bib_ref] Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine, Whitney [/bib_ref]. This 'herd immunity' effect has been most marked in the age groups of parents (20-39 years of age) and grandparents (above 65 years of age). Concerning other outcomes, the herd effect is less clear, with one study indicating a decrease of all-cause pneumonia and pneumococcal pneumonia in adults 18-39 years of age [bib_ref] Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine..., Grijalva [/bib_ref] , while another showed no impact at all for all-cause pneumonia in adults [bib_ref] Impact of the introduction of pneumococcal conjugate vaccine on rates of community..., Nelson [/bib_ref].
The efficacy of PPV in adults, including the elderly, has been evaluated in eight meta-analyses/systematic reviews (MA/SR) of randomized controlled trials (RCTs). The three most recent reviews have also included a systematic review of observational studies of invasive pneumococcal disease (IPD) [bib_ref] The 23-valent pneumococcal polysaccharide vaccine. Part I. Efficacy of PPV in the..., Melegaro [/bib_ref] [bib_ref] Vaccines for preventing pneumococcal infection in adults, Dear [/bib_ref] [bib_ref] The effectiveness of pneumococcal polysaccharide vaccines in adults: a systematic review of..., Conaty [/bib_ref] [bib_ref] Vaccines for preventing pneumococcal infection in adults, Moberley [/bib_ref]. During the last 2 years, one double-blind randomized controlled trial and some other studies on the effectiveness of PPV have been published [bib_ref] Clinical efficacy of anti-pneumococcal vaccination in patients with COPD, Alfageme [/bib_ref] [bib_ref] Effectiveness of pneumococcal polysaccharide vaccine in older adults, Jackson [/bib_ref] [bib_ref] Additive preventive effect of influenza and pneumococcal vaccines in elderly persons, Christenson [/bib_ref] [bib_ref] Protective effects of the 23-valent pneumococcal polysaccharide vaccine in the elderly population:..., Vila-Corcoles [/bib_ref] [bib_ref] Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in..., Maruyama [/bib_ref] [bib_ref] Effect of influenza and pneumococcal vaccines in elderly persons in years of..., Christenson [/bib_ref] [bib_ref] Effectiveness of pneumococcal vaccination in older adults with chronic respiratory diseases: results..., Ochoa-Gondar [/bib_ref] [bib_ref] Impact of pneumococcal vaccination on pneumonia rates in patients with COPD and..., Lee [/bib_ref] [bib_ref] Prevention of communityacquired pneumonia among a cohort of hospitalized elderly: benefit due..., Skull [/bib_ref].
The MA/SRs of RCTs have shown strong evidence of PPV efficacy in prevention of invasive pneumococcal disease (IPD) in healthy adults, including the elderly (40-75% protective efficacy), while the effect against IPD may be somewhat poorer in persons with chronic illnesses. The estimates of protection against IPD from SRs of observational studies have been consistent, homogenous and compatible with those of RCTs [bib_ref] The 23-valent pneumococcal polysaccharide vaccine. Part I. Efficacy of PPV in the..., Melegaro [/bib_ref] [bib_ref] Vaccines for preventing pneumococcal infection in adults, Dear [/bib_ref] [bib_ref] The effectiveness of pneumococcal polysaccharide vaccines in adults: a systematic review of..., Conaty [/bib_ref] [bib_ref] Vaccines for preventing pneumococcal infection in adults, Moberley [/bib_ref]. Reports of significant reductions in the incidence of IPD in the elderly after the introduction of large-scale vaccination programmes from two European countries support the effectiveness of the vaccine against IPD [bib_ref] Effects of a large-scale introduction of the pneumococcal polysaccharide vaccine among elderly..., Spindler [/bib_ref] [bib_ref] The impact and effectiveness of pneumococcal vaccination in Scotland for those aged..., Mooney [/bib_ref].
There is very limited evidence that PPV prevents all-cause pneumonia in the elderly or in other risk groups. However, a recent double-blind randomized controlled trial among about 1000 nursing home residents in Japan demonstrated that PPV was associated with a reduction of the incidence of all-cause pneumonia by 45% and of pneumococcal pneumonia by 64% [bib_ref] Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in..., Maruyama [/bib_ref]. There was also a significant higher death rate among persons with pneumococcal pneumonia in the placebo group, 35% (13/37) vs. 0% (0/14). This study supports earlier findings from recent cohort studies indicating that PPV is associated with a reduction of pneumonia overall, pneumococcal pneumonia, hospitalization for pneumonia and death due to pneumonia [bib_ref] Additive preventive effect of influenza and pneumococcal vaccines in elderly persons, Christenson [/bib_ref] [bib_ref] Protective effects of the 23-valent pneumococcal polysaccharide vaccine in the elderly population:..., Vila-Corcoles [/bib_ref] [bib_ref] Effect of influenza and pneumococcal vaccines in elderly persons in years of..., Christenson [/bib_ref] [bib_ref] Prior pneumococcal vaccination is associated with reduced death, complications, and length of..., Fisman [/bib_ref] [bib_ref] Effect of prior pneumococcal vaccination on clinical outcome of hospitalized adults with..., Mykietiuk [/bib_ref]. In contrast, some other cohort studies have found no protection against all-cause pneumonia or hospitalization for pneumonia [bib_ref] Effectiveness of pneumococcal polysaccharide vaccine in older adults, Jackson [/bib_ref] [bib_ref] Prevention of communityacquired pneumonia among a cohort of hospitalized elderly: benefit due..., Skull [/bib_ref].
In an open RCT, performed in adults with COPD, a high degree of protection against CAP due to S. pneumoniae or unknown aetiology was seen in persons <65 years of age, and especially in those with severe functional obstruction (FEV 1 < 40%) [bib_ref] Clinical efficacy of anti-pneumococcal vaccination in patients with COPD, Alfageme [/bib_ref]. In contrast, pneumococcal vaccination did not alter significantly the risk of overall CAP in a cohort study of older adults with chronic respiratory diseases [bib_ref] Effectiveness of pneumococcal vaccination in older adults with chronic respiratory diseases: results..., Ochoa-Gondar [/bib_ref].
In European studies, vaccination with PPV of the elderly has not been cost-saving, but shown moderate to good cost-effectiveness in preventing hospital admission for IPD [bib_ref] The 23-valent pneumococcal polysaccharide vaccine. Part II. A cost-effectiveness analysis for invasive..., Melegaro [/bib_ref] [bib_ref] An economic analysis of a pneumococcal vaccine programme in people aged over..., Mangtani [/bib_ref]. The most recent study [bib_ref] An economic analysis of a pneumococcal vaccine programme in people aged over..., Mangtani [/bib_ref] indicated that pneumoccoocal vaccination would be cost neutral if it was 75-89% efficacious against IPD or 28-38% against pneumococcal pneumonia in the elderly. If the vaccine efficacy against IPD was 50% the net cost for society would be 2500 per year of life saved. Using data on the effect of herd immunity from the USA, it has been estimated that it would be cost-effective from an adult point of view to vaccinate children in the UK with four doses of the seven-valent conjugate vaccine [bib_ref] Pneumococcal pneumonia in the UK -how herd immunity affects the cost-effectiveness of..., Mcintosh [/bib_ref].
The safety and immunogenicity of one revaccination with pneumococcal vaccine has been confirmed by several studies [bib_ref] Safety of varying dosages of 7-valent pneumococcal protein conjugate vaccine in seniors..., Jackson [/bib_ref] [bib_ref] Revaccination with the 23-valent pneumococcal polysaccharide vaccine in middle-aged and elderly persons..., Torling [/bib_ref] [bib_ref] Revaccination of adults with spinal cord injury using the 23-valent pneumococcal polysaccharide..., Waites [/bib_ref]. In a large randomized controlled trial patients who previously had received one dose of PPV were randomized to receive PPV or PCV, in four different dosages [bib_ref] Safety of varying dosages of 7-valent pneumococcal protein conjugate vaccine in seniors..., Jackson [/bib_ref]. Local side-effects were common, but usually mild. The frequency of local reactions in the PCV group depended on the dose given, and in the highest dosage group the risk of a reaction was comparable to that of PPV. In a prospective cohort study of 61 elderly persons (median age 75 years) revaccinated on average 5.3 years after the primary vaccination, significant increases of the geometric mean antibody concentration and geometric mean antibody fold increase were seen, although to lower levels than after primary vaccination [bib_ref] Revaccination with the 23-valent pneumococcal polysaccharide vaccine in middle-aged and elderly persons..., Torling [/bib_ref]. Thirty-six of 61 (59%) of patients responded with a fold increase >2, to two or more of six serotypes. Early revaccination may lead to a short-lived antibody rise, which could be due to an immunological suppression or tolerance [bib_ref] Initial and subsequent response to pneumococcal polysaccharide and protein-conjugate vaccines administered sequentially..., Musher [/bib_ref]. However, this suppressive effect seems to wane after some years and in studies where revaccination has been performed after 5 years or more persons have responded well [bib_ref] Revaccination with the 23-valent pneumococcal polysaccharide vaccine in middle-aged and elderly persons..., Torling [/bib_ref] [bib_ref] Revaccination of adults with spinal cord injury using the 23-valent pneumococcal polysaccharide..., Waites [/bib_ref].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review. To compare immunogenicity of PPV and PCV in healthy and high-risk adults SR 1B)
Kyaw et al. [bib_ref] Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae, Kyaw [/bib_ref] To study the effectiveness of reducing IPD in adults by vaccination of children with conjugate pneumococcal vaccine

## Rcs 4c+
Whitney et al. [bib_ref] Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine, Whitney [/bib_ref] To study the effectiveness of reducing IPD in adults by vaccination of children with conjugate pneumococcal vaccine

## Rcs 4c+
Melegaro and Edmunds [bib_ref] The 23-valent pneumococcal polysaccharide vaccine. Part I. Efficacy of PPV in the..., Melegaro [/bib_ref] To study the efficacy of PPV in adults above 50 years of age SR 1A)
Dear et al. [bib_ref] Vaccines for preventing pneumococcal infection in adults, Dear [/bib_ref] To study the efficacy of PPV in adults SR 1A)
Conaty et al. [bib_ref] The effectiveness of pneumococcal polysaccharide vaccines in adults: a systematic review of..., Conaty [/bib_ref] To study the efficacy of PPV in adults SR 1A)
Alfageme et al. [bib_ref] Clinical efficacy of anti-pneumococcal vaccination in patients with COPD, Alfageme [/bib_ref] To study the efficacy of PPV in adults with COPD

## Rct 2c+
Jackson et al. [bib_ref] Effectiveness of pneumococcal polysaccharide vaccine in older adults, Jackson [/bib_ref] To study the efficacy of PPV in adults above 65 years of age

## Rcs 4b+
Christenson et al. [bib_ref] Additive preventive effect of influenza and pneumococcal vaccines in elderly persons, Christenson [/bib_ref] To study the efficacy of PPV in adults above 65 years of age PCS 3B+
Vila-Co rcoles et al. [bib_ref] Protective effects of the 23-valent pneumococcal polysaccharide vaccine in the elderly population:..., Vila-Corcoles [/bib_ref] To study the efficacy of PPV in adults above 65 years of age

## Pcs 3b+
Fisman et al. [bib_ref] Prior pneumococcal vaccination is associated with reduced death, complications, and length of..., Fisman [/bib_ref] To study the efficacy of PPV in adults RCS 4C+
Mykietiuk et al. [bib_ref] Effect of prior pneumococcal vaccination on clinical outcome of hospitalized adults with..., Mykietiuk [/bib_ref] To study the efficacy of PPV in adults PCS 3C+
Melegaro et al. [bib_ref] The 23-valent pneumococcal polysaccharide vaccine. Part II. A cost-effectiveness analysis for invasive..., Melegaro [/bib_ref] To study cost-effectiveness of PPV in elderly persons

## Rcs 5b+
Mangtani et al. [bib_ref] An economic analysis of a pneumococcal vaccine programme in people aged over..., Mangtani [/bib_ref] To study cost-effectiveness of PPV in elderly persons

## Rcs 5b+
McIntosh et al. [bib_ref] Pneumococcal pneumonia in the UK -how herd immunity affects the cost-effectiveness of..., Mcintosh [/bib_ref] To study cost-effectiveness in adults after vaccination of children with PCV

## Rcs 5b+
Jackson et al. [bib_ref] Safety of varying dosages of 7-valent pneumococcal protein conjugate vaccine in seniors..., Jackson [/bib_ref] To compare safety of PPV and PCV in elderly persons

## Rct 2a+
Torling et al. [bib_ref] Revaccination with the 23-valent pneumococcal polysaccharide vaccine in middle-aged and elderly persons..., Torling [/bib_ref] To study the immune response to revaccination with PPV in elderly persons

## Pcs 3a+
Sisk [bib_ref] Prospective multicenter study of the causative organisms of community-acquired pneumonia in adults..., Saito [/bib_ref] To study cost-effectiveness of PPV in adults 50-54 years of age

## Rcs 5b+
Andrews [bib_ref] Incidence and characteristics of viral community-acquired pneumonia in adults, Jennings [/bib_ref] To study the efficacy of PPV in adults above 65 years of age

## Pcs 4c+
Pepper [bib_ref] Epidemiology and clinical outcomes of community-acquired pneumonia in adult patients in Asian..., Song [/bib_ref] To study cost-effectiveness of PPV in healthy adults

## Rcs 5b+
Ortqvist et al. [bib_ref] Non-response to specific serotypes likely cause for failure to 23-valent pneumococcal polysaccharide..., Ortqvist [/bib_ref] To study response to specific serotypes causing failure of 23-valent pneumococcal polysaccharide vaccine in the elderly

## Ccs 4a+
Musher et al. [bib_ref] Initial and subsequent response to pneumococcal polysaccharide and protein-conjugate vaccines administered sequentially..., Musher [/bib_ref] To study the initial and subsequent response to pneumococcal polysaccharide and protein-conjugate vaccines administered sequentially to adults who have recovered from pneumococcal pneumonia PCS 3B+
de Roux et al. [bib_ref] Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults:..., De Roux [/bib_ref] To compare pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults

## Rct 2b+
Grijalva et al. [bib_ref] Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine..., Grijalva [/bib_ref] To study pneumonia admissions after routine childhood immunization with pneumococcal conjugate vaccine in the USA

## Rcs 4b+
Nelson et al. [bib_ref] Impact of the introduction of pneumococcal conjugate vaccine on rates of community..., Nelson [/bib_ref] To study impact of the introduction of pneumococcal conjugate vaccine on rates of community-acquired pneumonia in children and adults

## Rcs 4a+
Moberley et al. [bib_ref] Vaccines for preventing pneumococcal infection in adults, Moberley [/bib_ref] Systematic review of vaccines for preventing pneumococcal infection in adults SR 1A+
Maruyama et al. [bib_ref] Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in..., Maruyama [/bib_ref] To study the efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents

## Rct 2a+
Christenson et al. [bib_ref] Effect of influenza and pneumococcal vaccines in elderly persons in years of..., Christenson [/bib_ref] To study the effect of influenza and pneumococcal vaccines in elderly people

## Pcs 3c+
Ochoa-Gondar et al. [bib_ref] Effectiveness of pneumococcal vaccination in older adults with chronic respiratory diseases: results..., Ochoa-Gondar [/bib_ref] To study the effectiveness of pneumococcal vaccination in older adults with chronic respiratory diseases PCS 3B)
Lee et al. [bib_ref] Impact of pneumococcal vaccination on pneumonia rates in patients with COPD and..., Lee [/bib_ref] To study the impact of pneumococcal vaccination on pneumonia rates in adult patients with COPD and asthma

## Rcs 4b+
Skull et al. [bib_ref] Prevention of communityacquired pneumonia among a cohort of hospitalized elderly: benefit due..., Skull [/bib_ref] To study whether influenza and/or pneumococcal vaccine prevents hospitalization because of communityacquired pneumonia in the elderly CCS 4B)
Johnstone et al. [bib_ref] Effect of pneumococcal vaccination in hospitalized adults with community-acquired pneumonia, Johnstone [/bib_ref] To study the effect of pneumococcal vaccination in hospitalized adults with community-acquired pneumonia

## Pcs 3b+
Waites et al. [bib_ref] Revaccination of adults with spinal cord injury using the 23-valent pneumococcal polysaccharide..., Waites [/bib_ref] To study the effects of revaccination of adults with spinal cord injury using the 23-valent pneumococcal polysaccharide vaccine

## Recommendations for implementation.
Recommendation: Active interventions should be used to enhance vaccination with either, or both, of the vaccines and is effective and needed to in order to achieve an adequate vaccination coverage of the targeted population [A1]. New studies have confirmed that different types of interventions (e.g. patient reminders or standing orders) are effective for increasing vaccination of the targeted population against influenza and pneumococcal disease [bib_ref] Inpatient computer-based standing orders vs physician reminders to increase influenza and pneumococcal..., Dexter [/bib_ref] [bib_ref] Project protect: pneumococcal vaccination in Washington State nursing homes, Jacobson [/bib_ref] [bib_ref] Performance measures, vaccinations, and pneumonia rates among high-risk patients in Veterans Administration..., Jha [/bib_ref].
Evidence [fig_ref] Table MA ,: meta-analysis [/fig_ref] , meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review. 1. = Systematic reviews and meta-analyses (of study types under grade 2 or 3) 2. = Randomized trials 3. = Prospective cohort 4. = Case-control, cross-sectional, retrospective cohort 5. = Case reports 6. = Expert opinion, consensus
[fig] FIG. 1: Streptococcus pneumoniae: proportion of invasive isolates non-susceptible to penicillin (PNSP) in 2008. *These countries did not report any data or reported <10 isolates. [/fig]
[fig] FIG. 2: Streptococcus pneumoniae: proportion of invasive isolates non-susceptible to erythromycin in 2008. From EARSS. *These countries did not report any data or reported <10 isolates. [/fig]
[fig] 1: selected exacerbations of COPD (see section 'Exacerbations of chronic obstructive pulmonary disease'); 2 cardiac failure; 3 insulin-dependent diabetes mellitus; or 4 a serious neurological disorder (stroke, etc.) [C3]. [/fig]
[table] TABLE 2: Aetiology of community-acquired pneumonia in the community (%). (Blank boxes indicate organism not sought) [/table]
[table] TABLE 3: Aetiology of community-acquired pneumonia in adults admitted to hospital (%). (Blank boxes indicate organism not sought) SP, Streptococcus pneumoniae; HI, Haemophilus influenzae; LP, Legionella pneumophila; MC, Moraxella catarrhalis; SA, Staphylococcus aureus; GNEB, Gram-negative enteric bacilli; PA, Pseudomonas aeruginosa; MP, Mycoplasma pneumoniae; CS, Chlamydia species (all); CPne, Chlamydophila pneumoniae; CPsi, Chlamydophila psittaci; CB, Coxiella burnetii. [/table]
[table] TABLE 4: Aetiology of community-acquired pneumonia in adults admitted to an ICU (%). (Blank boxes indicate organism not sought) SP, Streptococcus pneumoniae; HI, Haemophilus influenzae; LP, Legionella pneumophila; SA, Staphylococcus aureus; GNEB, Gram-negative enteric bacilli; MP, Mycoplasma pneumoniae; CS, Chlamydia species (all); CPsi, Chlamydophila psittaci; CB, Coxiella burnetii. [/table]
[table] TABLE 5: Microorganisms isolated in hospitalized elderly patients with community-acquired pneumonia (CAP) (%). (Blank boxes indicate organism not sought) [/table]
[table] TABLE 6: Aetiology of exacerbations in patients with COPD (%). (Blank boxes indicate organism not sought) SP, Streptococcus pneumoniae; HI, Haemophilus influenzae; MC, Moraxella catarrhalis; SA, Staphylococcus aureus; GNEB, Gram-negative enteric bacilli; PA, Pseudomonas aeruginosa; MP, Mycoplasma pneumoniae; CS, Chlamydia species (all); CPne, Chlamydophila pneumoniae; CPsi, Chlamydophila psittaci; CB, Coxiella burnetii; PI, Para-influenza; RI, Rhino-virus; RSV, Respiratory syncytial virus. [/table]
[table] TABLE 7: Microorganisms isolated in inpatients with non-cystic fibrosis bronchiectasis (%). (Blank boxes indicate organism not sought) [/table]
[table] Table MA ,: meta-analysis (or systematic review); RCT, randomized controlled trial; PCS, prospective cohort study; RCS, retrospective cohort study; CCS, case-control study; CSS, cross-sectional study; SR, systematic review [/table]
[table] 2: Repeated vaccinations are safe and do not lead to a decreased immune response [B1]. 3 In adults, inactivated, rather than live attenuated, vaccine should be used [A1]. 4 Yearly vaccination should be carried out for health care personnel, especially in settings where elderly persons or other high-risk groups are treated [B2]. 5 General vaccination of all healthy adults should not be carried out in the absence of robust cost-effectiveness data for vaccination [B1] [/table]