Highlights
- The MULTI-CAP trial found no significant difference in the primary endpoint of days alive and antibiotic-free at Day 28 between the intervention group (mPCR + PCT) and the control group.
- The intervention group experienced a significant reduction in cumulative antibiotic duration, with a median of 3 days fewer than the control group.
- Safety outcomes, including mortality and serious adverse events, were similar between the two management strategies.
- The results suggest that while molecular diagnostics can accelerate de-escalation, they may not influence global outcome measures that incorporate mortality.
Introduction: The Burden of CAP in Critical Care
Community-acquired pneumonia (CAP) remains a leading cause of admission to intensive care units (ICUs) worldwide, associated with high morbidity, mortality, and healthcare costs. The standard of care involves the rapid initiation of empiric broad-spectrum antibiotics. However, traditional microbiological cultures are often slow, requiring 48 to 72 hours for results, and frequently return negative in up to 50% of cases. This diagnostic delay leads to prolonged exposure to unnecessary broad-spectrum agents, contributing to the rise of antimicrobial resistance and drug-related toxicities.
In recent years, two diagnostic advancements have emerged to address this challenge: multiplex polymerase chain reaction (mPCR) and procalcitonin (PCT). mPCR offers the potential to identify respiratory pathogens and resistance genes within hours, while PCT serves as a host-response biomarker to guide the duration of therapy. The MULTI-CAP trial was designed to evaluate whether a strategy combining these two tools could superiorly reduce antibiotic exposure in the most severely ill patients.
The MULTI-CAP Trial: Study Architecture
Patient Population and Randomization
The MULTI-CAP trial was a multicenter, parallel-group, open-label, randomized controlled trial conducted across 20 ICUs in France. The study enrolled 406 non-immunocompromised adult patients admitted for severe CAP. Patients were randomized in a 1:1 ratio to either an intervention group or a control group. Inclusion criteria focused on patients requiring ICU-level support, such as mechanical ventilation or vasopressors, due to pneumonia symptoms appearing within 48 hours of admission.
The Intervention: A Dual-Biomarker and Molecular Approach
In the intervention group, clinicians utilized a broad-spectrum respiratory mPCR panel (identifying both bacterial and viral pathogens) in addition to conventional microbiological investigations (blood cultures, sputum cultures, and urinary antigens). An explicit antibiotic management algorithm was applied: clinicians were encouraged to discontinue or de-escalate antibiotics early based on the rapid mPCR results combined with serial serum PCT measurements.
The control group received only conventional microbiological investigations. In both groups, antibiotic discontinuation was systematically considered starting on Day 3 and reassessed daily until Day 7. This reassessment was guided by PCT values and kinetics—specifically targeting a discontinuation if PCT levels were below 0.25 ng/mL or had decreased by more than 80% from the peak value. This design is notable because it integrated PCT-guided stewardship into the “standard care” of the control group, effectively testing the additive value of mPCR.
Outcome Measures
The primary endpoint was the number of days alive and without any antibiotic from enrollment to Day 28. This composite endpoint accounts for both the duration of therapy and the survival of the patient, as patients who die are assigned zero antibiotic-free days. Secondary endpoints included cumulative antibiotic duration, ICU and hospital length of stay, 28-day mortality, and the incidence of serious adverse events.
Results: Analyzing the Primary and Secondary Outcomes
Primary Endpoint: Antibiotic-Free Days
Between October 2018 and March 2022, 385 patients were included in the intention-to-treat analysis. The results for the primary endpoint were neutral. The median number of days alive and without antibiotics at Day 28 was 19.0 days in the intervention group and 19.0 days in the control group. The difference was 0.0 days (95% CI, -4.0 to 4.0). This indicates that the combination of mPCR and PCT did not provide a superior benefit over conventional care (which included PCT) when measured by this specific composite metric.
Cumulative Antibiotic Duration and Safety
Despite the neutral primary endpoint, a significant difference was observed in the secondary analysis of antibiotic consumption. The cumulative duration of antibiotic therapy at Day 28 was 3 days shorter in the intervention group compared to the control group (95% CI, -5.1 to -0.9). This suggests that mPCR results allowed for earlier narrowing of spectrum or cessation of therapy in survivors.
Regarding safety, there were no significant differences in serious adverse events. Mortality at Day 28 was comparable between groups, as were the rates of ICU relapse of pneumonia and the duration of mechanical ventilation. These findings suggest that the more aggressive de-escalation enabled by mPCR did not compromise patient safety or clinical recovery.
Expert Commentary: Bridging the Gap Between Speed and Stewardship
The “Days Alive and Antibiotic-Free” Conundrum
The failure to meet the primary endpoint despite a reduction in cumulative antibiotic duration highlights a common challenge in critical care research. When using composite endpoints like “antibiotic-free days alive,” high mortality rates can dilute the observed effect of a stewardship intervention. If a patient dies early, they contribute zero days to the median, regardless of how quickly their antibiotics might have been managed. In the MULTI-CAP trial, the robust use of PCT in the control group likely raised the bar for the intervention, making it harder to show a statistical difference in the primary composite measure.
Clinical Utility of mPCR
The 3-day reduction in cumulative antibiotic duration is clinically significant. In the context of the ICU, reducing exposure by three days per patient can have a massive impact on the selective pressure for multi-drug resistant organisms. The trial demonstrates that mPCR is a powerful tool for “rule-in” and “rule-out” microbiology, providing clinicians with the confidence to stop broad-spectrum agents (such as those targeting MRSA or Pseudomonas) much earlier than they would when waiting for traditional culture growth.
However, the study also suggests that the mere availability of technology is not enough. The adherence to the algorithm and the clinical interpretation of mPCR (which can detect colonizers as well as pathogens) remain critical. The open-label nature of the trial means that clinician behavior was influenced by the knowledge of the PCR results, which is exactly how these tools are used in real-world practice.
Conclusion
The MULTI-CAP trial provides high-quality evidence that a management strategy combining multiplex PCR and procalcitonin does not increase the number of antibiotic-free days alive at Day 28 compared to a procalcitonin-guided standard of care. However, the clear reduction in total antibiotic duration without an increase in adverse outcomes supports the integration of rapid molecular diagnostics into ICU stewardship programs. For clinicians, the takeaway is that mPCR can safely accelerate the transition to targeted therapy, even if it does not fundamentally alter the survival-weighted duration of care in the most severe pneumonia cases.
Study Identification and Funding
The MULTI-CAP trial was registered with ClinicalTrials.gov (NCT03452826) and EudraCT (2017-A01615-48). The study was supported by various clinical research grants and the MULTI-CAP collaborative trial group.
References
1. Voiriot G, et al. Combined use of a multiplex PCR and serum procalcitonin to reduce antibiotic exposure in critically ill patients with community-acquired pneumonia: the MULTI-CAP randomized controlled trial. Intensive Care Med. 2025;51(8):1417-1430. doi: 10.1007/s00134-025-08014-9.
2. Metlay JP, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. American Journal of Respiratory and Critical Care Medicine. 2019;200(7):e45-e67.
3. Schuetz P, et al. Procalcitonin-guided antibiotic therapy algorithms. Expert Review of Anti-infective Therapy. 2017;15(6):557-568.
