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haemophilus influenzae type b conjugate vaccine PR P-T. Lancet 1994; 344:3626. Costantino P, Viti S, Podda A, Velmonte MA, et al. Development and phase 1 clinical testing of a conjugate vaccine against meningococcus A and C. Vaccine 1993;10:6918. Twumasi PA, Kumah S, Leach A, ODempsey TJD, et al. A trial of a Group A plus Group C meningococca l polysaccharide-protein conjugate vaccine in African infants. J Infect Dis 1995;171: 6328. Anderson EL, Bowers T, Mink CM, Kennedy DJ, et al. Safety and immunogenicity of meningococcal A and C polysaccharide conjugate vaccine in adults. Infect Immun 1994;62:3391-5. Lieberman JM, Chiu SS, Wong VK, Partridge S, et al. Safety and immunogenicity of a serogroups A/C Neisseria meningitidis oligosaccharide-protein conjugate vaccine in young children. JAMA 1996;275:1499503. Fairley CK, Begg N, Borrow R, Fox AJ, et al. Conjugate meningococcal A and C vaccin e: reactogenicity and immunogenicity in United Kingdom infants. J Infect Dis 1996;174:13603. Borrow R, Fairley CK, Begg N, Fox AJ, et al. Immunogenicity of a meningococcal A and C conjugate vaccine in UK infants. In: Zollinger W D, Frasch CE, Deal CD (eds). Abstracts of the tenth international pathogenic Neisseria conference, Baltimore, M D, 1996:2201. Frasch CE. Vaccines for prevention of meningococcal disease. Clin Microbiol Rev 1989;2:S134. Sierra GV, Campa HC, Varcacel N M, Garcia IL, et al.. Vaccine against group B Neisseria meningitidis: protection trial and mass vaccination results in Cuba. Natl Inst Public Health Ann (Oslo) 1991;14:195207. Boslego J, Garcia J, Cruz C, Zollinger W, et al and the Chilean National Committee for meningococcal disease. Efficacy, safety and immunogenicity of a meningococcal group B (15:P1.3) outer membrane protein vesicle vaccine in Iquique, Chile. Vaccine 1995:13:8219. de Moraes JC, Perkins BA, Camargo MC, Hidalgo NT, et al. Protective efficacy of a serogroup B meningococcal vaccine in Sao Paulo, Brazil. Lancet 1992;340: 10748. Noronha CP, Struchiner CJ, Halloran M E. Assessment of the direct effectiveness of BC meningococcal vaccine in Rio de Janeiro, Brazil: a case control study. Int J Epidemiol 1995;24:10507. Tappero J, Lagos R, Maldonado A, Herrera P, et al. Serum bactericidal activity elicited by two outer membrane protein serogroup B meningococca l vaccines among infants, pre-school children, and adults in Santiago, Chile. In: Zollinger W D, Frasch CE, Deal CD (eds). Abstracts of the tenth international pathogenic Neisseria conference, Baltimore, M D, 1996.

51 Peeters CCAM, Rumke HC, Sundermann LC, Rouppe van der Voort E, et al. Phase I clin ical trial with a hexavalent PorA containing meningococca l outer membrane vesicle vaccine. Vaccine 1996;14:100915. 52 Bjune G, Hoiby EA , Gronnesby JK, Arnesen O, et al. Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway. Lancet 1991;338:10936. 53 Perkins BA, Jonsdottir K, Briem H,

Griffiths E, et al. Immunogenicity of two efficacious outer membrane protein-based serogroup B meningococcal vaccines among young adults in Iceland. J Infect Dis 1998;177:68391. 54 Herbert MA, Heath PT, Mayon-White RT. Meningococcal vaccines for the United Kingdom. Commun Dis Rep 1995;5: R1305. 55 Hodgetts TJ, Brett A, Castle N. The early management of meningococcal disease. J Accid Emerg Med 1998;15:726.

Community acquired pneumonia

Roger Finch FRCP, FRCPath, Professor of Infectious Diseases, The City Hospital and University of Nottingham, Nottingham

pneum onia (CAP) as it presents to hospital.

Infections of the chest include a diverse range of conditions such as acute and chron ic bronc hitis, bronc hiectasis, pneumonia, lung abscess, pleurisy and empyema, whilst recurrent respiratory infections characterise those with cystic fibrosis. Because of its relative frequency, complexity and occasional fulminant and fatal nature, the focus of this article is comm unity acquired

Overview
The reported incidence of CAP in adults is 13 per 1,000 adults per annum. It affects all ages, although the incidence rises rapidly beyond 50 years of age. Risk factors include chronic disease, particularly of the lungs, sm okin g, alcoholism, institutional care and HIV infection. Approximately 80% of cases are managed in the community. Among

Key P oints

P neum onia is a com m on cause of hospitalisation and has a m or tality ranging from 510% to 50% in those requiring intensive care The m icrobial aetiology is diverse and unknow n in the m ajority of patients; Streptococcus pneum oniae rem ains the leading cause Initial assessment should include clues to the aetiology, risk factor and severity assessment crucial to optim ising m anagem ent and directing initial em pirical therapy Antibiotic resistance am ong respirator y pathogens is increasing and m ay in future affect the choice of penicillins and m acrolides in treating com m unity acquired pneum onia P revention includes im m unisation of risk groups against influenza and pneum ococcal infection, health education to control tobacco and alcohol abuse, and optim ising the control of any underlying predisposing condition

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those hospitalised, mortality rates of 510% rise to 50% in those requiring intensive care1.

Table 1. Microb ial causes of com m unity acquired pneum onia in adult s according to w here the patient is m anaged (data from recent prospective studies; reproduced from Ref 1 by permission of Adis Press International).
Comm unity (%) 136 014 01 03 01 126 03 016 03 019 014 Hospital (%) 776 111 04 016 07 029 03 018 03 016 010 Intensive care (%) 1036 012 022 030 032 07 06 Unknown 02 012 014

Microbial aetiology
Pneumonia is an all-embracing term for a wide range of mostly infectious illness whose natural history and disea se severity are affected by host and microbial factors. CAP has been much studied as it occurs within the community, hospital or intensive care setting. The diverse microbia l aetiolo gy is summarised in Table 1 according to the site of management. Streptococcus pneumoniae is the dominant pathogen. Oth er cause s of pneumo nia vary seasonally, for example, Legionnaires disease, or in periodicity, for example, Mycoplasma pneumoniae which produces epidemics ab out every four years. Zoonotic infections include psittacosis and Q fever. Haemophilus influenzae is more usually associated with chron ic lung disea se, while Staphylococcus aureus pneumonia may complicate influenza in some patients. Moraxella catarrhalis is a rare cause of pneumonia, associated with lung cancer and chronic lung disease. It is important to emphasise that viral pneumonia, other than influenza, may arise as a primary illness or as part of a polymicrobial pneumonia 2. The aetiology of pneumonia is undefined in about one- to two-thirds of cases according to the intensity of lab oratory investigation. The true frequency of Chlamydia pneumoniae as a cause of pneumonia remains uncertain ow ing to the patchy availability of reliable diagnostic tests.

Organism Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Legionella sp Gram-negative enteric bacteria Mycoplasma pneumoniae Chlamydia psittaci Chlamydia pneumoniae Coxiella burnetii Influenza viruses Other viruses

Diagnosis
The symptoms of pneumonia include fever, cough, sputum production and pleuritic chest pain. The features associated with pneumococcal, mycoplasma and legionella infections are unreliably predictive of aetiology 3. The presence of focal findings on examination is highly suggestive of pneumo nia, although radiographic evidence of recent lobar or segmental shadow ing without other

causes provide s the most reliable evidence. The prompt microscopic examination of fresh sputum by Gram stain remains helpful when there is a predominan t microorgan ism in a purulent specimen. A pure grow th of a single organism provides good evidence of causality 2 . Poo rly collected samples, tardily examined, are unhelpful. In the severely ill patient, consideration sho uld be given to obtaining respiratory secretions by either bronchosc opic sampling or percutaneous fine needle aspiration by a skilled operator. Positive cultures from norma lly sterile sites such as blood and pleural fluid have low sensitivity but high specificity. Urine examination for legionella antigen provides a rapid diagnosis of Legionnaires disease when positive. Baseline and convalescent sera are still required for the diagnosis of atypical infections. Although this is inevitably retrospective, it may have public health importance, as in the case of legionella infection.

determining the need for intensive care management, choice of antibiotic therapy and prognosis. Severity assessment is based on clinical, laboratory, radiographic and microbiolog ical information (Table 2), and should be used to evaluate all patients hospitalised with suspected CAP. The presence of two or more of the follow in g features is asso ciated with a 20% risk of mortality 2,4,5 :
l

respiratory rate: 30 breaths/ min or above diastolic blood pressure: 60 mmHg or less blood urea: greater than 7 mmol/ l.

Particular attention should be paid to assessing and correcting hypoxaemia and fluid imbalance, while admission to an intensive care unit should be considered in those with sev ere disea se (Table 3)6.

Antibiotic treatment
Initial antibiotic management is largely empirical, with choice of therapy guided by disease severity and the presence of risk factors, especially comorbidities such as pre-existin g chronic lun g, neurologica l, cardiovascular, renal or liver disease, diabetes mellitus 7,8, or a history of drug hypersensitiv ity. In recent years, the choice of therapy has been complicated by two trends: first, by a rising incidence of drug resis-

Management
Severity assessment
The key to management is an accurate history, which should include elucidating clues to the aetiology and risk factors and, most importantly, severity assessment. The last feature is critical in

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Table 2. Features of severe com m unity acquired pneum onia 2,4,5.

History Age 60 years Chronic lung disease Other chronic illness Ethanol abuse Investigations Blood urea >7 mmol/l W BC <4 x 109/l or >20 x 109/l Hypoxia (Po 2 <8 kPa) Acidosis Serum albumin <35 g/l Multilobar shadowing on CXR
CXR = chest x-ray W BC = white blood cell count

Table 3. Criteria for consider in g adm ission to an intensiv e care unit .

Intensive care unit admission is highly recommended in the presence of at least one of the follow ing: Severe respiratory failure: Respiratory rate >30 breaths/ min PO2/ FiO2 <250 mmHg (<200 mmHg if COPD) Need for mechanical ventilation Severe haemodynamic instability: Shock (systolic blood pressure <90 mmHg or diastolic <60 mmHg) Need of vasoactive drugs for more than 4 hours Urine output <20 ml/h (in absence of hypovolaemia) Severe acidosis (pH <7.30)

Clinical exam ination Atrial fibrillation Confusion Diastolic hypotension <60 mmHg Tachypnoea >30 breaths/ min Microbiological featur es Bacteraemia Legionnaires disease Staphylococcal or Gram-negative bacillary infection

tance among target pathogens such as H. influenzae. The b-lactamase production among H. influenzae is approximately 20%, although it varies geographically. Fortunately, this pathogen is an uncommon cause of CAP and, in general, is associated with chronic lung disease. Secondly, the pneumococcus remains the leading pathogen and must always be covered in the initial regimen, but there is a growing problem over the rapid spread of strains of S. pneumoniae with reduced susceptibility to penicillin. However, current levels of resistance have not yet been clearly linked to clinical failure with conventional doses of parenteral penicillin 9. None the less, higher do sage oral amoxycillin is increasingly recommended and appears to achieve adequate drug concentrations within the lung. Of additional concern is the rising frequency of resistance to erythromycin, often linked to penicillin resistance. Rates of 10% have been reported among strains submitted to a reference laboratory 10, although the true incidence of resistance remains uncertain. At present, erythromycin remains a suita ble alternative in patients allergic to penicillin, although close monitoring will be essential and this recommendation may require adjustment in the future. Several new quinolone antibiotic s possess greater Gram-positive activity.

These include sparfloxacin , grepafloxacin, levofloxacin and trovafloxacin (at the time of writing, sparfloxacin and trovafloxacin are not yet on sale in the UK, but are expected soon). These have all demonstrated clinical efficacy against S. pneumoniae, including those strain s resista nt to penicillin and/ or macrolides 1,11,12. They have the additional advantage of activity against atypical pathogens, including Legionella sp, and therefore offer the opportunity of monotherapy in the management of CAP. To date, experience with these agents is limited but encouraging. The recommendations for the initial management of CAP empiric al (summarised in Table 4) are based on a synthesis of published guidelines, recognition of the changing pattern of resistance among target pathogens and the availability of new agents, whilst also providing alternative therapy when there is intolerance to the preferred agents. Where microbiolog ical definition of the cause is established, treatment should be modified as indicated in Table 5. Transfer to oral therapy in those initially treated with intravenous agents should follow clinic al improvem ent. Most pneumonias will respond to seven days treatment, although severe staphyloco ccal and Gram-negative bacillary pneum onia often require more prolon ged treatment. Three

Severe disseminated intravascular coagulation Other severe organ failures

COPD = chronic obstructive pulmonary disease

weeks therapy is recommended for Legionnaires disease.

Complications
Most patients hospitalised with pneumonia recover. A more severe course accompanies bacteraemic illness and infection with some pneumococcal serotypes, for example, serotype 3 with which shock and disseminated intravascular coagulation may arise. A pleural effusion is more common with pneumococcal pneumonia, but usually resolves spontaneously. Large effusions require drainage; if they persist, empyema sh ould be considered. Empyema, which is more likely to complicate S. aureus pneumonia and that caused by Gram-negative bacilli, often loculates within the pleural space, so repeated drainage and occasio nally thoracotomy may be necessary. Local instillation of antibiotics is sometimes attempted, although systemically administered agents usua lly achieve

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Table 4. R ecom m ended initial em pir ical treatm ent of com m unit y acquired pneum onia adm itted to hosp ital.
Com or bidity Severity/ R egim en Non- severe Preferred Amoxycillin 0.51.0 g tds PO or Ampicillin 0.5 g q6h IV or Benzylpenicillin (Penicillin G) 1.2 g q6h IV Erythromycin* 250500 mg q6h PO or IV Amoxycillin/Clavulanate 625 mg tds PO or 1.2 g q8h IV

Absent

P resent

Alternative

Clarithromycin 250500 mg bd PO or Sparfloxacin** 400 mg/200 mg od PO or Cefuroxime 750 mg q8h IV

Severe Preferred Amoxycillin/Clavulanate 1.2 g q8h IV and Erythromycin 0.51.0 g q6h IV or Clarithromycin 500 mg q12h IV Rifampicin 600 mg q12h PO or IV Cefotaxime 1 g q8h IV or Ceftriaxone 2 g od IV and Erythromycin 0.51.0 g q6h IV or Clarithromycin 0.5 g q12h IV Rifampicin 600 mg q12h PO or IV Imipenem/ Meropenem 0.5 g q8h IV and Erythromycin 0.51.0 g q6h IV or Clarithromycin 0.5 g q12h IV and Erythromycin 0.51.0 g q6h IV Rifampicin 600 mg q12h PO or IV

Alternative

Cefuroxime 1.5 g q8h IV and Erythromycin 0.51.0 g q6h IV or Clarithromycin 0.5 g q12h IV Rifampicin 600 mg q12h PO or IV

* **

Alternative agents include clarithromycin and azithromycin. Alternative quinolones with Gram-positive activity include levofloxacin, grepafloxacin or trovafloxacin. Alternative agents for suspected legionella infection include ofloxacin, ciprofloxacin, sparfloxacin or doxycycline.

adequate therapeutic concentrations. Oth er less common complications include pericarditis and metastatic infection such as meningitis.

Prevention
Tobacco and alcohol abuse are established risk factors for pneumonia, and their control through health education remains an import ant target. Water supplies and air cooling systems in public buildings need regular maintenance to prevent legionella infection. Predisposing diseases such as cardiopulmonary disease and chronic renal failure should be optimally managed to reduce the risk of CAP. The use of pneumococcal vaccine is recommended in those with chronic diseases of the heart, lung, kidneys and liver (including cirrhosis), as well as those with hyposplenism or asplenia 13. It can be administered simultaneously with influenza

vaccine (which shares similar indications for use) but, unlike pneumococcal vaccine, is recommended to be given annually 13. Influenza vaccination is also recommended for all people over the age of 65 years.

References
1 Finch RG, Woodhead MA. Practical
considerations and guidelines for the management of community-acquired pneumonia. Drugs 1998;55:3145. 2 The British Thoracic Society and the Public Health Lab oratory Service. Community-acquired pneumonia in adults in British hospitals in 19821983: a survey of aetiology, mortality, prognostic factors and outcome. Q J Med 1987;62:195220. Macfarlane JT, Miller AC, Roderick Smith W H, Morris AH , et al. Comparative radiographic features of community acquired Legionnaires disease, pneumococca l pneumonia, mycoplasma pneumonia, and psitta cosis. Thorax 1984;39:2833. Farr BM, Sloman AJ, Fisch MJ. Predicting death in patients hospitalized for community-acquired pneumonia. Ann Intern Med 1991;115:42836. Karalus N C, Cursons RT, Leng RA, Mahood CB , et al. Community acquired pneumonia: aetiology and prognostic index evaluation. Thorax 1991; 46:4138.

Summary
CAP affects all ages but predominantly the elderly. The microbial aetiology is diverse and rarely established at the time of admission. Initial management includes assessment of severity, correction of dehydration and imbalances of gas exchange, and prompt administration of antibiotic . The regimens will vary by risk factor and severity assessment. Mortality remains high, especially in those requiring intensive care. Prevention includes control of underlying disease, smok ing and ethanol abuse, and the appro priate use of influenza and pneumococcal vaccines.

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Table 5. R ecom m ended treatment of m icrobiologically docum ented pneum onia.

Antibiot ic regim en Organism Streptococcus pneumoniae P referred Amoxycillin 0.5 g tds PO or Benzylpenicillin (Penicillin G) 1.2 g q6h IV Erythromycin 0.251.0 g q6h PO or IV (or other macrolide) Alternative Erythromycin 0.250.5 g qds PO or Ceftriaxone 2 g od IV Tetracycline 0.250.5 g qds PO or 0.5 g q12h IV or New quinolone* Quinolone PO or IV or Doxycycline 100200 mg od PO Rifampicin 600 mg q12h PO or IV Erythromycin 0.51.0 g q6h PO or IV

Mycoplasma pneumoniae Chlamydia pneumoniae

Legionella sp

Erythromycin 0.250.5 g q6h PO or IV Rifampicin 600 mg q12h PO or IV

Chlamydia psittaci Coxiella burnetii Staphylococcus aureus Haemophilus influenzae

Tetracycline 0.250.5 g qds PO or 0.5 g q12h IV Flucloxacillin 12 g q4h IV Non-b-lactamase-producing: Amoxycillin 0.5 g tds PO or Ampicillin 0.5 g q8h IV

Vancomycin 1 g q12h IV Cefuroxime 0.751.5 g q8h IV or Cefotaxime 12 g q8h IV or Ceftriaxone 2 g od IV or Quinolone PO or IV

b-lactamase-producing: Amoxycillin/Clavulanate 625 mg tds PO or 1.2 g ql2h IV Gram-negative enteric bacilli Cefotaxime 12 g q8h IV/ Ceftriaxone 12 g q12h IV Ciprofloxacin 400 mg q12h IV or Imipenem/ Meropenem 0.51.0 g q8h IV

*New quinolones include grepafloxacin, levofloxacin, sparfloxacin and trovafloxacin

European Respiratory Society. Guidelines for management of adult communityacquired pneumonia (ESOCA P). Eur Respir J 1998;11:98691. Fine MJ, Smith MA, Carson CA, Mutha SS, et al. Prognosis and outcomes of patients with community-acquired pneumonia a meta-analysis. JAMA 1996;275: 13441. British Thoracic Society. Guidelines for the management of community-acquired pneumonia in adults admitted to hospital. Br J Hosp Med 1993;49:34950.

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Klugman KP. The clinical relevance of in-vitro resistance to penicillin, ampicillin, amoxycillin and alternative agents, for the treatment of community-acquired pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. J Antimicrob Chemother 1996;38:13340. Laurichesse H, Robin F, Gerbaud L, Pochet P, et al. Empirical therapy for non-hospitalized patients w ith community-acquired pneumonia. Eur Respir J 1998;11:738. Gialdroni Grassi G, Brumpt I. Spar-

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floxacin empirical therapy in community-acquired pneumonia: results of a meta-analysis of two comparative studies. N Engl J Med 1995;49:4068. ODoherty B, Dutchman DA, Pettit R, Maroli A. Randomised, double-blind, comparative study of grepafloxacin and amoxycillin in the treatment of patients with community-acquired pneumonia. J Antimicrob Chemother 1997;40:7381. Salisbury DM, Begg NT (eds). Immunisation against infectious disease. London: HM SO, 1996.

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