key: cord-0035830-l4gl0rlc
authors: Bonten, Marc J.M.; Oosterheert, Jan Jelrik
title: Community-Acquired Pneumonia—Back to Basics
date: 2008
journal: Antibiotic Policies: Fighting Resistance
DOI: 10.1007/978-0-387-70841-6_11
sha: 96aecd2c639f9af4f1fbc69a563aef3bcb1cc0ab
doc_id: 35830
cord_uid: l4gl0rlc

Lower respiratory tract infections are among the most common infectious diseases worldwide and are caused by the inflammation and consolidation of lung tissue due to an infectious agent.(1) The clinical criteria for the diagnosis include chest pain, cough, auscultatory findings such as rales or evidence of pulmonary consolidation, fever, or leukocytosis.

Community-Acquired Pneumonia-Back to Basics Marc J. M. Bonten and Jan Jelrik Oosterheert Background Lower respiratory tract infections are among the most common infectious diseases worldwide and are caused by the inflammation and consolidation of lung tissue due to an infectious agent. 1 The clinical criteria for the diagnosis include chest pain, cough, auscultatory findings such as rales or evidence of pulmonary consolidation, fever, or leukocytosis. Radiographic evidence, such as the presence of new infiltrates on chest radiograph, and laboratory evidence can support the diagnosis. 2 Elderly and patients with underlying conditions, such as cerebro-and cardiovascular diseases, chronic obstructive pulmonary disease (COPD), and alcoholism, are at increased risk for developing lower respiratory tract infections and complicated courses of infection. 3, 4 Complications include the development of progressive pneumonia, pleural empyema, uncontrolled sepsis, and death, sometimes even despite appropriate antimicrobial treatment. 5 Because of differences in pathogenesis and causative microorganisms, healthcare-associated and community-acquired pneumonia (CAP) are usually distinguished. CAP represents a broad spectrum of disease severity, ranging from mild pneumonia that can be managed by general practitioners to severe pneumonia with septic shock needing treatment in the intensive care unit (ICU). Most cases of CAP are successfully managed in primary care and approximately 20 and 1% of patients need hospitalization or treatment in ICU, respectively. 6, 7 Despite the widespread availability of antibiotics and reduced mortality since their introduction, lower respiratory tract infections remain the most important infectious cause of death in the developed world. 8 For instance, absolute mortality due to pneumonia has increased in the past 10 years in the Netherlands and the United States. [8] [9] [10] [11] [12] Estimated annual costs for treating CAP were in excess of 1 billion US$ in the United Kingdom in 1997 and 9.7 billion US$ in the United States in 2001. 8, [13] [14] [15] Lower respiratory tract infections are most frequently caused by bacteria or viruses. Treatment should be directed toward the causative organisms, with antibiotics prescribed only for bacterial infections and being withheld for nonbacterial causes of inflammation. Yet, causative agents have usually not been identified at the time that treatment must be initiated and empirical therapy should, therefore, cover the most likely pathogens. This implies that it is unavoidable that empirical therapy frequently includes a wider range of pathogens and, thus, a broader antibiotic spectrum than a choice that exclusively covers the pathogen involved.

On a population level, the quantity of antibiotics prescribed is linearly related to antibiotic resistance and unnecessary antibiotic use should, therefore, be prevented. Despite this paradigm, overuse of antibiotics frequently occurs, especially in case of viral infections. 16 Yet, this goal to minimize unnecessary antibiotic use must be balanced constantly against the urge to cover all potential pathogens in order to prescribe optimal treatment for the individual patient. Therefore, optimizing therapeutic efficacy of empirical treatment, while preventing unnecessary antibiotic use have become important issues in the management of lower respiratory tract infections. In this chapter, etiologic, diagnostic, therapeutic, and preventive considerations are described to optimize antibiotic prescription for the individual patient with lower respiratory tract infections, while keeping antibiotic resistance development on a population level in mind.

Worldwide, Streptococcus pneumoniae is by far the most important pathogen for CAP. Other frequently isolated bacteria are Haemophilus influenzae and Staphylococcus aureus. [17] [18] [19] [20] [21] [22] [23] Incidences of atypical pathogens, such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila, are generally lower than those of the afore-mentioned bacteria, although variations may be large. 17, 18, 20, 23 Pseudomonas aeruginosa can be relevant in patients with structural lung damage, such as those with bronchiectasis or COPD. 24 Most frequent viral causes of CAP include influenza virus and parainfluenza virus. 23, 25 Viral pneumonias due to infection with influenza, respiratory syncytial virus, coronaviruses, parainfluenza virus, and even rhinoviruses can be life threatening in elderly and immunocompromised patients. Influenza pneumonia may be complicated by secondary bacterial infections caused by S. aureus, S. pneumoniae, H. influenzae, or other Gram-negative pathogens. 21, 26 Recently, coronaviruses have been recognized as causes of severe lower respiratory tract infections. The SARS coronavirus caused severe CAP associated with high mortality rates, even in previously healthy adults. 27, 28 Non-SARS coronaviruses such as the coronavirus OC43 have been associated with lower respiratory tract infections in children and adults. 25, [29] [30] [31] Human metapneumovirus is increasingly recognized as a cause of respiratory failure in children and of pneumonia in the elderly. 32, 33 Importantly, up to 60% of episodes of CAP remain of unknown etiology. 6 

Rapid and reliable diagnostic results are needed for a prudent and pathogentailored antibiotic strategy. Currently available methods for etiological diagnosis include clinical, radiological, and laboratory findings, Gram staining of sputum, urinary antigen tests, or specific DNA detection using real-time polymerase chain reactions (PCR).

Although some clinical features have been associated with specific causative microorganisms-such as high fever, acute onset of disease, chills, productive cough, and thoracic pain with S. pneumoniae, and preceding influenza with S. aureus-there is consensus that in most cases, the microbial cause of CAP cannot be predicted using clinical or radiographic features. [34] [35] [36] [37] [38] New opportunities include the use of systemic levels of C-reactive protein (CRP) and procalcitonin (PCT). Yet, although raised CRP and PCT levels have been claimed to be indicative for bacterial infections, CRP levels could not differentiate between bacterial and viral respiratory tract infections in adults, 39 nor could PCT in children admitted with CAP. 40, 41 From another perspective, though, PCT was used to reduce unnecessary antibiotic prescriptions in patients with clinical symptoms of LRTI, without subsequent adverse effect on patient outcomes. Of note, reduction of antibiotic use was primarily achieved through withholding of antimicrobial therapy for patients with acute bronchitis and only 36% of patients had CAP in this study. 42 

Routine diagnostic procedures to identify causative microorganisms include microbiological culturing of blood and sputum and serological testing of acute and reconvalescent blood samples. However, the clinical value of these conventional diagnostic methods in guiding treatment of CAP is limited because of low sensitivity and considerable delay. [43] [44] [45] [46] [47] Culturing other samples for which more invasive procedures are needed, such as pleural and bronchoalveolar fluids, might increase diagnostic yields, but inherently suffer from the same diagnostic delay. In one study, fiberoptic bronchoscopy provided an etiological diagnosis in 25% of patients in whom conventional diagnostic methods failed to identify a causative microorganism. 48 Yet, pathogen-directed empirical therapy in this study was not associated with better clinical outcome of patients. 49 Fiberoptic bronchoscopy should, therefore, be considered for cases of treatment failure without identified causative microorganism from conventional diagnostics. Importantly, even in study settings with extensive diagnostic testing, approximately 50% of episodes of CAP remain of unknown etiology [17] [18] [19] [20] [21] [22] [23] [34] [35] [36] [37] The use of sputum Gram staining in the diagnostic workup of CAP is controversial: its use is recommended by the Infectious Diseases Society of America (IDSA), but not by the American Thoracic Society (ATS). 50, 51 Advantages of sputum Gram staining include its wide availability and low costs. However, adequate sputum samples cannot always be obtained, either because there is no sputum production or because samples are not adequate for evaluation. Furthermore, sensitivity and specificity are unknown, some bacteria cannot be identified, and a uniform definition of a positive stain does not exist. 45, 46 Urinary Antigen Testing Two urinary antigen tests are available for diagnosing the microbial cause of CAP. The NOW S. pneumoniae urinary antigen test (Binax, Inc., Portland, Maine) detects, within 15 minutes, the C polysaccharide wall antigen common to all S. pneumoniae strains. 52 One study reported 90-100% specificity and 74% sensitivity. 53 Yet, specificity might be reduced due to nasopharyngeal carriage of pneumococci. 54 The other urinary antigen test detects L. pneumophila type I and test accuracy increases with severity of disease, with sensitivities varying from approximately 40% in mild to 95% in severe CAP. 55 Immediate (within 24 hours after hospital admission) therapy for Legionnaires' disease, as detected by this test, increased ICU-free survival as compared to therapy initiated after Ͼ 24 hours. 56 

Another approach is to identify viruses and "atypical" bacterial pathogens in respiratory samples through molecular techniques, such as polymerase chain reaction (PCR). Novel real-time Taq-Man PCR techniques are sensitive and specific and able to detect respiratory viruses in clinical specimens within hours. 25, 57 Yet, in a randomized trial, addition of real-time PCR analysis of respiratory viruses and atypical pathogens in nose and throat swabs to routine diagnostic workup, improved diagnostic yields but failed to reduce antibiotic use or healthcare-associated costs among patients admitted with lower respiratory tract infections (of whom 50% had CAP). 58 Therapy

A detailed description of the underlying mechanisms of antibiotic resistance is beyond the scope of this chapter. In brief, alterations in the bacterial proteins that bind penicillin can decrease binding affinity and antimicrobial susceptibility to penicillins in S. pneumoniae. Such strains are also more likely to be resistant to other antibiotics, such as macrolides, tetracyclins, and fluoroquinolones. For the treatment of pneumococcal pneumonia, ␤-lactam antibiotic concentrations should exceed the MIC for at least 40% of the time. 59 When strains with reduced susceptibility to penicillin are anticipated, this can be achieved with higher dosages of penicillin (e.g., 2 million units q 6 hours) or amoxicillin (e.g., 1 gram q 6 hours). In clinical studies, mortality rates of patients with bacteremic pneumococcal pneumonia and treated with ␤-lactam antibiotics were comparable for episodes caused by pneumococci susceptible and nonsusceptible to penicillin. 60 Macrolide resistance is either due to modification of the target site, encoded by the ermB gene, or an active efflux pump that removes macrolides from the cell, encoded by the mef gene. In S. pneumoniae, the erm gene is associated with high levels of resistance to all macrolides. Erythromycin resistance based on efflux mechanisms can be overcome by the use of newer macrolides, such as azithromycin. 60 The newer fluoroquinolones, such as levofloxacin and moxifloxacin, are active, in vitro, against most relevant significant aerobic Gram-positive cocci, the Enterobacteriaceae, H. influenzae, M. catarrhalis, Legionella species, M. pneumoniae, and C. pneumoniae, which make them attractive compounds for treatment of CAP. Development of resistance to fluoroquinolones, which can occur even during treatment, however, is a matter of serious concern. 61, 62 Resistance to fluoroquinolones results from mutations in the target enzymes (DNA gyrase and topoisomerase IV), thereby reducing the inhibitory effects of fluoroquinolones on bacterial DNA synthesis. Strains usually become fully resistant when both target genes are mutated. Other resistance mechanisms include alterations in the bacterial cell membrane and active efflux of the drug. 61, 62 Importantly, prevalence of antibiotic resistance varies geographically. For instance, prevalence of reduced susceptibility to penicillin among S. pneumoniae is around 40% in Spain and Ͻ 1% in the Netherlands (http://www.earss.rivm.nl). Furthermore, over 50% of macrolide resistance in Europe is caused by mutations in the ermB gene, 63 whereas presence of an efflux pump is the predominant resistance mechanism of S. pneumoniae to macrolides in the United States. 60 Therefore, decisions on empirical antimicrobial treatment should be based on local antibiotic resistance rates.

Recently, an emergence of infections, mostly skin infection but sporadically severe CAP, caused by so-called community-associated methicillin-resistant S. aureus (CA-MRSA), have been reported from the United States and Europe. 64, 65 CA-MRSA are resistant to all ␤-lactam antibiotics, but are frequently still susceptible to clindamycin, co-trimoxazole, and fluoroquinolones.

When organisms are known, recommended treatment should be aimed at the isolated pathogen (Table 11 .1). However, the initial treatment of CAP, as recommended in recent guidelines, is predominantly based on the clinical severity of presentation rather than the presumed causative pathogen (Table 11 .2). For the prediction of clinical severity, several risk classifications exist which include combinations of underlying illnesses, age, and clinical features. In clinical practice, broad-spectrum antibiotics should be prescribed more liberally in patients with "severe" CAP (SCAP). Therefore, a reliable prognostic model might be useful in tailoring empirical therapy in individual patients. Pragmatically, SCAP could be defined by the need of ICU admission. However, this definition does not include objective measurements and depends on local policies for ICU admission that may vary considerably between centers. 66 The ATS proposed to define SCAP on the presence of a certain set of minor and major clinical signs or symptoms. 50 The British Thoracic Society defined SCAP using a more or less similar set of "core," "additional," and "preexisting" adverse prognostic features. 67 Another algorithm to predict mortality risk and thus severity of CAP is the Pneumonia Severity Index (PSI), which classifies patients in five groups. In the development of this scoring system, 30-day mortality rates gradually increased per class from 0.1% in class I, to 31.1% in class V.The ATS criteria had a high sensitivity but low specificity for predicting ICU admission 68 and in another study only 17% of patients in risk class V of the PSI system had been admitted to ICU. 69 To what extent these criteria and algorithms can be used for choosing empirical therapy remains to be determined. 50, 67, 69, 70 In our view, clinical judgment, which is difficult to describe in objective terms, remains important in the management of patients with CAP.

Results of nonexperimental studies have suggested that, in the initial management of patients hospitalized with CAP who do not require ICU admission, combination therapy consisting of a ␤-lactam antibiotic plus a macrolide or monotherapy with one of the newer fluoroquinolones reduces mortality and length of hospitalization. [71] [72] [73] [74] [75] [76] [77] [78] Naturally, such strategies would increase the use of macrolides and fluoroquinolones and thus the selective antibiotic pressure for resistance. [79] [80] [81] The beneficial value of macrolides or fluoroquinolones might be the result of a larger than previously assumed role of atypical pathogens in the etiology of CAP, anti-inflammatory effects of macrolides, or resistance to ␤-lactams of the most important pathogens. However, the nonexperimental, and in almost all cases retrospective, design of these studies may have resulted in confounding by indication. Up till now, randomized controlled trials do not confirm these outcome differences.

The newer fluoroquinolones (levofloxacin and moxifloxacin) have been compared to ␤-lactam antibiotics (co-amoxiclav and ceftriaxone) with or without a macrolide in three randomized trials. Clinical and bacteriological success of fluoroquinolone treatment appeared to be better in two studies, 22, 82 and statistically significant differences in fever resolution and duration of hospitalization, in favor of fluoroquinolone treated patients, were also observed in two studies. 82, 83 Yet, the absolute differences were rather small (about 1 day for fever resolution and hospitalization), a significant survival benefit was not found, and results might have been influenced by protocol in at least one study, in which a switch to oral treatment for patients receiving ceftriaxone was not allowed before day 7. 83 In adults with nonsevere CAP, treatment failures were comparable for empirical regimens with atypical coverage as compared to ␤-lactam antibiotics in metaanalysis. 84 A similar conclusion was reached in another meta-analysis of 24 trials, evaluating more than 5000 patients, treated for CAP. A trend toward increased clinical success and better bacteriological eradication was found for patients receiving atypical coverage, especially for those infected with Legionella pneumophila. Yet, this trend disappeared when only high-quality studies were evaluated. 85 Therefore, the recommendation to use empirical treatment with either a ␤-lactam/macrolide combination or monotherapy with a new fluoroquinolone for patients hospitalized with CAP is based on studies providing, at most, level III evidence.

The recommended length of antimicrobial treatment of CAP is usually based on the causative pathogen, response to treatment, presence of comorbid illness, and complications. Current guidelines recommend to treat CAP caused by S. pneumoniae until the patient has been afebrile for 72 hours, whereas episodes caused by bacteria associated with pulmonary necrosis (e.g., S. aureus, P. aeruginosa, Klebsiella, and anaerobes) should be treated for about 2 weeks. 51 A duration of 2 weeks is also recommended for CAP caused by M. pneumoniae, C. pneumoniae, and legionnaires' disease in immunocompetent individuals. Treatment length could be reduced by using azithromycin, due to its long halflife in tissues, although longer courses are probably needed for Legionella infections. 51, 86 These recommendations on treatment duration are not based on results of controlled trials. Recently, treatment durations of 3 and 8 days with amoxicillin Ϯ clavulanic acid were compared in a randomized double-blind trial of 186 adult patients with mild CAP. At day 10, outcomes for clinical success, pathogen eradication, radiological response, and duration of hospitalization were similar for both groups, whereas adverse reactions occurred more frequently among patients receiving 8 days of amoxicillin. 87 In conventional treatment approaches, intravenous therapy is continued until definite clinical cure has been achieved. Based on nonrandomized studies in patients with mild to moderately severe CAP, patients hospitalized with CAP can be managed safely and more efficiently by an early switch from IV to oral medication. [88] [89] [90] [91] [92] [93] For patients with severe CAP, an early switch to oral antibiotic treatment also seems to reduce length of hospital stay (by approximately 2 days) and treatment associated costs, without adverse effects on treatment outcome. 94 Prevention Prevention of CAP, for instance through vaccination, may well reduce antibiotic use and thus resistance development. With regard to respiratory infections, vaccines are available against pneumococci and influenza. Currently, a 23valent pneumococcal polysaccharide vaccine (PPV), covering the 23 most prevalent serotypes of S. pneumoniae, is recommended in most Western countries for persons at high risk for developing CAP. However, the available data to support these recommendations are far from consistent. Nonexperimental retrospective studies suggest that PPV is effective and cost-saving in preventing invasive pneumococcal disease. 95, 96 However, confounding by indication might have played a considerable role in these studies affecting the validity of the results. Several clinical studies and systematic reviews yielded conflicting results with regard to the prevention of bacteremic pneumonia even in highrisk patients who were previously hospitalized with CAP. [96] [97] [98] [99] [100] [101] [102] Therefore, the real value of pneumococcal vaccination strategies, in terms of effects on nonbacteremic pneumonia and costs, needs further exploration, preferably in randomized controlled trials. 103, 104 Influenza vaccination is recommended for patients who have a high risk for influenza complications, like severe viral pneumonia or severe secondary bacterial infection. Patients at high risk for these complications can be identified based on host characteristics such as age, gender, comorbidity, and external factors, such as long-term immunosuppressive drug use or residence in closed communities with high transmission rates. 105 In meta-analysis vaccine effectiveness was 50% for preventing hospitalization and 68% for preventing death in high-risk patients. In addition to elderly patients, younger persons with highrisk medical conditions might also benefit from annual influenza vaccination. 101, 106, 107 Data on clinical effectiveness of the vaccine in reducing postinfluenza complications among high-risk persons of working age are limited and indicate no or at most limited benefits from vaccination. 102, 105, 108 Quantitative effects on antibiotic use of influenza vaccination are unknown, but it is tempting to argue that an effective influenza vaccination program might reduce antibiotic use.

CAP is still among the most frequently encountered infections and accounts for considerable antibiotic consumption. Strategies to fight antibiotic resistance on a population level include several basic approaches: only treat when necessary, prescribe antibiotics for bacterial infections only, only treat causative pathogens, and reduce duration of treatment as much as possible.

Physicians caring for CAP patients should balance these principles against the optimal treatment of the individual patient, which frequently includes broadspectrum antibiotics as empirical therapy, especially in patients with severe CAP. As clinical features cannot adequately predict the causative microorganism, establishing an etiological diagnosis by means of urinary antigen tests or realtime PCR techinques may enhance streamlining of therapy, thereby reducing antibiotic pressure. Current guidelines advise broad spectrum antibiotics either with combinations of ␤-lactam antibiotics plus macrolides or monotherapy with fluoroquinolones for empirical treatment of severe CAP. Yet, different definitions are used for CAP severity and the recommendation of early broadspectrum therapy is not supported by high-level evidence. The effects of these recommendations on resistance development are not clear, but should be a reason for concern.

More restrictive and prudent, but still responsible, use of antibiotics for CAP could possibly be achieved by improving techniques to establish etiological diagnoses, by optimizing empirical treatment through randomized trials, by optimizing duration of therapy, and implementation of vaccination strategies. However, these hypotheses remain to be proven.

Community-acquired pneumonia

General guidelines for the evaluation of new anti-infective drugs for the treatment of respiratory tract infections

Risk factors for pneumonia in the elderly

Risk factors for acquiring pneumococcal infections

Causes and factors associated with early failure in hospitalized patients with community-acquired pneumonia

Severe community-acquired pneumonia. Etiology, epidemiology, and prognosis factors. French Study Group for Community-Acquired Pneumonia in the Intensive Care Unit

Severe community-acquired pneumonia. Epidemiology and prognostic factors

Trends in infectious diseases mortality in the United States

Mortality associated with influenza and respiratory syncytial virus in the United States

Pneumonia and influenza death rates-United States, 1979-1994

Trends in hospitalizations for pneumonia among persons aged 65 years or older in the United States

The increase in pneumonia-related morbidity and mortality among adults in the Netherlands and possible explanations for it

Community-acquired pneumonia: The annual cost to the National Health Service in the UK

Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance study in Ohio. The Community-Based Pneumonia Incidence Study Group

The cost of treating patients with community-acquired pneumonia

Antibiotic therapy of community respiratory tract infections: Strategies for optimal outcomes and minimized resistance emergence

Etiology of community acquired pneumonia: Impact of age, comorbidity and severity

Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: Implications for management guidelines

The etiology of community-acquired pneumonia at an urban public hospital: Influence of human immunodeficiency virus infection and initial severity of illness

Multiple pathogens in adult patients admitted with community-acquired pneumonia: A one year prospective study of 346 consecutive patients

Community-acquired pneumonia: Etiology, epidemiology, and outcome at a teaching hospital in Argentina

Randomized controlled trial of sequential intravenous (i.v.) and oral moxifloxacin compared with sequential i.v. and oral coamoxiclav with or without clarithromycin in patients with community-acquired pneumonia requiring initial parenteral treatment

Aetiology of community-acquired pneumonia; a prospective study among adults requiring admission to hospital

Guidelines for severe community-acquired pneumonia in the western world

Frequent detection of human coronaviruses in clinical specimens from patients with respiratory tract infection by use of a novel real-time reverse-transcriptase polymerase chain reaction

Rhinovirus and coronavirus infection-associated hospitalizations among older adults

Identification of a novel coronavirus in patients with severe acute respiratory syndrome

A novel coronavirus associated with severe acute respiratory syndrome

Relative rates of non-pneumonic SARS coronavirus infection and SARS coronavirus pneumonia

An outbreak of coronavirus OC43 respiratory infection in Normandy, France

Identification of a new human coronavirus

Human metapneumovirus: A newly emerging respiratory pathogen

A newly discovered human pneumovirus isolated from young children with respiratory tract disease

Prediction of microbial aetiology at admission to hospital for pneumonia from the presenting clinical features

Comparative radiographic features of community-acquired legionnaires' disease, pneumococcal pneumonia, mycoplasma pneumonia and psittacosis

Comparative clinical and laboratory features of legionella with pneumococcal and mycoplasma pneumonias

Early recognition of Streptococcus pneumoniae in patients with community-acquired pneumonia

Contributions of symptoms, signs, erythrocyte sedimentation rate, and C-reactive protein to a diagnosis of pneumonia in acute lower respiratory tract infection

Clinical items not helpful in differentiating viral from bacterial lower respiratory tract infections in general practice

Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children

Serum procalcitonin, C-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children

Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: Clusterrandomised, single-blinded intervention trial

The impact of blood cultures on antibiotic therapy in pneumococcal pneumonia

Applying sputum as a diagnostic tool in pneumonia: Limited yield, minimal impact on treatment decisions

Sputum Gram's stain in community acquired pneumonia: A meta analysis

What diagnostic tests are needed for community-acquired pneumonia

Limited usefulness of initial blood cultures in community acquired pneumonia

Value of intensive diagnostic microbiological investigation in low-and high-risk patients with communityacquired pneumonia

Comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: A prospective randomised study

Guidelines for the management of adults with community acquired pneumonia

Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America

Cross-reactions between pneumococci and other streptococci due to C polysaccaride and F antigen

Evaluation of a rapid immunochromatographic test for detection of Streptococcus pneumoniae antigen in urine samples from adults with community-acquired pneumonia

Evaluation of Binax NOW, an assay for the detection of pneumococcal antigen in urine samples, performed among pediatric patients

Sensitivity of three urinary antigen tests associated with clinical severity in a large outbreak of Legionnaires' disease in the Netherlands

Legionnaires' disease at a Dutch flower show: Prognostic factors and impact of therapy

Simultaneous detection of influenza viruses A and B using real-time quantitative PCR

Impact of rapid detection of viral and atypical bacterial pathogens by real-time polymerase chain reaction for patients with lower respiratory tract infection

Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosing of mice and men

Treatment of drug-resistant pneumococcal pneumonia

Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia

Quinolone resistance among pneumococci: Therapeutic and diagnostic implications

Prevalence and characterization of the mechanisms of macrolide, lincosamide, and streptogramin resistance in isolates of Streptococcus pneumoniae

Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles

Staphylococcus aureus pneumonia: Emergence of MRSA in the community

Defining severe community-acquired pneumonia

BTS Guidelines for the Management of Community Acquired Pneumonia in Adults

Severe community-acquired pneumonia. Assessment of severity criteria

A prediction rule to identify low-risk patients with community acquired pneumonia

Defining community acquired pneumonia severity on presentation to hospital: An international derivation and validation study

Addition of a macrolide to a betalactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia

Effect of macrolides as part of initial empiric therapy on medical outcomes for hospitalized patients with community-acquired pneumonia

Antimicrobial selection for hospitalized patients with presumed community-acquired pneumonia: A survey of nonteaching US community hospitals

Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia

Empiric antibiotic therapy and mortality among medicare pneumonia inpatients in 10 western states

Bacteremic pneumococcal pneumonia in one American city: A 20-year longitudinal study, 1978-1997

Effect of macrolides as part of initial empiric therapy on length of stay in patients hospitalized with communityacquired pnuemonia

Monotherapy may be suboptimal for severe pneumococcal pneumonia

Antibiotic resistance among gramnegative bacilli in US intensive care units: Implications for fluoroquinolone use

Geographic diversity and temporal trends of antimicrobial resistance in Streptococcus pneumoniae in the United States

Predicted effects on antibiotic use following the introduction of British or North American guidelines for community-acquired pneumonia in the Netherlands

A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia

Treatment with sequential intravenous or oral moxifloxacin was associated with faster clinical improvement than was standard therapy for hospitalized patients with communityacquired pneumonia who received initial parenteral therapy

Effectiveness of beta lactam antibiotics compared with antibiotics active against atypical pathogens in non-severe community acquired pneumonia: meta-analysis

Empirical atypical coverage for inpatients with community-acquired pneumonia: Systematic review of randomized controlled trials

Is a 5 day course of azithromycin enough for infections caused by Legionella pneumophila?

Three versus eight days of amoxicillin in mild to moderate-severe CAP. Program and Abstracts of the 44th Interscience Conference of Antimicrobial Agents and Chemotherapy

Achieving a safe and early discharge for patients with community-acquired pneumonia

Early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with communityacquired pneumonia

Early switch from intravenous to oral antibiotics and early hospital discharge: A prospective observational study of 200 consecutive patients with community-acquired pneumonia

A prospective randomized study of inpatient iv. antibiotics for community-acquired pneumonia. The optimal duration of therapy

A prospective randomized study of inpatient iv. antibiotics for community-acquired pneumonia. The optimal duration of therapy

Efficacy and safety of oral and early-switch therapy for community-acquired pneumonia: A randomized controlled trial

Effectiveness of early switch from intravenous to oral antibiotics in servere community acquired pneumonia: multicentre randomised trial

Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people

Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group

Resistance among Streptococcus pneumoniae: Implications for drug selection

Vaccines for pneumonia and new antiviral therapies

Pneumococcal vaccination of the elderly: Do we need another trial?

The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease

Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in adults aged 65 years or older: A prospective study

Clinical practice. Influenza vaccination for healthy young adults

Pneumococcal vaccination and pneumonia: Even a low level of clinical effectiveness is highly cost-effective

Cost-effectiveness of pneumococcal vaccination of older people: A study in 5 western European countries

Influenza vaccination. Who needs them and when?

Clinical effectiveness of influenza vaccination in persons younger than 65 years with high-risk medical conditions: The PRISMA study

The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature

Prevention and early treatment of influenza in healthy adults