Infection

Bacterial pneumonia
Michael R Loebinger Robert Wilson

is the seventh leading cause of death in the USA,2 and the third leading cause of death (7.9%) in females in the UK.

Pathology and pathogenesis

Pneumonia occurs due to invasion of the lower respiratory tract by microbes. Inhalation of airborne pathogens, aspiration of gastric and nasopharyngeal flora and spread from other infected sites are the most common routes for microbes to access the lower respiratory tract. The development of pneumonia and its severity is then a balance between bacterial (virulence, inoculum size) and host factors (host defences, e.g. physical, specific and non-specific immune responses). Pathologically, the alveoli and interstitium of the lung are filled with inflammatory cells and fibrin, and the microbe responsible can usually be recovered by culture. The most common bacterial microbes responsible for pneumonia are listed in Table 1.

Abstract
Bacterial pneumonia remains one of the leading causes of morbidity and mortality. National and international guidelines addressing the management of pneumonia have been developed over the last several years, with the aim of improving the care and outcomes of pneumonia. This article addresses many of these management issues with reference to changes in management for particular patient groups. The importance of stratifying risk and immediate emergency department management is discussed. In addition, response to therapy and follow-up management is examined. This article discusses the evidence behind present practice and possible future directions for pneumonia management with the advent of new biomarkers.

Diagnosis
History and examination A full history and examination should be performed. Specific features that suggest a particular aetiology of the pneumonia should be elicited. Pleuritic chest pain, acute onset and high fever are thought to be characteristic of Streptococcus pneumoniae, whereas a multisystem involvement, the clustering of cases, and a history of foreign travel may alert the physician to the possibility of Legionella pneumophila. A study comparing Chlamydia pneumoniae and S. pneumoniae found that patients with the former were more likely to have headaches and a longer duration of symptoms before hospital attendance.3 Mycoplasma pneumoniae infections are similar and outbreaks occur every five years or so. Staphylococcus aureus pneumonia often follows viral infections, such as influenza. The history should also focus on particular features of the host, including co-morbidities, particularly chronic respiratory conditions (making gram-negative organisms, particularly Haemophilus influenzae and Pseudomonas aeruginosa more likely) and any form of immunodeficiency, which makes the possibility of an unusual pathogen more likely.

Keywords antibiotics; bacteria; community-acquired pneumonia; infection; pneumonia; vaccination

Pneumonia is an acute respiratory illness secondary to infection and inflammation of the lung parenchyma. Patients typically present with fever, cough, sputum production and pleuritic chest pain, and have evidence of new consolidation on chest radiography. Bacteria are the most common aetiological agents, and this article concentrates on bacterial pneumonia. However, viruses, fungi and parasites can also cause pneumonia.

Epidemiology
Pneumonia is commonly classified into community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), defined as the development of pneumonia after 48 hours of hospitalization. Pneumonia is very common especially in the young and old populations. CAP has an incidence of 511/1000 adults. Of these, 2242% will require admission to hospital with a mortality of 512%. ICU admissions are necessary in 510% of hospital admissions with a mortality of over 50% in this population.1 HAP has a greater associated mortality than CAP. Despite advances in treatment of pneumonia, mortality remains high. Pneumonia

Aetiologies of community-acquired pneumonia in hospital studies

Microbe Streptococcus pneumoniae Chlamydia pneumoniae Mycoplasma pneumoniae Haemophilus influenzae Legionella spp. Chlamydia psittaci Staphylococcus aureus Moraxella catarrhalis All viruses Percentage 39 13.1 10.8 5.2 3.6 2.6 1.9 1.9 12.8

Michael R Loebinger MA MRCP is an MRC Clinical Training Fellow and Specialist Registrar in Respiratory and General Medicine at the Host Defence Unit, Royal Brompton Hospital, London, UK. Competing interests: none declared. Robert Wilson MD FRCP is an NHS Consultant at the Host Defence Unit, Royal Brompton Hospital, London, UK. Competing interests: none declared.

The percentage given is the mean from five studies with n=1137.1

Table 1

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Infection

No individual clinical findings can reliably diagnose pneumonia, but a normal chest examination makes the diagnosis unlikely.1 Investigations Patients with suspected pneumonia should have a chest X-ray (CXR), to demonstrate consolidation, on which an accurate diagnosis of pneumonia is based (Figure 1). Other CXR findings may include air bronchograms, cavitation and parapneumonic effusions. Bloods tests should also be performed, including full blood count, inflammatory markers, and renal and hepatic indices, the derangement of which may indicate increased severity (see below) or a multisystem involvement characteristic of atypical (Mycoplasma, Chlamydia, Legionella) pneumonias. An assessment of oxygen saturation should also be made. The sensitivity of routine sputum and blood cultures from patients with community-acquired pneumonia is low, particularly in non-severe CAP.4 As such, guidelines suggest that blood cultures can be omitted in patients with low-risk CAP.5 Nevertheless, a full range of microbiological investigations should always be performed with patients with severe CAP. These include blood and sputum cultures and urinary antigen tests for pneumococcus and legionella infections. Legionella antigen testing has been shown to directly influence management decisions and reduce both mortality and the need for intensive care.6,7 Present British Thoracic Society (BTS) guidelines suggest that all hospitals admitting patients with CAP should have access to a rapid testing and reporting service for legionella urine antigen.5 Other atypical pneumonia microbes are investigated with paired serological tests. Severity assessment and site of care decisions Significant variations exist in admission rates for patients with pneumonia. In view of this, a variety of severity assessments have been developed to categorize patients into prognostic groups to aid in management decision. The most popular models are detailed below. The pneumonia severity index (PSI) classifies patients into five risk categories based on 20 different variables. It has been validated in over 38,000 hospitalized patients with CAP.8

The CURB-65 score separates patients into three (low, intermediate or high) mortality groups based on five simple measures:9  confusion  urea >7 mmol/l  respiratory rate >30/min  blood pressure (BP); systolic BP <90 mmHg or diastolic BP <60 mmHg  age (>65 years). This was based on a prospective study of over 1000 CAP patients from three countries. The presence of one or fewer of these features points to a low mortality (1.5%) and the possible suitability for home treatment, whereas the presence on assessment of three or more features is suggestive of a severe pneumonia with a higher mortality (22%) and the necessity for consideration of ICU support (Figure 2). The simplicity of the CURB-65 score has led to its recommendation by the BTS.5 Although these severity scores can improve decision making regarding the most suitable location for the institution of CAP management, it is important that they are not used in isolation. Studies have shown some patients with low CURB-65 or PSI scores require hospital admission, including to the ICU, and these may include patients with complications of pneumonia, exacerbations of underlying diseases, and multiple risk factors below the required score thresholds.10

Treatment
Antimicrobial treatment The likely aetiological agent cannot be accurately predicted from clinical and radiographical feaures alone. Consequently, most initial antibacterial treatment is empirical and based on the most common microbes (see above), with specific knowledge of local pathogens and resistance. Patients admitted to hospital with pneumonia should receive the first antibiotic dose in the emergency department.2 The present updated BTS guidelines for CAP, and the American Thoracic Society guidelines for HAP, suggest treatment as shown in Figure 3.2,5 In view of the low

Consolidation on chest X-ray (CXR). a Right upper lobe pneumonia, b multilobar pneumonia. Figure 1

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Infection

The CURB-65 risk stratification for CAP9

Assessment Risk stratify Low mortality (1.5%) Management Consider home treatment

Confusion (mental test score 8) Urea (>7 mmol/l) Respiratory rate (30/min) Blood pressure (Systolic <90 mmHg, Diastolic 60 mmHg) 65 years and above

Moderate mortality (9.2%)

Consider hospital treatment

High mortality (22%)

Severe pneumonia, consider intensive care

Figure 2

level of penicillin-resistant S. pneumoniae in the UK, amoxicillin plus a macrolide are suggested for first-line non-severe bacterial pneumonia. Respiratory fluoroquinolones (moxifloxacin, levofloxacin) are suggested as alternatives. Severe pneumonia should be treated with a -lactam or cephalosporin antibiotic, plus macrolide.

Empirical treatment in particular populations The rationale of empirical treatment is to cover the most likely aetiological agents. In certain groups of patients, these may alter from those described in Table 1 and, consequently, empirical antimicrobials should differ from the general CAP guidelines described above.

Antibiotic management guidelines for community-acquired and hospitalacquired pneumonia

Community-acquired pneumonia (CAP) Assessment Not severe home treated Preferred treatment Amoxycillin po (0.51 g tds) Alternative Macrolide po

Not severe hospital treated

Amoxycillin + macrolide po/iv

Levofloxacin po/iv (0.5 g odbd) moxifloxacin po (0.4 g od)

Severe hospital treated

Co-amoxyclav iv (1.2 g tds) or cephalosporin iv + macrolide rifampicin

Levofloxacin po/iv (0.5 g bd) + benzyl penicillin iv (1.2 g qds)

Hospital-acquired pneumonia (HAP) Early (<5 days)/ low risk of resistance As for CAP

Late (5 days)/ high risk of resistance

Depends on local micro advice, but often need broad spectrum including cover gram-negative, Pseudomonas aeruginosa + methicillin-resistant Staphylococcus aureus .

Figure 3

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Infection

Hospital-acquired pneumonia is defined as pneumonia that occurs 48 hours or more after hospital admission. It is often further categorized into late onset ( 5 days after admission) or early onset (<5 days). Patients with late-onset HAP, and those with preceding antibiotic therapy, are more likely to have resistant organisms and need a broader spectrum of antibiotic cover. Common pathogens include Gram-negative bacteria, including P. aeruginosa, Escherichia coli, Klebsiella pneumoniae and Acinetobacter species. Gram-positive organisms, such as S. aureus and methicillin-resistant S. aureus (MRSA), are also common. It is very important in hospital-acquired infection to be aware of local patterns of infection and resistance. However, broad spectrum cover typically includes -lactams or cephalosporins or carbapenems with antipseudomonal cover and further gram-negative cover and MRSA cover (e.g. piperacillin/tazobactam or ceftazidime or meropenem, plus aminoglycoside plus teicoplanin, vancomycin or linezolid) The incidence of HAP is about 1% of hospital admissions.11 Nursing homes: a prospective study comparing nursing home residents with pneumonia to an age-matched population of patients admitted with CAP showed no difference in the causative organisms. As such, present UK guidelines suggest treating this group no differently from CAP patients.12 Chronic respiratory infections (bronchiectasis/cystic fibrosis): patients with bronchiectasis or cystic fibrosis will usually have previous results of aetiological organisms during infections. Empirical treatment regimens should ensure cover of these microbes. Gram-negative organisms are particularly common in patients with chronic respiratory disease. Cover should also include P. aeruginosa, if patients are known carriers. Typical empirical regimes would include cephalosporin or -lactam or carbapenem antibiotics with P. aeruginosa cover (e.g. ceftazidime or pipericillin/tazobactam or meropenem), and increased gram-negative cover with the addition of an aminoglycoside. Cystic fibrosis patients, in particular, are likely to have care in a specialized unit and it is good practice to seek advice with regards to antibiotic choice. Immunocompromised patients: these patients will be at increased risk of pneumonia; however, the type of immunodeficiency will

affect the most likely microbial agent. A reduction in humoral immunity predisposes to bacteria, especially S. aureus, S pneumoniae, H. influenzae. Cellular immunity deficiencies may predispose to viruses, bacteria, fungi and protozoa; whereas a reduction in neutrophil activity will predispose to bacteria and fungi. A study of 200 patients with a range of causes of immunodeficiency (52 organ transplant, 53 bone marrow transplant, 68 haematological malignancy, 27 immunosuppressive agents) showed that the aetiology of the pneumonia was bacterial in 48, fungal in 33, and viral in 20, with the most common bacterial agents being S. aureus and P. aeruginosa.13 First-line empirical regimens differ locally, but usually have broad-spectrum Gram-positive and negative cover (e.g. pipericillin/tazobactam or meropenem, plus an aminoglycoside). Consideration of fungal and Pneumocystis jiroveci cover should be made in this group of patients. Impaired airway protection: patients with impaired airway protection must be covered for anaerobic bacteria in addition to normal CAP empirical therapy. This group of patients may include alcoholics, patients with seizures, strokes, recent dental procedures, or neuromuscular disorders. Empirical treatment may include metronidazole, in addition to a -lactam or cephalosporin. The anatomy of the airways leads to the right lower lobe being most commonly affected in aspiration pneumonia. Specific microbe-directed treatment: the importance of empirical treatment regimens is demonstrated by the fact that in normal clinical practice, the aetiological agent responsible for the pneumonia will be defined only in between a third and a quarter of cases.1 Furthermore, in some cases identification of the microbe can be made only late in the illness by paired serological tests (e.g. Mycoplasma pneumoniae). Nevertheless, specific treatment for individual microbes is available and the BTS recommendations are shown in Table 2. Other treatment Non-invasive ventilation (NIV) has been successfully used in patients with chronic obstructive pulmonary disease and some studies have also shown a possible role in pneumonia. Several studies have shown some improvement, with a randomized controlled trial of 56 patients with CAP and hypoxia demonstrating

Recommended antimicrobial therapy for aetiologically determined pneumonia5

Microbe Streptococcus pneumoniae Chlamydia pneumoniae Mycoplasma pneumoniae Haemophilus influenzae Legionella spp. Chlamydia psittaci Staphylococcus aureus Methicillin-resistant S. aureus Pseudomonas aeruginosa Table 2 Preferred Amoxycillin po (0.51 g tds) or benzylpenicillin iv (1.2 g qds) Clarithromycin po/iv (500 mg bd) Erythromycin po/iv (500 mg qds) Co-amoxyclav po/iv (0.625/1.2 g tds) Clarithromycin po/iv (500 mg bd) +/ rifampicin Tetracycline po (250500 mg qds) Flucloxacillin iv (12 g qds)+/ rifampicin Vancomycin iv (1 g bd) Ceftazidime iv (2 g tds)+ aminoglycoside iv Alternatives Macrolide, cephalosporin Fluoroquinolone Tetracycline Cephalosporin, fluoroquinolone Fluoroquinolone Macrolide Teicoplanin, linezolid Teicoplanin, linezolid Ciprofloxacin, piperacillin/tazobactam, carbapenem

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that NIV led to a reduced need for intubation and a reduction in ICU stay.14 The use of NIV may also improve intermediateterm mortality.2 However, it is clear that these patients need very close observation as up to 50% deteriorate on NIV and need intubation, and hence trials should be performed only in ICU/high dependency unit (HDU) environments.15

Progress and follow-up

Satisfactory Uncomplicated cases of pneumonia often start improving in the first few days. Intravenous antibiotic treatment can be switched to oral therapy when improvement is being made clinically, and when the patient is haemodynamically stable and is able to take medicines orally. In general, about two-thirds of patients reach these criteria within the first three days of treatment.2 Most patients with pneumonia are still treated for 710 days with antibiotics; however, there are few well designed studies accurately defining the optimal length of antibiotic treatment. A study comparing a five-day regimen of high dose levofloxacin seemed at least as effective as a ten-day course of lower dose levofloxacin in CAP.16 This was replicated in a randomized study of patients receiving three days of intravenous amoxicillin followed by either five days of oral amoxicillin or placebo.17 Present guidelines suggest that patients should be treated with antibiotics for at least five days and discontinuation should not be before the patient has been apyrexial for at least 48 hours and has no more than one feature of clinical instability related to the pneumonia (e.g. tachycardia, hypotension, tachypnoea, hypoxia, abnormal mental state).2 Similarly, patients should not be discharged if they have more than one of the above features in the preceding 24 hours. These guidelines were the result of a prospective multicentre study which showed that 20% of 680 patients left hospital with 1 or more unstable features in the preceding 24 hours and that these features were correlated to readmission rates.18 After discharge, patients should be reviewed 68 weeks later to ensure that recovery has been complete and the CXR shadowing has resolved. Unsatisfactory If a patient fails to respond optimally to initial pneumonia management, they should be carefully reviewed. The problem may be that of an inadequate antibiotic, either because of a resistant or unsuspected microbe (tuberculosis should always be suspected), or because of inadequate absorption or dose of the antibiotic. Patients should have a further microbiological culture screen in cases of non-response. Response may also be limited by immunodeficiency and review should exclude this as a contributing factor to the lack of response to treatment. There are several local and distant complications of pneumonia that can ensue. These may include parapneumonic effusions and empyemas that may require chest tube drainage and an increase of antibiotic cover to include anaerobic bacteria in addition to the empirical pneumonia antimicrobial therapy. Lung abscess is a rare complication of pneumonia. Most of these patients will respond to antibiotics; however, prolonged courses may be necessary, as may surgical drainage. It is also important to consider that the original diagnosis of pneumonia may be incorrect. Underlying carcinomas may
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resent with radiographic shadowing which does not resolve, p and bronchoalveolar carcinomas typically present with diffuse parenchymal shadowing and sputum production. Cryptogenic organizing pneumonia and eosinophilic pneumonia can also mimic infective pneumonia in their presentation, with radiographic shadowing accompanied by pyrexia and raised inflammatory markers. These conditions may be suspected by findings on high-resolution CT scans.

Prevention
Vaccination is available against S. pneumoniae, the most common cause of CAP. S. pneumoniae is a capsulated organism with strains and virulence determined by capsule type. The pneumococcal polysaccharide vaccine contains a polysaccharide mix of the most common purified 23 capsular types. The vaccine has been shown to be effective in preventing pneumococcal disease, invasive disease, and mortality related to pneumonia, however, these results have not translated into the subgroups at high risk.19,20 Present recommendation for the use of this vaccination is for patients over 5 years with immunodeficiency and chronic diseases where the risk of pnemococcal infection is increased. The conjugated pneumococcal polysaccharide vaccine contains polysaccharide from 7 capsular types, which is then conjugated to protein. The covalent coupling of the polysaccharide antigens to the carrier proteins produce a T-cell reponse and increased immunogenicity. This vaccine should be used in children under five years of age who are at increased risk of pneumococcal disease. The use of this conjugated vaccine in children has been shown to alter the most common serotypes in adults. However, it is thought that host factors are more important than the advent of non-vaccine serotype infection in determining outcome.21 Smoking cessation is also an important part of pneumonia prevention. As well as increasing comorbidities, it is associated with a risk of S. pneumoniae bacteraemia and Legionella pneumophila infection.2

Future treatment
New biomarkers are being used to help improve and direct management of pneumonia. Procalcitonin is a precursor peptide for the hormone calcitonin and is specifically raised in bacterial infections, being released from parenchymal tissues of the body. Procalcitonin has been demonstrated to have greater sensitivity (88% vs 75%) and specificity (81% vs 67%) than C-reactive protein in bacterial infections.22 In a study in CAP, procalcitonin concentrations have been used to decide whether antibiotics should be given on a daily basis. The outcome of this procalcitonindirected treatment group was compared to a matched control group treated with antibiotics according to usual practice. The authors showed a significant reduction in antibiotic use with no change in clinical outcomes, suggesting a possible future use of biomarker-directed treatment of pneumonia.23

References 1  British Thoracic Society guidelines for the management of community acquired pneumonia in adults. Thorax 2001; 56(suppl 4): IV164.

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2  Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44(suppl 2): S2772. 3  Kauppinen MT, Saikku P, Kujala P, Herva E, Syrjala H. Clinical picture of community-acquired Chlamydia pneumoniae pneumonia requiring hospital treatment: a comparison between chlamydial and pneumococcal pneumonia. Thorax 1996; 51: 18589. 4 Theerthakarai R, El Halees W, Ismail M, Solis RA, Khan MA. Nonvalue of the initial microbiological studies in the management of nonsevere community-acquired pneumonia. Chest 2001; 119: 18184. 5  Macfarlane JT, Boldy D. 2004 update of BTS pneumonia guidelines: whats new? Thorax 2004; 59: 36466. 6  Lettinga KD, Verbon A, Weverling GJ, et al. Legionnaires disease at a Dutch flower show: prognostic factors and impact of therapy. Emerg Infect Dis 2002; 8: 144854. 7  Lim WS, Macfarlane JT, Boswell TC, et al. Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines. Thorax 2001; 56: 296301. 8 Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify lowrisk patients with community-acquired pneumonia. N Engl J Med 1997; 336: 24350. 9  Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003; 58: 37782. 10  Arnold FW, Ramirez JA, McDonald LC, Xia EL. Hospitalization for community-acquired pneumonia: the pneumonia severity index vs clinical judgment. Chest 2003; 124: 12124. 11  Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171: 388416. 12  Lim WS, Macfarlane JT. A prospective comparison of nursing home acquired pneumonia with community acquired pneumonia. Eur Respir J 2001; 18: 36268.

13  Peckham D, Elliott MW. Pulmonary infiltrates in the immunocompromised: diagnosis and management. Thorax 2002; 57(suppl 2): II3I7. 14 Confalonieri M, Potena A, Carbone G, Porta RD, Tolley EA, Umberto MG. Acute respiratory failure in patients with severe community-acquired pneumonia. A prospective randomized evaluation of noninvasive ventilation. Am J Respir Crit Care Med 1999; 160: 158591. 15  British Thoracic Society Standards of Care Committee. Non-invasive ventilation in acute respiratory failure. Thorax 2002; 57: 192211. 16  Dunbar LM, Wunderink RG, Habib MP, et al. High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clin Infect Dis 2003; 37: 75260. 17  el Moussaoui R, de Borgie CA, van den BP, et al. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. BMJ 2006; 332: 1355. 18  Halm EA, Fine MJ, Kapoor WN, Singer DE, Marrie TJ, Siu AL. Instability on hospital discharge and the risk of adverse outcomes in patients with pneumonia. Arch Intern Med 2002; 162: 127884. 19 Cornu C, Yzebe D, Leophonte P, Gaillat J, Boissel JP, CucheratM. Efficacy of pneumococcal polysaccharide vaccine in immunocompetent adults: a meta-analysis of randomized trials. Vaccine 2001; 19: 478090. 20 French N. Use of pneumococcal polysaccharide vaccines: no simple answers. J Infect 2003; 46: 7886. 21  Alanee SR, McGee L, Jackson D, et al. Association of serotypes of Streptococcus pneumoniae with disease severity and outcome in adults: an international study. Clin Infect Dis 2007; 45: 5254. 22  Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 2004; 39: 20617. 23 Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006; 174: 8493.

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