LABORATORIO DE URGENCIAS

Clinical Outcomes and Safety of 7-Day Versus 14-Day Antibiotic Therapy for Bloodstream Infections in Adults


A systematic review and meta-analysis with trial sequential analysis

Chen-Wei Wu, Chih-Cheng Lai, Jheng-Yan Wu, Mei-Chuan Lee 
      Department of Intensive Care Medicine, Chi-Mei Medical Center, Tainan, Taiwan
       School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung City, Taiwan
       Department of Nutrition, Chi Mei Medical Center, Tainan, Taiwan
       Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
       Department of Pharmacy, Chi-Mei Medical Center, Tainan, Taiwan

J. of Infection and Public Health (Mai, 2025);18

Bloodstream infections (BSIs) remain a major type of infection  and represent a critical medical challenge with significant morbidity and mortality rates [1–5]. The pathogenesis of these infections involves complex microbiological and immunological mechanisms, typically initiated by the translocation of pathogenic microorganisms from localized infection sites, such as the lungs, urinary tract, skin or catheter, into the bloodstream. A wide range of microbial organisms—including Gram-positive and Gram-negative bacteria, as well as certain fungal species—are implicated in these infections  [6,7]. Effective management requires not only timely source control but also the selection of appropriate antimicrobial agents tailored to individual risk factors and local resistance patterns [8,9]. Within this management framework, antimicrobial stewardship plays a crucial role in ensuring judicious antibiotic use, encompassing both the selection of the right agent and the determination of appropriate treatment duration. Among the various stewardship considerations, optimizing antibiotic duration for BSIs is particularly critical, as both overtreatment and undertreatment can result in significant adverse consequences. Despite this recognized importance, however, the optimal duration of antibiotic therapy for BSIs remains uncertain. Historically, the duration of antibiotic treatment for BSIs has varied widely in clinical practice, largely driven by expert opinion rather than high-quality evidence. The conventional recommendation of 14 days of therapy became entrenched due to concerns about relapse, particularly in the context of inadequate source control or immunocompromised hosts [10]. However, prolonged antibiotic use carries significant downsides, including the emergence of antimicrobial resistance, higher incidence of adverse drug reactions, increased risk of Clostridioides difficile infection, and unnecessary healthcare costs [11].
Conversely, overly short courses may lead to treatment failure or recurrence. This clinical dilemma underscores the uncertainty and complexity in determining the optimal treatment duration for BSIs. While the efficacy of short-course antibiotic therapy has been established in various infections, such as community-acquired pneumonia (CAP), ventilator-associated pneumonia (VAP), and acute pyelonephritis (APN) [12–15], the extrapolation of these findings to BSIs remains uncertain due to fundamental differences in disease pathophysiology and clinical severity. A previous meta-analysis focusing on uncomplicated Gram-negative bacteremia offered preliminary support for short-course therapy but was limited by small sample sizes and the predominance of observational data, with only two included studies being randomized controlled trials (RCTs) [16].
The recently published BALANCE trial provided more definitive evidence by demonstrating non-inferiority of 7-day versus 14-day antibiotic therapy in a large, multicenter, randomized cohort of hospitalized patients with bacteremia [17]. Building on these findings, our systematic review and meta-analysis—with incorporation of trial sequential analysis (TSA)—aims to synthesize the most up-to- date and methodologically rigorous evidence. By including data from both older and newly published RCTs, our study addresses critical gaps in prior meta-analyses, enhances statistical robustness, and provides a clearer framework for clinicians to optimize antibiotic duration in the treatment of BSIs.

MATERIALS AND METHODS

Protocol registration
This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [18].
The study protocol was registered in PROSPERO under registration number CRD42024621999. Inclusion and exclusion criteria
Population (P): Our review focused on adult patients (≥18 years) with BSIs, as defined by at least one positive blood culture. The included studies enrolled adults with uncomplicated bacteremia.
Patients were included regardless of ICU or non-ICU setting; all included studies enrolled hospitalized patients regardless of care location. Intervention and Comparison (I/C): Patients receiving a 7-day antibiotic regimen were compared with those receiving a 14-day regimen. Both treatment durations were defined by the protocols of each RCT and commenced from the first day of effective therapy.
Outcomes (O):
The primary outcomes were 90-day all-cause mortality and relapse of bacteremia. Secondary outcomes included adverse events such as acute kidney injury, diarrhea, allergic reactions, and Clostridioides difficile infections.
Eligible studies included RCTs assessing antibiotic use in patients diagnosed with bacteremia. Studies were required to report clinical outcomes and safety outcomes comparing a 7-day antibiotic regimen to a 14-day regimen. Exclusion criteria included non-randomized trials, studies involving immunosuppressed patients, or those focusing on conditions requiring extended antibiotic therapy, such as endocarditis. Additionally, studies involving populations under 18 years of age were excluded.
Search strategy
A systematic literature search was conducted across PubMed, Embase, and the Cochrane Library using a detailed strategy that combined Medical Subject Heading (MeSH) terms, Emtree terms, free-text keywords, and synonyms related to antibacterial agents,  bacteremia, therapy duration, and RCTs.
The search included studies published up to November 24, 2024 (the actual date the search was performed), without language restrictions. The complete search strategy was detailed in Table S1.
Assessment of risk of bias
Two independent reviewers (CWW and CCL) evaluated the risk of bias in the included studies using the Cochrane Risk of Bias 2.0 tool  [19], focusing on six domains: allocation, performance, attrition, detection, reporting, and overall bias. Results were categorized as low risk, some concerns, or high risk of bias, with disagreements resolved by discussion or consultation with a third reviewer, MCL.
Data extraction and statistical analysis
Data on study characteristics, demographics, interventions, and outcomes were extracted independently by two reviewers. Discrepancies were addressed through consensus.
Outcomes
The clinical outcome was defined as all-cause mortality within 90 days of the bloodstream infection diagnosis, based on the date of the initial positive blood culture, as well as relapse of bacteremia. Safety outcomes included acute kidney injury, diarrhea, allergic re actions, and Clostridioides difficile infections. Dichotomous outcomes were summarized as risk ratios (RRs) with 95 % confidence intervals (CIs). Pooled estimates were calcu lated using a random-effects model based on the DerSimonian and Laird method [20]. Heterogeneity was assessed using the I² statistic, with predefined thresholds for low (I² ≤ 25 %), moderate (25 % < I² ≤ 75 %), and high (I² > 75 %) heterogeneity [21]. For outcomes with moderate to high heterogeneity, leave-one-out sensitivity analyses were performed to assess the contribution of individual studies [22]. Funnel plots were used to evaluate publication bias for primary outcomes [23].
Trial sequential analysis (TSA)
TSA was applied to the primary outcome to address random er rors and assess the conclusiveness of results [24]. Parameters in cluded a type I error rate of 5 %, a type II error rate of 20 %, and an expected risk reduction of 20 %. TSA analyses were performed using version 0.9.5.10 beta of the TSA software developed by the Co penhagen Trial Unit.
Certainty of evidence
The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the certainty of evidence for each outcome. Factors such as study design, risk of bias, consistency, directness, and precision were considered. Evidence quality was categorized: high, moderate, low, or very low using GRADEpro GDT software [22].

RESULTS

Description of included studies
The flowchart illustrates the study selection process for a meta- analysis. A total of 1570 records were identified from PubMed (n = 879), Cochrane CENTRAL (n = 370), Embase (n = 316), and other sources (n = 5). After removing 220 duplicates, 1350 records re mained. Screening excluded 789 non-RCTs, leaving 561 records. Following a review of 92 full-text articles, four studies were included in the meta-analysis. The primary exclusions were 469 studies not meeting the PICO framework and 88 articles excluded for reasons such as being protocols (n = 35), neonatal studies (n = 30), or mis matched treatment durations (n = 23) (Fig. 1). Four RCTs conducted between 2013 and 2023 were included in this meta-analysis, enrolling a total of 2408 patients in the 7-day treatment group and 2386 in the 14-day group [17,25–27]. These multicenter trials were performed across Israel, Switzerland, Spain, and seven other countries as part of the BALANCE trial. All studies evaluated adult patients with BSIs, primarily due to aerobic gram- negative bacteria or Enterobacterales. Three of the four trials were designed as noninferiority studies, and all compared clinical out comes between fixed 7-day and 14-day antibiotic regimens initiated from the first day of effective therapy (Table 1). Table 2 summarizes the baseline characteristics of patients in cluded in the four RCTs.
In Yahav 2019 [25], the median age was 71 years for both 7-day and 14-day groups, with female percentages of 51 % and 54.7 %, re spectively. Bacterial acquisition was predominantly hospital-based, with urinary tract infections (UTIs) being the primary source, fol lowed by abdominal, respiratory, and vascular infections.
Von Dach 2020 [26] with a median age of 78 years (7-day group) and 80 years (14-day group), with 63 % female participation in the 7-day group. Community-acquired infections were the most common, supple mented by hospital and healthcare-associated sources, with UTIs and abdominal infections being the primary origins.
Notably, mul tiple drug resistance (MDR) data indicated Extended Spectrum β- Lactamase (ESBL) rates of 6.5 % (7-day) and 7.8 % (14-day). Molina 2022 [27] reported a median age of 65 (7-day) and 68 (14-day), with female representation of 49.2 % and 45.7 %. Community-acquired infections were the most frequent, followed by hospital and healthcare sources, with Escherichia coli and Klebsiella pneumoniae being the major pathogens isolated from UTIs, abdominal, re spiratory, and vascular infections. BALANCE 2024 [17] included pa tients aged 70 in both groups, with female representation around 46–47 %. Community-acquired infections dominated, with UTIs, re spiratory, and abdominal infections being the most common, with MDR rates consistent with known bacterial resistance patterns (Table 2).
Risk of bias
The risk of bias assessments revealed varying levels of rigor across the studies.
Yahav et al. [25]. had some concerns but effec tively mitigated risks through rigorous randomization, blinding, and protocol adherence.
Von Dach et al. [26]. was assessed as low risk, with strong randomization, blinding, and minimal missing data.
Molina et al. [27]. showed some concerns related to its open-label design but maintained robust randomization and baseline management.
The BALANCE study [17] had minor bias concerns due to its open-label design after day 7 but remained methodologically strong overall. These studies demonstrated robust methodologies, with some variability in managing open-label design challenges. It is worth noting that the “some concerns” ratings were primarily driven by the open-label design of several trials. However, the main out comes assessed—such as mortality and relapse—were objective in nature and thus less prone to bias, minimizing the potential impact on overall findings (Fig.S1).
Outcomes
Fig. 2 presents the clinical outcomes comparing 7-day and 14-day treatment durations. Fig. 2A shows no significant difference in 90- day all-cause mortality between the 7-day and 14-day groups (RR 0.94, 95 % CI 0.79–1.12, p = 0.51, I²=6 %). Fig. 2B demonstrates that relapse of bacteremia within 90 days was also not significantly dif ferent between the two treatment durations (RR 1.15, 95 % CI 0.80–1.64, p = 0.45, I²=0 %). The safety outcomes comparing 7-day and 14-day treatment durations are shown across four panels. For acute kidney injury (Fig. 3A), there was no significant difference between the two groups (RR 1.02, 95 % CI 0.62–1.66, p = 0.95, I²=0 %). For diarrhea (Fig. 3B), the risk was also similar between the groups (RR 0.76, 95 % CI 0.44–1.33, p = 0.34, I²=0 %). Regarding allergic reactions (Fig. 3C), no statistically significant difference was observed (RR 0.65, 95 % CI 0.36–1.18, p = 0.16, I²=0 %).
Finally, the risk of Clostridioides difficile infections (Fig. 3D) was comparable between the 7-day and 14-day regimens (RR 0.88, 95 % CI 0.56–1.38, p = 0.58, I²=0 %).
TSA
The TSA for clinical outcomes showed that for 90-day all-cause mortality (Fig. 4A), a required sample size of 62,083 was not reached, and the cumulative Z-curve did not cross the boundaries, indicating no significant difference. Similarly, for relapse of bacteremia within 90 days (Fig. 4B), the required sample size of 83,372 was not reached, and the Z-curve did not cross the boundaries, indicating inconclusive evidence. The TSA analysis for safety outcomes indicated inconclusive re sults across the evaluated AEs. For acute kidney injury (Fig. 5A), a required sample size of 83,372 patients was identified, but the cu mulative Z-curve did not reach the trial sequential monitoring boundaries. Similarly, for diarrhea (Fig. 5B) and allergy (Fig. 5C), the required sample sizes of 10,083 and 16,922 patients, respectively, were not reached, and the Z-curves remained below the monitoring thresholds. For Clostridioides difficile infections (Fig. 5D), the cumu lative Z-curve also fell below the boundaries without reaching the required information size.
Sensitivity analysis
Table S2 presents the results of the leave-one-out sensitivity analysis for comparisons between 7-day and 14-day treatment durations. The analysis shows that excluding any single study does not significantly alter the RRs or heterogeneity (I²) for outcomes, including 90-day all-cause mortality, relapse of bacteremia within 90 days, acute kidney injury, diarrhea, allergy, and Clostridioides difficile infections. Risk ratios remained within overlapping con fidence intervals across all outcomes, and heterogeneity values are consistently low, indicating the robustness of the overall findings.
Publication bias
Assessment of publication bias using funnel plots was not con ducted, as fewer than ten studies were included for each outcome. According to Cochrane Guidelines, the reliability of detecting asymmetry is substantially limited in meta-analyses with a small number of studies. Certainty of evidence
Table S3 presents the GRADE framework evaluation of evidence certainty for patients with bloodstream infections receiving 7-day and 14-day antibiotic regimens. The certainty of evidence was con sistently rated as low for all outcomes, including 90-day all-cause mortality, relapse of bacteremia, acute kidney injury, diarrhea, al lergy, and Clostridioides difficile infections. These ratings were based on data from RCTs and were influenced by wide confidence intervals overlapping the null effect and insufficient study sample sizes.

DISCUSSION

This meta-analysis of 4 RCTs involving 4794 patients compared 7-day versus 14-day antibiotic regimens for BSIs. Patients receiving 7-day therapy showed similar 90--day all-cause mortality (RR 0.94, 95 % CI 0.79–1.12, p = 0.51, I²=6 %) and relapse rates (RR 1.15, 95 % CI 0.80–1.64, p = 0.45, I²=0 %) to those treated for 14 days. These results, derived from low-heterogeneity studies and robust in sensitivity analyses, align with prior evidence supporting short-course anti biotics in other infections such as CAP, VAP, and APN [12–15]. Our study extends this evidence to BSIs in adults. Our findings are further supported by previous meta-analyses examining antibiotic treatment duration in BSI [16,28]. Li et al. [16] analyzed patients with gram-negative bacteremia across 2 RCTs, one prospective study, and 3 retrospective studies, finding no significant differences between short-course and long-course antibiotic treatments in 30-day mortality (RR, 0.85; 95 % CI, 0.65–1.13), 30-day recurrent bacteremia (RR, 1.07; 95 % CI, 0.68–1.67), 90-day mortality (RR, 0.84; 95 % CI, 0.57–1.24), and 90- day recurrent bacteremia (RR, 0.98; 95 % CI, 0.50–1.89). Similarly, another meta-analysis [28] examining 6 non-randomized studies of adults with uncomplicated Staphylococcus aureus bacteremia showed no significant differences between short and prolonged antibiotic therapy in 90-day mortality (OR, 1.09; 95 % CI, 0.82–1.46) or 90-day recurrence or relapse of bacteremia (OR, 0.72; 95 % CI, 0.31–1.68). However, these previous meta-analyses [16,28] primarily included non-RCTs, and one [16] included pe diatric populations. Our study strengthens the existing evidence by focusing exclusively on RCTs in adult populations, thereby of fering higher-quality support for short-course antibiotic use in BSI without compromising clinical efficacy. Beyond clinical outcomes, our safety analysis revealed no sig nificant differences between 7-day and 14-day courses in AEs, in cluding acute kidney injury, diarrhea, allergic reactions, and Clostridioides difficile infections. These safety findings align with Li et al. [16], who reported no significant differences between short- course and long-course antibiotic treatments in overall AEs (RR, 1.14; 95 % CI, 0.89–1.45), Clostridioides difficile infection (RR, 0.86; 95 % CI, 0.40–1.86), or antibiotic resistance development (RR, 1.19; 95 % CI, 0.66–2.14).
These findings support the safe use of shorter antibiotic regimens, which may reduce unnecessary exposure while preserving clinical outcomes and patient safety. While the TSA did not reach the required information size to achieve formal statistical conclusiveness, and the cumulative Z- curve did not cross futility boundaries, our TSA indicated that proving a statistically significant difference in clinical outcomes between 7-day and 14-day antibiotic courses would require an ex tremely large sample size, making such a study highly resource-in tensive and potentially unfeasible. The BALANCE trial [17], the largest RCT included in our analysis, adopted a non-inferiority design to address this challenge. Given its substantial sample size and rig orous methodology, it provides strong evidence supporting the non- inferiority of the 7-day regimen with a narrow 4 % margin. While the TSA did not reach the required information size to achieve formal statistical conclusiveness, the consistency of results across trials and the lack of excess harm in the shorter-duration arm provide clini cally meaningful reassurance. In practice, clinicians often face the need to act on the best available evidence, particularly when pro longed antibiotic use carries well-documented risks, including toxicity, resistance, and increased healthcare costs.
Waiting for de finitive statistical power may not always be feasible or ethical, especially in the context of stewardship efforts. From a policy and implementation standpoint, the current findings support adoption of shorter-course protocols in appropriate populations. Integration of 7-day regimens into clinical pathways, alongside electronic prompts and reassessment tools, can help optimize antibiotic use and contribute to system-level antimicrobial stewardship goals.
Taken together, these findings suggest that a 7-day antibiotic course is a reasonable and effective option for stable, non-high-risk BSI patients, offering comparable clinical outcomes to a 14-day re gimen. The routine use of prolonged therapy should be reconsidered,) particularly in light of stewardship efforts aimed at minimizing unnecessary antibiotic exposure. Incorporating shorter-duration re gimens into clinical workflows - supported by electronic decision aids, standardized reassessment protocols, and multidisciplinary collaboration—can help ensure safe implementation while pro moting best practices in antimicrobial use. This study has several limitations. First, all included RCTs ex cluded immunocompromised patients and those with endovascular infections, limiting the generalizability of our findings to these high- risk populations.
Therefore, the conclusions of this meta-analysis apply only to immunocompetent adults with uncomplicated bloodstream infections. Caution is therefore advised against extra polating these findings to high-risk populations (e.g., patients with endocarditis or neutropenia). Second, while one RCT with the largest sample size may have had a disproportionate influence on the overall findings, leave-one-out sensitivity analyses confirmed the stability and consistency of our results. Third, subgroup analyses by infection source, causative pathogens, and antibiotic dosages were not feasible due to insufficient granularity in the reported data. This clinical heterogeneity underscores the need for future pathogen- or source-specific trials to better define the optimal treatment dura tion. Fourth, although 90-day all-cause mortality was chosen as the primary outcome due to its objectivity and widespread availability across trials, we acknowledge that it is not a direct measure of clinical recovery. Its selection was therefore driven by practical considerations related to data consistency rather than clinical spe cificity, and should be interpreted as a methodological limitation.

CONCLUSION

This meta-analysis of multiple RCTs demonstrates that a 7-day antibiotic course achieves comparable clinical outcomes and toler ability compared to a 14-day course for BSIs in adults. Although the TSA did not reach the required information size, the substantial sample size and robust design of the BALANCE trial provide strong 8 C.-
W. Wu, C.-C. Lai, J.-Y. Wu et al. Journal of Infection and Public Health 18 (2025) 102852 evidence for the non-inferiority of the 7-day regimen.
These results align with antimicrobial stewardship principles, suggesting that re duced antibiotic exposure can maintain patient outcomes without compromising clinical effectiveness. All outcomes in the GRADE assessment were rated as low cer tainty, indicating limited confidence in the effect estimates and suggesting that the true effects may differ substantially.
Therefore, these findings should be interpreted with caution and viewed as suggestive rather than definitive. Our results indicate that a 7-day antibiotic course yields clinical outcomes comparable to a 14-day regimen in non–high-risk populations. While 7-day therapy ap pears safe and effective for uncomplicated BSIs, individualized decisions should consider patient-specific risk factors and clinical response.
However, high-risk groups, such as immunocompromised  individuals or those with endovascular infections, were excluded from the analyzed trials. Further research is needed to evaluate the safety and efficacy of shorter antibiotic durations in high-risk population

NOTE: This is a broad summary of a published article. Full text, tables, graphs, figures, 
             and further details can be found in the journal mentioned at the beginning.

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