Effects of age, comorbidity and adherence to current antimicrobial guidelines on mortality in hospitalized elderly patients with community-acquired pneumonia

Despite significant reductions in deaths due to community-acquired pneumonia (CAP) between 2009 and 2013, lower respiratory tract infections (LRTI) remain a leading cause of death in China, responsible for more than 19 deaths per 100,000 people per year [1]. In 2013, LRTI ranked 2nd among causes of global years of life lost [2]. CAP remains a significant threat, especially to the elderly, and it is the most common cause of infectious disease-related hospitalization and death [3, 4].

Among elderly patients with CAP, predictors of death include increased age [5‐9], underlying comorbidity [5‐7] and severity of illness [3, 6, 9]. Studies have reported mortality rates of elderly patients with CAP ranging from 6.4% to 33% [9‐13], roughly doubling as age increased from 65 to 69 years to > 90 years [5]. An increasing number of studies suggest that adherence to CAP guidelines improves patient outcomes and decreases healthcare costs [14‐20]. The analysis conducted by the Community-Acquired Pneumonia Organization (CAPO) International Study database showed that for hospitalized CAP patients aged ≥65 years, adherence to the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines was associated with a dramatically significant decrease in the time to achieve clinical stability, shorter length of stay (LOS) and lower overall mortality compared with non-adherent therapy [17]. Moreover, adherence was a cost-effective strategy for patients in general wards [20]. For patients hospitalized in the ICU, a retrospective study found that guideline-concordant therapy was associated with decreased mortality [21]. In contrast, studies by Rossio [22] and Wilson [23] found that adherence to guidelines did not affect mortality among patients with CAP.

As the life span of the global population continues to increase, the number of elderly patients hospitalized with CAP will increase accordingly, placing greater demands on available healthcare resources and highlighting the importance of understanding the epidemiology of CAP among the elderly. Existing studies about hospitalized CAP patients aged ≥65 years have largely focused on North American and European populations. Chinese adult CAP guidelines were most recently updated in April 2016; however, in clinical practice, to what degree physicians need to tailor their treatment approach to comply with such guidelines and whether these changes actually improve patient outcomes both require assessment. To address these important questions, a multicenter, retrospective observational study was conducted by the CAP-China network. The objectives of the study included a comparison of the common treatment patterns in the 2014 to 2016 guidelines and an investigation of the influences of age, comorbidity and antimicrobial regimens adherent to the current 2016 CAP guideline on the mortality of hospitalized elderly patients with CAP.

This is the first retrospective multicenter study to assess the influences of age, comorbidity and antimicrobial treatment on outcomes of hospitalized elderly patients with CAP in China. The major findings of our study were as follows: 1) the overall in-hospital mortality and 60-day mortality rates were relatively low, 5.7% and 7. 6%, respectively, and age was the independent prognostic factor most associated with mortality; 2) 60% of patients had two or more comorbidities; congestive heart failure and long-term bedridden condition were independent risk factors of 60-day mortality; 3) 62.1% of patients received non-adherent treatment with antibiotics active for this genus.

In the present study, the breakdown of age was similar to data reported from a study in Spain, which enrolled 2149 patients aged ≥65 years [32]. The comorbidity ratios in our study were higher than those previously reported [5, 32, 33].

The proportion of non-adherent regimens (62.1%) in our study was significantly greater than in the CAPO study [17] and other studies [20‐22]. For patients without risk factors for PA infection in general wards, overtreatment with anti-pseudomonal β-lactam regimens approached 80%, far greater than the data reported by Egger, which showed only 1% [20]. The wide-spread use of Pseudomonas-active carbapenem (other than ertapenem) was critical. This inappropriate use of carbapenems placed unnecessary pressure on bacteria to develop resistance, thus increasing the risk of Carbapenem-resistant Enterobacteriaceae (CRE). The reason for widespread overtreatment of general ward patients is unclear but is likely multifactorial. Clearly, part of the reason is that patients included in this study were treated before Chinese CAP guidelines were published. For physicians, choice of treatment should follow guidelines, and therefore, significant changes in treatment patterns are required. Furthermore, some patients may have received prior outpatient antibiotics that were consistent with the guidelines but that failed. A patient’s intent to be cured as soon as possible after admission and the burden of an average day of hospitalization may force the physician to treat more aggressively on admission, making the “first-choice, empiric therapy” more consistent with a second-line regimen. We can also see a low detection rate (14.0%) of pathogens and high detection rate of gram-negative bacilli (71.3%) in our data; pre-hospitalization antibiotic abuse and real or perceived risk of multi-drug-resistant pathogens may also have prompted physicians to overtreat to avoid failure. Better regional epidemiology data are critical to avoid the over-use of broad-spectrum agents.

Our data did not identify a relationship between non-compliance (either overtreatment or undertreatment) and mortality, as in previously published studies [22, 23]. There are a number of explanations for this observation. First, the best predictor of mortality was the severity of illness. In our study, CURB-65 was also confirmed as a risk factor of mortality. Thus, if guidelines did not capture patient severity to a sufficient degree, antibiotic choices might be appropriate for the patient but still be non-compliant with guidelines. Furthermore, patients transferred from other facilities or those who received outpatient antibiotics had an “initial” regimen influenced substantially by prior choices that were unsuccessful. Second, 2016 CAP guidelines might have been inferior to the 2014 standard-of-care. This seems unlikely but cannot be ruled out based on these data. Finally, this study gathered data only on the reported initial antimicrobial therapy, which may have been subsequently changed.

The overall mortality was lower than prior studies from the United States [5, 6, 11, 13], Europe [12] and Japan [9], due to a higher proportion of patients with lower risk scores. Meanwhile, compared with Malaysia, Indonesia and the Philippines [34], the mortality was higher. In fact, approximately 90% of hospitalized elderly CAP patients in China were of low to moderate risk. In a population-based study including 590 patients over 65 years old, the in-hospital mortality of low to moderate risk was 12.0% classified by CURB-65 score [35]. Luna and coworkers [6] reported an overall 30-day mortality rate of 8.2% in CAP patients, although they found little increase with age until patients were aged over 80 years, in contrast to our data. However, it is also possible that we were unable to fully assess the patients’ severity based on this chart review, and patients did receive appropriate site-specific care and initial antibiotic treatment on admission, especially based on possible prior antibiotic treatment [36, 37], resulting in appropriate infection control with reduced mortality rates.

We found many factors associated with a higher mortality rate; however, in the multivariate analysis, only 8 factors remained associated with increased 60-day mortality. Age was one of them, similar to the findings of previous studies [5, 13, 32, 33, 38]. It is widely acknowledged that the PSI is greatly affected by age. Given that the mean age of patients in this study was 77.4 ± 7.4 years; this would significantly affect the severity ratings for patients older than 75 years. Congestive heart failure was the only predictor of comorbidities related with mortality. Riquelme [13] reported that bedridden status was associated with a worse prognosis among elderly patients with CAP, consistent with our finding. CURB-65 is the most commonly used scoring system to assess severity of pneumonia. Data from Ochoa-Gondar O [35] demonstrated that CURB-65 was a good rule in predicting short-term mortality among elderly CAP patients. Data in our study showed that increased CURB-65 score was associated with increased 60-day mortality. Glucose level and heart rate were also risk factors of mortality. Higher glucose levels suggest that infection is more difficult to control. Heart rate is a component of PSI or SMART-COP score [39]; usually, the faster the heart rate, the more severe the infection. Although serum albumin was an acute phase reactant, the production of which dropped sharply by the liver in an inflammatory environment, it was not a good marker of nutrition status, and our study found that albumin was a protective factor against mortality, coinciding with figures from Hong Kong [40]. SaO₂ was another protective factor against mortality; low oxygen clearly suggests more severe infections.

Some limitations of the present study deserve consideration. First, this was a retrospective observational study. Inevitably, we encountered some missing data, making it impossible to calculate PSI scores in nearly half of all patients. While a potential confounder, CURB-65 scores were less affected by missing data, but our study had a slightly higher proportion of patients with less severe pneumonia (CURB score < 2) compared with previous studies [29, 41]. Second, some cases of pneumonia may have been overlooked due to miscoding or because requiring a primary pneumonia ICD-10 code was too restrictive. Third, antimicrobial therapy was initiated prior to hospitalization for many patients; therefore, the initial antimicrobial regimen captured in this study was not necessarily the actual initial antimicrobial regimen that the patient received. This is especially true for patients transferred from other hospitals who were not excluded from the study.