Study design and setting
This prospective, observational, cohort study enrolled consecutive patients with CAP hospitalized in the non-ICU ward of Kurashiki Central Hospital between October 2010 and November 2016. CAP was diagnosed based on the IDSA/ATS guidelines1 as the presence of at least one of the clinical symptoms of cough, sputum, fever, dyspnea, and pleuritic chest pain, plus at least one finding of coarse crackles on auscultation or elevated inflammatory biomarkers, in addition to a new infiltrate on chest radiography. The exclusion criteria were age <15 y, ICU transfer on admission, β-lactam antibiotics and azithromycin not used as initial treatment, hospital-acquired pneumonia (caused more than 48 h from admission), and healthcare-associated pneumonia23. The criteria for healthcare-associated pneumonia are as follows: (1) hospitalization for ≥2 days in the preceding 90 days; (2) residence in a nursing home or extended care facility; (3) receiving infusion therapy including antibiotics; (4) receiving outpatient hemodialysis or peritoneal dialysis within 30 days before admission; and (5) home wound care.
This study was performed as a clinical study for pneumonia (UMIN000004353) and was approved by the institutional review board of Kurashiki Central Hospital (approval number 641). This study was also conducted in accordance with the amended Declaration of Helsinki. Based on the Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Ministry of Health, Labour and Welfare, the research participants were notified or the public was made aware of information concerning the research on the Internet. All patients gave their informed consent to participate in this study by being given opportunities to refuse to participate (opt-out system).
In all patients, the severity of pneumonia was assessed on admission with the use of the CURB-65 score [confusion, urea >7 mmol/L, respiratory rate ≥30 breaths/min, low blood pressure (systolic <90 mmHg or diastolic ≤60 mmHg), and age ≥65 y]15, PSI16, and IDSA/ATS severe pneumonia criteria1. Patients who meet the major criteria of the IDSA/ATS for severe pneumonia (i.e., mechanical ventilation with endotracheal intubation and/or septic shock requiring vasopressors) are usually treated in the ICU; therefore, in this study, we adapted the minor criteria. Patients who fulfilled at least three minor criteria were classified as having severe pneumonia1. We also defined a CURB-65 score of 3–5 points and PSI classes IV and V as severe pneumonia, and a CURB-65 score of 0–2 points and PSI classes I–III are non-severe pneumonia, in accordance with previous reports1,15,24,25.
All patients received antimicrobial agents based on the decision of the attending physician and according to the CAP guidelines of the Japanese Respiratory Society4. We typically use β-lactam antibiotics, such as a β-lactam/β-lactamase inhibitor combination or cephalosporin, as the initial treatment for patients with CAP hospitalized in the non-ICU ward26. We may use β-lactam and macrolide combination therapy if the patients are clinically suspected to have been infected by atypical pathogens. In our hospital, patients who needed mechanical ventilation and/or vasopressor drugs were basically treated in the ICU. Patients with severe hypoxemia and/or shock who did not need mechanical ventilation and vasopressor were also treated in the ICU, depending on the discretion of the attending physician.
To detect the causative microorganisms of CAP, we examined sputum and blood cultures and collected blood to measure serum antibodies on admission. A bacterial cause was identified if the following criteria were met: (1) positive sputum culture of more than 1+ on a qualitative test or 105 on a quantitative test, with significant Gram stain; (2) positive blood culture, excluding bacterial contaminants; (3) positive pleural fluid culture; (4) positive urinary antigen test for Streptococcus pneumoniae and Legionella pneumophila; (5) seroconversion or a four-fold increase in the antibodies for Mycoplasma pneumoniae and C. pneumoniae; and (6) ≥1:320 on a single particle agglutination antibody test for M. pneumonia (FUJIREBIO; Tokyo, Japan) or ≥2.0 cutoff index on a C. pneumoniae IgM antibody test (Hitazyme® assay; Hitachi Chemical, Tokyo, Japan).
The primary outcome was 30-day in-hospital mortality. We checked all the patients’ charts after 30 days from discharge who were discharged alive within 30 days from admission to see whether they had died or been readmitted.
Continuous variables were expressed as median and interquartile range, and categorical variables were expressed as counts (percentage). Continuous variables were analyzed using a non-parametric Mann–Whitney U-test, and categorical variables were assessed using Fisher’s exact test. We analyzed whether β-lactam and azithromycin combination therapy (azithromycin combination therapy), in comparison with β-lactam monotherapy, improved the prognosis of mild to severe pneumonia in all patients and in patients grouped according to the two severity classes (i.e., non-severe and severe) based on the existing severity scoring systems (CURB-65, PSI, and IDSA/ATS severe criteria). For comparison of the 30-day mortality between β-lactam monotherapy and azithromycin combination therapy, we used propensity score (PS) methods to reduce biases and the influence of the patients’ characteristics, such as age, comorbidities, and vital signs, laboratory examinations, and pneumonia severity, on the effects of treatment on outcome. Among the four PS methods, stratification, matching, weighting, and covariate adjustment27, IPTW was selected for analysis because it has been reported to result in a lower mean squared error when estimating treatment effects28. The PS was estimated by multivariate logistic regression analysis involving 15 covariates: age, sex, chronic obstructive pulmonary disease, malignancy, performance status, aspiration pneumonia, systolic blood pressure, respiratory rate, C-reactive protein, albumin, blood urea nitrogen, platelet, PSI score, CURB-65 class, and IDSA/ATS severe pneumonia classification. We selected these 15 variables because they were significantly different between the two treatment groups and have been reported to be prognostic factors15,16,26 that can influence the selection of therapy, although not significantly. We dealt with incorrect standard errors using robust standard errors, and used the R package ‘sandwich’ (version 2.5-0; Vienna, Austria). All statistical tests were two-tailed, a P value of <0.05 was considered significant. Analyses were performed using R (version 3.0.3).