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

      Abstract

      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.

      Keywords

      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 [
      • Woodhead M
      • Blasi F
      • Ewig S
      • et al.
      Guidelines for the management of adult lower respiratory tract infections.
      ]. 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 [
      • Woodhead M
      • Blasi F
      • Ewig S
      • et al.
      Guidelines for the management of adult lower respiratory tract infections.
      ] 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 [
      • Woodhead M
      • Blasi F
      • Ewig S
      • et al.
      Guidelines for the management of adult lower respiratory tract infections.
      ] 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 15 261 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 [
      • American Thoracic Society
      • Infectious Disease Society of North America
      Guidelines for the management of adults with hospital‐acquired, ventilator‐associated, and healthcare‐associated pneumonia.
      ,
      • Kollef MH
      • Shorr A
      • Tabak YP
      • Gupta V
      • Liu LZ
      • Johannes RS
      Epidemiology and outcomes of health‐care‐associated pneumonia: results from a large US database of culture‐positive pneumonia.
      ,
      • Micek ST
      • Kollef KE
      • Reichley RM
      • Roubinian N
      • Kollef MH
      Health care‐associated pneumonia and community‐acquired pneumonia: a single‐center experience.
      ,
      • El Solh AA
      • Pietrantoni C
      • Bhat A
      • Bhora M
      • Berbary E
      Indicators of potentially drug‐resistant bacteria in severe nursing home‐acquired pneumonia.
      ,
      • El‐Solh AA
      • Pietrantoni C
      • Bhat A
      • et al.
      Microbiology of severe aspiration pneumonia in institutionalized elderly.
      ,
      • Carratala J
      • Mykietiuk A
      • Fernandez‐Sabe N
      • et al.
      Health care‐associated pneumonia requiring hospital admission: epidemiology, antibiotic therapy, and clinical outcomes.
      ,
      • Garb JL
      • Brown RB
      • Garb JR
      • Tuthill RW
      Differences in etiology of pneumonias in nursing home and community patients.
      ,
      • Lim WS
      • Macfarlane JT
      A prospective comparison of nursing home acquired pneumonia with community acquired pneumonia.
      ,
      • Marrie TJ
      • Blanchard W
      A comparison of nursing home‐acquired pneumonia patients with patients with community‐acquired pneumonia and nursing home patients without pneumonia.
      ,
      • Meehan TP
      • Chua‐Reyes JM
      • Tate J
      • et al.
      Process of care performance, patient characteristics, and outcomes in elderly patients hospitalized with community‐acquired or nursing home‐acquired pneumonia.
      ,
      • Naughton BJ
      • Mylotte JM
      • Ramadan F
      • Karuza J
      • Priore RL
      Antibiotic use, hospital admissions, and mortality before and after implementing guidelines for nursing home‐acquired pneumonia.
      ,
      • Shindo Y
      • Sato S
      • Maruyama E
      • et al.
      Health‐care‐associated pneumonia among hospitalized patients in a Japanese community hospital.
      ,
      • Shorr AF
      • Zilberberg MD
      • Micek ST
      • Kollef MH
      Prediction of infection due to antibiotic‐resistant bacteria by select risk factors for health care‐associated pneumonia.
      ,
      • Venditti M
      • Falcone M
      • Corrao S
      • Licata G
      • Serra P
      Outcomes of patients hospitalized with community‐acquired, health care‐associated, and hospital‐acquired pneumonia.
      ,
      • Webster D
      • Chui L
      • Tyrrell GJ
      • Marrie TJ
      Health care‐associated Staphylococcus aureus pneumonia.
      ,
      • Zilberberg MD
      • Shorr AF
      • Micek ST
      • Mody SH
      • Kollef MH
      Antimicrobial therapy escalation and hospital mortality among patients with health‐care‐associated pneumonia: a single‐center experience.
      ].

       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).

       Acute Bronchitis (AB)

      An acute illness, occurring in a patient without chronic lung disease, with symptoms including cough, which may or may not be productive and associated with other symptoms or clinical signs that suggest LRTI and no alternative explanation (e.g. sinusitis or asthma).

       Influenza

      An acute illness, usually with fever, together with the presence of one or more of headache, myalgia, cough or sore throat.

       Suspected community-acquired pneumonia (CAP)

      An acute illness with cough and at least one of new focal chest signs, fever >4 days or dyspnoea/tachypnoea, and without other obvious cause.

       Definite community-acquired pneumonia (CAP)

      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 [
      • Johansson N
      • Kalin M
      • Tiveljung‐Lindell A
      • Giske CG
      • Hedlund J
      Etiology of community‐acquired pneumonia: increased microbiological yield with new diagnostic methods.
      ].
      • 1
        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 [
        • Ewig S
        • Torres A
        • Angeles Marcos M
        • et al.
        Factors associated with unknown aetiology in patients with community‐acquired pneumonia.
        ].
      • 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% [
        • Korppi M
        Mixed microbial aetiology of community‐acquired pneumonia in children.
        ].
      In hospitalized adult non-immunocompromised patients, polymicrobial CAP occurred in 6–26% [
      • Gutierrez F
      • Masia M
      • Rodriguez JC
      • et al.
      Community‐acquired pneumonia of mixed etiology: prevalence, clinical characteristics, and outcome.
      ,
      • de Roux A
      • Marcos MA
      • Garcia E
      • et al.
      Viral community‐acquired pneumonia in nonimmunocompromised adults.
      ,
      • Angeles Marcos M
      • Camps M
      • Pumarola T
      • et al.
      The role of viruses in the aetiology of community‐acquired pneumonia in adults.
      ,
      • Lauderdale TL
      • Chang FY
      • Ben RJ
      • et al.
      Etiology of community acquired pneumonia among adult patients requiring hospitalization in Taiwan.
      ,
      • Wattanathum A
      • Chaoprasong C
      • Nunthapisud P
      • et al.
      Community‐acquired pneumonia in southeast Asia: the microbial differences between ambulatory and hospitalized patients.
      ,
      • Saito A
      • Kohno S
      • Matsushima T
      • et al.
      Prospective multicenter study of the causative organisms of community‐acquired pneumonia in adults in Japan.
      ,
      • Jennings LC
      • Anderson TP
      • Beynon KA
      • et al.
      Incidence and characteristics of viral community‐acquired pneumonia in adults.
      ,
      • Song JH
      • Oh WS
      • Kang CI
      • et al.
      Epidemiology and clinical outcomes of community‐acquired pneumonia in adult patients in Asian countries: a prospective study by the Asian network for surveillance of resistant pathogens.
      ]. Gutierrez et al. [
      • Gutierrez F
      • Masia M
      • Rodriguez JC
      • et al.
      Community‐acquired pneumonia of mixed etiology: prevalence, clinical characteristics, and outcome.
      ] 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. [
      • Angeles Marcos M
      • Camps M
      • Pumarola T
      • et al.
      The role of viruses in the aetiology of community‐acquired pneumonia in adults.
      ] 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. [
      • de Roux A
      • Ewig S
      • Garcia E
      • et al.
      Mixed community‐acquired pneumonia in hospitalised patients.
      ] 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 [
      • Song JH
      • Oh WS
      • Kang CI
      • et al.
      Epidemiology and clinical outcomes of community‐acquired pneumonia in adult patients in Asian countries: a prospective study by the Asian network for surveillance of resistant pathogens.
      ]. Jennings et al. [
      • Jennings LC
      • Anderson TP
      • Beynon KA
      • et al.
      Incidence and characteristics of viral community‐acquired pneumonia in adults.
      ] 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 [
      • Johansson N
      • Kalin M
      • Tiveljung‐Lindell A
      • Giske CG
      • Hedlund J
      Etiology of community‐acquired pneumonia: increased microbiological yield with new diagnostic methods.
      ]. 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 [
      • Centers for Disease Control and Prevention (CDC)
      Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) – United States, May–August 2009.
      ].
      Table 1 summarizes the microbiological aetiologies of LRTI in the community. Studies have investigated the microbiological causes of CAP in outpatients (Table 2) and patients admitted to hospital (Table 3) or to the intensive care unit (Table 4). Most studies of mild infections suggest that microbial aetiologies in outpatients are similar to those in hospitalized patients [
      • Almirall J
      • Bolibar I
      • Vidal J
      • et al.
      Epidemiology of community‐acquired pneumonia in adults: a population‐based study.
      ,
      • Anzueto A
      • Niederman MS
      • Tillotson GS
      Etiology, susceptibility, and treatment of acute bacterial exacerbations of complicated chronic bronchitis in the primary care setting: ciprofloxacin 750 mg b.i.d. versus clarithromycin 500 mg b.i.d. Bronchitis Study Group.
      ,
      • Blasi F
      • Cosentini R
      • Raccanelli R
      • et al.
      Emerging pathogens of community‐acquired pneumonia: a two‐year prospective study.
      ,
      • Bohte R
      • van Furth R
      • van den Broek PJ
      Aetiology of community‐acquired pneumonia: a prospective study among adults requiring admission to hospital.
      ,
      • Brandenburg JA
      • Marrie TJ
      • Coley CM
      • et al.
      Clinical presentation, processes and outcomes of care for patients with pneumococcal pneumonia.
      ,
      • El Solh AA
      • Sikka P
      • Ramadan F
      • Davies J
      Etiology of severe pneumonia in the very elderly.
      ,
      • Ginesu F
      • Pirina P
      • Deiola G
      • Ostera S
      • Mele S
      • Fois AG
      Etiology and therapy of community‐acquired pneumonia.
      ,
      • Gomez J
      • Banos V
      • Ruiz GJ
      • et al.
      Prospective study of epidemiology and prognostic factors in community‐acquired pneumonia.
      ,
      • Gowardman J
      • Trent L
      Severe community acquired pneumonia: a one‐year analysis in a tertiary referral intensive care unit.
      ,
      • Hedlund J
      • Kalin M
      • Ortqvist A
      Recurrence of pneumonia in middle‐aged and elderly adults after hospital‐treated pneumonia: aetiology and predisposing conditions.
      ,
      • Hirani NA
      • Macfarlane JT
      Impact of management guidelines on the outcome of severe community acquired pneumonia.
      ,
      • Jokinen C
      • Heiskanen L
      • Juvonen H
      • et al.
      Microbial etiology of community‐acquired pneumonia in the adult population of 4 municipalities in eastern Finland.
      ,
      • Jones RN
      • Croco MA
      • Kugler KC
      • Pfaller MA
      • Beach ML
      Respiratory tract pathogens isolated from patients hospitalized with suspected pneumonia: frequency of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 1997).
      ,
      • Leroy O
      • Vandenbussche C
      • Coffinier C
      • et al.
      Community‐acquired aspiration pneumonia in intensive care units. Epidemiological and prognosis data.
      ,
      • Leroy O
      • Bosquet C
      • Vandenbussche C
      • et al.
      Community‐acquired pneumonia in the intensive care unit: epidemiological and prognosis data in older people.
      ,
      • Logroscino CD
      • Penza O
      • Locicero S
      • et al.
      Community‐acquired pneumonia in adults: a multicentric observational AIPO study.
      ,
      • Lorente ML
      • Falguera M
      • Nogues A
      • Gonzalez AR
      • Merino MT
      • Caballero MR
      Diagnosis of pneumococcal pneumonia by polymerase chain reaction (PCR) in whole blood: a prospective clinical study.
      ,
      • Lim WS
      • Macfarlane JT
      • Boswell TC
      • et al.
      Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines.
      ,
      • Marrie TJ
      • Peeling RW
      • Fine MJ
      • Singer DE
      • Coley CM
      • Kapoor WN
      Ambulatory patients with community‐acquired pneumonia: the frequency of atypical agents and clinical course.
      ,
      • Meijer A
      • Dagnelie CF
      • de Jong JC
      • et al.
      Low prevalence of Chlamydia pneumoniae and Mycoplasma pneumoniae among patients with symptoms of respiratory tract infections in Dutch general practices.
      ,
      • Menendez R
      • Cordoba J
      • de La CP
      • et al.
      Value of the polymerase chain reaction assay in noninvasive respiratory samples for diagnosis of community‐acquired pneumonia.
      ,
      • Michetti G
      • Pugliese C
      • Bamberga M
      • et al.
      Community‐acquired pneumonia: is there difference in etiology between hospitalized and out‐patients?.
      ,
      • Olaechea PM
      • Quintana JM
      • Gallardo MS
      • Insausti J
      • Maravi E
      • Alvarez B
      A predictive model for the treatment approach to community‐acquired pneumonia in patients needing ICU admission.
      ,
      • Ruiz M
      • Ewig S
      • Marcos MA
      • et al.
      Etiology of community‐acquired pneumonia: impact of age, comorbidity, and severity.
      ,
      • Socan M
      • Marinic‐Fiser N
      • Kraigher A
      • Kotnik A
      • Logar M
      Microbial aetiology of community‐acquired pneumonia in hospitalised patients.
      ,
      • Sopena N
      • Sabria M
      • Pedro‐Botet ML
      • et al.
      Prospective study of community‐acquired pneumonia of bacterial etiology in adults.
      ,
      • Steinhoff D
      • Lode H
      • Ruckdeschel G
      • et al.
      Chlamydia pneumoniae as a cause of community‐acquired pneumonia in hospitalized patients in Berlin.
      ].
      TABLE 1Aetiology of lower respiratory tract infection in the community (%). (Blank boxes indicate organism not sought)
      ReferencenSPHIMCSAMPCSCPneCBVirusInfluenza
      Boldy et al. [
      • Boldy DA
      • Skidmore SJ
      • Ayres JG
      Acute bronchitis in the community: clinical features, infective factors, changes in pulmonary function and bronchial reactivity to histamine.
      ]
      423.03.03.008.00021.010.0
      Creer et al. 2006 [
      • Creer DD
      • Dilworth JP
      • Gillespie SH
      • et al.
      Aetiological role of viral and bacterial infections in acute adult lower respiratory tract infection (LRTI) in primary care.
      ]
      8018.86.31.21.261.323.8
      Everett [
      • Everett MT
      Major chest infection managed at home.
      ]
      1876.02.006.04.0
      Fransen and Wolontis [
      • Fransen H
      • Wolontis S
      Infections with viruses, Mycoplasma pneumoniae and bacteria in acute respiratory illness. A study of hospitalized patients, patients treated at home, and healthy subjects.
      ]
      788.03.03.03.020.012.0
      Graffelman et al. [
      • Graffelman AW
      • Knuistingh NA
      • le CS
      • Kroes AC
      • Springer MP
      • van den Broek PJ
      A diagnostic rule for the aetiology of lower respiratory tract infections as guidance for antimicrobial treatment.
      ]
      1456.29.02.19.01.339.030.3
      Holm et al. [
      • Holm A
      • Nexoe J
      • Bistrup LA
      • et al.
      Aetiology and prediction of pneumonia in lower respiratory tract infection in primary care.
      ]
      364641<13<12410
      Hopstaken et al. [
      • Hopstaken RM
      • Coenen S
      • Butler CC
      Treating patients not diagnoses: challenging assumptions underlying the investigation and management of LRTI in general practice.
      ]
      2472.913.82.9
      Macfarlane et al. [
      • Macfarlane JT
      • Colville A
      • Guion A
      • Macfarlane RM
      • Rose DH
      Prospective study of aetiology and outcome of adult lower‐respiratory‐tract infections in the community.
      ]
      20630.08.021.00.50.58.05.0
      Macfarlane et al. [
      • Macfarlane J
      • Holmes W
      • Gard P
      • et al.
      Prospective study of the incidence, aetiology and outcome of adult lower respiratory tract illness in the community.
      ]
      31617.19.82.27.317.419.37.3
      Shaw and Fry [
      • Shaw AB
      • Fry J
      Acute infections of the chest in general practice.
      ]
      4016.014.010.05.03.0011.011.0
      Range3–303–141–31–100.5–90–30–0.56–614–30
      SP, Streptococcus pneumoniae; HI, Haemophilus influenzae; LP, Legionella pneumophila; MC, Moraxella catarrhalis; SA, Staphylococcus aureus; GNEB, Gram-negative bacilli; MP, Mycoplasma pneumoniae; CS, Chlamydia species (all); CPne, Chlamydophila pneumoniae; CPsi, Chlamydophila psittaci; CB, Coxiella burnetii.
      TABLE 2Aetiology of community-acquired pneumonia in the community (%). (Blank boxes indicate organism not sought)
      ReferencenSPHILPMCSAGNEBMPCSCPneCPsiCBVirusInfluenza
      Almirall et al. [
      • Almirall J
      • Morato I
      • Riera F
      • et al.
      Incidence of community‐acquired pneumonia and Chlamydia pneumoniae infection: a prospective multicentre study.
      ]
      10512.402.9007.615.215.20011.40
      Almirall et al. [
      • Almirall J
      • Bolibar I
      • Vidal J
      • et al.
      Epidemiology of community‐acquired pneumonia in adults: a population‐based study.
      ]
      23211.60.42.200.43.99.502.214.28.2
      Beovic et al. [
      • Beovic B
      • Bonac B
      • Kese D
      • et al.
      Aetiology and clinical presentation of mild community‐acquired bacterial pneumonia.
      ]
      10913.83.61.82.70.924.821.10.9
      Berntsson et al. [
      • Berntsson E
      • Lagergard T
      • Strannegard O
      • Trollfors B
      Etiology of community‐acquired pneumonia in out‐patients.
      ]
      549.311.1037.03.73.7013.07.4
      Blanquer et al. [
      • Blanquer J
      • Blanquer R
      • Borras R
      • et al.
      Aetiology of community acquired pneumonia in Valencia, Spain: a multicentre prospective study.
      ]
      4812.5012.50012.50020.814.6
      BTS et al. [
      • The British Thoracic Society and the Public Health Laboratory Service
      Community‐acquired pneumonia in adults in British hospitals in 1982–1983: a survey of aetiology, mortality, prognostic factors and outcome.
      ]
      676.0000003.028.010.0
      Dulake and Selkon [
      • Dulake C
      • Selkon J
      The incidence of pneumonia in the UK – preliminary findings from Newcastle and London.
      ]
      3619.014.0002.0022
      Foy et al. [
      • Foy HM
      • Cooney MK
      • McMahan R
      • Grayston JT
      Viral and mycoplasmal pneumonia in a prepaid medical care group during an eight‐year period.
      ]
      225612.020.025.08.0
      Holm et al. [
      • Holm A
      • Nexoe J
      • Bistrup LA
      • et al.
      Aetiology and prediction of pneumonia in lower respiratory tract infection in primary care.
      ]
      48154002080134
      Jokinen et al. [
      • Jokinen C
      • Heiskanen L
      • Juvonen H
      • et al.
      Microbial etiology of community‐acquired pneumonia in the adult population of 4 municipalities in eastern Finland.
      ]
      3044143101210192
      Marrie et al. [
      • Marrie TJ
      • Peeling RW
      • Fine MJ
      • Singer DE
      • Coley CM
      • Kapoor WN
      Ambulatory patients with community‐acquired pneumonia: the frequency of atypical agents and clinical course.
      ]
      14922.810.72.72.7
      Marrie et al. [
      • Marrie TJ
      • Poulin‐Costello M
      • Beecroft MD
      • Herman‐Gnjidic Z
      Etiology of community‐acquired pneumonia treated in an ambulatory setting.
      ]
      5075.94.91512
      Melbye et al. [
      • Melbye H
      • Berdal BP
      • Straume B
      • Russell H
      • Vorland L
      • Thacker WL
      Pneumonia – a clinical or radiographic diagnosis? Etiology and clinical features of lower respiratory tract infection in adults in general practice.
      ]
      3611.10013.98.3033.319.4
      Michetti et al. [
      • Michetti G
      • Pugliese C
      • Bamberga M
      • et al.
      Community‐acquired pneumonia: is there difference in etiology between hospitalized and out‐patients?.
      ]
      119003.40032.816.06.79.205.93.4
      Miyashita et al. [
      • Miyashita N
      • Fukano H
      • Mouri K
      • et al.
      Community‐acquired pneumonia in Japan: a prospective ambulatory and hospitalized patient study.
      ]
      10612.34.71.90.927.41.9
      Wattanathum et al. [
      • Wattanathum A
      • Chaoprasong C
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      9813.318.229.636.7
      Woodhead et al. [
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      23636.010.00.501.01.01.01.0013.08.0
      Range0–360–140–130–30–10–11–331–167–370–90–32–330–19
      SP, Streptococcus pneumoniae; HI, Haemophilus influenzae; LP, Legionella pneumophila; MC, Moraxella catarrhalis; SA, Staphylococcus aureus; GNEB, Gram-negative enteric bacilli; MP, Mycoplasma pneumoniae; CS, Chlamydia species (all); CPne, Chlamydophila pneumoniae; CPsi, Chlamydophila psittaci; CB, Coxiella burnetii.
      TABLE 3Aetiology of community-acquired pneumonia in adults admitted to hospital (%). (Blank boxes indicate organism not sought)
      ReferencenSPHILPSAMCGNEBPAMPCSCPneCPsiCBVirusInfluenza
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      2077.72.44.83.91.05.38.210.110.10.00.0
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      33426.97.82.41.21.53.35.70.38.14.2
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      45334.05.72.00.90.00.917.92.91.17.17.1
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      660342523916111454
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      16342677<111211<1<1
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      52010.832.90.40.9
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      34212.65.61.50.00.30.03.26.16.10.00.0
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      493
      26.8% were outpatients.
      16.81.84.30.40.23.22.27.76.10.44.12.8
      Holmberg [
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      14746.99.52.70.72.00.05.41.40.010.910.2
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      5020.016.04.00.02.02.04.00.00.020.010.0
      Huang et al. [
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      389
      36.2% were outpatients.
      3.120.60.51.50.36.210.84.4
      Jennings et al. [
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      30431114233110
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      19371<11232200154
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      43910.51.12.05.718.03.23.02.5
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      11625.911.24.32.60.96.93.40.90.04.3
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      6135.93.62.81.10.83.93.34.23.1
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      11435.10.91.82.60.02.69.61.80.9
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      12775.63.115.02.40.00.82.45.50.88.75.5
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      5392.2–8.1
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      8050.06.31.33.80.01.30.00.00.06.36.3
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      18423.91.60.50.00.01.614.10.50.01.11.61.6
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      608.36.711.71.71.73.38.36.71.70.01.71.7
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      40026.3131.53.33.5429.31.30.53
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      27746.23.63.60.71.11.49.71.10.01.10.015.52.5
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      25413.86.33.10.40.82.03.91.20.0
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      1657.31.82.42.40.027.310.31.210.918.213.3
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      44215.42.53.82.70.02.59.33.20.08.84.1
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      39516.56.34.31.81.06.33.33.80.52.89.95.8
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      232
      16% were outpatients.
      24.618.53.93.42.21.70.45.28.76.52.20.916.4
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      15911.310.62.53.83.88.2123
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      12613.50.82.40.812.53.16.37.17.10
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      9551261216366
      Sopena et al. [
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      33020.32.113.90.60.00.31.515.80.01.2
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      2378.65.16.37.76.3
      Wattanathum et al. [
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      14722.42.75.43.417.70.76.816.3
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      21011.41.91.43.80.01.414.31.42.914.812.4
      Range3–761–211–140–40–40–330–120–180–160–180–60–111–240–13
      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.
      a 26.8% were outpatients.
      b 36.2% were outpatients.
      c 16% were outpatients.
      TABLE 4Aetiology of community-acquired pneumonia in adults admitted to an ICU (%). (Blank boxes indicate organism not sought)
      ReferencenSPHILPSAGNEBMPCSCPsiCBVirusInfluenza
      Alkhayer et al. [
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      5714797142
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      3218.49.211.6
      Hirani and Macfarlane 1997 [
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      5717.5015.812.31.805.3010.58.8
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      13232.610.63.03.810.60.80.81.55.351.5
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      26211.53.88.03.83.13.11.501.95
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      5317.01.09.007.002.000
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      6717.93.010.41.56.000001.51.5
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      11242.90.91.81.826.8
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      5822.4013.808.600001.751.7
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      20420.15.311.22.45.80.9
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      3633.38.338.38.32.8000013.92.8
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      5032030.010020008.04.0
      Range12–430–120–300–190–270–70–20–60–20–170–9
      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.
      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 [
      • Garcia‐Vidal C
      • Carratala J
      • Fernandez‐Sabe N
      • et al.
      Aetiology of, and risk factors for, recurrent community‐acquired pneumonia.
      ].
      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 [
      • Berglund C
      • Molling P
      • Sjoberg L
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      Predominance of staphylococcal cassette chromosome mec (SCCmec) type IV among methicillin‐resistant Staphylococcus aureus (MRSA) in a Swedish county and presence of unknown SCCmec types with Panton‐Valentine leukocidin genes.
      ]. 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 [
      • Gillet Y
      • Issartel B
      • Vanhems P
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      Association between Staphylococcus aureus strains carrying gene for Panton‐Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients.
      ,
      • Hageman JC
      • Uyeki TM
      • Francis JS
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      Severe community‐acquired pneumonia due to Staphylococcus aureus, 2003–04 influenza season.
      ,
      • Lina G
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      ,
      • Davis SL
      • Perri MB
      • Donabedian SM
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      Epidemiology and outcomes of community‐associated methicillin‐resistant Staphylococcus aureus infection.
      ].
      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 [
      • van der HW
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      ].
      The importance of viruses as causal agents has been confirmed in LRTI [
      • Creer DD
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      • Gillespie SH
      • et al.
      Aetiological role of viral and bacterial infections in acute adult lower respiratory tract infection (LRTI) in primary care.
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      • de Roux A
      • Marcos MA
      • Garcia E
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      Viral community‐acquired pneumonia in nonimmunocompromised adults.
      ,
      • Angeles Marcos M
      • Camps M
      • Pumarola T
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      The role of viruses in the aetiology of community‐acquired pneumonia in adults.
      ,
      • Flamaing J
      • Engelmann I
      • Joosten E
      • Van RM
      • Verhaegen J
      • Peetermans WE
      Viral lower respiratory tract infection in the elderly: a prospective in‐hospital study.
      ]. In the majority of aetiological CAP studies looking for viruses and bacteria, viruses are the most common aetiological agents after S. pneumoniae [
      • Angeles Marcos M
      • Camps M
      • Pumarola T
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      The role of viruses in the aetiology of community‐acquired pneumonia in adults.
      ,
      • Johnstone J
      • Majumdar SR
      • Fox JD
      • Marrie TJ
      Viral infection in adults hospitalized with community‐acquired pneumonia: prevalence, pathogens, and presentation.
      ].
      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 [
      • Beigel JH
      • Farrar J
      • Han AM
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      Avian influenza A (H5N1) infection in humans.
      ,
      • Chotpitayasunondh T
      • Ungchusak K
      • Hanshaoworakul W
      • et al.
      Human disease from influenza A (H5N1), Thailand, 2004.
      ]. The hantavirus pulmonary syndrome was recognized in 1983, but was retrospectively identified using serological testing in patients who had a similar illness in 1959 [
      • Miedzinski L
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      ]. 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 [
      • Patrick DM
      • Petric M
      • Skowronski DM
      • et al.
      An outbreak of human Coronavirus OC43 infection and serological cross‐reactivity with SARS Coronavirus.
      ,
      • Drosten C
      • Gunther S
      • Preiser W
      • et al.
      Identification of a novel coronavirus in patients with severe acute respiratory syndrome.
      ]. 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 [
      • Chowell G
      • Bertozzi SM
      • Colchero MA
      • et al.
      Severe respiratory disease concurrent with the circulation of H1N1 influenza.
      ]. 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 (Table 5). There are large variations, depending on the elderly threshold, where patients live and comorbidities. However, Gutierez et al. [
      • Gutierrez F
      • Masia M
      • Mirete C
      • et al.
      The influence of age and gender on the population‐based incidence of community‐acquired pneumonia caused by different microbial pathogens.
      ] 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. [
      • Ingarfield SL
      • Celenza A
      • Jacobs IG
      • Riley TV
      The bacteriology of pneumonia diagnosed in Western Australian emergency departments.
      ] emphasize that enterobacteriacae accounted for more than 25% of isolates in patients older than 65 years.
      TABLE 5Microorganisms isolated in hospitalized elderly patients with community-acquired pneumonia (CAP) (%). (Blank boxes indicate organism not sought)
      ReferencenPatientsSPHILPMCSAGNEBMPCSCBVirusInfluenzaAspiration
      El-Solh et al. [
      • El Solh AA
      • Sikka P
      • Ramadan F
      • Davies J
      Etiology of severe pneumonia in the very elderly.
      ]
      57≥80 years Home14794717222
      El-Solh et al. [
      • El Solh AA
      • Sikka P
      • Ramadan F
      • Davies J
      Etiology of severe pneumonia in the very elderly.
      ]
      47≥80 years Nursing Home9202292000
      Fernandez-Sabé et al. [
      • Fernandez‐Sabe N
      • Carratala J
      • Roson B
      • et al.
      Community‐acquired pneumonia in very elderly patients: causative organisms, clinical characteristics, and outcomes.
      ]
      305≥80 years Home235130.70.30810
      Flamaing 2003 [
      • Flamaing J
      • Engelmann I
      • Joosten E
      • Van RM
      • Verhaegen J
      • Peetermans WE
      Viral lower respiratory tract infection in the elderly: a prospective in‐hospital study.
      ]
      165≥80 years Home & Nursing Home3.61.24.20.630.926.1
      Gutierrez et al. [
      • Gutierrez F
      • Masia M
      • Rodriguez JC
      • et al.
      Community‐acquired pneumonia of mixed etiology: prevalence, clinical characteristics, and outcome.
      ]
      136≥75 years Home19.10.71.5006.62.23.73.72.2
      Huang et al. [
      • Huang HH
      • Zhang YY
      • Xiu QY
      • et al.
      Community‐acquired pneumonia in Shanghai, China: microbial etiology and implications for empirical therapy in a prospective study of 389 patients.
      ]
      126≥60 years2.414.30.80.82.412.77.16.3
      Jokinen et al. [
      • Jokinen C
      • Heiskanen L
      • Juvonen H
      • et al.
      Microbial etiology of community‐acquired pneumonia in the adult population of 4 municipalities in eastern Finland.
      ]
      140≥60 years Home4843313120
      Riquelme et al. [
      • Riquelme R
      • Torres A
      • El‐Ebiary M
      • et al.
      Community‐acquired pneumonia in the elderly: a multivariate analysis of risk and prognostic factors.
      ]
      101≥65 years Home18.83138.95.9
      Saito et al. [
      • Saito A
      • Kohno S
      • Matsushima T
      • et al.
      Prospective multicenter study of the causative organisms of community‐acquired pneumonia in adults in Japan.
      ]
      114≥65 years Home28.20.22.63.53.57.91.89.60.913.2
      Zalacain 2003 [
      • Zalacain R
      • Torres A
      • Celis R
      • et al.
      Community‐acquired pneumonia in the elderly: Spanish multicentre study.
      ]
      503≥65 years Home & Nursing Home19.55.43.80.61.64.42.02.62.21.20.6
      Range2–482–200–90–47–293–200–72–130–60–310–26
      SP, Streptococcus pneumoniae; HI, Haemophilus influenzae; LP, Legionella pneumophila; MC, Moraxella catarrhalis; SA, Staphylococcus aureus; GNEB, Gram-negative enteric bacilli; MP, Mycoplasma pneumoniae; CS, Chlamydia species (all); CB, Coxiella burnetii.
      Table 6 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 [
      • Eller J
      • Ede A
      • Schaberg T
      • Niederman MS
      • Mauch H
      • Lode H
      Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function.
      ,
      • Miravitlles M
      • Espinosa C
      • Fernandez‐Laso E
      • Martos JA
      • Maldonado JA
      • Gallego M
      Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD.
      ,
      • Alamoudi OS
      Bacterial infection and risk factors in outpatients with acute exacerbation of chronic obstructive pulmonary disease: a 2‐year prospective study.
      ,
      • McManus TE
      • Marley AM
      • Baxter N
      • et al.
      Respiratory viral infection in exacerbations of COPD.
      ,
      • Roche N
      • Kouassi B
      • Rabbat A
      • Mounedji A
      • Lorut C
      • Huchon G
      Yield of sputum microbiological examination in patients hospitalized for exacerbations of chronic obstructive pulmonary disease with purulent sputum.
      ,
      • Hutchinson AF
      • Ghimire AK
      • Thompson MA
      • et al.
      A community‐based, time‐matched, case‐control study of respiratory viruses and exacerbations of COPD.
      ,
      • Diederen BM
      • van der Valk PD
      • Kluytmans JA
      • Peeters MF
      • Hendrix R
      The role of atypical respiratory pathogens in exacerbations of chronic obstructive pulmonary disease.
      ,
      • Ko FW
      • Ip M
      • Chan PK
      • et al.
      A 1‐year prospective study of the infectious etiology in patients hospitalized with acute exacerbations of COPD.
      ]. P. aeruginosa should be suspected in patients who have been treated with antibiotics and in those not vaccinated against influenza [
      • Monso E
      • Garcia‐Aymerich J
      • Soler N
      • et al.
      Bacterial infection in exacerbated COPD with changes in sputum characteristics.
      ]. 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 [
      • Murphy TF
      • Brauer AL
      • Eschberger K
      • et al.
      Pseudomonas aeruginosa in chronic obstructive pulmonary disease.
      ].
      TABLE 6Aetiology of exacerbations in patients with COPD (%). (Blank boxes indicate organism not sought)
      ReferenceSamplenSPHIMCSAGNEBPAMPCSCPneCPsiCBVirusInfluenzaPIRVAdvRSV
      Alamoudi [
      • Alamoudi OS
      Bacterial infection and risk factors in outpatients with acute exacerbation of chronic obstructive pulmonary disease: a 2‐year prospective study.
      ]
      Sputum13941225912
      Beaty et al. [
      • Beaty CD
      • Grayston JT
      • Wang SP
      • Kuo CC
      • Reto CS
      • Martin TR
      Chlamydia pneumoniae, strain TWAR, infection in patients with chronic obstructive pulmonary disease.
      ]
      Serology444.5
      Carilli et al. [
      • Carilli AD
      • Gohd RS
      • Gordon W
      A virologic study of chronic bronchitis.
      ]
      Serology468.78.74.3017.4
      Eadie et al. [
      • Eadie MB
      • Stott EJ
      • Grist NR
      Virologic studies in chronic bronchitis.
      ]
      Serology474.32.123.40
      Eller et al. [
      • Eller J
      • Ede A
      • Schaberg T
      • Niederman MS
      • Mauch H
      • Lode H
      Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function.
      ]
      Sputum21197.647.118.96.6
      Erkan et al. [
      • Erkan L
      • Uzun O
      • Findik S
      • Katar D
      • Sanic A
      • Atici AG
      Role of bacteria in acute exacerbations of chronic obstructive pulmonary disease.
      ]
      Sputum, Serology7553561917
      Fagon et al. [
      • Fagon JY
      • Chastre J
      • Trouillet JL
      • et al.
      Characterization of distal bronchial microflora during acute exacerbation of chronic bronchitis. Use of the protected specimen brush technique in 54 mechanically ventilated patients.
      ]
      PSB548263.54.563.5
      Groenewegen and Wouters 2003 [
      • Groenewegen KH
      • Wouters EF
      Bacterial infections in patients requiring admission for an acute exacerbation of COPD; a 1‐year prospective study.
      ]
      Sputum17114.022.22.92.37.6
      Gump et al. [
      • Gump DW
      • Phillips CA
      • Forsyth BR
      • McIntosh K
      • Lamborn KR
      • Stouch WH
      Role of infection in chronic bronchitis.
      ]
      Serology11627.642.2410.321.66.90.833.612.97.83.44.3
      Hutchinson et al. [
      • Hutchinson AF
      • Ghimire AK
      • Thompson MA
      • et al.
      A community‐based, time‐matched, case‐control study of respiratory viruses and exacerbations of COPD.
      ]
      Sputum, Swab, Serology1485112276121123211811
      Karnak et al. [
      • Karnak D
      • Beng‐sun S
      • Beder S
      • Kayacan O
      Chlamydia pneumoniae infection and acute exacerbation of chronic obstructive pulmonary disease (COPD).
      ]
      Serology3834.034.0
      Ko et al. [
      • Ko FW
      • Ng TK
      • Li TS
      • et al.
      Sputum bacteriology in patients with acute exacerbations of COPD in Hong Kong.
      ]
      Sputum4184.023.12.01.25.26.3
      Ko et al. [
      • Ko FW
      • Ip M
      • Chan PK
      • et al.
      A 1‐year prospective study of the infectious etiology in patients hospitalized with acute exacerbations of COPD.
      ]
      Sputum, Swab, Serology643410304400512
      Lamy et al. [
      • Lamy ME
      • Pouthier‐Simon F
      • Debacker‐Willame E
      Respiratory viral infections in hospital patients with chronic bronchitis. Observations during periods of exacerbation and quiescence.
      ]
      Serology492.028.624.56.1
      Lieberman et al. [
      • Lieberman D
      • Ben Yaakov M
      • Lazarovich Z
      • Ohana B
      • Boldur I
      Chlamydia pneumoniae infection in acute exacerbations of chronic obstructive pulmonary disease: analysis of 250 hospitalizations.
      ]
      Serology6211.311.3
      McManus 2008 [
      • McManus TE
      • Marley AM
      • Baxter N
      • et al.
      Respiratory viral infection in exacerbations of COPD.
      ]
      Sputum1363722472
      McNamara et al. [
      • McNamara MJ
      • Phillips IA
      • Williams OB
      Viral and Mycoplasma pneumoniae infections in exacerbations of chronic lung disease.
      ]
      Serology429.50042.811.9
      Miravitlles et al. [
      • Miravitlles M
      • Espinosa C
      • Fernandez‐Laso E
      • Martos JA
      • Maldonado JA
      • Gallego M
      Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD.
      ]
      Sputum9110229715
      Mogulkoc et al. [
      • Mogulkoc N
      • Karakurt S
      • Isalska B
      • et al.
      Acute purulent exacerbation of chronic obstructive pulmonary disease and Chlamydia pneumoniae infection.
      ]
      Serology Sputum498.28.26.16.122.422.4
      Monsòet al. [
      • Monso E
      • Ruiz J
      • Rosell A
      • et al.
      Bacterial infection in chronic obstructive pulmonary disease. A study of stable and exacerbated outpatients using the protected specimen brush.
      ]
      PSB2910.334.56.96.9
      Murphy et al. [
      • Murphy TF
      • Brauer AL
      • Grant BJ
      • Sethi S
      Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response.
      ]
      Sputum10410
      Papi et al. [
      • Papi A
      • Bellettato CM
      • Braccioni F
      • et al.
      Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations.
      ]
      Sputum6412.514.110.96.34.76.348.410.93276
      Roche et al. [
      • Roche N
      • Kouassi B
      • Rabbat A
      • Mounedji A
      • Lorut C
      • Huchon G
      Yield of sputum microbiological examination in patients hospitalized for exacerbations of chronic obstructive pulmonary disease with purulent sputum.
      ]
      Sputum200826669
      Rohde et al. [
      • Rohde G
      • Wiethege A
      • Borg I
      • et al.
      Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case‐control study.
      ]
      Sputum Nasal lavage85562072515
      Rosell et al. [
      • Rosell A
      • Monso E
      • Soler N
      • et al.
      Microbiologic determinants of exacerbation in chronic obstructive pulmonary disease.
      ]
      PSB8673070169
      Ross et al. [
      • Ross CA
      • McMichael S
      • Eadie MB
      • Lees AW
      • Murray EA
      • Pinkerton I
      Infective agents and chronic bronchitis.
      ]
      Serology125000010.41.63.2
      Seemungal et al. [
      • Seemungal T
      • Harper‐Owen R
      • Bhowmik A
      • et al.
      Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease.
      ]
      Serology Culture16800.60.65.40.623.2
      de Serres et al. [
      • De SG
      • Lampron N
      • La FJ
      • et al.
      Importance of viral and bacterial infections in chronic obstructive pulmonary disease exacerbations.
      ]
      Sputum, Swab, Serology10845410871329637
      Soler et al. [
      • Soler N
      • Torres A
      • Ewig S
      • et al.
      Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation.
      ]
      PSB508.022.08.08.018.018.014.02.02.012.010.0
      Range8–280–423–114–225–190–180–100–340.3412–490–290–250–430–17
      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.
      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) [
      • Lieberman D
      • Lieberman D
      • Gelfer Y
      • et al.
      Pneumonic vs nonpneumonic acute exacerbations of COPD.
      ]. 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 [
      • Buscho RO
      • Saxtan D
      • Shultz PS
      • Finch E
      • Mufson MA
      Infections with viruses and Mycoplasma pneumoniae during exacerbations of chronic bronchitis.
      ]. 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 [
      • Sethi S
      • Evans N
      • Grant BJ
      • Murphy TF
      New strains of bacteria and exacerbations of chronic obstructive pulmonary disease.
      ].
      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 Table 7; they highlight the high frequency of Pseudomonas infection, particularly in the case of impaired lung function.
      TABLE 7Microorganisms isolated in inpatients with non-cystic fibrosis bronchiectasis (%). (Blank boxes indicate organism not sought)
      ReferenceSamplenSPHIMCSAGNEBPAMPNTM
      Angrill et al. [
      • Angrill J
      • Agusti C
      • de CR
      • et al.
      Bacterial colonisation in patients with bronchiectasis: microbiological pattern and risk factors.
      ]
      PSB75832318154
      Chan et al. [
      • Chan TH
      • Ho SS
      • Lai CK
      • et al.
      Comparison of oral ciprofloxacin and amoxycillin in treating infective exacerbations of bronchiectasis in Hong Kong.
      ]
      Sputum32195334
      Ho et al. [
      • Ho PL
      • Chan KN
      • Ip MS
      • et al.
      The effect of Pseudomonas aeruginosa infection on clinical parameters in steady‐state bronchiectasis.
      ]
      Sputum1006105383323
      King et al. [
      • King PT
      • Holdsworth SR
      • Freezer NJ
      • Villanueva E
      • Holmes PW
      Microbiologic follow‐up study in adult bronchiectasis.
      ]
      Sputum897478431222
      Nicotra et al. [
      • Nicotra MB
      • Rivera M
      • Dale AM
      • Shepherd R
      • Carter R
      Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort.
      ]
      Sputum12310.630.12.47.34430.922.8
      O'Donnell et al. [
      • O’Donnell AE
      • Barker AF
      • Ilowite JS
      • Fick RB
      Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group.
      ]
      Sputum34925
      Range6–1110–323–718–5315–332–43–23
      SP, Streptococcus pneumoniae; HI, Haemophilus influenzae; MC, Moraxella catarrhalis; SA, Staphylococcus aureus; GNEB, Gram-negative enteric bacilli; PA, Pseudomonas aeruginosa; MP, Mycoplasma pneumoniae; NTM, non-tuberculous Mycobacteria.
      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 FEV1 (<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) [
      • Angrill J
      • Agusti C
      • de CR
      • et al.
      Bacterial colonisation in patients with bronchiectasis: microbiological pattern and risk factors.
      ]. In a study of 100 patients with steady-state bronchiectasis, the presence of P. aeruginosa in the sputum was associated with a lower FEV1/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) [
      • Ho PL
      • Chan KN
      • Ip MS
      • et al.
      The effect of Pseudomonas aeruginosa infection on clinical parameters in steady‐state bronchiectasis.
      ]. In that study, FEV1/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 β-lactams is due to alterations of penicillin-binding proteins (PBP). PBPs interact with β-lactams enzymatically by forming a covalent complex via the active-site serine. The loss of affinity for the PBPs affects all β-lactams, although this may vary substantially depending on the drug. The affinity for a given β-lactam is different for different PBPs, and conversely, one PBP has distinct affinities for different β-lactams. Therefore point mutations reducing the affinity for one β-lactam do not necessarily affect the affinity for another compound [
      • Spratt BG
      • Pardee AB
      Penicillin‐binding proteins and cell shape in E. coli.
      ]. 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 β-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 [
      • Doit C
      • Loukil C
      • Fitoussi F
      • Geslin P
      • Bingen E
      Emergence in france of multiple clones of clinical Streptococcus pneumoniae isolates with high‐level resistance to amoxicillin.
      ].
      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 β-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 [
      • Carratala J
      • Marron A
      • Fernandez‐Sevilla A
      • Linares J
      • Gudiol F
      Treatment of penicillin‐resistant pneumococcal bacteremia in neutropenic patients with cancer.
      ].
      Amoxicillin remains the most active of all oral β-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 [
      • Yu VL
      • Chiou CC
      • Feldman C
      • et al.
      An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome.
      ].
      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. 1). 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 Finland 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. 1).
      Figure thumbnail gr1
      FIG. 1Streptococcus pneumoniae: proportion of invasive isolates non-susceptible to penicillin (PNSP) in 2008. *These countries did not report any data or reported <10 isolates.
      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, 6, 9, 14, 19F and 33, 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%) [
      • Borg MA
      • Tiemersma E
      • Scicluna E
      • et al.
      Prevalence of penicillin and erythromycin resistance among invasive Streptococcus pneumoniae isolates reported by laboratories in the southern and eastern Mediterranean region.
      ].
      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 [
      • Moore MR
      • Gertz Jr, RE
      • Woodbury RL
      • et al.
      Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005.
      ]. 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 β-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 [
      • Ardanuy C
      • Rolo D
      • Fenoll A
      • Tarrago D
      • Calatayud L
      • Linares J
      Emergence of a multidrug‐resistant clone (ST320) among invasive serotype 19A pneumococci in Spain.
      ].
      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 [
      • Clinical and Laboratory Standards Institute
      ]. In accordance with the penicillin breakpoints, the doses of suitable β-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 [
      • Peterson LR
      Penicillins for treatment of pneumococcal pneumonia: does in vitro resistance really matter?.
      ].
      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) [
      • File TM
      • Garau J
      • Jacobs MR
      • Wynne B
      • Twynholm M
      • Berkowitz E
      Efficacy of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2000/125 mg) in adults with community‐acquired pneumonia caused by Streptococcus pneumoniae, including penicillin‐resistant strains.
      ].
      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 (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. 2).
      Figure thumbnail gr2
      FIG. 2Streptococcus pneumoniae: proportion of invasive isolates non-susceptible to erythromycin in 2008. From EARSS. *These countries did not report any data or reported <10 isolates.
      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%) [
      • Borg MA
      • Tiemersma E
      • Scicluna E
      • et al.
      Prevalence of penicillin and erythromycin resistance among invasive Streptococcus pneumoniae isolates reported by laboratories in the southern and eastern Mediterranean region.
      ].
      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 [
      • Weisblum B
      Erythromycin resistance by ribosome modification.
      ,
      • Syrogiannopoulos GA
      • Grivea IN
      • Tait‐Kamradt A
      • et al.
      Identification of an erm(A) erythromycin resistance methylase gene in Streptococcus pneumoniae isolated in Greece.
      ].
      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) [
      • Johnston NJ
      • De Azavedo JC
      • Kellner JD
      • Low DE
      Prevalence and characterization of the mechanisms of macrolide, lincosamide, and streptogramin resistance in isolates of Streptococcus pneumoniae.
      ]. 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 [
      • Farrell DJ
      • Douthwaite S
      • Morrissey I
      • et al.
      Macrolide resistance by ribosomal mutation in clinical isolates of Streptococcus pneumoniae from the PROTEKT 1999‐2000 study.
      ].
      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 [
      • Lonks JR
      • Garau J
      • Gomez L
      • et al.
      Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin‐resistant Streptococcus pneumoniae.
      ]. 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 [
      • Daneman N
      • McGeer A
      • Green K
      • Low DE
      Macrolide resistance in bacteremic pneumococcal disease: implications for patient management.
      ].
      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 [
      • Doern GV
      Macrolide and ketolide resistance with Streptococcus pneumoniae.
      ].
      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 β-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 [
      • Anderson R
      • Steel HC
      • Cockeran R
      • et al.
      Comparison of the effects of macrolides, amoxicillin, ceftriaxone, doxycycline, tobramycin and fluoroquinolones, on the production of pneumolysin by Streptococcus pneumoniae in vitro.
      ].
      Fluoroquinolones: Resistance to quinolones occurs in a stepwise fashion, with mutations being observed first in 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) [
      • Pan XS
      • Ambler J
      • Mehtar S
      • Fisher LM
      Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae.
      ]. 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 [
      • Blondeau JM
      • Zhao X
      • Hansen G
      • Drlica K
      Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae.
      ].
      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% [
      • de la Campa AG
      • Ardanuy C
      • Balsalobre L
      • et al.
      Changes in fluoroquinolone‐resistant Streptococcus pneumoniae after 7‐valent conjugate vaccination, Spain.
      ].
      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 [
      • Farrell DJ
      • Felmingham D
      • Shackcloth J
      • et al.
      Non‐susceptibility trends and serotype distributions among Streptococcus pneumoniae from community‐acquired respiratory tract infections and from bacteraemias in the UK and Ireland, 1999 to 2007.
      ].
      Haemophilus influenzae. Beta-lactams: β-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 β-lactamase-stable cephalosporins or β-lactam plus β-lactamase-inhibitor combinations. In addition, H. influenzae isolates carrying amino acid substitutions in the ftsI gene (encoding PBP 3) are phenotypically recognized as β-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 β-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 β-lactam producers was 7.6%, with a range of 0.7–17.6% [
      • Jansen WT
      • Verel A
      • Beitsma M
      • Verhoef J
      • Milatovic D
      Longitudinal European surveillance study of antibiotic resistance of Haemophilus influenzae.
      ]. Although rare, β-lactamase-negative ampicillin-resistant (BLNAR) and β-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 [
      • Peric M
      • Bozdogan B
      • Jacobs MR
      • Appelbaum PC
      Effects of an efflux mechanism and ribosomal mutations on macrolide susceptibility of Haemophilus influenzae clinical isolates.
      ]. 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 [
      • Morrissey I
      • Maher K
      • Williams L
      • Shackcloth J
      • Felmingham D
      • Reynolds R
      Non‐susceptibility trends among Haemophilus influenzae and Moraxella catarrhalis from community‐acquired respiratory tract infections in the UK and Ireland, 1999–2007.
      ].
      In Greece, resistance to tetracycline increased from 1.6% in 1996 to 38% in 2005 [
      • Kofteridis DP
      • Notas G
      • Maraki S
      • et al.
      Antimicrobial susceptibilities of 930 Haemophilus influenzae clinical strains isolated from the island of Crete, Greece.
      ].
      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 [
      • Critchley IA
      • Brown SD
      • Traczewski MM
      • Tillotson GS
      • Janjic N
      National and regional assessment of antimicrobial resistance among community‐acquired respiratory tract pathogens identified in a 2005–2006 U.S. Faropenem surveillance study.
      ].
      Moraxella catarrhalis. The susceptibility of M. catarrhalis has changed little since 1999. It is interesting to note that, despite almost universal β-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 β-lactamases can be found that are phenotypically identical: the BRO-1 and BRO-2 types. Both enzymes are readily inactivated by β-lactamase inhibitors, and all isolates are still susceptible to amoxicillin in combination with clavulanic acid. Other enzyme-stable β-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 [
      • Waites KB
      • Crabb DM
      • Bing X
      • Duffy LB
      In vitro susceptibilities to and bactericidal activities of garenoxacin (BMS‐284756) and other antimicrobial agents against human mycoplasmas and ureaplasmas.
      ,
      • Waites KB
      • Crabb DM
      • Duffy LB
      In vitro activities of ABT‐773 and other antimicrobials against human mycoplasmas.
      ]. 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 β-lactams and glycopeptides. Sulphonamides, trimethoprim, polymixins, nalidixic acid and rifampin are also inactive [
      • Waites KB
      • Talkington DF
      Mycoplasma pneumoniae and its role as a human pathogen.
      ]. 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 [
      • Matsuoka M
      • Narita M
      • Okazaki N
      • et al.
      Characterization and molecular analysis of macrolide‐resistant Mycoplasma pneumoniae clinical isolates obtained in Japan.
      ,
      • Morozumi M
      • Hasegawa K
      • Kobayashi R
      • et al.
      Emergence of macrolide‐resistant Mycoplasma pneumoniae with a 23S rRNA gene mutation.
      ,
      • Morozumi M
      • Iwata S
      • Hasegawa K
      • et al.
      Increased macrolide resistance of Mycoplasma pneumoniae in pediatric patients with community‐acquired pneumonia.
      ]. 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 [
      • Dumke R
      • von BH
      • Luck PC
      • Jacobs E
      Occurrence of macrolide‐resistant Mycoplasma pneumoniae strains in Germany.
      ]. In France, among M. pneumoniae-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 [
      • Peuchant O
      • Menard A
      • Renaudin H
      • et al.
      Increased macrolide resistance of Mycoplasma pneumoniae in France directly detected in clinical specimens by real‐time PCR and melting curve analysis.
      ]. 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 [
      • Stralin K
      • Soderquist B
      Staphylococcus aureus in community‐acquired pneumonia.