Use of C-reactive protein to guide antibiotic therapy in hospitalized patients: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-1993864/v1

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Use of C-reactive protein to guide antibiotic therapy in hospitalized patients: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-1993864/v1

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published 03 May, 2023

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Background: C-reactive protein (CRP) is an acute-phase marker used in clinical practice to identify and monitor inflammatory and infectious processes. Recent data suggest that CRP might be useful in guiding antibiotic therapy discontinuation among critical care patients. This meta-analysis analyzed the benefits and risks of CRP-guided protocols to define antibiotic therapy discontinuation in hospitalized patients in comparison with standard treatment.

Methods: Studies were searched in four databases: Medline, Embase, CENTRAL, and LILACS. The reference lists of the articles retrieved, and related review studies were hand-screened to find eligible trials that might have been missed. Primary endpoints included the duration of antibiotic therapy for the index episode of infection. The secondary endpoint was the all-cause hospital mortality and infection relapses. Risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Random effects were used to pool the mean differences and odds ratio of individual studies. The protocol was registered in PROSPERO (CRD42021259977).

Results: The search strategy retrieved 5209 titles, out of which 03 studies met the eligibility criteria and were included in this meta-analysis. 727 patients were analyzed, of whom 278 were included in the intervention group and 449 were included in the control group. 55,7% of all patients were women. Meta-analysis indicated that experimental groups (CRP-guided) had a shorter duration of antibiotic therapy (days) [MMD= -1.82, 95%IC -3.23; -0.40], with no difference in mortality [OR =1.19 95%IC 0.67-2.12] or occurrence of infection relapse [OR =3.21 95%IC 0.85-12.05] between the two groups.

Conclusion: The use of CRP-guided protocol reduced the total amount of time required for antibiotic therapy when compared to standard protocols of treatment in hospitalized patients with an acute bacterial infection. We did not observe statistical differences in mortality and infection relapse rates.

Adult

C-reactive protein (CRP)

anti-bacterial agents

duration of therapy

circulating biomarkers

C-reactive protein (CRP) is a well-known biomarker classically associated with acute inflammatory processes, including infections, trauma, surgery, tissue necrosis, cell injury, and autoimmune conditions [1–4]. The serum concentration of CRP notably rises after the onset of inflammation, in response to IL-6 production, which activates the CRP gene, allowing its expression by hepatocytes. IL-1 and endogenous steroids, to a lesser extent, also contribute to CRP production [2].

CRP has been widely used in clinical practice as an index of ongoing infectious processes during hospitalizations and a marker of the effectiveness of antimicrobial therapy. It has been used in clinical practice for three major roles, with variable levels of evidence: (1) identification of systemic inflammatory processes; (2) definition of prognosis, follow-up, and treatment guidance during infectious processes; and (3) screening tool of infectious or inflammatory diseases [5]. Recently, CRP has been tested by several studies to help the decision regarding antibiotic discontinuation [6–9], especially in light of the ascending rates of bacterial multi-resistance secondary to the overuse of antibiotics. The comparison between CRP and procalcitonin (PCT) in sepsis recognition and management of antimicrobial therapy is frequently made, however, none of them was consensually recognized as an ideal biomarker for sepsis [10, 11].

We still lack solid evidence to support the use of CRP-based protocols to guide antibiotic therapy duration in hospitalized patients. Hence, in this meta-analysis, we sought to investigate the usefulness and safety of a CRP-guided protocol to discontinue antibiotic therapy in hospitalized patients with suspected or confirmed bacterial infection.

This systematic review was based on recommendations from the Cochrane Guidelines for Systematic Reviews of Interventions (Cochrane Library, 2021) [12] and was written according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. The review protocol was registered at the PROSPERO under registration CRD42021259977.

Search strategy

To identify randomized clinical trials assessing the use of CRP-based protocols to guide antibiotic therapy duration, we conducted a comprehensive systematic search using the electronic databases Medline (by PubMed), Embase, CENTRAL (by Cochrane Library), and LILACS (by Biblioteca Virtual em Saúde). Additionally, the reference lists of the articles retrieved, and related review studies were hand-screened to find eligible trials that might have been missed.

Records were not excluded based on language or date of publication. The search for information was conducted until October 2021. Descriptors were identified in Medical Subject Headings (MeSH), Descritores em Ciências da Saúde (Decs) and Embase Subject Headings (Emtree). The search strategy was adapted based on descriptors in each database and is presented in the Supplementary Material.

Outcomes

The primary outcome was the duration of antibiotic therapy for the first episode of infection, in days. Secondary outcomes included: (1) all-cause hospital mortality, and (2) relapse of infection, defined according to the source article's criteria.

Eligibility criteria

We included randomized controlled trials that evaluated hospitalized adults (18 years old or older) with a clinical indication for antibiotic therapy defined by the assistant medical team. The eligibility criteria involved studies conducted with patients admitted to the intensive care unit (ICU), ward, or emergency room (ER), with suspected or confirmed bacterial infection and in use of antibacterial treatment. We included studies whose protocol compared a CRP-based strategy of antibiotic therapy (intervention) versus standard criteria (e.g., local protocols, international guidelines) without CRP.

We excluded studies that involved patients with bacterial infection requiring long-duration antibiotic therapy (i.e., infective endocarditis, deep pyogenic abscess, osteomyelitis) or severely immunocompromised patients (HIV infection with CD4 + lymphocytes counts < 200 cells/mm³ or solid organ or bone marrow transplantation, current intensive antineoplastic chemotherapy and other similar modalities of immunosuppression) and studies not reporting the data required for the measurement of this review's pre-defined endpoints.

Duplicate studies or studies with unclear information - and which we did not receive any response from the corresponding author(s) after email, studies conducted in non-critically ill patients, research that did not evaluate CRP or observational studies, narrative, integrative, systematic reviews, or meta-analysis were excluded. Also, studies that have a non-standard protocol design for CRP evaluation in antibiotic therapy discontinuation were excluded.

Study selection

Electronic search results from pre-defined databases were uploaded using the Rayyan Qatar Computing Research Institute [14]. After excluding duplicate articles, two authors independently carried out the process of title and abstract exclusion, and a third resolved eventual disagreements. Then, the full text of the remaining articles was checked to evaluate their eligibility.

Data extraction

Two independent authors extracted information from the selected primary studies and an additional reviewer resolved disagreements. The following information was extracted: author, year of publication, journal name, location, age median, sexes, number of patients (intervention group and control group), CRP-guided protocol (cut-offs, percentage of reduction), CRP test and method, comparator, type of infection, ICU and hospital length of stay, duration of antibiotic use, death, recurrence of infection.

Quality assessment

Two investigators independently assessed the risk of bias in the selected studies according to the Cochrane Collaboration’s tool for assessing the risk of bias (RoB 2 instrument provided by the Cochrane Collaboration) [15]. Any disagreement was solved by a third reviewer. The responses to the questionnaires could be classified as: “yes”, “no”, “unclear” or “not applicable”. Based on the recommendations of this tool, a judgment of each domain was recorded as “high”, “moderate”, “low” or “very low” risk of bias.

Meta-analysis

A random-effects model was used for pooling the results of included studies, as clinical heterogeneity was expected. The treatment effect was projected by forest plots. Heterogeneity between studies was assessed through Cochran’s Q test, and the p-value for trend < 0.10 was considered statistically significant. The I² test was carried out to evaluate the magnitude of heterogeneity between studies. It was considered low when I² <25.0%; moderate when I² ≥25 and ≤ 75% and high when I² >75.0%. Analyses were performed in the Review Manager software, version 5.4.

The search strategy retrieved 2,196 titles after duplicate records removal, out of which 03 studies met the eligibility criteria and were included in this meta-analysis (Fig. 1). Assessed studies investigated the value of CRP-based protocols in comparison with non-CRP-based protocols in the task of reducing antibiotic exposure in patients admitted to the ICU, ward, and emergency room. Any study involving patients admitted to the ward or the emergency room met the pre-specified eligibility criteria for this review. Of the three randomized controlled trials included in the final analysis, two were carried out in two Brazilian university hospitals in 2013 and 2020, respectively, and the last one was carried out in three Switzerland hospitals in 2020. The main characteristics and findings of the included studies are presented in table 1 and table 2.

A total of 727 patients were analyzed, of whom 278 were included in the intervention group (CRP) and 449 were included in the control group. Men comprised 44.3% of all patients (322 subjects), whereas 55.7% were women (405 subjects). The average age of the patients included in the three studies was 59.8 ± 16.8 (mean ± SD) (Oliveira et al, 2013), 61 (51 – 68) (Borges et al.,), and 79 (68- 86) von Dach et al.,) years, respectively.

Table 1. Main characteristics of the included studies

Author, year, journal

General scenario profile

Age and sex distribution

CRP test and method and comparator group

Oliveira, C. F. et al., 2013, Crit Care Med

Oct;41(10):2336-2343.

Patients with severe sepsis or septic shock, admitted to the intensive care units at two university hospitals in Brazil; the authors compared the duration of antibiotic therapy between the group treated with the aid of a CRP-based protocol versus a procalcitonin-based protocol. A control group without biomarkers was lacking. They observed the PCT protocol was not superior to the CRP protocol level for reducing the use of antibiotics (Duration of antibiotic therapy in PCT protocol: 8.1 (3.7) days vs Duration of antibiotic therapy in CRP protocol: 7.2 (3.5) days; p=0.25)

Mean age (years)

CRP: 59.6±18.5 Procalcitonin: 59.6±13.3

Total: 59.8 ± 16.8

Male n (%):

CRP: 26 (45,61%)

Procalcitonin: 31 (54,39%)

Total: 57 (60.6%)

Females: n (%)

CRP: 19 (42,2%)

Procalcitonin: 18 (48,8%)

Total: 37 (39.4%)

Method: Discontinuation of antibiotic therapy based on serum levels of CRP (CRP < 25 mg/L or decrease ≥ 50%) and PCT (PCT < 0.1 ng/ml or decrease ≥ 90%) associated with SOFA score analysis.

Borges, I. et al., 2020, Crit Care. Jun;24: 281.

Critically-ill patients admitted to the ICU of a university hospital in Brazil; authors compared the duration of antibiotic therapy using a CRP-based protocol versus an evidence-based strategy without the use of biomarkers. They observed that the CRP-based strategy was viable in reducing antibiotics exposure (Intervention group median: 7 (5–8.8), Control group median: 7 (7–11.3), p=0.011).

Median age (years)

CRP: 62 (53-68)

Control: 60 (49-70) years

Total: 61 (51-68) years

Male n (%):

CRP: 34 (50%)

Control: 34 (50%)

Total: 68 (52,3%)

Females n (%):

CRP: 30 (48,4)

Control: 32 (51,6%)

Total: 62 (47.7%)

Method: Duration of antibiotic therapy based on serum levels of CRP (CRP < 35 mg/L or decrease ≥ 50%) versus a standard protocol without the use of biomarkers.

von Dach, E. et al., 2020, JAMA

Jun;323(21):2160-2169.

Patients with gram-negative uncomplicated bacteremia in three Switzerland hospitals; authors compared the duration of antibiotic therapy guided by CRP levels versus two fixed-length antibiotic therapy groups (7 and 14 days). It was found that the CRP protocol was noninferior to the fixed-day treatment protocols treatment

Median age (years)

CRP guided: 78 (69-86)

7 days: 78 (69-86)

14 days: 80 (67-85)

Total: 79 (68-86)

Male; n (%):

CRP guided: 64 (32,5%)

7 days: 62 (31,5)

14 days: 71 (36%)

Total: 197 (39%)

Females n (%):

CRP guided: 105 (34,3%)

7 days: 107 (35%)

14 days: 94 (30,7%)

Total: 306 (61%)

Method: Duration of antibiotic therapy based on serum levels of CRP (decrease ≥75% from its peak associated with the absence of fever for the previous 48 hours) versus a fixed length of therapy (7 and 14 days).

Table 2. Main findings the included studies

Author, year, journal

Intervention evaluated

Number of intervention patients

CRP cut-off

CRP test and method

Comparator

Oliveira, C. F. et al., 2013, Crit Care Med.

CRP-guided discontinuation of antibiotic therapy in patients with sepsis or septic shock.

*Patients with a SOFA score > 10 and a positive blood culture result received at least 7 days of antibiotic therapy.

- CRP < 25 mg/L (if initial CRP < 100 mg/L) or 7 days of antibiotic therapy

- Decrease ≥ 50% (if initial CRP ≥ 100 mg/L) or 7 days of antibiotic therapy.

Reactive test VITROS (Johnson & Johnson Clinical Diagnostics, Inc., Rochester, NY).

Discontinuation of antibiotic therapy guided by procalcitonin serum levels in patients with sepsis or septic shock considering initial clinical status and the SOFA score.

**Patients with a SOFA score > 10 and a positive blood culture result received at least 7 days of antibiotic therapy.

Borges, I. et al., 2020, Crit Care Med.

Duration of antibiotic therapy guided by daily monitoring of CRP serum levels in critically ill infected adult patients

- CRP < 35 mg/L (if initial CRP < 100 mg/L)

- CRP decrease ≥ 50% (if initial CRP ≥ 100 mg/L)

Test for the quantitative determination of serum CRP concentration (Vitros-Johnson & Johnson, USA).

Best practices for rational use of antibiotics according to the best evidence established in the literature for duration of antibiotic treatment, microbiological data, and estimated previous time regarding the infectious site.

von Dach, E. et al., 2020, JAMA.

CRP-guided antibiotic treatment duration in adults hospitalized with gram-negative bacteremia.

170

Once serum CRP had decreased to 75% from its peak and if fever was absent for at least 48 hours.

At 14-day of treatment (if by day 14 the CRP level had not decreased to 75% of its maximum value, it was no longer used to guide therapy)

CRP was measured via immunoturbidimetry (more details about the method were not provided).

The CRP group was compared to two fixed-length antibiotic therapy groups (7 and 14 days). Local guidelines-oriented antibiotics choice, including changes in the route of administration when appropriate.

Outcomes

Regarding the duration of antibiotic therapy (in days), pooled results from the random-effects model indicated that experimental groups (CRP-guided) had a lower duration of antibiotic therapy (days) compared to the control groups [Mean difference = -1.82, 95% IC: -3.23; 0.40]. There was significant heterogeneity among the studies I2 = 86% (Figure 02).

The pooled results from the random-effects model indicated that no difference in mortality was observed between the intervention groups and the control groups [OR =1.19 95% IC: 0.67-2.12]. There was no heterogeneity among the studies I2 = 0%. (Figure 03).

Likewise, there was no significant difference in the occurrence of infection relapse between the groups using the CRP-guided strategy and the control groups [OR =3.21 95%IC 0.85-12.05]. There was no heterogeneity among the studies I2 = 0% (Figure 04).

Only two of the three studies have measured the length of stay in hospital and ICU. Borges et al [8] found that the length of stay in the hospital was longer in the CRP group than in the control group (31.5 (16-53) vs. 25.5 (15-43)), however, this difference was not statistically significant (p value 0.356). The same group found no difference between the groups the length of stay in ICU (CRP - 8 (4-15); Control - 8 (4-17); p value 0.414)). Similarly, Oliveira et al [9] found that the length of stay was not statistically significant in both scenarios, despite the shorter length of stay recorded in CRP groups both in ICU (CRP - 12 (7-18); PCT - 14 (9-24); p value 0.164) and hospital (CRP - 25 (13-52); PCT - 36 (20-59); p value 0.175).

In this systematic review and meta-analysis, we found that the CRP-guided strategy reduced the duration of antibiotic therapy in hospitalized patients with acute bacterial infections without apparent harm. Antibiotic stewardship programs require the implementation of many complementary actions to obtain positive and consistent results. Biomarkers guidance of antibiotic therapy is one of these strategies, with increasing evidence of benefit during the last two decades. Most of the high-level evidence in this field comes from studies using procalcitonin (PCT) as the guide biomarker, notably in patients with respiratory tract infections. Many original studies and individual data meta-analyses have shown the efficacy and safety of PCT to safely reduce antibiotics exposure, with an apparent improvement in mortality [16].

The widespread use of PCT as a tool to guide antibiotic therapy is limited by the elevated costs of this marker and its poor availability in low and medium-income countries. Therefore, CRP arises as an interesting alternative, since it is a cheaper and widely available biomarker compared to PCT. In addition, clinicians have much more experience with CRP. In recent years, some studies have suggested that CRP might be as useful as PCT to help in the strategy of rational use of antibiotics. More specifically, CRP-guided protocols have been tested to guide the decision of antibiotic therapy interruption among hospitalized patients, using well-controlled standard care as comparators. Recently, Borges et al. [8] showed a reduction of one day in the median duration of antibiotic therapy for the first episode of infection (from 7 to 6 days) among critically ill patients with suspected or confirmed infection. These results were in accordance with the study of Von Dach et al. [7], which showed that the CRP-guided strategy and a fixed length of 7 days of antibiotic therapy were not inferior to a fixed length of 14 days of treatment for uncomplicated gram-negative bacteremia.

In a randomized controlled trial to test a protocol guided by CRP concentration as compared to a PCT-based strategy, Oliveira et al. [9] found that the former approach was not inferior in reducing the length of antibiotic therapy, namely in primo infection cases. It was also observed that a ceiling of 7 days of antibiotics is safe for most patients with sepsis, regardless of the support of biomarkers. This finding was corroborated by PCT in other studies with a similar context [9].

Despite allowing a lower antibiotic exposure, CRP protocols used in the intervention groups of the studies included in this review were not associated with a higher mortality rate. In two of the three studies analyzed, the absolute number of deaths was higher in CRP groups, but this finding was not statistically relevant. Concerning infection relapse - an important parameter to identify inefficiency of treatment and clinical failure - no statistical difference was observed between the groups.

The need for judicious use of antibiotics is recognized in the main guidelines of recommendation for sepsis management, even though adding biomarkers such as PCT to the clinical evaluation in the decision of discontinuing the antibiotic therapy has not been recognized as a high-evidenced approach [17]. Reasons to explain this interpretation of the literature data are the inevitably open-label nature of the intervention in the published trials, limitations regarding safety issues, and scarcity of studies proving that these biomarkers-based strategies are cost-effective. As mentioned above, due to its large availability, we believe CRP may be a suitable candidate for this goal.

This study has two main limitations that deserve to be mentioned. First, only three studies were eligible for our review and there is heterogeneity among them regarding some outcomes of interest. However, we believe that the low number of studies available is an additional reason to gather their results aiming to generate more robust evidence. Despite the single-center nature and the small sample of participants included in two of these studies, all of them had a good performance in the methodological quality assessment. Second, two out of the three studies included in this review were conducted by the same research team and all of them were single, double or triple center studies. All these issues certainly limit the generalizability (external validation) of their findings.

In this meta-analysis of three randomized controlled trials, we found that, as compared to standard control groups based on the best current evidence for antibiotic therapy, the CRP-guided strategy safely reduced the length of treatment with antibiotics in hospitalized patients with acute bacterial infections. Large well-designed multicenter studies are highly desirable to confirm our findings.

CRP - C-reactive protein

Decs - Descritores em Ciências da Saúde (Descriptors in Health Sciences)

Emtree - Embase Subject Headings

ER - Emergency room

ICU - Intensive care unit

IL-1 - interleukin-1

IL-6 - interleukin-6

MeSH - Medical Subject Headings

PCT - Procalcitonin

PRISMA - Preferred Reporting Items for Systematic Reviews and Meta-Analyses

SOFA score - Sequential Organ Failure Assessment score

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Competing interests

The authors declare that they have no competing interests.

Funding

This work was partially supported by the Brazilian National Council of Research Development, Coordination of High Education Level Personnel, and the Foundation of Research of Minas Gerais.

Authors' contributions

R.F.D., N.S.G., V.N. and A.C.S.S. designed and conceived the systematic review and meta-analysis. R.F.D., A.C.R.B.P., U.G.H., M.O.R.B.C., J.R.A.A., J.C.K., R.A.M.S., performed the literature searches and conducted the title, abstract, and full-text screening. U.G.H., M.O.R.B.C., J.R.A.A., J.C.K. and R.A.M.S. conducted data extraction and risk of bias assessments. R.F.D. and A.C.R.B.P. drafted the manuscript. N.S.G., V.N. and A.C.S.S. coordinated the study. All authors contributed to the interpretation of the results and critically reviewed the manuscript

Acknowledgements

We would like to acknowledge and to deeply thank Dr Angela Huttner for kindly providing complementary information from the study published by her group.

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No competing interests reported.

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You are reading this latest preprint version

Use of C-reactive protein to guide antibiotic therapy in hospitalized patients: a systematic review and meta-analysis

Status:

Journal Publication

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Abstract

Figures

Introduction

Methods

Search strategy

Outcomes

Eligibility criteria

Study selection

Data extraction

Quality assessment

Meta-analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

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