This study found that almost half of the patients admitted to the ICU due to CAP died within one year after the acute episode. Additionally, patients with a higher Charlson comorbidity index, SAPS II, septic shock, and respiratory failure had a higher probability of dying within one year of the acute CAP hospitalisation in the ICU. After a comprehensive statistical analysis of this large prospective cohort, our results suggest that macrolide-based treatment reduces long-term mortality in patients admitted to the ICU due to CAP. Although results regarding coverage of atypic microorganisms with fluoroquinolones proved to be a protector factor at 6m, this was a vague association that was not maintained thereafter.
Different studies have shown that long-term morbidity and mortality rates in CAP patients are elevated. Mortensen et al. [27], in a prospective cohort study with 1555 CAP patients, found that 8.7% of patients died within 90 days, and 30.3% died within 5 years of the acute presentation. Also, in a multicentric study of 3415 adults with CAP prospectively enrolled, Johnstone et al. found that 30-day, 1-year, and 3.8-year mortality rates were 12%, 28%, and 53%, respectively. These studies are not specific to patients with CAP admitted to the ICU; however, these align with our results. We found a 6m and 12m mortality rate of 37.0% and 43.7%, respectively, demonstrating that mortality in patients with CAP admitted to the ICU is unacceptably high and undoubtedly increases the economic burden even after hospital discharge.
Several risk factors have been associated with higher mortality in patients with CAP. Regarding severity, the utility of the SAPS II score among long-term outcomes is still debatable [28]. On top of that, other scores as the higher Charlson comorbidity Index, are associated with higher mortality during hospitalisation due to CAP [29]. Still, some medical conditions included in this score have been individually associated with worse long-term clinical outcomes. Almirall et al.[30], a systematic review confirmed that older age increases long-term fatal outcomes in CAP hospitalised patients. On the other hand, respiratory failure patients continue to have an increased mortality risk in the following months and years after the ICU discharge [31, 32]. Similarly, Wang et al. found that one-year mortality was significantly higher than in-hospital mortality in patients hospitalised with respiratory failure (41% vs 24%, p = 0.01)[33]. Finally, sepsis patients exhibited increased all-cause mortality rates up to 5 years after the acute infection [34]. This preliminary data aligns with our study's results.
Empiric antibiotic treatment has been described as the cornerstone of CAP management [13], and macrolide-based vs non-macrolide-based therapy is controversial in the literature [35, 36]. Some preclinical studies have demonstrated that macrolides block bacterial toxins and have potential immunomodulatory properties that control disease progression [8, 20, 37]. However, other studies have not found differences between these interventions. Postma et al. [38] developed a cluster-randomised crossover trial with CAP patients admitted to non-ICU wards; 739 patients received macrolide-based treatment, 656 β-lactam alone, and 888 fluoroquinolones alone. The 90-day mortality was 11.1%, 9.0%, and 8.8%, respectively, concluding that non-macrolide-based treatment was a non-inferior strategy when analysing 90-day mortality. Nevertheless, Waterer G et al. [35] identified problems with the methodology. For instance, 25% of the cohort had no radiological confirmation of pneumonia. Over one-third of patients in the monotherapy β-lactam strategy received a macrolide antibiotic, resulting in an unbalanced intervention and a substantial risk of bias.
König et al. used a machine learning cross-validation scheme with 4898 patients with moderate CAP from an observational, prospective, multinational study [39]. They found that patients treated with non-macrolide-based treatment had a higher 180-day mortality than macrolide-based treatment (8.1% vs 7.6%; OR 1.06 [95% CI: 0.82–1.36]). A post hoc analysis of a cohort study of 594 CAP patients with low drug-resistant pathogen risk was performed by Okumura et al.[40]. It showed that those treated with macrolide treatment had better clinical outcomes regarding 30-day mortality, 13.8% for non-macrolide-based treatment and 1.8% for macrolide-based (OR 0.28 [95% CI: 0.09–0.87]). Notably, these and other studies have demonstrated the acute benefit of macrolide-based treatment in patients with severe CAP. Still, they have not assessed the long-term implications of macrolides. Strikingly, our study is the first to identify a medication used during acute infection that could improve long-term outcomes. Thus, our results are novel and have important implications for clinical practice. To improve clinical outcomes, patients with CAP admitted to the ICU should be treated with macrolide-based antibiotic treatment. This therapy may also reduce long-term mortality and impact healthcare systems.
Our study has certain limitations that are important to acknowledge. First, this is a monocentric, observational, non-randomised study design. However, we included an extensive sample size of over three thousand patients over 10 years. Moreover, we conducted a TMLE (that simulates an RCT) to adjust results for potential confounding variables, controlling the risk of bias and enabling greater statistical power. Second, patients were enrolled in a high-income country, making it difficult to extrapolate and replicate the methodology to validate this data in low- and middle-income countries. However, clarithromycin is an inexpensive medication that could be used in limited-resource settings with myriad potential benefits. Nevertheless, it is essential to highlight that azithromycin has a lower interaction potential. Third, no standardised protocols of antimicrobial treatment, doses, start time, and total days of administration were used, which also restricted the stratification analysis by these data. Nevertheless, macrolides are available globally and are used frequently in patients admitted to the hospital in the ICU with CAP using standard dosing. Also, the centres in this study used internationally accepted guidelines for using empirical antibiotics. Finally, we could not differentiate patients diagnosed with HCAP in our cohort. This might be a limitation because patients with HCAP were considered at risk of CAP due to P. aeruginosa and MRSA. Consequently, patients with HCAP were recommended to receive antipseudomonal and anti-MRSA coverage. However, no recommendation about macrolide usage was available for these patients; therefore, this classification may not interfere with our results. Also, we performed a sensitivity analysis excluding these patients and confirmed our results.
In conclusion, our study used a robust statistical analysis to demonstrate that macrolide-based treatment is associated with lower long-term mortality by reducing over one-third of the hazard risk; therefore, the benefit observed during acute hospitalisation is sustained over time. Thus, these data provide further justification for using macrolide-based treatment in patients with CAP admitted to the ICU to reduce the long-term burden of this prevalent disease. Additional prospective studies are required to support these conclusions.