Duration of antibiotic therapy in critically ill patients: a randomized controlled trial of a clinical and C-reactive protein-based protocol versus an evidence-based best practice strategy without biomarkers

Increasing concerns about antimicrobial abuse and development of bacterial resistance have fueled the search for the objective and rational use of antibiotics. There is growing evidence supporting the use of shorter antibiotic courses to treat various types of infection, with clinical outcomes similar to those obtained with longer treatments [1‐6]. Individualization of antibiotic treatment time has been gaining importance [7‐10]. This measure prevents unnecessary exposure to antibiotics while reducing the risk of therapeutic failure in those with a late response.

Circulating inflammatory biomarkers have been used as a guide to support treatment individualization. One useful marker is procalcitonin (PCT), whose benefit in reducing antibiotic treatment time was demonstrated in several studies [11‐16], including a potential reduction in the mortality of critically ill patients [14‐16]. Nevertheless, the high cost of PCT testing reduces its availability in some settings [10, 17]. In this context, C-reactive protein (CRP) may be a reasonable low-cost alternative [10, 16, 18]. A recent meta-analysis demonstrated that the PCT-guided algorithms only showed a survival benefit when used in combination with CRP, along with other specificities [16]. Nevertheless, few studies testing a CRP-guided strategy have been conducted in adult critical ill patients. A recent single-center clinical trial involving patients with sepsis suggested that CRP may be a useful marker to guide antibiotic treatment time, when compared to a PCT strategy [19].

The objective of this study was to test the impact of a decision flowchart based on CRP serum levels and clinical features on the duration of antibiotic therapy in critically ill infected patients, compared to a control group treated according to the best available evidence for rational antibiotic treatment in this population.

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 therapy [1‐3, 5, 8], only when considering the index infection episode. For this first treated episode, 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 1 day in the median duration of antibiotic therapy in the intervention group. It should be stressed that these findings did not translate into more antibiotic-free days or in a reduced antimicrobial exposure.

Given the benefits offered by the rational use of antibiotics, including the reduction of multiresistant bacteria [5, 29, 30], treatment costs [31], frequency of adverse effects [32], and less interference with microbiome, objective criteria to define the ideal treatment length is warranted. CRP is a low-cost and affordable biomarker [10], routinely used in intensive care, that has been shown relate to prognosis in studies involving different populations with serious infectious conditions [17, 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 groups [10], which varied from 10 [11] to 15 days [12]. 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 7 days in comparison with the control, which received 10 days treatment, or 14 days for patients in intensive care settings [35]. 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 7 days for the duration of the therapy, independently of the levels of biomarkers [19]. 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 5 days as the median treatment time compared to 7 days for controls [14]. It is noteworthy that the population included in the present work was significantly more severely ill than the patients included in the Dutch study [14] (septic shock 32.3% vs. 18.5%, respectively), which reinforces the value of our results, even if incipient.

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 for the first infection episode. Further, 1-day reduction in median duration of antibiotic treatment was found in the per-protocol analysis and in different post hoc analyses of subgroups. Specifically, in patients of lower severity and complexity (e.g., 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 pneumonia [36]. Patients who had appropriate initial empirical antibiotic therapy may have presented better results by the lower interference of inadequate initial antibiotics in treatment time [28, 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 strategy [16].

The rate of adherence to the protocol reported herein was higher than that reported in previous clinical trials [13, 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.

Despite such promising findings, 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 may be effective and safe in some specific scenarios, although further studies, with a sample size powered for safety analysis, should be conducted to confirm this hypothesis. Ideally, in settings with a less complex patient profile, where single courses of antibiotics are held more often.

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 studies [11, 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 infection with non-fermenting Gram-negative bacteria was not an exclusion criterion, patients with this 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 7).

A protocol based on daily monitoring of CRP levels may support a tailored time of antibiotic therapy in critically ill patients in a single infection episode, but without reducing the total exposure of these patients to antimicrobials. The subtle time reduction observed in the group of patients undergoing CRP-guided therapy may be potentially impacting in less complex scenarios, since it was observed even in a scenario of judicious use of antibiotics. CRP-guided strategy is feasible. Further studies are needed to add up to these findings, to properly assess safety outcomes and to evaluate the real impact of this strategy in clinical practice.