In this randomized clinical trial, we investigated the usefulness of a CRP-based protocol to reduce the duration of antibiotic therapy in critically ill patients undergoing an evidence-based judicious use of antibiotics strategy. We found lower antibiotic exposure in the intervention patients in comparison to controls, who were treated according to the best practice in antibiotic therapy1,2,3,5,8. Despite a similar median time of therapy, there was a narrower distribution of this parameter in the CRP-arm patients. Moreover, in the CRP group, more patients had their antimicrobial therapy suspended up to the fifth day of follow-up, with a significant lower antibiotic exposure in the time-to-event analysis. Finally, the analysis per protocol revealed a reduction of one day in the median duration of antibiotic therapy in the intervention group.
Given the benefits offered by the rational use of antibiotics, including the reduction of multiresistant bacteria5,29,30, treatment costs31, frequency of adverse effects32, and less interference with microbiome, objective criteria to define the ideal treatment length is warranted. CRP is a low-cost and affordable biomarker10, routinely used in intensive care, that has been shown relate to prognosis in studies involving different populations with serious infectious conditions17,20,33,34.
Previous studies using biomarkers, notably PCT, included control groups in which the therapeutic strategy was freely determined by the assistant team. This strategy may have led to excessively long treatment duration of the control groups10, which varied from 1011 to 15 days12. A meta-analysis involving data from more than 4000 patients on PCT-guided antibiotic therapy of acute respiratory infections, revealed that the PCT-guided group was treated for seven days in comparison with the control, which received 10 days treatment, or 14 days for patients in intensive care settings35. In our study we used the best standard of care in the control group, not the usual care as described above.
More recently, two studies have tested the usefulness of biomarker-guided antibiotic therapy compared to controls using shorter therapies. In a single center study, Oliveira et al found that a PCT-based protocol was not superior to a protocol based on serum CRP levels for reducing the use of antibiotics in sepsis. It is worth highlighting the fact that in this study the researchers originally stipulated a maximum of seven days for the duration of the therapy, independently of the levels of biomarkers19. In a larger Dutch study, de Jong et al. showed the usefulness of PCT to reduce the duration of antibiotic therapy in critically ill patients, with five days as the median treatment time compared to seven days for controls14. It is noteworthy that the population included in the present work was significantly more severely ill than the patients included in the Dutch study14 (septic shock 32.3% vs. 18.5%, respectively), which reinforces the value of our results.
Although our study showed no difference in median duration of antibiotics in the ITT analysis, there were more patients which received shorter durations of antibiotics in the CRP-arm. Also, there was less exposure in the CRP group in the cumulative curve of antibiotic suspension. Further, one-day reduction in median duration of antibiotic treatment was found in the per-protocol analysis and in different post-hoc analyzes of subgroups. Specifically, in patients of lower severity and complexity (eg, community-acquired infections and SAPS-3 < 50%) the difference found may be justified by the easier application of the decision flowchart. In patients with respiratory tract infection, there is an already known better CRP performance in patients with pneumonia36. Patients who had appropriate initial empirical antibiotic therapy may have presented better results by the lower interference of inadequate initial antibiotics in treatment time28;37. These preliminary findings reinforce the potential role of a CRP-guided protocol in reducing antibiotic exposure in hospitalized infected patients. Interestingly, in a recent published meta-analysis, authors found that the use of PCT-algorithms to guide antibiotic therapy was associated with increased survival especially when combined with a CRP-guided strategy16.
The rate of adherence to the protocol reported herein was higher than that reported in previous clinical trials13;14. Patients were included when in intensive care and followed up until hospital discharge or death. Therefore, interventions were also applied in other hospital units. This strategy allowed the high rates of adhesion to the protocol, and proved feasible from the logistic point of view.
Other relevant investigated outcomes, such as antibiotic-free days and total time of antibiotic therapy during follow-up revealed similar between groups. Also, no statistically significant differences were found in safety and survival outcomes. These findings suggest that CRP-guided therapy is safe, although further studies, with a sample size powered for these analysis, should be conducted to confirm this hypothesis.
Our study has several limitations that should be mentioned. This was a single center study, restricted to two intensive care units of a high complexity hospital. Therefore, the findings lack external validity and cannot be extrapolated to other populations. In addition, the inherent open design may have biased the results, favoring the alternative hypothesis. Third, there was a high rate of non-inclusion among the patients evaluated for potential eligibility. Although this scenario has been observed in several similar studies11;14, this fact limits the population to which the protocol can be applied, especially immunosuppressed population. It remains unclear how these patients, including those with immunosuppressive dose corticosteroid therapy, respond to CRP-guided antibiotic therapy. Also, although infections with non-fermenting Gram-negative bacteria was not an exclusion criterion, patients with these kind of infection were poorly represented in this study. Fourth, there was an apparent trend towards higher mortality in the CRP-guided therapy group, with no statistically significant difference. However, sepsis-associated mortality was quite similar between the two groups, as well as recurrent infection rates. Also, mortality rate of patients who had early suspension of antibiotics, according to study protocols, was lower than the overall mortality rate, and similar between intervention and control groups (Additional file 8).