Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality globally, significantly driving antibiotic use in hospitalized patients. Frequently, the causative agent remains unidentified, leading to antibiotic overtreatment. This overuse contributes to antimicrobial resistance, increasing the risk of complications like *Clostridioides difficile* infection. Antibacterial resistance is escalating, causing higher morbidity and mortality rates. Current CAP guidelines don't recommend multiplex PCR panels for initial microbiological diagnosis, and guidance on conventional methods lacks consistency and high-quality evidence. This study aimed to determine if adding multiplex real-time PCR to conventional microbiological testing was a safe and effective strategy for reducing antibiotic use in hospitalized CAP patients.

Existing literature highlights the significant problem of antibiotic overuse in CAP treatment due to difficulties in identifying causative pathogens. Studies have demonstrated the link between prolonged antibiotic treatment and adverse events, including *C. difficile* infection. The increasing global burden of antimicrobial resistance underscores the urgent need for strategies to optimize antibiotic use. While some studies have explored rapid diagnostic tests like multiplex PCR, their impact on antibiotic stewardship in CAP remains inconclusive and lacks robust high-quality evidence to guide clinical practice. The inconsistency in current guidelines regarding microbiological testing further emphasizes the need for well-designed clinical trials to evaluate the efficacy of novel diagnostic tools.

This was a randomized, controlled, open-label trial (RADICAP) conducted across four Spanish hospitals between February 20, 2020, and April 24, 2023. 315 patients were assessed for eligibility; 73 were excluded, leaving 242 patients randomized (1:1) to either multiplex real-time PCR plus conventional microbiological testing (n=119) or conventional microbiological testing alone (n=123). The primary endpoint was days of antibiotic therapy (DOT), analyzed using intention-to-treat and per-protocol analyses. Baseline characteristics were well-balanced between groups. Multiplex PCR was performed primarily on sputum (65.2%) and nasopharyngeal swabs (34.7%). Conventional testing included Gram stain, sputum culture, blood cultures, and urine antigen tests for *Streptococcus pneumoniae* and *Legionella pneumophila*. The Biofire® FilmArray® Pneumonia Plus panel was used for multiplex PCR, detecting 15 bacterial and 9 viral pathogens. Data were analyzed using appropriate statistical methods (Wilcoxon rank-sum test for primary endpoint and chi-squared or Wilcoxon rank-sum tests for secondary endpoints). An interim analysis was performed, and due to concerns regarding futility and slow recruitment (influenced by the COVID-19 pandemic), the study was halted early.

A total of 242 patients were included in the intention-to-treat analysis. The median DOT was 10.04 days in the multiplex PCR plus conventional testing group and 11.3 days in the conventional testing alone group (difference -1.04 days; 95% CI, -2.42 to 0.17; p = 0.093). This difference was not statistically significant. An etiological diagnosis was established in significantly more patients in the multiplex PCR group (63.9% vs. 26.2%, p < 0.001). The most common pathogens identified were *Streptococcus pneumoniae*, *Legionella pneumophila*, and *Haemophilus influenzae*. Polymicrobial infections and viral infections were more frequent in the multiplex PCR group. Secondary endpoints showed a significantly shorter time to switch from intravenous to oral antibiotics and a shorter time to reach an etiological diagnosis in the multiplex PCR group. Significantly fewer patients in the multiplex PCR group required ICU admission. There were no significant differences in other secondary endpoints, including adverse events and 30-day mortality.

This study's findings do not support the routine use of multiplex real-time PCR for initial microbiological testing in hospitalized adults with CAP. Although multiplex PCR provided a faster etiological diagnosis and allowed for a faster switch to oral antibiotics, it did not significantly reduce the overall duration of antibiotic therapy. The lack of impact on the primary outcome might be due to several factors, including the early termination of the trial due to futility and the inherent complexity of CAP management, where clinical judgment plays a crucial role. The study's strength lies in its randomized controlled design, but the limitations warrant consideration.

The RADICAP trial failed to demonstrate a significant reduction in antibiotic use with the addition of multiplex real-time PCR to standard microbiological testing for hospitalized CAP patients. Further research might explore alternative strategies to improve the diagnostic accuracy of CAP and optimize antibiotic use, focusing on patient subgroups and specific clinical scenarios.

The study was stopped early due to futility and slow recruitment affected by the COVID-19 pandemic. This early termination might have limited the ability to detect a smaller but still clinically meaningful difference in antibiotic use. The relatively small sample size might also have reduced the statistical power to detect differences between groups. The use of different sample types for PCR testing introduces potential heterogeneity.