Published ahead of print on March 1, 2007, doi:10.1164/rccm.200603-350OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200603-350OC
A Worldwide Perspective of Atypical Pathogens in Community-acquired Pneumonia1 Division of Infectious Diseases, Department of Medicine, and 2 Department of Health Promotion and Behavioral Sciences, University of Louisville, Louisville, Kentucky; 3 University of Alberta Hospital, Sturgeon Community Hospital, Grey Nuns Hospital, and Royal Alexandra Hospital, Edmonton, Alberta, Canada; 4 Department of Medicine, S. Maria della Misericordia Hospital, Udine, Italy; 5 Istituto Malattie Respiratorio, University of Milan, Istituto di Ricerca e Cura a Carattere Scientifico, Policlinico, Milan, Italy; 6 Instituto Nacional del Torax, Santiago, Chile; 7 Summa Health System, Akron, Ohio; 8 Joan XXIII University Hospital, Tarragona, Spain; 9 Hospital Universitario La Fe, Valencia, Spain; 10 Sanatorio 9 de Julio, Tucuman, Argentina; and 11 Hospital de Clinicas, Buenos Aires, Argentina Correspondence and requests for reprints should be addressed to Forest W. Arnold, D.O., Division of Infectious Diseases, University of Louisville, Carmichael Building, Room 208E, 512 South Hancock Street, Louisville, KY 40292. E-mail: f.arnold{at}louisville.edu
Rationale: Controversy still exists in the international literature regarding the need to use antimicrobials covering atypical pathogens when initially treating hospitalized patients with community-acquired pneumonia (CAP). In different regions of the world, monotherapy with a  -lactam antimicrobial is common. Objectives: We sought to correlate the incidence of CAP due to atypical pathogens in different regions of the world with the proportion of patients treated with an atypical regimen in those same regions. In addition, we sought to compare clinical outcomes of patients with CAP treated with and without atypical coverage. Methods: A secondary analysis was performed using two comprehensive international databases. World regions were defined as North America (I), Europe (II), Latin America (III), and Asia and Africa (IV). Time to reach clinical stability, length of hospital stay, and mortality were compared between patients treated with and without atypical coverage. Measurements and Main Results: The incidence of CAP due to atypical pathogens from 4,337 patients was 22, 28, 21, and 20% in regions I–IV, respectively. The proportion of patients treated with atypical coverage from 2,208 patients was 91, 74, 53, and 10% in regions I–IV, respectively. Patients treated with atypical coverage had decreased time to clinical stability (3.7 vs. 3.2 d, p < 0.001), decreased length of stay (7.1 vs. 6.1 d, p < 0.01), decreased total mortality (11.1 vs. 7%, p < 0.01), and decreased CAP-related mortality (6.4 vs. 3.8%, p = 0.05). Conclusions: The significant global presence of atypical pathogens and the better outcomes associated with antimicrobial regimens with atypical coverage support empiric therapy for all hospitalized patients with CAP with a regimen that covers atypical pathogens.
Key Words: pneumonia, mycoplasma • pneumonia, pneumococcal • atypical • community-acquired infection • empiric antibiotic
In an attempt to help the practicing physician in the selection of appropriate empiric therapy for hospitalized patients with community-acquired pneumonia (CAP), national organizations in multiple countries have developed guidelines for treating CAP. Despite these contributions, however, controversy still exists in the literature regarding the best drug regimen to use as empiric therapy for CAP. Guidelines from the United States, Canada, Germany, Japan, and parts of the Latin American region recommend using a regimen that covers atypical pathogens in all hospitalized patients with CAP (1–5). On the other hand, guidelines from other countries or regions of the world still recommend using a -lactam regimen while leaving the addition of a macrolide as an option (6–9). The controversy regarding the need to cover for atypical pathogens is primarily due to two significant unresolved questions. The first is related to the incidence of atypical pathogens as an etiology of CAP in different regions of the world. Because the identification of atypical pathogens requires special laboratory tests that are not readily available, studies to evaluate local incidence of atypical pathogens are difficult to perform (10). Even when local studies are performed, because the diagnostic tests for atypical pathogens are not well standardized among laboratories, it is difficult to compare data on incidence from different studies using different laboratories. The second is related to the contradictory results found in literature when outcomes are compared in patients with CAP treated with or without coverage for atypical pathogens (11). In an attempt to investigate some of the controversies in the field of atypical pathogens in CAP, we designed a study with the following objectives: first, to evaluate in different regions of the world the incidence of atypical pathogens in patients with CAP; second, to define if there is a correlation of the incidence of atypical pathogens in a region with the proportion of patients treated with empiric therapy covering atypical pathogens in the same region; and third, to compare early and late CAP outcomes for hospitalized patients treated empirically with antimicrobials with and without coverage for atypical pathogens. Some of the results of these studies have been previously reported in the form of abstracts (12, 13).
A secondary analysis was performed using two comprehensive international databases: The University of Louisville infectious diseases atypical pathogens reference laboratory database and the Community-Acquired Pneumonia Organization (CAPO) database.
University of Louisville Infectious Diseases Atypical Pathogens Reference Laboratory Database
The CAPO Database
Study Definitions
Study Design
Statistical Analysis The difference in the proportions of patients who reached clinical stability within 7 days was compared for the two groups and the 95% confidence interval (CI) around the difference was used to conclude whether the groups differed. This type of analysis was also done to compare the groups on hospital stays of fewer than 30 days and all-cause mortality.
The incidence of atypical pathogens and the incidence of initial antimicrobial therapy with coverage for atypical pathogens for each region of the world are depicted in Table 1. Although the range of atypical pathogens is 20 to 28%, the range between groups receiving therapy for atypical pathogens was 10 to 91% (p < 0.01). There were 2,220 patients who received atypical coverage compared with 658 patients who did not. Totals of 1,100 patients (62%) and 256 patients (58%) in each group were male, respectively (p = 0.15). The mean age was 65.2 and 66.4 years, respectively (p = 0.25). A total of 201 patients (11%) were admitted to an ICU from the group who received atypical coverage, whereas 33 patients (8%) were admitted to an ICU from the group who did not receive atypical coverage (p = 0.02). The proportion of patients in each risk class with and without atypical coverage is outlined in Figure 1. The most common antimicrobial regimens prescribed in each group are listed in Table 2.
The time to clinical stability for patients with and without atypical coverage is depicted in Figure 2. The mean time to clinical stability was 3.2 days (SD, 1.7) for those who received atypical coverage (n = 1,186), and 3.7 days (SD, 1.6) for those who did not receive atypical coverage (n = 272). The mean difference, 0.5 days (95% CI, 0.29–0.73), was significant (p < 0.01). The multivariate analysis for time to clinical stability is shown in Figure 3. Patients with an atypical regimen reached clinical stability sooner, whereas patients with altered mental status or admission to an ICU reached clinical stability later.
LOS for up to 30 days for hospitalized patients with and without atypical coverage is depicted in Figure 4. The mean LOS for patients who were hospitalized for 30 days or fewer was 8.8 days (SD, 7.2) for those who received atypical coverage (n = 2,220) and 9.6 days (SD, 7.0) for those who did not receive atypical coverage (n = 658). The mean difference, 0.72 days (95% CI, 0.96–1.33), was significant (p < 0.02). If the LOS was censored at 14 days, then a mean difference of 0.95 days was more significant (6.1 vs. 7.1 d; 95% CI, 0.56–1.34; p < 0.01). The multivariate analysis for LOS is shown in Figure 5. Patients with an atypical regimen were discharged sooner, whereas patients admitted to an ICU were discharged later.
Total in-hospital mortality for patients with and without atypical coverage is depicted in Figure 6. Patients with an atypical regimen died less often. The multivariate analysis for total in-hospital mortality is shown in Figure 7. Patients died less often when administered an atypical regimen or given antimicrobials within 8 hours of admission. Patients died more often if they had a higher risk class, altered mental status, or hypotension. The multivariate analysis for CAP-related in-hospital mortality is shown in Figure E1 and Tables E5, E9, and E13. A comparison of the percentage difference of four outcomes for patients who received treatment for atypical pathogens compared with those who did not is represented in Figure 8. Patients prescribed an atypical regimen reached clinical stability sooner and died less often, but did not necessarily have a shorter LOS.
The outcomes for regions I, II, and III are depicted in Figures E2–E13. No region-specific data were analyzed for region IV (Asia and Africa) because this region had minimal representation in our study. An atypical regimen was not significant in any region when a subanalysis was performed, although the p values did approach 0.05 for mortality in regions I and III (Tables E4 and E12). An elevated risk class and change in mental status were associated with worse outcomes in region I (Tables E2–E5) and region II (Tables E6–E9). In region III, an elevated risk class and admission to an ICU were associated with a longer time to clinical stability and LOS, whereas a change in mental status was associated with a longer time to clinical stability and higher mortality (Tables E10–E13).
This study indicates that, although the incidence of atypical pathogens is relatively similar in all regions of the world, there are significant differences in the proportion of patients who are treated with an empiric regimen that covers for atypical pathogens. This study also indicates that, in hospitalized patients with CAP, initial empiric therapy with coverage for atypical pathogens is associated with decreased time to clinical stability, decreased duration of hospitalization, and decreased patient mortality. Using a comprehensive workup for atypical pathogens, we were able to define a very similar incidence in all regions, with approximately one of four patients with CAP with evidence of atypical pathogens. Even though M. pneumoniae was the most common atypical pathogen identified in all regions of the world, the second most common was C. pneumoniae in North and South America, and L. pneumophila in Europe. Overall, these results are likely to be generalizable because the data on the incidence of atypical pathogens are from multiple sites, from a large number of patients with CAP, and were generated using the same laboratory over a 7-year time period. Although all North American guidelines strongly recommend covering typical and atypical pathogens in all hospitalized patients with CAP, 9% of hospitalized patients in North America (region I) did not receive empiric therapy that covered atypical pathogens. We documented a lack of coverage for atypical pathogens in 26% of patients in region II, 47% of patients in region III, and 90% of patients in region IV. The significant difference in the proportion of hospitalized patients that receive atypical coverage may be a reflection of the emphasis on coverage for atypical pathogens given by a particular country's national CAP guidelines. Published studies on the effect of covering atypical pathogens in total patient mortality offer contradictory results. A beneficial effect of an atypical regimen on total mortality has been reported in six studies with a combined total study population of 17,192 patients hospitalized with CAP (17–22). On the other hand, a lack of beneficial effect on total mortality has been reported in three studies with a combined total study population of 12,735 patients hospitalized with CAP (23–25). Our research of patients hospitalized with CAP adds another study in which a favorable effect in outcomes can be documented with a regimen that covers atypical pathogens. This current controversy may be explained in part due to the fact that total mortality in some patients with CAP is due to factors unrelated to initial antimicrobial therapy. Initial antimicrobial therapy with or without atypical coverage will have no influence in a patient that died of factors not related to the pulmonary infection. It has been estimated that mortality may not be directly related to the pulmonary infection in up to half of hospitalized patients with CAP (26, 27). One of the strengths of our study is that a beneficial effect on mortality for patients treated with an atypical regimen was found for all-cause mortality as well as for only CAP-related mortality. In an attempt to control for other factors that may confound the outcome of mortality, we evaluated all patients for certain recognized factors that are associated with mortality in hospitalized patients with CAP. The results of our multivariate analysis were consistent with the published literature indicating an increased risk for mortality in patients with elevated risk class, admission to ICU, multilobar infiltrates, pleural effusion, altered mental status, increased respiratory rate, and hypotension. All of these variables characterized severity of pneumonia at the time of presentation and cannot be modified. We identified three variables that were amenable to modification which were associated with a decreased risk for mortality: antibiotic administration within 8 hours, performing an oxygenation assessment, and empiric therapy with a regimen that covered atypical pathogens. Another strength of our study is the generalizability of the CAPO database study population with an overall mortality rate of greater than 10%. Pharmaceutical trials often exclude patients who are likely to die shortly after admission; hence, our study is more consistent with "real life" populations. Because the outcomes of mortality and length of stay may be influenced by factors not directly related to the pulmonary infection, some investigators consider that the best outcome to evaluate the response to antimicrobial therapy is time to clinical stability (28). Our study is the first one to evaluate the effect of covering for atypical pathogens in time to clinical stability. We documented a significant decrease in time to clinical stability in patients who were treated with atypical coverage. Using the CAPO international database, we recently demonstrated a strong correlation of patient risk class not only with mortality and LOS but also with time to clinical stability (29). In the current study, the beneficial effect of atypical coverage on time to clinical stability was maintained after adjusting for risk class. In our population of hospitalized patients with CAP, empiric therapy with a regimen that covers atypical pathogens produced a consistent benefit for the early study outcomes (time to clinical stability and LOS), as well as for the late study outcomes (total mortality and CAP-related mortality). The beneficial effect of antibiotics with atypical coverage is more difficult to be recognized in ambulatory patients with CAP because, in this population, time to clinical stability is not measured and mortality is a very rare outcome. This may explain why a recent meta-analysis failed to find a beneficial effect of a regimen with coverage for atypical pathogens in patients with mild CAP (30). The primary limitation of this study is the retrospective nature, and subsequently the lack of control for unmeasured confounders. A prospective study would also allow for patients in each risk class to be distributed equally between the two groups: those who would receive coverage for atypical pathogens and those who would not. A major limitation of the etiologic findings is that the samples came from patients enrolled in drug trials. These trials used enrollment criteria that limit the generalizability of the etiologic data presented in this study. Because this was not a randomized trial, an important limitation of the outcomes analysis is the possibility of indication bias. Despite efforts to control for confounders, treating physicians may have selected atypical coverage for subgroups of patients who were destined to have better outcomes. Our analysis was also limited by the low number of patients with CAP enrolled from Asia and Africa. The implication of finding a 22% global incidence of atypical pneumonia may affect future research in CAP. For example, additional studies addressing the use of procalcitonin levels to guide duration of antimicrobial therapy will need to consider a comprehensive evaluation for atypical pathogens because more than 50% of patients with low procalcitonin levels were found to have atypical pneumonia (31, 32). As compliance with CAP guidelines has been associated with improved outcomes (33), future studies in that area might consider defining compliance based on guidelines that recommend covering atypical pathogens for all hospitalized patients with CAP (1, 2). In summary, this study has three primary conclusions. First, using comprehensive diagnostic tests, atypical pathogens were found to be present in a considerable and similar proportion of patients with CAP from all regions of the world. Second, there were significant variations in the number of hospitalized patients with CAP who were treated with empiric therapy that cover for atypical pathogens. Third, patients who were treated with antimicrobial regimens with coverage for atypical pathogens had a shorter time to clinical stability, a decreased length of hospitalization, and a decreased mortality. Our data strongly support the concept that all hospitalized patients with CAP should receive empiric therapy with a regimen that covers typical and atypical pathogens.
The authors acknowledge the assistance of Elizabeth Smigielski, Associate Professor with the Kornhauser Health Sciences Library at the University of Louisville, and Ginny Sciortino with the Division of Infectious Diseases at the University of Louisville. CAPO investigators and affiliations: Dr. Raul Nakamatsu, Veterans Affairs Medical Center, Louisville, KY; Dr. John Myers and Dr. Guy Brock, University of Louisville, KY; Dr. Jose Bordon, Providence Hospital, Washington, DC; Dr. Peter Gross, Hackensack University Medical Center, Hackensack, NJ; Dr. Karl Weiss, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, Canada; Dr. Delfino Legnani, Ospedale L. Sacco, Milan, Italy; Dr. Roberto Cosentini, Policlinico, Milan, Italy; Dr. Maria Bodi, Hospital Universitario Joan XXIII, Tarragona, Spain; Dr. Antoni Torres, Instituto de Neumonologia y Cirugia Toracica, Barcelona, Spain; Dr. Jose Porras, Hospital Sant Pau i Santa Tecla, Tarragona, Spain; Dr. Harmut Lode, City Hosp. E.v.Behring/Lungenklinik Heckeshorn, Berlin, Germany; Dr. Jorge Roig, Hospital Nostra Senyora de Meritxell, Escaldes, Andorra; Dr. Guillermo Benchetrit, IDIM A. Lanari, Buenos Aires, Argentina; Dr. Gustavo Lopardo, Hospital Profesor Bernardo Houssay, Buenos Aires, Argentina; Dr. Lautaro de Vedia, Hospital Francisco J. Muniz, Buenos Aires, Argentina; Dr. Jorge Corral, Hospital Dr Oscar Alende, Mar del Plata, Argentina; Dr. Jorge Martinez, Instituto Medico Platense, La Plata, Argentina; Dr. Jose Gonzalez, Hospital Enrique Tornu, Buenos Aires, Argentina; Dr. Alejandro Videla, Hospital Universitario Austral, Buenos Aires, Argentina; Dr. Carlos Victorio, Clinica Uruguay, Entre Rios, Argentina; Dr. Eduardo Rodriguez, Hospital Español de La Plata, La Plata, Argentina; Dr. Maria Rodriguez, Hospital Rodolfo Rossi, La Plata, Argentina; Dr. Gur Levy, Hospital Universitario de Caracas, Caracas, Venezuela; Dr. Federico Arteta, Hospital Luis Gomez Lopez-Ascardio, Barquisimeto, Venezuela; Dr. Alejandro Diaz Fuenzalida, Pontifica Universidad de Chile, Santiago, Chile; Dr. Maria Parada, Clinica las Condes, Santiago, Chile; Dr. Juan Luna, Hospital Nacional Roosevelt, Guatemala.
Parts of this article were presented at the 2004 Infectious Diseases Society of America conference, October 1, 2004, and at the 2005 International Conference of the American Thoracic Society, May 24, 2005.
* A complete list of study investigators may be found before the reference section. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200603-350OC on March 1, 2007 Conflict of Interest Statement: F.W.A. has received $500 funding from Pfizer and $750 from Ortho-McNeil for speaking within the last 3 years. J.T.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.S.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.J.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.B. has received consulting fees from Pfizer, Sanofi-Aventis (S-A), Altana, Wyeth, Schering-Plough (S-P), and GlaxoSmithKline (GSK); lecture fees from Bayer, S-A, Pfizer, Abbott, Altana, GSK; and grant support from Pfizer, Altana, and Abbott. P.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.M.F. in the last 3 years has received funding from the following companies for the following relationships: for recent research funding from Ortho-MacNeil, Oscient, Pfizer, S-A; for consultancies from Bayer, GSK, Merck, Ortho-MacNeil, Oscient, Pfizer, S-A, S-P, Wyeth; for Speaker's Bureaus from Abbott, GSK, Merck, Ortho McNeil, Oscient, Pfizer, S-A, S-P, and Wyeth. The aggregate amount received for the preceding 3 years exceeds $10,000 for each of the pharmaceutical manufacturers listed. J.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.M. has received $2,000 for speaking in a conference sponsored by Pfizer in 2005. L.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.M.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.A.R. in the preceding 3 years has received a grant from Bayer/S-P in the amounts of $355,000 for a clinical trial from October 2004 through April 2006. He also received a grant from Pfizer Pharmaceuticals in the amount of $250,000 for a clinical trial that is currently in progress. Received in original form March 9, 2006; accepted in final form February 23, 2007
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