Antibiotic treatment duration for patients with bloodstream infection: a systematic review and meta-analysis

Objectives: The optimal duration of therapy for primary bloodstream infection (BSI) and BSI secondary to major organ system infections has been poorly dened. A systematic review and meta-analysis was performed to evaluate the impact of short ( ≤ 10 days)and long course(>10 days) of antibiotic treatment on clinical outcomes in patients with BSI. Methods: We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials(RCTs) and cohort studies from inception to the 1st of October 2020. We included studies involving patients with BSI. All authors reported our primary outcome of all-cause mortality and clearly comparing short versus long course of antibiotic treatment with clinically relevant secondary outcomes(source control and relapse). Results were expressed as odds ratio (OR) with accompanying 95% condence interval (CI). Results: Six studies including 3593 patients were included. The primary outcome of this meta-analysis showed that there was no statistically signicant difference in the all-cause mortality between two groups (OR=1.10; 95% CI, 0.82 to 1.48; P=0.52; Chi 2 =7.57; I 2 =34%) . Secondary outcomes demonstrated that there was no statistically signicant difference in the source control(OR=0.82; 95% CI, 0.61 to 1.10; P=0.18; Chi 2 =2.68; I 2 =25%)and relapse(OR=1.20; 95%CI,0.71 to 2.01; P=0.49; Chi 2 =0.26; I 2 =0%) between two groups. Conclusions: Short course of antibiotic treatment is not associated with either an increased risk of mortality or an increased odds of relapse compared with longer antibiotic treatment course for BSI. Furthermore, short course of antibiotic therapy is non-inferior to long course in terms of source control. Further large-scale RCTs are still required to conrm these results.


Introduction
Bloodstream infection (BSI) is de ned by positive blood cultures in a patient with systemic signs of infection and may be either secondary to a documented source or primary-that is, without identi ed origin [1]. Timely administration of the appropriate antibiotic treatment remains the cornerstone for favorable clinical outcome in patients with BSI [2][3][4]. However, the optimal duration of therapy for primary BSI and BSI secondary to major organ system infections has been poorly de ned [5]. Su cient duration of antimicrobial therapy is required to prevent clinical failure and relapse. However, the risk of a longer antibiotic course may lead to Clostridium di cile infection, development of microbial resistance, potential need for central line access, venous thrombosis, line infection and bacteremia and increased cost [6].
A multicenter observational study of patients who have BSI in Canadian intensive care units(ICUs) suggests that most patients are treated with 2-week courses of antimicrobials, but with substantial practice heterogeneity among individual patients and with no clear relationship between duration of treatment and survival [7]. The current Infectious Diseases Society of America(IDSA) guidelines suggest that the duration of treatment for intravascular catheter related BSI should be between 7 and 14 days [8], but there is no consensus on the optimal duration of the antimicrobial therapy for non-catheter related BSI. The lack of data on the appropriate treatment duration for this subset of patient leads to uncertainty, usually resolved by prolonged treatment durations.
Since the optimal duration of the antibiotic treatment for patients with BSI remains unknown, we conducted a meta-analysis which extracted results from published studies to evaluate the impact of short and long course of antibiotic treatment on clinical outcomes in patients with BSI.

Methods
This systematic review and meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [9].Ethical approval was not necessary for this study because it was a review of the published literature.

Search strategy
We searched the PubMed, Cochrane, and Embase databases for studies from inception to the 1st of October 2020 using the following search terms: bloodstream infection, bacteremia, duration of treatment, antibiotic treatment duration, optimal duration, antibacterial treatment, antibiotics, antibacterial agents, short course, long course, sepsis. The search was slightly adjusted according to the requirements of the different databases. The authors' personal les and reference lists of relevant review articles were also reviewed. The ow chart of the search strategies is summarized in Fig. 1.

Types of outcome measures
The primary outcome was all-cause mortality, all-cause mortality included hospital mortality, 28-day mortality,30-day mortality and 90-day mortality.
Secondary outcomes were source control and relapse. Weighted means were calculated based on the number of patients in each study.

Study selection
The inclusion criteria were as follows: (1) RCTs as well as prospective and retrospective cohort studies;(2) patients with BSI;(3) all authors reported our primary outcome of all-cause mortality;(4)clearly comparing short(≤ 10 days) versus long course(> 10 days) of antibiotic treatment with clinically relevant secondary outcomes. We excluded studies that did not de ne the duration of treatment based on the 10-day limit and studies without clear comparisons of the outcomes. In addition, we excluded review articles and studies about pediatric.

Quality assessment
Two reviewers (YL and JY) independently performed quality assessment. The quality of studies was assessed using the Newcastle-Ottawa Scale(NOS) for cohort studies [10]. NOS allocates a maximum of 9 points according to the quality of the selection, comparability, and outcomes of the cohort study populations. Study quality was de ned as poor (0-3), fair (4-6) or good (7)(8)(9). The quality of the included cohort studies is presented in Table 1.  with 95% con dence intervals (CI) was calculated for dichotomous variables. A random-effects model was used to pool studies with signi cant heterogeneity, as determined by the chi-squared test (P < 0.10) and inconsistency index (I 2 ≥ 50%) [11]. A P-value < 0.05 was set as the threshold of statistical signi cance.

Study characteristics
The search strategy identi ed 1269 studies, and the data were from six cohort studies comprising 3593 patients (Table 2) [12][13][14][15][16][17]. The characteristics of the included studies are shown in Table 2. A total of six eligible studies were published between 2013 and 2019. Among these studies, two studies were conducted in USA, one study was conducted in Spain, one study was conducted in Colombia, one study was conducted in Canada and one study was conducted in China/Taiwan. Four of these studies were single-center studies and two were multicenter studies. The de nitions of short and long course of antibiotic treatment in studies included in the meta-analysis are outlined in Table 3. in the long-course group). There was no statistically signi cant difference in the all-cause mortality between two groups (OR = 1.10; 95% CI, 0.82 to 1.48; P = 0.52; Chi 2 = 7.57; I 2 = 34%) (Fig. 2). A funnel plot was used to assess the publication bias (Fig. 3).

Source control.
Three of included studies were analyzed to assess the source control. There was no statistically signi cant difference in the source control between two groups (OR = 0.82; 95% CI, 0.61 to 1.10; P = 0.18; Chi 2 = 2.68; I 2 = 25%) (Fig. 4).

Relapse.
Three of included studies were analyzed to assess the relapse. Relapse included recurrence within 3 months, restarting antibiotics for the same infection and relapse of bacteremia. There was no statistically signi cant difference in the relapse between two groups (OR = 1.20; 95% CI,0.71 to 2.01; P = 0.49; Chi 2 = 0.26; I 2 = 0%) (Fig. 5).

Discussion
The optimal duration of treatment for BSI has not been established. Prescribing practices vary widely, and durations of therapy can range from fewer than 7 days to greater than 14 days. The catheter-related BSI guidelines suggest a 7-to 14-day course of therapy for Gram-negative bacteremia [18]. However, these recommendations are largely consensus based and have poor evidence. A national survey of Canadian ID and critical care specialists identi ed signi cant practice variation in the recommended duration of antibiotic treatment for BSI. The most commonly recommended treatment duration for BSI was 14 days, but more than one-half of clinicians recommended shorter treatment durations (usually 7 days or 10 days) [19].
This systematic review and meta-analysis of six studies including 3593 patients compared short(≤ 10 days) and long course(> 10 days) of antibiotic treatment on clinical outcomes in patients with BSI. We found that the all-cause mortality was about 5.5% and we did not identify an increased all-cause mortality among patients treated with shorter durations compared with those treated with longer durations. In addition, we found short course of antibiotic therapy to be non-inferior to long course in terms of source control and relapse. The extensive use of antibiotics worldwide is closely related to the increasing issues of antimicrobial resistance and antibiotic-associated infections [20,21]. Long-course antibiotic treatment, as used for BSI, plays a critical role in this context. Among patients with suspected bloodstream infections, broad-spectrum antibiotics must be initiated empirically because early adequate empiric treatment is associated with improved survival [22,23]. Due to the rising prevalence of resistant organisms, the tailoring or de-escalation of these empiric regimens is not possible even when blood culture and susceptibility results become available. Patients must then remain on broad-spectrum agents for their full treatment course [24].Therefore, decreasing the duration of antibiotic treatment to the bare minimum required to treat infections is a reasonable approach to reduce the prevalence of resistance [25]. Of course, It is important to evaluate the e cacy of short-course antimicrobial therapy to avoid treatment failure and recurrence.
Shorter courses of antibiotics may reduce drug related adverse events, duration of hospitalization, emergence of antibacterial resistance and superinfections, including fungal and Clostridium di cile infection [26]. When judging of duration of antibiotic treatment, there is this second time point at 5-7 days. The decision of escalation/de-escalation/no change or dose adjustments should be taken after 2-3 days when microbiological specimens became available [27]. The effectiveness of therapy should be assessed after one week of treatment on clinical and microbiological resolution of the infection. This will include defervescence and resolution of organ failures and shock, negative subsequent cultures, the absence of endocarditis or metastatic sites of infection and no implanted prosthesis which are all required to de ne an uncomplicated infection [28]. Problems with source control and/or superinfections at the source will also uncover around that time point. If those are resolved and the pathogen or the source is not speci cally requiring extended treatments antibiotic therapy can be safely stopped.
Up to 30-50% of antimicrobial use in most hospitals is inappropriate, with the most common culprit being an excessive duration of therapy [29]. Shorter durations of therapy have been explored for a number of infectious diseases and have been shown to be equally e cacious compared with longer courses of therapy. Appropriate use of antibiotics includes a variety of strategies, such as generating hospital antibiograms, encouraging the use of narrow spectrum antibiotics when feasible, and facilitating the transition from IV to oral antibiotic therapy reducing the need for central line placement [6]. Reducing treatment length in BSI could induce earlier discharge from the hospital, decreased risk of hospital-acquired infections, decreased risk of severe adverse events, and an increased quality of life. Additionally, from a national and international perspective, decreasing the consumption of antibiotics will play an important role in preventing resistance development and secure future antimicrobial treatment [30].
Our meta-analysis has several limitations. First, the number of included studies is small. Further randomized clinical studies should be conducted in order to con rm the results. Second, many of the secondary outcomes such as source control or relapse were not included in all of the studies examined in this meta-analysis. Third, there was still substantial heterogeneity among the included studies. Very heterogeneous populations were included in both prospective and retrospective studies. In addition, de nitions of short and long course of antibiotic treatment were widely different among included studies which supposed a limitation to interpret results. Therefore, our ndings should be interpreted with caution.

Conclusion
Short course of antibiotic treatment is not associated with either an increased risk of mortality or an increased odds of relapse compared with longer antibiotic treatment course for BSI. Furthermore, short course of antibiotic therapy is non-inferior to long course in terms of source control. Further largescale RCTs are still required to determine the effectiveness and appropriate duration of antibiotic therapy of BSI.

Key Messages
Short course(≤10 days) of antibiotic treatment is not associated with either an increased risk of mortality or an increased odds of relapse compared with longer antibiotic treatment course for BSI.
Short course of antibiotic therapy is non-inferior to long course in terms of source control.  Forest plot for all-cause mortality.

Figure 3
Funnel plot for all-cause mortality.

Figure 4
Forest plot for source control.

Figure 5
Forest plot for relapse.