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Seminar

Community-acquired pneumonia

Patricia D Brown, Stephen A Lerner

This seminar reviews the aetiology, clinical presentation, approach to diagnosis, and management of immunocompetent adults with community-acquired pneumonia (CAP). Pneumonia is a common clinical entity, particularly among the elderly. A thorough understanding of the epidemiology and microbiology of CAP is essential for appropriate diagnosis and management. Although the microbiology of CAP has remained relatively stable over the last decade, there is new information on the incidence of atypical pathogens, particularly in patients not admitted to hospital, and new information on the incidence of pathogens in cases of severe CAP and in CAP in the elderly. Recent studies have provided new data on risk factors for mortality in CAP, which can assist the clinician in decisions about the need for hospital admission. The emergence of antimicrobial resistance in Streptococcus pneumoniae, the organism responsible for most cases of CAP, has greatly affected the approach to therapy, especially in those patients who are treated empirically. Guidelines for the therapy of CAP have been published by the American Thoracic Society, the British Thoracic Society, and, most recently, the Infectious Diseases Society of America. These guidelines differ in their emphasis on empirical versus pathogenic-specific management. Pneumonia is a common clinical disorder with an estimated incidence of 12 cases per 1000 population per year.1 In the USA, pneumonia is the sixth most important cause of death, and the estimated cost of treatment, including direct patient-care costs and lost wages, is more than US$20 billion per year.1 In the UK the cost of treating community-acquired pneumonia (CAP) is estimated to be 4407 million per year, and 32% of CAP patients need hospital treatment, which accounts for 96% of this cost.2 CAP is thought to account for 10 million physician visits per year in the USA. There, an estimated 258 cases per 100 000 population, and 962 cases per 100 000 population aged over 65 years, need hospital treatment for CAP.3,4 Current medical research issues include the importance of new pathogens such as legionella and Chlamydia pneumonia2 in the aetiology of CAP, the emerging drug resistance among strains of Streptococcus pneumoniae, and the effective prediction of the risk of mortality, which may help in decisions as to which CAP patients should be admitted to hospital. Guidelines have been written by various expert panels to help the selection of appropriate antimicrobial therapy. The epidemiology and potential microbial aetiologies of pneumonia in immunosuppressed patients are not included in this seminar. colleagues,6 all patients studied were those who needed hospital admission for CAP. The number of cases of CAP caused by atypical pathogens (legionella, Mycoplasma pneumoniae, C pneumoniae) varied between studies. Possible explanations for this variation include true variation in the occurrence of atypical pathogens in different geographical areas, demographic variation between study populations, and different laboratory techniques used in the microbiological diagnosis of pneumonia. The proportion of CAP patients coinfected with one or more pathogens also varied, from less than 10% of patients to 389% of patients.11 In a series of 149 relatively young CAP patients not admitted to hospital (mean age 41 years [SD 15]) from Halifax, Nova Scotia, Canada, microbial causes were determined by serology alone. Atypical pathogens accounted for almost half of the pneumonias in these patients, with little comorbidity.12 The microbiology of severe CAP in patients admitted to intensive-care units is similar to that in other patients admitted to hospital with CAP. S pneumoniae is generally the most commonly isolated pathogen, although H influenzae and gram-negative bacilli may account for slightly more cases of severe CAP. However, gramnegative bacilli are generally found only in patients with underlying chronic disorders such as chronic obstructive pulmonary disease,13 and Pseudomonas aeruginosa is found only rarely in immunocompetent patients with no severe underlying structural lung disease.14 The reported occurrence of the atypical pathogens also varies in this subgroup of patients. Moine and colleagues15 showed that in a series of 132 patients with severe CAP who were admitted to an intensive-care unit, six (46%) had an atypical pathogen; four of the six isolates were Legionella pneumophila. No cause was shown in 28% of the patients in that series. Torres and colleagues13 found L pneumophila in 14% of pneumonias and S pneumoniae in 15% of pneumonias in 92 patients with severe CAP. M pneumoniae was the third most common isolate (6% of cases). No cause was shown in 48% of patients in that 1295

Aetiology
Six large-scale studies of the aetiology of CAP (table 1510) showed that S pneumoniae is still the most common cause of CAP, with respiratory viruses and Haemophilus influenzae also commonly implicated. Except for the patients studied by Woodhead and
Lancet 1998; 352: 1295302
Division of Infectious Diseases, Department of Internal Medicine, Wayne State University School of Medicine (P D Brown MD) , and Division of Infectious Diseases, Harper Hospital, 3990 John R, Detroit, MI 48201, USA (S A Lerner MD) Correspondence to: Dr Stephen A Lerner

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Study Location

Year

Number of Rank order microbial cause (%) patients 1 2 116 236 359 106 346 334

4 GNB 7 GNB 15 Chlamydia spp 6 GNB 8 Legionella spp 162 Mycoplasma spp 6

Unknown 35 45 33 33 194 45

5 6 7 8 9 10

Paris, France Nottingham, UK Pittsburgh, USA Adelaide, Australia Beer-Sheva, Israel Leiden, Netherlands

198384 198485 198687 198788 199192 199193

S pneumoniae 26 S pneumoniae 36 S pneumoniae 15 S pneumoniae 42 S pneumoniae 428 S pneumoniae 27

H influenzae 12 Viral 13 H influenzae 11 Viral 18 Mycoplasma spp 292 Viral 8

M tuberculosis 10 H influenzae 10 Legionella spp 7 H influenzae 9 Chlamydia spp 179 H influenzae 8

Legionella spp 4 S aureus 1 Gram-negative bacilli 6 Mycoplasma spp 8 Viral 101 Chlamydia spp 3

Modified from Fang et al.7

Table 1: Causes of CAP

series. Torres and colleagues13 also summarised data from five series of severe CAP. In all five series, S pneumoniae was the most common pathogen; and in three of the five L pneumophila was the second most common isolate. In the other two studies, M pneumoniae and Klebsiella pneumoniae were the second most frequently isolated pathogens.13 In an analysis of 11 studies of the microbiology of CAP in the elderly, Woodhead16 showed that in 785 patients over 65 years old S pneumoniae was again the most common cause of CAP. H influenzae, gramnegative bacilli, respiratory viruses, and Staphylococcus aureus accounted for more cases of pneumonia in the elderly than in people under the age of 65. The atypical pathogens, especially M pneumoniae, accounted for a smaller proportion of pneumonias in people over 65. However, Marston and colleagues4 showed a much higher incidence of M pneumoniae and C pneumoniae in elderly patients with CAP than was reported in previous studies. Accurate information on the incidence of various pathogens in elderly patients is especially important for the selection of appropriate antimicrobial therapy, since more than 90% of deaths caused by pneumonia occur in the elderly.16 Few studies have analysed seasonal variation in the incidence of common pneumonia pathogens. In a prospective study of 346 patients with CAP admitted to hospital over 1 year, Lieberman and colleagues17 found that most pathogens showed no seasonal variation, except for the respiratory viruses, which were more common in winter and spring and were rare in autumn, and for M pneumoniae, which was most common in spring. However, this study was done in southern Israel, which has less climatic variation than Europe and North America. No specific cause is found in 2550% of patients with CAP. As a result, many patients with CAP must be treated empirically.

the elderly, or from a true physiological effect of ageing, is unknown. Fever occurs in 80% of patients; 80% have crackles on auscultation and signs of consolidation are present in 30% of patients.1

Initial investigation and diagnosis

Chest radiography should be used to confirm the clinical diagnosis of pneumonia. Although particular radiography patterns may suggest a particular group of pathogens, a microbiological diagnosis should not be based solely on radiography. In our experience, patients who are substantially volume-depleted may initially present with a normal chest radiograph; in such cases infiltrates may be shown only after adequate rehydration. The resolution of infiltrates after successful therapy may take several weeks or several months, but it is not known whether every CAP patient needs follow-up radiography to show that infiltrates have cleared. Young non-smokers who are healthy at a 6-week follow-up visit generally do not need radiography to show pneumonia resolution. In the USA, the Centers for Disease Control and Prevention recommend serological tests for HIV-1 infection in patients aged 1554 years with pneumonia who are admitted to a hospital where the proportion of HIV-positive patients among those discharged is 1 in 1000 or more. Patients in hospital with CAP should have a complete blood count and measurements of electrolytes, blood urea nitrogen and serum creatinine, liver-function tests, and arterial oxygenation (arterial blood-gas analysis or pulse oximetry). Although Chalasani and colleagues retrospective study19 suggested that routine blood cultures in non-immunosuppressed patients admitted to hospital with CAP are of limited clinical use and questionable cost-effectiveness, we think that blood cultures should be done for all patients ill enough to be admitted to hospital with pneumonia, especially given current increases in microbial resistance to drug treatments. Patients with pleural effusions of sufficient volume should undergo diagnostic thoracentesis, which may confirm a microbiological diagnosis and which will rule out the possibility of an empyema that would necessitate chest-tube drainage. Sahn20 recommends thoracentesis for any effusion measuring more than 10 mm on a lateral decubitus chest radiograph. Pleural-fluid analysis should include gram stain and culture, a cell count and differential, and protein, lactate dehydrogenase, glucose, and pH measurements. Stains and cultures for mycobacterial and fungal pathogens should be done in selected cases. The usefulness of a gram stain and culture of expectorated sputum to guide initial antimicrobial therapy and to confirm a microbiological diagnosis is debated by infectious-disease specialists and pulmonologists. Guidelines for the management of CAP from the American Thoracic Society21 call for empirical antibiotic therapy. Guidelines from the British Thoracic

Clinical presentation
Fever with cough, sputum production, dyspnoea, and pleuritic chest pain, are the presenting symptoms of pneumonia. In the past, many clinicians thought that they could differentiate between pneumonia caused by one of the atypical pathogens and typical pneumonia caused by S pneumoniae and other bacteria, because the two types had different clinical presentations. However, it is not possible to predict microbial aetiology reliably by use of presenting signs and symptoms.7,12 Extrapulmonary symptoms, including headache, myalgia, arthralgia, and gastrointestinal symptoms, are reported in 1030% of patients with CAP.1 Elderly patients report fewer symptoms than patients under 65 years of age, even after control for increased morbidity and severity of illness.18 Whether this tendency results from a diminished subjective response to symptoms in 1296

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Society22 state that the presence of a predominant organism in a Grams stain of a good quality specimen is a specific but not sensitive test which provides presumptive diagnostic information. Guidelines for the management of CAP from the Infectious Diseases Society of America also call for sputum gram stain, but admit that the recommendation is based mainly on expert opinion without strong supporting evidence.23 We feel strongly that an attempt to obtain sputum for gram stain and culture should be made in all patients with CAP who are admitted to hospital. Results of gram stains are useful in the initial selection of antimicrobial therapy, and culture results can confirm or alter the initial diagnostic impression and help to refine an appropriate therapy. Culture and antimicrobial susceptibility results also aid the compilation of data on trends in the prevalence and susceptibility patterns of various pathogens in local communities. A gram stain positive for pneumonia should have more than 25 polymorphonuclear leucocytes and fewer than ten epithelial cells in each low-power field.24 The presence of a predominant organism (at least eight to ten organisms in each high-power field) that is morphologically compatible with a likely pulmonary pathogen is acceptably specific for diagnosis of CAP.25 Culture confirmation should always be sought, given that antimicrobial resistance is increasing. However, many of the pathogens that cause pneumonia may colonise the respiratory tract without causing disease, and thus culture results must be interpreted together with the results of the gram stain. Some patients with CAP produce either no sputum at all or no specimen of adequate quality. Previous antimicrobial therapy may also affect the gram-stain results. The clinician or clinical microbiologist must be experienced in analysis of sputum gram stains. Inexperienced clinicians can make interpretative errors that can have adverse effects on patient care.26 The start of antibiotic therapy should not be delayed unduly if an adequate sputum specimen cannot be obtained at first. Meehan and colleagues27 found that in elderly patients with pneumonia 30-day mortality was lower after administration of antibiotics within 8 h of arrival at hospital than after delayed treatment.27 At our institution, we advise that the start of therapy is delayed for no longer than 6 h by attempts to obtain an adequate sputum sample for diagnostic studies. Fibreoptic bronchoscopy with protected brush culture can be of diagnostic value in CAP, but diagnostic success may be significantly reduced in patients who have been on antibiotic therapy for several days.28 This invasive procedure should generally be reserved for critically ill patients or for those who are severely immunosuppressed. In CAP caused by Legionella spp, M pneumoniae, and C pneumoniae, the best strategies for diagnosis are uncertain at present. Serological diagnosis can be made for all three pathogens but it is of limited practical use, since it gives a diagnosis only in retrospect. Sputum culture for Legionella spp has 8090% sensitivity and 100% specificity, but it requires special media and selective techniques that may not be available in all laboratories. Immunofluorescence techniques have a sensitivity of 5070%, and a DNA probe for the detection of antigen in sputum has a sensitivity of 2575%.29 Urinary antigen detection by

radioimmunoassay has a sensitivity of 8099% and a specificity of 99%;29 the sensitivity is not greatly decreased even after antimicrobial therapy starts. At present, antigen-detection tests can detect only L pneumophila serogroup 1, although this serogroup is estimated to cause 7090% of legionella cases. M pneumoniae also requires special techniques for culture, but results may take a week or more to process, so clinical use is limited. Rapid antigen-detection tests are not currently available for widespread clinical use. C pneumoniae is an obligate intracellular pathogen, and therefore culture is difficult. A PCR enzyme immunoassay may eventually allow more rapid diagnosis.30 At present, we do not recommend tests for one of the atypical pathogens as part of the routine investigation of all patients with CAP. Edelstein29 recommends tests for legionella in patients who do not respond to -lactam antibiotics, in areas with a high prevalence of community-acquired legionella, in cases of epidemic-associated pneumonia, and in patients with a recent travel history or occupational exposure to water, especially if a sputum gram stain shows many polymorphonuclear cells and no apparent pathogen. CAP patients not treated in hospital should have chest radiography and laboratory tests to assess severity of the disorder and to help assess the need for a hospital stay. If possible, sputum should be obtained for gram stain and culture.

Mortality
For patients not admitted to hospital, the mortality from CAP is less than 1%.1 In a meta-analysis of studies of outcome in CAP,31 the overall mortality for hospitaladmitted patients was 137%, that for elderly patients 176%, and that for bacteraemic patients 196%. The mortality of CAP patients who needed admission to an intensive-care unit was 365%. There have been several studies of risk factors for mortality in CAP; poor prognostic factors that would influence the decision to admit a patient with CAP to hospital are listed in the panel.32 Fine and colleagues33 analysed data on more than 14 000 patients with CAP to derive a prediction rule based on age, comorbidity, abnormal physical findings,
Risk factors in patients with CAP* Age >65 years Comorbidity Diabetes, renal failure, heart failure, chronic lung disease, alcoholism, hospital admission within previous year, immunosuppression, neoplastic disease Clinical findings Respiratory rate >30 breaths/min Systolic blood pressure <90 mm Hg or diastolic pressure <60 mm Hg Body temperature >383C Altered mental status Evidence of extrapulmonary sites of infection Laboratory findings White cell count <4 or >30109 L pO2 798 kPa on room air Renal insufficiency Multilobar involvement or significant pleural effusion Packed-cell volume <30%
*Adapted from Bartlett and Mundy.32

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and laboratory abnormalities, which enables patients to be stratified among five risk categories with respect to 30-day mortality. The prediction rule was validated with retrospective data from two additional cohorts of patients with CAP. Although the prediction rule may prove valuable in the future to guide decisions about the need for hospital treatment, it has not been evaluated prospectively. The decision to admit to hospital must still be a clinical judgment, aided by clinical assessment and laboratory data that show a poor prognosis in CAP. In addition to treatment guidelines, many institutions have developed clinical pathways for CAP management. However, there are not enough data available for definite conclusions to be drawn about the effects of treatment guidelines and management pathways on clinical outcomes and cost of care.

Antibiotic therapy
Although the susceptibility profile of S pneumoniae, the main pathogen involved in CAP, is changing, the susceptibilities of the other important CAP pathogens remain fairly predictable. Thus, it is important to find out whether S pneumoniae is the main pathogen as soon as a patient with CAP presents to medical attention.

in S pneumoniae. Lower, but increasing, rates of penicillin non-susceptibility have been reported elsewhere in Europe, including Germany42 and Switzerland.43 Colonisation and infection with non-susceptible S pneumoniae are more common in some groups of people than in others. Higher rates of penicillin nonsusceptibility have been reported in children,36,44 in white than in African-American patients,36,44 in residents of nursing homes, and in HIV-positive people.45 These differences are probably related to greater exposure to antibiotics among these categories of people and, presumably, to increased selection of antibiotic-resistant strains. Therefore, it is important that S pneumoniae strains isolated from patients in different settings within every community are tested for susceptibility, so that current patterns can be monitored and appropriate therapy designed. In a prospective study in Spain, where high bacterial resistance to penicillin is common, ClavoSanchez and colleagues46 found by multivariate analysis that -lactam treatment within the previous 3 months, alcoholism, and isolation of S pneumoniae from sputum but not from a normally sterile body site were risk factors for penicillin resistance in the isolated strain.

Susceptibility to penicillin Over the past 30 years, strains of S pneumoniae with diminished susceptibility to penicillin have emerged and spread worldwide.34 These strains have retained their virulence, and they cause infections indistinguishable from those caused by susceptible isolates. Isolates of S pneumoniae are categorised as penicillin-susceptible (minimum inhibitory concentration [MIC] 01 g/mL) or non-susceptible (>01 g/mL). The strains in the latter category are further subdivided into intermediate (10 g/mL) and resistant (20 g/mL). The prevalence of S pneumoniae isolates in these penicillin-susceptibility categories varies widely between nations, between communities, and even among different populations of patients within a community. The results of surveillance of S pneumoniae isolates by the Centers for Disease Control and Prevention throughout the USA in 197987 showed that only 5% of strains were penicillin-intermediate, and there was virtually no penicillin resistance.35 By 199394, 109% of strains were penicillin-intermediate and 32% were penicillinresistant.36 Similar work in Canada in 19949537 showed that 84% of strains were penicillin-intermediate, and 33% of strains were penicillin-resistant, although earlier studies had not reported resistant strains. In a study of S pneumoniae bacteraemia in 199194 in Ohio, USA, Plouffe and colleagues38 showed that the proportion of penicillin-intermediate isolates rose progressively from 31% in 1991 to 116% in 1994 and the proportion of penicillin-resistant strains rose from 09% to 24%. In Spain, decreasing bacterial susceptibility to penicillin was recognised earlier than in most of the rest of Europe and North America. Isolates from a 10-year prospective study of S pneumoniae pneumonia at a medical centre in Barcelona showed increases in penicillin nonsusceptibility from 13% penicillin-intermediate strains in 198488 to 20% in 198993, with the proportion of resistant isolates increasing from 6% to 15% during 198493.39 In particular, South Africa40 and Hungary41 have very high prevalence of penicillin non-susceptibility
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Susceptibility to cephalosporins Although strains of S pneumoniae with lowered susceptibility to penicillin generally show cross-resistance to cephalosporins, third-generation cephalosporins such as cefotaxime and ceftriaxone are still generally effective against S pneumoniae. The activity of these thirdgeneration drugs against most penicillin-intermediate and resistant strains is still higher than that of penicillin.37,47,48 However, mutational alterations of penicillin-binding proteins that produce resistance to -lactam antibiotics may have differential effects on resistance to penicillins and cephalosporins.4951 As a result, in some strains the degree of resistance to cephalosporins exceeds that of resistance to penicillins, so extrapolation from the penicillin susceptibility of a strain to its response to cephalosporins is unwise. Cross-resistance to other antibiotics Cross-resistance to other antipneumococcal antibiotics has been shown in many strains of S pneumoniae that have diminished susceptibility to penicillins and cephalosporins.37,40,41,48,52 The cross-resistance is not complete, and the mechanisms are not understood. Nonetheless, cross-resistance is sufficiently common to compromise the potential use of substitutes for -lactams in the treatment of -lactam-resistant S pneumoniae infections. These substitute drugs include erythromycin, the newer macrolides (clarithromycin, azithromycin), clindamycin, doxycycline and other tetracyclines, and co-trimoxazole. Alternative antibiotics Other antibiotics do retain their activity against -lactam-resistant pneumococci. All strains of S pneumoniae, including those fully resistant to penicillin, are susceptible to vancomycin at present.37,53 Although the MICs of imipenem are higher in penicillin-resistant S pneumoniae, almost all of these strains remain clinically susceptible to imipenem.37,48,53 In addition, the activity of the fluoroquinolones against strains of S pneumoniae appears not to vary with penicillin susceptibility.37,43,48,54

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Setting and pathogen

Preferred treatment

Other options Quinolone* Quinolone Azithromycin Clindamycin

Outpatient (oral therapy) S pneumoniae Phenoxymethylpenicillin Amoxicillin H influenzae Cefuroxime Amoxycillin/clavulanate S aureus Cloxacillin Dicloxacillin Hospital ward (parenteral therapy) S pneumoniae Benzylpenicillin

H influenzae

Cefuroxime

S aureus

Nafcillin

Gram-negative bacilli

Cephalosporin,|| with or without aminoglycoside

Cephalosporin Imipenem Vancomycin Ampicillin/sulbactam Cephalosporin|| Quinolone First-generation cephalosporin Clindamycin Vancomycin Ceftazidime or imipenum, with or without aminoglycoside Imipenem Vancomycin Quinolone Ampicillin/sulbactam Cephalosporin|| Quinolone First-generation cephalosporin Clindamycin Vancomycin Imipenem, with or without aminoglycoside Quinolone

Intensive-care (parenteral therapy) S pneumoniae Cephalosporin

H influenzae

Cefuroxime

preclude effective therapy of pneumococcal pneumonia and sepsis with high-dose penicillin.39,68,69 For S pneumoniae strains with higher levels of penicillin resistance, it is not clear whether high-dose penicillin therapy is adequate. Third-generation cephalosporins such as cefotaxime or ceftriaxone are appropriate alternatives to penicillin, at least when their MICs are 2 g/mL or less. Highly penicillin-resistant S pneumoniae can be treated with imipenem and meropenem, although as penicillin resistance rises further, MICs of these carbapenems might eventually reach levels that make standard doses ineffective. Other options include vancomycin, and the antipneumococcal quinolones levofloxacin, sparfloxacin, grepafloxacin, and trovafloxacin. Medical centres must monitor the susceptibility of local isolates of S pneumoniae; further increase of penicillin and cephalosporin MICs above 2 g/mL would indicate a shift from these -lactams to other agents for the treatment of pneumococcal infection. Physicians must be aware of the susceptibility pattern of pneumococci in the community that they serve.

S aureus

Nafcillin

Gram-negative bacilli

Ceftazidime, with or without aminoglycoside

*Antipneumococcal quinolone (levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin). High-dose (12 million units per day). Cefotaxime or ceftriaxone. Levofloxacin or trovafloxacin, ||Cefotaxime, ceftriaxone, or ceftizoxime.

Table 2: Initial antibiotic treatment for CAP when the aetiological agent is evident from sputum gram stain

Nonetheless, the fluoroquinolones differ in their intrinsic activity against S pneumoniae. Ciprofloxacin has relatively poor activity against some strains, but the newer quinolones are more active generally against pneumococci (activity of trovafloxacin>grepafloxacin sparfloxacin>levofloxacin in vitro).5456 There are few reports of pneumococcal resistance to trovafloxacin and grepafloxacin, owing to their more recent introduction into clinical use. Quinolones tend to cause the selection of resistance to themselves and to other quinolones in most bacteria that have been studied. Thus, the use of quinolones should be limited, and clinicians should be alert to the possible emergence of quinolone resistance in S pneumoniae.

Antibiotic susceptibility of other CAP pathogens The other main typical bacterial pathogen in CAP, H influenzae, is generally susceptible to cefuroxime, to third-generation cephalosporins (cefotaxime, ceftriaxone, ceftizoxime), and to the fluoroquinolones. H influenzae is less susceptible to the newer macrolides (activity of azithromycin>clarithromycin). The macrolides, including erythromycin,57,58 and the fluoroquinolones5867 also have in-vitro activity and clinical efficacy against the atypical CAP pathogens M pneumoniae, C pneumoniae, and legionella. Treatment options for penicillin-resistant S pneumoniae At present, penicillin resistance in strains of S pneumoniae (MICs generally up to 2 g/mL) can be overcome with high-dose intravenous benzylpenicillin (at least 12106 U per day).53 Current levels of resistance to penicillin and cephalosporins in S pneumoniae do not

Initial therapy of CAP Our recommended approach to the initial therapy of CAP is shown in tables 2 and 3. For the treatment of pneumococcal pneumonia in patients not admitted to hospital, an antipneumococcal quinolone (levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin) could be used if multidrug resistance in S pneumoniae is sufficiently prevalent in the local area to preclude the routine use of a penicillin for mild infection. However, we would not use such a drug routinely, because widespread use might lead to selection of quinolone resistance among S pneumoniae, other CAP pathogens, and other organisms colonising the patient. Erythromycin is the preferred macrolide in cases with no diagnostic sputum gram stain because of its low cost, although azithromycin or clarithromycin are acceptable options if the sideeffects of erythromycin are intolerable. Azithromycin might also be preferred for convenience (5 days of oncedaily therapy, compared with 710 days of multiple daily doses of other drugs). Again, a quinolone could be used empirically in such cases when there is a high prevalence of multidrug-resistant S pneumoniae. Since S pneumoniae may be resistant to penicillins, macrolides, and doxycycline, outpatients treated with these drugs empirically or for suspected S pneumoniae must be told to return for further assessment if response to therapy is poor. If the patient is admitted to a general ward and a gram-stained smear of sputum or empyema fluid shows S pneumoniae, high-dose benzylpenicillin should be adequate, as long as laboratory data show that the penicillin MICs of isolates in the local community are 2 g/mL or less. If the patient is allergic to penicillin, a
Treatment setting Preferred treatment Other options

Outpatient (oral therapy) Macrolide, doxycycline Hospital ward (parenteral therapy) Intensive-care unit (parenteral therapy)

Levofloxacin, sparfloxacin, grepafloxacin, or trovafloxacin Cefotaxime or ceftriaxone Levofloxacin or trovafloxacin +erythromycin Cefotaxime or ceftriaxone Imipenemaminoglycoside aminoglycoside +erythromycin +erythromycin Levofloxacin or trovafloxacin

Table 3: Initial empirical antibiotic treatment for CAP when diagnostic sputum gram-stain is unavailable

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cephalosporin (cefotaxime, ceftriaxone) could be used if the allergic reaction is not anaphylactic. Acceptable substitutes for benzylpenicillin or a cephalosporin for -lactam-allergic patients would be intravenous vancomycin or a quinolone. Levofloxacin and trovafloxacin are available for parenteral and oral use. If the prevalence of high-level resistance to penicillin (MIC 4 g/mL) and cephalosporins (MIC 4 g/mL) is above 5%, penicillins or cephalosporins cannot be used routinely, so vancomycin, a quinolone, or imipenem would have to be used. If the sputum gram stain is non-diagnostic or if no sputum is available for examination, treatment should aim not only at S pneumoniae but also more broadly. In such cases, we recommend treatment with a high-dose regimen of a cephalosporin (cefotaxime, ceftriaxone) and with a macrolide such as erythromycin. Alternatively, quinolone monotherapy can be used. If a CAP patient needs intensive care and the sputum gram stain indicates S pneumoniae, we would treat with high-dose cephalosporin, or with imipenem, vancomycin, or a quinolone, if resistance to cephalosporins is too high to permit their routine use. If the gram-stained smear of sputum or empyema fluid is not diagnostic (table 3), we recommend the addition of erythromycin to the treatment regimen of high-dose cephalosporin with or without an aminoglycoside. Alternatively, if there is concern about the possibility of P aeruginosa in patients with severe underlying structural lung disease such as cystic fibrosis or bronchiectasis, imipenem and erythromycin with or without an aminoglycoside, or quinolone monotherapy could be used. Since pharmacokinetic studies of azithromycin have shown that most of the drug is cleared quickly from the circulation, intravenous azithromycin may not be appropriate in patients who might be bacteraemic. If diagnostic information becomes available that shows a specific pathogen (eg, a culture isolate from sputum, blood, or empyema, or a urine antigen or sputum fluorescent-antibody test positive for legionella), susceptibility results, or both, the treatment regimen should be narrowed accordingly.

Prevention of pneumococcal infection

Even with optimum antibiotic therapy, the mortality from pneumococcal bacteraemia, usually with underlying pneumonia, has remained at about 25%.39 The emergence of antibiotic resistance in S pneumoniae, which has complicated the approach to therapy, has encouraged immunisation against pneumococcal infection. The pneumococcal 23-valent polysaccharide vaccine is safe, but its protective efficacy is not certain; some studies7274 and a meta-analysis of randomised controlled trials75 have shown rates of protection against pneumococcal bacteraemia of 5670% in the elderly. We support current recommendations on immunisation with pneumococcal polysaccharide vaccine from the Advisory Committee on Immunisation Practices (ACIP)76 for immunocompetent adults who are at least 65 years old, at increased risk for illness or death associated with pneumococcal disease because of chronic illness (eg, cardiovascular disease, pulmonary disease, renal failure, diabetes mellitus, alcoholism, cirrhosis, cerebrospinal leaks), or who live in settings with a high risk of pneumococcal disease such as homeless shelters. The duration of protective antibody response is not known, and whether patients should be revaccinated every 6 years because of waning antibody concentrations remains controversial.77 Influenza is a serious seasonal cause of CAP, especially in the elderly. Therefore, the ACIP also recommends yearly influenza vaccination for people thought to be at high risk of complications of influenza infection, which may include bacterial superinfecting pneumonia, and for people in close contact with high-risk individuals.78 Despite some improvement in rates of pneumococcal and influenza vaccination among people aged 65 years or older in the USA,79 the US Centers for Disease Control and Prevention80 showed that most patients admitted to hospital with pneumonia are not offered pneumococcal or influenza vaccine.

Conclusion
In light of the prevalence of CAP and the evolution of resistance in the most common bacterial CAP pathogen, we strongly advise that physicians obtain specimens for culture of CAP pathogens and analyse patterns of susceptibility, especially of S pneumoniae, in their communities, that they use antibiotics appropriately and prudently, according to prevailing susceptibilities when empirical treatment is called for, and that they immunise their susceptible patients with pneumococcal and influenza vaccines.
References
1 2 Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994; 18: 50105. Guest JF, Morris A. Community acquired pneumonia: the annual cost to the National Health Service in the UK. Eur Respir J 1998; 10: 153034. Centers for Disease Control and Prevention. Premature deaths, monthly mortality, and monthly physician contactsUnited States. MMWR Morb Mortal Wkly Rep 1997; 46: 556. Marston BJ, Plouffe JF, File TM, et al. Incidence of communityacquired pneumonia requiring hospitalizations: results of a population-based active surveillance study in Ohio. Arch Intern Med 1997; 157: 170918. Lvy M, Dromer F, Brion N, Leturdu F, Carbon C. Communityacquired pneumonia: importance of initial noninvasive bacteriologic and radiographic investigations. Chest 1988; 92: 4348. Woodhead MA, Macfarlane JT, McCracken JS, Rose DH, Finch RG. Prospective study of the aetiology and outcome of pneumonia in the community. Lancet 1987; i: 67174.

Subsequent therapy Once the patients condition is clearly improving in response to therapy (eg, normalising temperature, improved respiratory status, resolved leucocytosis), and once he or she is haemodynamically stable and able to ingest and absorb oral medication, treatment can be switched to the oral route.70,71 This eliminates the need for intravenous access, simplifies therapy, and reduces cost. The patient could then be discharged to complete therapy at home. If the pathogen is S pneumoniae and its susceptibilities are known, the use of phenoxymethylpenicillin or amoxicillin, an oral thirdgeneration cephalosporin such as cefpodoxime, a macrolide, or a quinolone, should be considered. For H influenzae, agents shown in table 2 can be used. If the cause of the pneumonia is unknown, use of a macrolide or a quinolone might be most prudent. The total course of therapy should be 710 days, depending on the severity of the patients condition. If the patient has had evidence of sepsis and the response to therapy has been slow, treatment might be extended to 14 days. Some researchers have advocated therapy for 21 days in cases of infection due to L pneumophila.
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SEMINAR 7 Fang G, Fine M, Orloff J, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multicenter study of 359 cases. Medicine 1990; 69: 30716. Lim I, Shaw DR, Stanley DP, Lumb R, McLennan G. A prospective hospital study of the aetiology of community-acquired pneumonia. Med J Aust 1989; 151: 8791. Porath A, Schlaeffer F, Lieberman D. The epidemiology of community-acquired pneumonia among hospitalized adults. J Infect 1997; 34: 4148. Bohte R, vanFurth R, van den Brock PJ. Aetiology of communityacquired pneumonia: a prospective study among adults requiring admission to hospital. Thorax 1995; 50: 54347. Lieberman D, Schlaeffer F, Bolden I, et al. Multiple pathogens in adult patients admitted with community-acquired pneumonia: a one year prospective study of 346 consecutive patients. Thorax 1996; 51: 17984. Marrie TJ, Peeling RW, Fine MJ, Singer DE, Coley CM, Kapoor WN. 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SEMINAR 60 Sparfloxacin and levofloxacin. Med Lett Drugs Ther 1997; 39: 4143. 61 Ortqvist A, Valtonen M, Cars O, Wahl M, Saikku P, Jean C. Oral empiric treatment of community-acquired pneumonia: a multicenter, double-blind, randomized study comparing sparfloxacin with roxithromycin. Chest 1996; 110: 1499506. 62 Aubier M, Lode H, Gialdroni-Grassi G, et al. Sparfloxacin for the treatment of community-acquired pneumonia: a pooled data analysis of two studies. J Antimicrob Chemother 1996; 37 (suppl A): 7382. 63 Donowitz GR, Brandon ML, Salisbury JC, et al. Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized, double-masked, comparative multicenter study. Clin Ther 1997; 19: 93653. 64 Topkis S, Swarz H, Breisch SA, Maroli AN. Efficacy and safety of grepafloxacin 600 mg daily for 10 daily in patients with communityacquired pneumonia. Clin Ther 1997; 19: 97578. 65 Grepafloxacina new fluoroquinolone. Med Lett Drugs Ther 1998; 40: 1718. 66 Gooding B-B, Jones RN. In vitro antimicrobial activity in CP-99,219, a novel azabicyclo-naphthyridone. Antimicrob Agents Chemother 1993; 37: 34953. 67 Trovafloxacin. Med Lett Drugs Ther 1998; 40: 3031. 68 Friedland IR, Klugman KP. Antibiotic-resistant pneumococcal disease in South African children. Am J Dis Child 1992; 146: 92023. 69 Tan TQ, Mason EO Jr, Kaplan SL. Systemic infections due to Streptococcus pneumoniae relatively resistant to penicillin in a childrens hospital: clinical management and outcome. Pediatrics 1992; 90: 92833. 70 Mandell LA, Bergeron MC, Gribble MJ, et al. Sequential antibiotic therapy: effective management and patient care. Can J Infect Dis 1995; 6: 306. 71 Ramirez JS, Srinath L, Ahkee S, Huang A, Raff MJ. Early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with community-acquired pneumonia. Arch Intern Med 1995; 155: 127376. 72 Sims RV, Steinmann WC, McConville JH, King LR, Zwick WC, Schwartz JS. The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med 1988; 108: 65357. 73 Shapiro ED, Berg AT, Austrian R, et al. The protective efficacy of polyvalent pneumococal polysaccharide vaccine. N Engl J Med 1991; 325: 145460. 74 Koivula I, Sten M, Makela PH. Clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial. Am J Med 1997; 103: 28190. 75 Fine MJ, Smith MA, Carson CA, et al. Efficacy of pneumococcal vaccination in adults: a meta-analysis of randomized controlled trials. Arch Intern Med 1994; 154: 266677. 76 Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 1997; 46: 124. 77 Ely EW. Pneumonia in the elderly: diagnostic and therapeutic challenges. Infect Med 1997; 14: 64354. 78 Centers for Disease Control and Prevention. Update on adult immunization: recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 1997; 40: 194. 79 Centers for Disease Control and Prevention. Pneumococcal and influenza vaccination levels among adults aged > or =65 years United States, 1995. MMWR Morb Mortal Wkly Rep 1997; 46: 91319. 80 Centers for Disease Control and Prevention. Missed opportunities for pneumo-coccal and influenza vaccination of Medicare pneumonia inpatients12 western states. MMWR Morb Mortal Wkly Rep 1997; 46: 91923. Gleckman R, DeVita J, Hibert D, et al. Sputum gram stain assessment in community-acquired bacteriemic pneumonia. J Clin Microbiol 1988; 26: 84649. Tuomanen EI, Austrian R, Masure HR. Pathogenesis of pneumococcal infection. N Engl J Med 1995; 332: 128084. Stout JE, Yu VL. Legionellosis. N Engl J Med 1997; 337: 68287. Bryant RE, Salmon CJ. Pleural empyema. Clin Infect Dis 1996; 22: 74762.

Further reading
Mundy LM, Auwaerter PG, Oldach D, et al. Community-acquired pneumonia: impact of immune status. Am J Respir Crit Care Med 1995; 152: 130915. Riquelme R, Torres A, El-Ebiary M, et al. Community-acquired pneumonia in the elderly: a multivariate analysis of risk and prognostic factors. Am J Respir Crit Care Med 1996; 154: 145055.

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