Abbreviations:CAP community-acquired pneumonia, CDC Centers for Disease Control and Prevention, DRSP drug-resistant Streptococcus pneumoniae, DRSPTWG Drug-Resist ant Steptococcus pneumoniae Therapeutic Working Group, ERS European Respiratory Society, IDSA Infectious Diseases Society of America
Community-acquired pneumonia (CAP) is a common disorder that is potentially life threatening, especially in older adults and those with co-morbid disease. Despite substantial progress in therapeutic options, CAP remains a significant cause of morbidity and death worldwide, and continues to cause major controversies with regard to antimicrobial management. The importance of CAP has led to the publication of guidelines from numerous international organizations over the past decade; the purpose of which is to optimize care and improve outcome.
In north America, the Canadian Infectious Diseases Society, the Canadian Thoracic Society and the American Thoracic Society initially published guidelines in 1993; these were followed by guidelines from the Infectious Diseases Society of America (IDSA) in 1998. In Europe, CAP guidelines published in France, Spain, the UK, Italy, and The Netherlands during 1991–1996 highlighted regional differences in epidemiology and approaches to disease management, and prompted the publication in 1998 of consensus European guidelines, under the auspices of the European Respiratory Society (ERS) . Several other international organizations have also published recommendations over this time period.
Continuing changes and advances in the field have led to revisions by the Canadian group and IDSA in 2000 [2,3]. The American Thoracic Society were also finalizing revised guidelines, which at the time of this submission had not yet been published. In addition the Japanese Respiratory Society published guidelines in 2000 . Each of these guidelines variably addresses the most important management decisions concerning the management of CAP, such as the role of diagnostic studies, site of care (outpatient versus inpatient care), antimicrobial therapy, and prevention. For this brief review, I will focus on recommendations included in the newly published guidelines for empirical therapy for both outpatients and inpatients; and will also include a comparison with the European consensus group published in 1998, as well as a recently published statement by the Centers for Disease Control and Prevention (CDC): Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group (DRSPTWG) .
General recommendations for antimicrobial therapy
For the development of guidelines, most organizations have relied on prospectively performed studies of CAP on which to base recommendations. Published data and expert opinion have served as major driving forces behind these documents. Because of differences in the epidemiology of CAP as well as the unique features of the healthcare delivery system of each country, it is understandable that each international organization considers it important to develop its own set of strategies.
Recommendations for empirical antimicrobial therapy from the representative guidelines (ERS, Japanese Respiratory Society, Canadian Infectious Diseases Society and the Canadian Thoracic Society, IDSA, CDC-DRSPTWG) are summarized in Table 1. Although the IDSA guidelines stress the importance of attempting to define the etiological agents so that directed therapy can be implemented, it is acknowledged that the majority of patients will be treated empirically. This is particularly the case for outpatients in whom little diagnostic testing is emphasized. Moreover, even at tertiary level university centers, where multiple diagnostic testing methods are used for patients who require hospitalization, an etiological agent is found in only 50% (approximately) of cases.
The selection of specific antimicrobial regimens for empirical therapy in the guidelines is based largely on the most likely pathogens, in-vitro activity, and clinical studies. Clearly, all groups believe that S. pneumoniae is the single most important pathogen. However, there is an increasing emphasis on treating atypical organisms in some of the guidelines, most notably those from north America.
Recommendations for outpatients
Variations in recommended antimicrobial agents reflect differences in approaches to therapy. Such differences include the significance of ‘atypical’ pathogens, the approach to ‘macrolide-resistant’S. pneumoniae, and the reliance on the ‘syndromes’ approach to CAP.
Both of the new north American guidelines variably recommend a macrolide, doxycycline, or an antipneumoccocal fluoroquinolone as treatment options. The rationale is to provide coverage of S. pneumoniae and the atypical pathogens (most commonly Mycoplasma pneumoniae and Chlamydia pneumoniae), which have been shown to be prevalent as causative agents in epidemiological studies in north America (although the criteria for etiological diagnosis can be questioned in many studies, see Hammerschlag, pp. 181–186). As there is no convincing association between individual symptoms and physical findings with specific etiology, the rationale is to direct the initial, empirical, therapy towards these most likely causes. In the Canadian statement, outpatients are stratified into those without modifying factors, for whom a macrolide may be used, and those with modifying factors (such as chronic obstructive lung disease or the use of recent antibiotics or steroids) for whom fluoroquinolones are considered appropriate. The IDSA statement indicates that the selection considerations between the three options should be influenced by regional antibiotic susceptibility patterns for S. pneumoniae and the presence of risk factors for drug-resistant S. pneumoniae (such as the use of antimicrobial agents within the previous 3 months). The statement further indicates that ‘for older patients or those with underlying disease, a fluoroquinolone may be a preferred choice; some authorities prefer to reserve fluoroquinolones for such patients’. The CDC statement is similar but stresses that fluoroquinolones should be reserved for cases associated with failure or because of allergy to other agents, or cases caused by documented drug-resistant S. pneumoniae (DRSP). The rationale is that the fear of widespread use may lead to the development of fluoroquinolone resistance among the respiratory pathogens (as well as other pathogens colonizing treated patients).
A significant difference between the north American guidelines compared with the European guidelines is the positioning of macrolides (and doxycycline) for empirical therapy. The primary agents recommended in the European statement are beta-lactams, primarily penicillins (particularly aminopenicillins). The rationale is that these agents are effective against S. pneumoniae; and when given in high doses are even effective for most strains with decreased sensitivity to penicillin (see Klugman and Feldman, pp. 173–179). The European statement does include the macrolides as alternative agents ‘in a previously fit young adult, especially during M. pneumoniae epidemics. . . ’. The difference in the expression of macrolide-resistant S. pneumoniae in north America compared with Europe partly explains this variance. In the United States, most macrolide resistance is a result of increased drug efflux encoded by mef and with MIC of less than 32 μg/ml. It is possible that this resistance may be overcome by achievable levels of the newer macrolides (i.e. clarithromycin, azithromycin). In Europe, most macrolide resistance is caused by ribosomal methylase encoded by erm; this results in high-grade resistance to macrolides that cannot be overcome. In addition, at the time of the development of the north American guidelines, cases of macrolide failure for outpatients, particularly for cases not associated with risks for DRSP, had been infrequent. Of note, however, are two recent reports describing patients treated with oral macrolides who failed therapy and required admission to the hospital for therapy of DRSP [6,7].
The Japanese statement emphasizes early distinction on clinical grounds as to suspected bacterial or atypical etiology. This statement thus promotes a ‘syndromes’ approach in an attempt to differentiate an etiological category on the basis of clinical parameters. Differentiation is based on the following nine criteria: age, the presence of underlying disorders, epidemic pneumonia, ‘stubborn cough’, slow pulse, physical examination chest findings, peripheral white blood count, chest X-ray findings, and sputum Gram stain. On the basis of this distinction, the Japanese group recommends a ‘penicillin type’ drug when bacterial pneumonia is suspected and there are no microbiological data available to indicate a specific organism. When atypical pneumonia is suspected, a macrolide or tetracycline type drug is recommended.
Inpatients (patients admitted to the hospital)
Both of the north American revised guidelines recommend treatment with a beta-lactam plus a macrolide or monotherapy with a fluoroquinolone. The rationale for recommending these regimens is based on studies showing that these regimens were associated with a significant reduction in mortality, compared with that associated with the administration of cephalosporin alone [8,9]. Such studies did not have a sufficient number of patients treated only with macrolides to justify conclusions about that category as monotherapy, although recent studies suggest that azithromycin intravenous monotherapy is equivalent to a beta-lactam (cefuroxime) plus erythromycin. The recommendations in the ERS guidelines are fairly similar, with the difference that the beta-lactam-containing regimen includes the macrolide as an option (i.e. ‘±’). However, it must be acknowledged that this statement predates the studies mentioned above. The Japanese statement stratifies patients on the basis of age and the presence of underlying illness, with an ‘injection use fluoroquinolone’ recommended for the first category and a combination regimen for the second category.
For patients with severe CAP who require admission to an intensive care unit, the guidelines recommend comprehensive antimicrobial therapy to cover S. pneumoniae (including DRSP), Legionella and the possibility of Pseudomonas in selected cases.
Clinicians are now presented with several sets of new guidelines for the same clinical entity. These guidelines are intended to provide clinicians with general principles of disease management, and it is envisaged that these will be adapted to suit regional circumstances, local hospital practices, and individual patient characteristics.
In terms of the recommendations for empiric therapy, they are more similar than they are different. Differences are partly related to variations in local epidemiology and the clinical relevance of antimicrobial resistance. They all reflect thoughtful consideration by a panel of experts and should be viewed as recommendations for strategies of care and not definite step-wise rules of care. Indeed, clinicians must interpret such statements in the context that these recommendations cannot apply to all hypothetical settings. Rather, these statements represent general state of the art documents, which require continuing change because of the changes in our understanding of this important infection.
1. Huchon G, Woodhead M, and the European Study on Community Acquired Pneumonia Committee. Management of adult community-acquired lower respiratory tract infections. Eur Respir Rev 1998;8:391–426.
2. Matsushima T (editor), and the Japanese Respiratory Society Community-Acquired Pneumonia Treatment Guideline Creation Committee. Diagnostic and treatment guideline formulation committee for community-acquired pneumonia of the Japanese Respiratory Society. Tokyo: Japanese Respiratory Society, General Managing Director Ando Masayuki; 2000.
3. Heffelfinger JD, Dowell SF, Jorgensen JH, et al., and the Drug-Resistant Streptococcus pneumoniae
Therapeutic Working Group. Management of community-acquired pneumonia in the era of pneumococcal resistance. Arch Intern Med2000;160:1399–1408.
4. Bartlett JG, Dowell SF, Mandell LA, et al. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000; 31:347–362.
5. Mandell LA, Manic TJ, Grossman RF, et al., and the Canadian Community-Acquired Pneumonia Working Group. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 2000;31:383–421.
6. Fogarty C, Goldschmidt R, Bush K. Bacteremic pneumonia due to multi-drug resistant pneumococci in 3 patients treated unsuccessfully with azithromycin and successfully with levofloxacin. Clin Infect Dis 2000; 31:613–615.
7. Kelly MA, Weber DJ, Gilligan P, Cohen MS. Breakthrough pneumococcal bacteremia in patents being treated with azithromycin and clarithromycin. Clin Infect Dis 2000; 31:1008–1011.
8. Gleason PP, Meehan TP, Fine JM, et al.
Association between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med 1999; 159:2562–2572.
9. Dudas V, Hopefl A, Jacobs R, Guglielmo J. Antimicrobial selection for hospitalized patients with presumed community-acquired pneumonia: a survey of nonteaching US community hospitals. Ann Pharmacother 2000; 34:446–452.