Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus a beta-lactam agent versus a beta-lactam agent alone

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1 Eur J Clin Microbiol Infect Dis (2005) 24: DOI /s ARTICLE E. García Vázquez J. Mensa J. A. Martínez M. A. Marcos J. Puig M. Ortega A. Torres Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus a beta-lactam agent versus a beta-lactam agent alone Published online: 22 March 2005 C Springer-Verlag 2005 Abstract A cohort of 1,391 patients with communityacquired pneumonia of unknown etiology, atypical pneumonia, Legionella pneumophila pneumonia, viral pneumonia, or pneumococcal pneumonia was studied according to a standard protocol to analyse whether the addition of a macrolide to β-lactam empirical treatment decreases mortality rates. Patients admitted to the intensive care unit were excluded. Severity was assessed using the PORT score. An etiological diagnosis was achieved in 498 (35.8%) patients (292 infections due to Streptococcus pneumoniae). Treatment was chosen by the attending physician according to his/her own criteria: β-lactam agent in 270 and β-lactam agent plus a macrolide in 918 cases. The mortality rate was 13.3% in the group treated with a β-lactam agent alone and 6.9% in the group treated with a β-lactam agent plus a macrolide (p=0.001). The percentage of PORT-group V patients was 32.6% in the group treated with a beta-lactam agent alone compared to 25.7% in the group who received a β-lactam agent plus a macrolide (p=0.02). After controlling for PORT score, the odds of fatal outcome was two times higher in patients treated with a beta-lactam agent alone than in those treated with a β-lactam agent plus a E. García Vázquez ( ) J. Mensa J. A. Martínez M. Ortega Infectious Diseases Department, Hospital Clinic Universitari, Barcelona, Spain elisag@eresmas.net Tel.: Fax: M. A. Marcos J. Puig Microbiology Department, Hospital Clinic Universitari, Barcelona, Spain A. Torres Institute of Pneumology and Thoracic Surgery, IDIBAS, Hospital Clinic Universitari, Barcelona, Spain E. García Vázquez Servicio de Medicina Interna-Infecciones, Hospital Universitario Virgen de la Arrixaca, Ctra. Madrid-Cartagena, El Palmar (Murcia), Spain macrolide (adjusted OR = 2, 95%CI ). The results suggest that the addition of a macrolide to an initial β-lactam-based antibiotic regimen is associated with lower mortality in patients with community-acquired pneumonia, independent of severity of infection, thus supporting the recommendation of a β-lactam-agent plus a macrolide as empirical therapy. Introduction Community-acquired pneumonia (CAP) remains a significant cause of both mortality and morbidity [1, 2]. Clinical features alone do not permit accurate identification of the specific respiratory pathogen, and thus empirical antibiotic therapy should be started pending microbiological results. Most published guidelines on treatment take into consideration the severity of the pneumonia, but it is probably mandatory to treat for Streptococcus pneumoniae, as it is the most common cause of CAP and death due to CAP. The Canadian Thoracic Society [3], the American Thoracic Society [4], and the British Thoracic Society [5] guidelines recommend either combined empirical therapy (β-lactam agent plus a macrolide) or an antipneumococcal fluoroquinolone for treatment of severe pneumonia, and the British Thoracic Society also advises combined empirical therapy for adults with nonsevere CAP to empirically treat both bacterial and atypical pathogens [5]. These recommendations have probably been supported by several recent observational studies suggesting that mortality and length of stay of patients admitted to the hospital with CAP [6 9] or bacteraemic pneumococcal pneumonia [10 12] are decreased by initial antimicrobial regimens consisting of a macrolide plus a β-lactam agent. Nevertheless, only three of these investigations [6, 8, 12] specified that the lower mortality associated with combination therapy remained significant after adjusting for several prognostic factors such as age, severity of disease, comorbidity, delay in initiation of antimicrobial therapy, transfer from a long-term care facility, and need for ICU admission.

2 191 The aim of our study was to assess whether combined empirical treatment (β-lactam agent plus a macrolide) of patients with CAP adjusted for severity at admission (using the PORT score) is associated with lower in-hospital mortality. Our cohort of 1,518 patients with CAP studied at our institution was analysed according to a standard protocol from October 1996 to December We also performed a subanalysis of patients with pneumococcal pneumonia and patients without a microbiological diagnosis. Patients and methods From October 1996 to December 2001, a cohort of 1,518 consecutive patients >14 years of age with acute symptoms consistent with CAP were studied according to a standard protocol in the Respiratory and Infectious Diseases Service at the Hospital Clinic Universitari in Barcelona, Spain, an 800-bed university teaching hospital. Cases due to gramnegative bacilli were excluded. As a result, a total of 1,391 patients with CAP of unknown etiology, atypical pneumonia, Legionella pneumophila pneumonia, viral pneumonia, or pneumococcal pneumonia were included in the analysis. Data were recorded prospectively, but the analysis was performed retrospectively. CAP was defined as the presence of a new infiltrate on chest radiograph along with appropriate clinical history and physical signs of lower respiratory tract infection in a patient not hospitalised within the previous month and in whom no alternative diagnosis emerged during follow-up. Clinical, laboratory and radiological features at presentation as well as other epidemiological data were recorded on a specific questionnaire and entered in a computer database. Severity of CAP was assessed within the first day of admission using the PORT (Patients Outcome Research Team) score [13]. Part of this study population has been described previously [14, 15]. Patients with neutropenia (neutrophil count, < /l), HIV infection, tuberculosis, fungal infection, and those treated with steroids in a prednisone-equivalent dosage of more than 20 mg per day for 2 weeks or longer were not included. Patients who were admitted to the intensive care unit immediately from the emergency department were also excluded. Although since 1999 our guidelines recommend the use of a β-lactam agent plus a macrolide for patients with CAP, the initial empirical therapy was chosen by the attending physician according to his or her own criteria. Only patients receiving a β-lactam agent or a β-lactam agent plus a macrolide from the time of admission (first 24 h) were considered for the analyses. Patients were observed from the time of diagnosis of CAP until in-hospital death or discharge. Microbiological investigations When possible, standard tests included microscopic examination of one sputum sample, culture of two blood samples, and serological testing of two serum samples (obtained 4 8 weeks apart). Sampling by pleural puncture, transthoracic needle puncture, tracheobronchial aspiration (in mechanically ventilated patients), and protected specimen brush (PSB) or bronchoalveolar lavage (BAL) was performed according to clinical indication or at the discretion of the attending physician. Expectorated sputum samples were collected in the emergency department prior to initiation of antibiotic therapy and were examined by Gram stain and accepted as suitable for culture if they satisfied the standard criteria of (i) <10 squamous epithelial cells per low-power field and (ii) >25 polymorphonuclear cells per low-power field. Such validated sputum samples, along with blood culture samples, undiluted and serially diluted tracheobronchial aspirates, and PSB and BAL fluid samples were plated onto the following media: sheep blood agar, CDC agar, chocolate agar, and Sabouraud agar. Undiluted PSB and BAL fluid samples were also cultured onto charcoal-yeastextract agar. Microorganisms were identified according to standard methods. From the year 2001, urine was also collected in the acute phase of illness for detection of soluble pneumococcal antigen by antibody assay (Binax S. pneumoniae urinary antigen test; Binax, Portland, OR, USA) and of L. pneumophila antigen by enzyme immunoassay (Bio Test Legionella pneumoniae urinary antigen test; Trinity Biotech, Bray, Ireland). The etiology of pneumonia was considered definitive if one of the following criteria was met: (i) bacterial pathogen isolated from blood (in the absence of an apparent extrapulmonary focus); (ii) bacterial pathogen isolated from pleural fluid or transthoracic needle aspiration cultures; (iii) seroconversion (i.e., a fourfold increase in IgG titre for Chlamydia pneumoniae, Chlamydia psitacci, L. pneumophila, Coxiella burnetii, and respiratory viruses (influenza viruses A and B, parainfluenza viruses 1 3, respiratory syncytial virus, and adenovirus); (iv) a single IgM titre for C. pneumoniae ( 1:32), C. burnetii ( 1:80), or Mycoplasma pneumoniae (any titre); (v) detection of L. pneumophila or S. pneumoniae urinary antigen; and (vi) quantitative bacterial growth of 105 cfu/ml in tracheobronchial aspirates, 10 3 cfu/ml in PBS, or 10 4 cfu/ml in BAL. Statistical analysis Mortality after the first 24 h after admission was analysed in relation to treatment (β-lactam agent vs. β-lactam agent plus macrolide) and adjusted for severity (using the PORT score). A subanalysis of patients with pneumococcal CAP and of those without a microbiological diagnosis was also performed. Descriptive data for continuous variables are presented as means ± standard deviations (SD) and as rates in case of categorical variables; statistical comparisons of the latter were made by the chi-square test with Yates correction or Fisher s exact test when appropriate. Statistical significance was defined as a two-tailed p value of <0.05. To assess the independent relationship between treatment and death, a

3 192 Table 1 Etiological diagnosis in 498 patients with CAP Causative organism S. pneumoniae 292 H. influenzae 78 L. pneumophila 54 C. pneumoniae 30 C. psitacci 1 M. pneumoniae 31 C. burnetii 12 Virus 50 No. of patients a a A single pathogen was identified in 447 patients and mixed etiology in 51 patients stepwise logistic regression procedure was done, with inhospital death as the dependent variable. All statistical values were calculated using the SPSS 9.0 software package. Results A total of 1,391 patients with CAP of unknown etiology, atypical CAP, L. pneumophila CAP, or viral or pneumococcal CAP were included in the analysis. An etiological diagnosis was achieved in 498 (35.8%) patients. S. pneumoniae was the most frequent cause of CAP in those patients in whom an etiological diagnosis was obtained (292 cases). Among the 498 patients with a microbiological diagnosis, a single pathogen was identified in 447 patients and mixed pathogens in 51 (10%) (Table 1). Of the 1,391 patients who met the inclusion criteria, 1,188 were treated with the study antibiotics: 918 (66%) received a β-lactam agent plus a macrolide and 270 (19.4%) a β- lactam agent alone. In all patients, cefotaxime, ceftriaxone, and amoxicillin-clavulanic acid were the β-lactam agents used and erythromycin, clarithromycin, and azithromycin the macrolides used. The mean age of the patients was 64 years (±19.85) in the β-lactam group versus years (±17.49) in the β-lactam plus macrolide group (p=0.007). A total of 99 (8.3%) patients died during hospitalisation. Mortality according to PORT group was 3.5% in group III, 6.7% in group IV, and 20% in group V. By univariate analysis, in-hospital mortality was higher in patients treated with a β-lactam agent alone (36 of 270 [13.3%]) than in those treated with a combination of a β- lactam agent and a macrolide (63 of 918 [6.9%]) (p=0.001). Table 2 summarises the distribution of patients in both treatment groups according to PORT score. The rate of PORTgroup V patients in the population treated with a β-lactam agent alone was 32.6% compared to 25.7% in the group who received β-lactam agent plus a macrolide (p=0.02). The distribution of patients in both treatment groups according to CAP severity (PORT score) and mortality is shown in Table 3. After controlling for PORT score, the odds of fatal outcome was two times higher in patients treated with a β-lactam agent alone than in those treated with a β-lactam agent plus a macrolide (adjusted OR=2, 95% CI ) (Table 4). A subgroup analysis of patients without an etiological diagnosis of CAP showed again that the inclusion of a macrolide as part of the initial regimen was associated with lower mortality (49 of 579 [8.5%] patients vs. 28 of 180 [15.6%] patients) (p=0.006) (Table 3). The distribution of patients in both treatment groups according to CAP severity (PORT score) is presented in Table 2. The proportion of PORT-group V patients in the β-lactam population was 35% compared to 27.5% in the group of patients who received a β-lactam agent plus a macrolide (p=0.06).when controlling for PORT score, the odds of fatal outcome was two times higher in patients treated without Table 2 Distribution of patients in the treatment groups according to PORT score (univariate analysis) Treatment group PORT group (%) a p value I-II III IV V Total patients (n=1,188) β-lactam (n=270) * 32.6* β-lactam plus macrolide (n=918) * 25.7* 0.03* CAP group, no etiological diagnosis (n=759) β-lactam (n=180) * 35* β-lactam plus macrolide (n=579) * 27.5* 0.06 Pneumococcal pneumonia group (n=255) β-lactam (n=61) * 25* β-lactam plus macrolide (n=194) * 27.2* 0.67* Atypical pneumonia group (n=104) β-lactam (n=10) * 37.5* β-lactam plus macrolide (n=94) * 12.8* 0.03* a Information about PORT group was available for 1,066 patients in the general group (227 in β-lactam group vs. 839 in β-lactam-macrolide group), for 660 patients in the group with no etiological diagnosis (143 in β-lactam group vs. 517 in β-lactam-macrolide group), for 251 patients in the pneumococcal pneumonia group (60 in β-lactam group vs. 191 in β-lactam-macrolide group), and for 94 patients in the atypical pneumonia group (8 in β-lactam group vs. 86 in β-lactam-macrolide group) *p value refers to statistical analysis of these rates (percentage of patients in β-lactam group vs. β-lactammacrolide group for PORT groups IV and V separately)

4 193 Table 3 Mortality according to initial empirical antibiotic treatment and according to PORT score (univariate analysis) Treatment group Mortality p value Mortality by PORT group a (%) p value No. (%) I II III IV V All patients (n=1188) β-lactam (n=270) 36 (13.3) * 27* β-lactam plus macrolide (n=918) 63 (6.9) * 17.6* <0.05* CAP group, no etiological diagnosis (n=759) β-lactam (n=180) 28 (15.6) * 28* β-lactam plus macrolide (n=579) 49 (8.5) * 22.5* <0.05* Pneumococcal pneumonia group (n=255) β-lactam (n=61) 6 (9.8) * 26.7* β-lactam plus macrolide (n=194) 11 (5.7) * 9.6* <0.05* Atypical pneumonia group (n=104) β-lactam (n=10) 0 (0) 0 0 0* 0* β-lactam plus macrolide (n=94) 3 (3.2) * 9.1* <0.05* a Information about PORT group was available for 1,066 patients in the general group (227 in β-lactam group vs. 839 in β-lactam-macrolide group), for 660 patients in the group with no etiological diagnosis (143 in β-lactam group vs. 517 in β-lactam-macrolide group), for 251 patients in the pneumococcal pneumonia group (60 in β-lactam group vs. 191 in β-lactam-macrolide group), and for 94 patients in the atypical pneumonia group (8 in β-lactam group vs. 86 in β-lactam-macrolide group) *p value refers to statistical analysis of these rates (percent mortality in β-lactam group vs. β-lactammacrolide group for PORT groups IV and V separately) Table 4 Variables associated with in-hospital mortality (logistic regression analysis) Factors associated with mortality Odds ratio 95%CI All patients β-lactam group PORT class 3 Comparison group CAP patients, no etiological diagnosis β-lactam group PORT class 3 Comparison group Pneumococcal pneumonia patients β-lactam group PORT class 3 Comparison group the macrolide/β-lactam combination (adjusted OR=1.96, 95%CI ) (Table 4). A total of 292 patients had pneumococcal pneumonia. Treatment consisted of a β-lactam agent alone in 61 cases and a β-lactam agent plus a macrolide in 194 cases. Mortality rates in the two treatment groups were 9.8% and 5.7%, respectively (p=0.255) (Table 3). When controlling for PORT score, treatment with a β-lactam agent alone was not an independently associated risk factor for mortality (adjusted OR=1.90, 95%CI ) (Table 4). A total of 104 patients had atypical CAP (due to Mycoplasma pneumoniae, C. pneumoniae, L. pneumophila, or C. burnetii). Treatment consisted of a β-lactam agent alone in 10 cases and a β-lactam agent plus a macrolide in 94 cases. Mortality rates were 0% and 3.2%, respectively (p=0.566) (Table 3). Multivariate analysis was not performed due to the small sample size (only 3 patients with the final outcome, i.e., death). In those patients for whom information was available, neither the prior use of antibiotics nor the presence of symptoms before hospital admission was statistically associated with a different outcome (p>0.05). Discussion Many aspects of the apparently beneficial effect of the β- lactam and macrolide combination remain speculative and controversial. We have evaluated a series of patients with CAP initially treated with β-lactam agents in order to assess whether the inclusion of a macrolide as part of an empirical β-lactam-based regimen was associated with lower in-hospital mortality. The results showed that treatment of CAP with a β-lactam agent alone was an independent predictor of death after controlling for CAP severity using the PORT score, thus supporting the findings of other authors published in recent years [6, 7, 7 12]. There is probably not a single satisfactory explanation for the independent association between combination treatment (macrolide plus a β-lactam agent) and the reduction

5 194 in mortality. Otherwise, there might be several reasons to explain the beneficial effect of adding a macrolide to β- lactam treatment in patients with CAP. First, the prevalence of atypical organisms in hospitalised patients with CAP might be considerable. Porath et al. [16] found 67.5% of coinfected patients to have pneumococcal pneumonia. Although this is probably a very high rate, the rate of mixed infections (atypical and bacterial pathogens) has been described as varying from 10% to 25% [17]. In our series, 51 of 498 (10%) cases had a mixed etiology. The presence of atypical pathogens may explain the variation in the prognosis of CAP treated with a β-lactam/macrolide combination, as temporal variability in the incidence of atypical CAP is a fact. However, coinfection probably cannot explain the benefit of the addition of a macrolide in all cases of CAP, and moreover, it is uncertain whether the treatment of copathogens such as C. pneumoniae affects outcome [18]. Thus, in our series the beneficial effect of the macrolides remains when a subanalysis is carried out for those pneumonia cases without microbiological diagnoses (adjusted OR=1.96, 95%CI ) (Table 4), but we could not perform a multivariate analysis in patients with atypical pneumonia due to the small sample size (only 3 patients with the final outcome, death) (Table 4). A second theoretical possibility might have been a synergistic effect of macrolides and β-lactam agents. Contrary to this, there is evidence that the combination of a β-lactam and a macrolide is antagonistic both in vitro and in an animal model [19]. In our experience, the combination of a macrolide and penicillin in vitro, if not synergistic, might at least not be antagonistic when the β-lactam agent is administered first, followed some hours later by the macrolide, which in fact probably reflects clinical practice [20]. A third explanation of the benefit of adding macrolides in the treatment of CAP might be their anti-inflammatory effect. This might help to explain the findings of Stahl et al. [7], who investigated the effect of macrolides on the length of stay in patients with CAP when macrolides were administered within the first 24 h of admission and found that inflammation could be inhibited in the early stages of illness. If the effect of macrolides is related to the treatment of atypical agents, their role in shortening the length of stay would be independent of whether they are administered within or after 24 h of admission. There is some evidence that macrolides may inhibit interleukin production and may reduce proinflammatory effects of various bacterial products [21 23]. Stuertz et al. [24] described the increased release of lipoteichoic acids from S. pneumoniae as a result of exposure to β-lactam agents. Wang et al. [25] analysed the modulation of inflammation and the prevention of septicaemia and death when rats with pneumococcal pneumonia were treated with a combination of ceftriaxone plus interleukin 10 (a potent anti-inflammatory cytokine) compared to those in which only ceftriaxone or interleukin 10 was administered. In humans, Rello et al. [26] identified radiological progression, probably resulting from an excessive inflammatory response, as a predictor of death. Macrolides might lessen the inflammatory response generated by microbial proliferation and increased by treatment with β-lactam agents. This might explain their beneficial effect in pneumococcal pneumonia, although in our series this effect was not statistically significant, maybe due to the small sample size (adjusted OR=1.90, 95%CI ) (Table 4). Mortality according to PORT group was 3.5% in group III, 6.7% in group IV, and 20% in group V. These mortality rates are lower than those reported by Fine et al. [13]. A very likely explanation for this difference is that we excluded from the study cases of CAP due to gram-negative bacilli and/or patients admitted to the intensive care unit. The mean age was 64 years in the β-lactam group and 68.5 year in the β-lactam plus macrolide group. Although this difference is statistically different (p=0.007) and is higher in the combination treatment group, we believe it is probably not clinically relevant. The present work has the caveats of any observational study in which empirical antimicrobial therapy has not been randomised. Another possible limitation of our study is that single-agent therapy was the predominant therapy at the start of study, and the combined option was the predominant treatment in later years. Even after controlling for PORT score, the odds of fatal outcome were two times higher in patients treated with a β-lactam agent alone than in those treated with a β-lactam agent plus a macrolide (adjusted OR=2, 95%CI ) (Table 4); nevertheless, we cannot exclude that other aspects of care which may influence outcome (e.g., severity assessment on admission, O 2 therapy, nutrition policy, earlier access to intensive care units, staffing levels, speed with which antibiotics were given on admission) might have changed over time. Therefore, a definitive resolution to the controversy about the benefit of adding macrolides to β-lactam treatment on a standard basis can only be reached by performing a randomised prospective study. In conclusion, the data from this study suggest that the addition of a macrolide to an initial β-lactam-based antibiotic regimen is associated with lower in-hospital mortality in patients with CAP, independent of the severity of infection. 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